Flavonoids. Chemistry, Biochemistry and Applications 9780849320217, 0849320216

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FLAVONOIDS Chemistry, Biochemistry and Applications

FLAVONOIDS Chemistry, Biochemistry and Applications Edited by

Øyvind M. Andersen Kenneth R. Markham

Boca Raton London New York

A CRC title, part of the Taylor & Francis imprint, a member of the Taylor & Francis Group, the academic division of T&F Informa plc.

Published in 2006 by CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2006 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8493-2021-6 (Hardcover) International Standard Book Number-13: 978-0-8493-2021-7 (Hardcover) Library of Congress Card Number 2005048626 This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Flavonoids : chemistry, biochemistry, and applications / edited by Øyvind M. Andersen and Kenneth R. Markham. p. cm. Includes bibliographical references and index. ISBN 0-8493-2021-6 (alk. paper) 1. Flavonoids. I. Andersen, Øyvind M. II. Markham, Kenneth R. QP671.F52F53 2005 612’.01528--dc22

2005048626

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Editors

Øyvind M. Andersen, a full professor of chemistry since 1993, has specialized in the chemistry of natural compounds. Since 2002, he has been head of the Department of Chemistry, University of Bergen, Norway. He received his Ph.D. degree in 1988 from the University of Bergen. He is author or coauthor of 100 journal articles, seven book chapters, and five patents, and has supervised over 40 M.Sc. and Ph.D. students in the fields of anthocyanins and other flavonoids. The activities of Dr. Andersen’s research group have led to the establishment of several flavonoid-based companies. Most of his research projects concentrate on structural elucidation of new compounds, while others are methodology based and relate to NMR spectroscopy and various chromatographic techniques. Some of the projects focus on anthocyanin properties with the objective of exploring their pharmaceutical potential and their use as colorants in food. Kenneth R. Markham (Ken) has recently retired from his position as group leader and distinguished scientist at Industrial Research Ltd., a New Zealand Crown Research Institute. Following completion of his B.Sc. and M.Sc. (Hons) at Victoria University, Wellington, New Zealand, and his Ph.D. in chemistry (University of Melbourne, Australia, 1963), he returned to Chemistry Division, D.S.I.R., in Lower Hutt, New Zealand, to work on xanthone chemistry. His interest in flavonoids began during a 2-year postdoctoral with Professor Tom Mabry at the University of Texas at Austin (1965– 1967). The coauthored book The Systematic Identification of Flavonoids resulted from this interaction. On his return to New Zealand, Dr. Markham established and led the ‘‘Natural Products’’ section, predominantly devoted to the study of flavonoids with particular emphasis on the chemotaxonomy of New Zealand bryophytes, ferns, and gymnosperms. This work was carried out in conjunction with both local botanists and colleagues at the University of Saarbrucken (Professors Zinsmeister, Mues, and Geiger). In 1979, he worked as a visiting scientist with Professor Jeffrey Harborne at the University of Reading. This again resulted in the publication of a popular book, Techniques of Flavonoid Identification. Dr. Markham’s flavonoid research continued at Industrial Research Ltd. and has led him into studies as diverse as plant chemotaxonomy, plant evolution, plant UV protection, historical Antarctic ozone levels, propolis and bee pollen bioactives, G.E. modification of flower color, and subcellular chemistry, to name but a few. His work has been reported in some 280 publications, including 18 invited chapters and two books, and has been recognized over the years through awards such as the Chemical Society’s Easterfield Medal, Fellowship of the Royal Society of New Zealand, a Ministerial Award for Excellence in Scientific Research, and the 1999 Pergamon Phytochemical Prize.

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Preface

It is with great pleasure that we accepted the offer by CRC Press to assemble and edit this compilation of reviews on flavonoids and their properties and functions for the present volume. We considered the volume timely in that the last book of this general type, The Flavonoids — Advances in Research Since 1986 (edited by Jeffrey B. Harborne), appeared over a decade ago. Since then, advances in the flavonoid field have been nothing short of spectacular. These advances are particularly evident in the contributed chapters that cover: the discovery of a variety of new flavonoids; the application of advanced analytical techniques; genetic manipulation of the flavonoid pathway; improved understanding of flavonoid structures and physiological functions in plants and animals; and, perhaps most importantly, the significance of flavonoids to human health. Whilst the updating aspect of the chapters is seen as the prime contribution of this book, an effort also has been made to include a summary of previous knowledge in the field to enable the reader to place new advances in this context. Chapters 1 and 2 review the application of contemporary isolation, quantification, and spectroscopic techniques in flavonoid analysis, while Chapter 3 is devoted to molecular biology and biotechnology of flavonoid biosynthesis. Individual chapters address the flavonoids in food (Chapter 4) and wine (Chapter 5), and the impact of flavonoids and other phenolics on human health (Chapter 6 and, in part, Chapter 16). Chapter 8 reviews newly discovered flavonoid functions in plants, while Chapter 9 is the first review of flavonoid–protein interactions. Chapters 10 to 17 discuss the chemistry and distribution of the various flavonoid classes including new structures reported during 1993 to 2004. A complete listing of all known flavonoids within the various flavonoid classes are found in these later chapters and the Appendix, and to date a total of above 8150 different flavonoids has been reported. It is difficult to overstate the importance of recent advances in research on flavonoids, and we are sure that the information contained within this book will prove to be invaluable to a wide range of researchers, professionals, and advanced students in both the academic and industrial sectors. We are greatly indebted to our authors, and are delighted that so many of the world’s leading researchers in a variety of flavonoid-related fields have been willing, so generously, to share their knowledge and experience with others through their contribution to this volume. We are also very grateful to Lindsey Hofmeister, Erika Dery, Jill Jurgensen, and Tanya Gordon at Taylor and Francis, and Balaji Krishnasamy at SPI Publisher Services for their support and interest throughout the preparation of this book. Øyvind M. Andersen and Kenneth R. Markham Historical Advances in the Flavonoid Field — A Personal Perspective Having been associated with flavonoid research for the past 40 years, and having witnessed the spellbinding changes that have taken place in the field during this time, it is too tempting by far not to take this opportunity to document for future researchers a brief personal perspective on developments in the flavonoid field over this period. I emphasize that this is

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but a personal perspective on progress, and as such will surely exhibit some bias and deficiencies. To the aggrieved I offer my apologies. In the early 1960s, flavonoids were widely viewed as metabolic waste products that were stored in the plant vacuole. Whilst there was interest at that time in their function as flower colorants, and in their distribution between plant taxa, the earliest investigations of their biosynthesis had just begun. In this respect it is informative to note that Tom Geissman’s 1962 compilation of reviews in The Chemistry of Flavonoid Compounds includes nothing at all on biological function, and details only paper chromatography and absorption spectroscopy as analytical tools. At this time too, information on flavonoid distribution within the plant kingdom was still incomplete. For example, even as late as 1969 Bate-Smith wrote (in Chemical Plant Taxonomy edited by T. Swain) that flavonoids are rarely found in any but vascular plants. But within a few years of this statement, Markham, Porter, and others reported the widespread presence of flavonoids in mosses and liverworts and even their occurrence in an alga, Nitella hookeri. This, incidentally, remains the sole example of the occurrence of flavonoids in algae. To date, flavonoids have been found in all major categories of green plants except for the Anthocerotae. By 1967 little had changed with regard to the application of physical techniques to flavonoid structure determination, with NMR and GLC yet to make an impact on the field. About this time, however, there was an upsurge in the application of flavonoid distribution to the emerging field of chemotaxonomy. Leading these researches were groups at the University of Texas at Austin (led by Tom Mabry, Ralph Alston, and Billy Turner) and at the University of Reading (led by Jeffrey Harborne). Alston and Turner’s pioneering work on the tracking of plant hybridization through flavonoid analyses is still quoted today, as also is much of the anthocyanin structure and flavonoid distributional work detailed by Harborne in his 1967 book, Comparative Biochemistry of the Flavonoids. Rapid advances in the application of physical techniques to flavonoid structure analysis began appearing in the literature in the mid- to late-1960s, and these were well documented in a series of books beginning in 1970 with Mabry, Markham, and Thomas’ The Systematic Identification of Flavonoids, which reviewed, for the first time, the considerable advances made in the application of shift reagents in UV–visible absorption spectroscopy, the use of GLC for sugar analyses, and the application of 1H NMR spectroscopy to flavonoid structure analysis. At this time, CCl4-soluble TMS ether derivatives were widely used for NMR studies in the absence of readily obtainable deuterated solvents. These same derivatives, together with permethylated derivatives, were commonly also used to make flavonoid glycosides sufficiently volatile for early applications of electron impact mass spectrometry to flavonoid structure analysis (first summarized in the 1974 ‘‘Advances’’ book, The Flavonoids, Chapter 3). Contemporaneously, and detailed in the above volume, rapid advances were being reported in the structure analysis of C-glycosides (Chopin and Brouillant, Chapter 12) and in the biosynthesis of flavonoids (Hahlbrock and Grisebach, Chapter 16). A growing awareness of the physiological, metabolic, and evolutionary value of flavonoids was also beginning to emerge. Tony Swain, for example, was in the initial stages of formulating his innovative interpretations of the evolution of flavonoids, and the part that their ‘‘chemoecology’’ played in the evolution of plants (e.g., see Chapter 20 in The Flavonoids, 1974). The next major advance in flavonoid structural techniques was the application of 13C NMR spectroscopy. This has arguably had the greatest impact on flavonoid structure analysis since the invention of paper chromatography around 1900. For the first time, complete flavonoid structures, including flavonoid aglycones together with sugar types and linkages, could be determined using a single technique. Admittedly, the development of advanced two-dimensional techniques has further revolutionized structure analysis since the earliest applications of this technique to flavonoids in the mid-1970s, and the appearance of

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the first review article by Markham and Chari in 1982 (The Flavonoids — Advances in Research, Chapter 2). Advances in technology have diminished the sample size required for spectral analysis by more than 100 times for both 13C and 1H NMR techniques. In the early 1960s, 100-mg samples were required for proton work and in the late 1970s the same sized samples were required for carbon-13 studies. Modern flavonoid researchers will also be aware of the impact that the more recently developed mass spectrometry techniques such as FAB, MALDI-TOF, and electrospray have had on the ability of researchers to elucidate complex flavonoid glycosidic structures through the ready determination of accurate molecular weights and limited fragmentation patterns. Similarly, the development of advanced methods of separation such as capillary electrophoresis, HPLC, and, latterly, HPLC–MS, has recently revolutionized the qualitative and quantitative analysis of flavonoid mixtures. Chemotaxonomic studies involving comparative distributional data have accordingly been vastly facilitated. Techniques such as those referred to above have enabled previously intractable flavonoid structural problems to be solved. Particularly good examples of this are to be found amongst the many complex structures currently being reported for ‘‘blue’’ flower pigments based on anthocyanins elaborated in an often intricate manner with large numbers of sugars, acyl groups, other flavonoids, and occasionally including metal ions. Returning once again to the questions of function and uses, the old concept of flavonoids being merely the by-products of cellular metabolism, which are simply compartmentalized in solution in the cell vacuole, is well and truly past its use-by date. For a start, studies have revealed that flavonoids are also commonly found on the outer surfaces of leaves and flowers, albeit only the aglycone form. Additionally, flavonoids have been shown over the past few years to be found in the cell wall, the cytoplasm, in oil bodies, and associated with the nucleus and cell proteins, as well as in the vacuole. Even in the vacuole, flavonoids are not necessarily found free in solution. For example, protein-bound flavonoids have been isolated from lisianthus and other flowers in which a structurally specific binding has been identified (in anthocyanic vacuolar inclusions). It is probable that flavonoid location and specific protein binding properties will ultimately prove to relate directly to their function in plants. Amongst the many functions now known to be performed by plant flavonoids are those of UV protection, oxidant or free radical protection, modulation of enzymic activity, allelopathy, insect attraction or repulsion, nectar guides, probing stimulants, viral, fungal, and bacterial protection, nodulation in leguminous plants, pollen germination, etc., and it is likely that this is only the tip of the iceberg. Flavonoids, it would seem, have been vital components of plants, ever since their (purported) development at the time plant life emerged from the aquatic environment, and needed protection from UV light in an atmosphere lacking today’s protective ozone layer. The continued widespread accumulation of flavonoids by virtually all land-based green plants lends support to this view. Intriguingly, it is now possible to exert some precise control over plant flavonoid composition. Manipulation of the flavonoid biosynthetic pathway in plants via genetic engineering has progressed rapidly in recent years. This has been expedited by the extensive information made available through the earlier studies of flavonoid biosynthesis pioneered in the 1960s and 1970s (see above). Genetic manipulation of the flavonoid pathway in plants has enormous potential to, for example, produce new flower colors, enhance the nutritional value of crops, and improve crop protection from UV light, microorganisms, insects, and browsing animals. Indeed, much of this work has been underway for some time and shows great promise. Plant flavonoids have been shown in recent years to be of vital significance to mankind as well as to plants. They have been strongly implicated as active contributors to the health benefits of beverages such as tea and wine, foods such as fruit and vegetables, and even,

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recently, chocolate. The widely lauded ‘‘Mediterranean diet,’’ for example, is thought to owe much of its benefits to the presence of flavonoids in the food and beverages. In the early 1990s, Hertog published aspects of the ‘‘Zutphen Elderly Study,’’ and, in so doing, provided for the first time a sound epidemiological correlation between high food flavonoid intake and a lowering in the risk of coronary heart disease. This study also produced the first reliable estimates of average daily flavonoid intake at around 23 mg, a figure much lower than the 1000 mg that had been proposed in the 1970s. The major sources of flavonoids (in the Dutch population) were found to be tea, onions, and apples. Other potential health benefits of dietary flavonoids are too numerous to mention here. Suffice it to say that our understanding of the importance of flavonoids in the human diet is continuing to advance rapidly. One suspects that much of the physiological activity associated with flavonoids can be attributed to (i) their proven effectiveness as antioxidants and free radical scavengers, (ii) to their metal complexing capabilities (a capability that drove early advances in absorption spectroscopy and NMR studies), and (iii) to their ability to bind with a high degree of specificity to proteins. Because of the incredible advances that have taken place, my involvement in flavonoid studies over the past 40 years has been exciting and stimulating. I feel privileged to have been part of the discovery process. During this period flavonoids as a natural product group have risen from relative obscurity (at least in the popular media) to such prominence that educated people in the West are now not only aware of the name, but also aware of the publicized health benefits associated with their consumption. At an academic level too, although flavonoid structure elucidation is rapidly becoming a mature science thanks to technological advances, studies of their bioavailability and physiological activity in both animals and plants is likely to become the new frontier. Exciting advances in the understanding of this physiological activity will undoubtedly lead to the more widespread application of flavonoids in the improvement of human health and in crop quality. A major influence, especially in the latter, is likely to be brought about through skilful genetic manipulation of the flavonoid biosynthetic pathway. We await this progress with eager anticipation. Kenneth R. Markham Industrial Research Ltd Lower Hutt, New Zealand

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List of Contributors

Jonathan E. Brown School of Biomedical & Molecular Sciences University of Surrey Guildford, Surrey, U.K.

Kevin S. Gould School of Biological Sciences University of Auckland Auckland, New Zealand

Ve´ronique Cheynier INRA Unite de Recherche Biopolymeres et Aromes Montpellier, France

Rene´e J. Grayer Jodrell Laboratory Royal Botanic Gardens, Kew Richmond, Surrey, U.K.

Mike Clifford School of Biomedical & Molecular Sciences University of Surrey Guildford, Surrey, U.K.

Kurt Hostettmann Laboratoire de Pharmacognosie et Phytochimie Universite´ de Gene`ve Gene`ve, Switzerland

Olivier Dangles UMR A 408 Safety and Quality of Food Products Avignon, France

Maurice Jay Universite´ Claude Bernard – Lyon I Villeurbanne, France

Kevin M. Davies Crop & Food Research Palmerston North, New Zealand

Monica Jordheim Department of Chemistry University of Bergen Bergen, Norway

Claire Dufour UMR A 408 Safety and Quality of Food Products Avignon, France

Janet A.M. Kyle Rowett Research Institute Aberdeen, Scotland, U.K.

Garry G. Duthie Rowett Research Institute Aberdeen, Scotland, U.K. Daneel Ferreira Natural Products Center University of Mississippi Oxford, Mississippi Torgils Fossen Department of Chemistry University of Bergen Bergen, Norway

Carolyn Lister Crop & Food Research Christchurch, New Zealand Jannie P.J. Marais Natural Products Center University of Mississippi Oxford, Mississippi Andrew Marston Laboratoire de Pharmacognosie et de Phytochimie Universite´ de Gene`ve Gene`ve, Switzerland

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Kathy E. Schwinn Crop & Food Research Palmerston North, New Zealand Desmond Slade Natural Products Center University of Mississippi Oxford, Mississippi K.M. Valant-Vetschera Institut fuer Botanik der Universitaet Wien Wien, Austria Nigel C. Veitch Jodrell Laboratory Royal Botanic Gardens, Kew Richmond, Surrey, U.K.

Christine A. Williams School of Plant Sciences The University, Whiteknights Reading, U.K. Helen Wiseman Department of Nutrition and Dietetics King’s College London London, U.K. Eckhard Wollenweber Institut fu¨r Botanik TU Darmstadt Darmstadt, Germany

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Contents

1. Separation and Quantification of Flavonoids................................................................. 1 Andrew Marston and Kurt Hostettmann 2. Spectroscopic Techniques Applied to Flavonoids ........................................................ 37 Torgils Fossen and Øyvind M. Andersen 3. Molecular Biology and Biotechnology of Flavonoid Biosynthesis .............................. 143 Kevin M. Davies and Kathy E. Schwinn 4. Flavonoids in Foods .................................................................................................... 219 Janet A.M. Kyle and Garry G. Duthie 5. Flavonoids in Wine...................................................................................................... 263 Ve´ronique Cheynier 6. Dietary Flavonoids and Health — Broadening the Perspective .................................. 319 Mike N. Clifford and J.E. Brown 7. Isoflavonoids and Human Health................................................................................ 371 Helen Wiseman 8. Flavonoid Functions in Plants..................................................................................... 397 Kevin S. Gould and Carolyn Lister 9. Flavonoid–Protein Interactions ................................................................................... 443 Olivier Dangles and Claire Dufour 10. The Anthocyanins........................................................................................................ 471 Øyvind M. Andersen and Monica Jordheim 11. Flavans and Proanthocyanidins................................................................................... 553 Daneel Ferreira, Desmond Slade, and Jannie P.J. Marais 12. Flavones and Flavonols ............................................................................................... 617 K.M. Valant-Vetschera and E. Wollenweber 13. Flavone and Flavonol O-Glycosides ........................................................................... 749 Christine A. Williams 14. C-Glycosylflavonoids................................................................................................... 857 Maurice Jay, Marie-Rose Viricel, and Jean-Franc¸ois Gonnet

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15. Flavanones and Dihydroflavonols............................................................................... 917 Rene´e J. Grayer and Nigel C. Veitch 16. Chalcones, Dihydrochalcones, and Aurones ............................................................. 1003 Nigel C. Veitch and Rene´e J. Grayer 17. Bi-, Tri-, Tetra-, Penta-, and Hexaflavonoids ............................................................ 1101 Daneel Ferreira, Desmond Slade, and Jannie P.J. Marais Appendix — Checklist for Isoflavonoids ......................................................................... 1129 Øyvind M. Andersen Index................................................................................................................................. 1199

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Separation and Quantification of Flavonoids Andrew Marston and Kurt Hostettmann

CONTENTS 1.1 1.2 1.3

Introduction .................................................................................................................. 1 Extraction ..................................................................................................................... 2 Preparative Separation.................................................................................................. 3 1.3.1 Preliminary Purification..................................................................................... 3 1.3.2 Preparative Methods.......................................................................................... 4 1.3.2.1 High-Performance Liquid Chromatography ....................................... 4 1.3.2.2 Medium-Pressure Liquid Chromatography ......................................... 5 1.3.2.3 Centrifugal Partition Chromatography ............................................... 6 1.4 Analytical Methods....................................................................................................... 9 1.4.1 Sample Preparation............................................................................................ 9 1.4.2 Thin-Layer Chromatography........................................................................... 10 1.4.3 High-Performance Liquid Chromatography.................................................... 13 1.4.4 High-Performance Liquid Chromatography–Ultraviolet Spectrophotometry. 16 1.4.5 High-Performance Liquid Chromatography–Mass Spectrometry ................... 20 1.4.6 High-Performance Liquid Chromatography–Nuclear Magnetic Resonance ... 24 1.4.7 Capillary Electrophoresis................................................................................. 30 1.5 Outlook ....................................................................................................................... 30 References ........................................................................................................................... 32

1.1 INTRODUCTION Essential to the study of flavonoids is having the means available for their separation (analytical and preparative) and isolation. The importance of this aspect of flavonoid research can be seen in the number of review articles that refer to their chromatography.1–6 However, the information is usually spread out over chapters in books or occurs in isolated sections devoted to individual classes of these polyphenols. This chapter, therefore, aims to present a brief unified summary of general techniques, with reference to the different categories of structure: flavones and flavonols (and their glycosides), isoflavones, flavanones, chalcones, anthocyanins, and proanthocyanidins. In earlier times, thin-layer chromatography (TLC), polyamide chromatography, and paper electrophoresis were the major separation techniques for phenolics. Of these methods, TLC is still the workhorse of flavonoid analysis. It is used as a rapid, simple, and versatile method for following polyphenolics in plant extracts and in fractionation work. However, the majority of published work now refers to qualitative and quantitative applications of highperformance liquid chromatography (HPLC) for analysis. Flavonoids can be separated, 1

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quantified, and identified in one operation by coupling HPLC to ultraviolet (UV), mass, or nuclear magnetic resonance (NMR) detectors. Recently, the technique of capillary electrophoresis (CE) has been gaining attention. One feature that is of immense benefit for flavonoid analysis is the presence of the phenyl ring. This excellent chromophore is, of course, UV active and provides the reason why flavonoids are so easy to detect. Their UV spectra are particularly informative, providing considerable structural information that can distinguish the type of phenol and the oxidation pattern. A number of techniques have been used for the preparative separation of flavonoids. These include HPLC, Diaion, Amberlite XAD-2 and XAD-7, and Fractogel TSK/Toyopearl HW-40 resins, gel filtration on Sephadex, and centrifugal partition chromatography (CPC).7 The choice of methods and strategies varies from research group to research group and depends often on the class of flavonoid studied.

1.2 EXTRACTION Flavonoids (particularly glycosides) can be degraded by enzyme action when collected plant material is fresh or nondried. It is thus advisable to use dry, lyophilized, or frozen samples. When dry plant material is used, it is generally ground into a powder. For extraction, the solvent is chosen as a function of the type of flavonoid required. Polarity is an important consideration here. Less polar flavonoids (e.g., isoflavones, flavanones, methylated flavones, and flavonols) are extracted with chloroform, dichloromethane, diethyl ether, or ethyl acetate, while flavonoid glycosides and more polar aglycones are extracted with alcohols or alcohol–water mixtures. Glycosides have increased water solubility and aqueous alcoholic solutions are suitable. The bulk of extractions of flavonoid-containing material are still performed by simple direct solvent extraction. Powdered plant material can also be extracted in a Soxhlet apparatus, first with hexane, for example, to remove lipids and then with ethyl acetate or ethanol to obtain phenolics. This approach is not suitable for heat-sensitive compounds. A convenient and frequently used procedure is sequential solvent extraction. A first step, with dichloromethane, for example, will extract flavonoid aglycones and less polar material. A subsequent step with an alcohol will extract flavonoid glycosides and polar constituents. Certain flavanone and chalcone glycosides are difficult to dissolve in methanol, ethanol, or alcohol–water mixtures. Flavanone solubility depends on the pH of water-containing solutions. Flavan-3-ols (catechins, proanthocyanidins, and condensed tannins) can often be extracted directly with water. However, the composition of the extract does vary with the solvent — whether water, methanol, ethanol, acetone, or ethyl acetate. For example, it is claimed that methanol is the best solvent for catechins and 70% acetone for procyanidins.8 Anthocyanins are extracted with cold acidified methanol. The acid employed is usually acetic acid (about 7%) or trifluoroacetic acid (TFA) (about 3%). The use of mineral acid can lead to the loss of attached acyl groups. Extraction is typically performed with magnetic stirring or shaking but other methods have recently been introduced to increase the efficiency and speed of the extraction procedure. The first of these is called pressurized liquid extraction (PLE). By this method, extraction is accelerated by using high temperature and high pressure. There is enhanced diffusivity of the solvent and, at the same time, there is the possibility of working under an inert atmosphere and with protection from light. Commercially available instruments have extraction vessels with volumes up to about 100 ml. In a study involving medicinal plants, solvent use was

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reduced by a factor of two.9 The optimization of rutin and isoquercitrin recovery from older (Sambucus nigra, Caprifoliaceae) flowers has been described. Application of PLE gave better results than maceration — and shorter extraction times and smaller amounts of solvent were required.10 PLE of grape seeds and skins from winemaking wastes proved to be an efficient procedure for obtaining catechin and epicatechin with little decomposition, provided the temperature was kept below 1308C.11 As its name suggests, supercritical fluid extraction (SFE) relies on the solubilizing properties of supercritical fluids. The lower viscosities and higher diffusion rates of supercritical fluids, when compared with those of liquids, make them ideal for the extraction of diffusioncontrolled matrices, such as plant tissues. Advantages of the method are lower solvent consumption, controllable selectivity, and less thermal or chemical degradation than methods such as Soxhlet extraction. Numerous applications in the extraction of natural products have been reported, with supercritical carbon dioxide being the most widely used extraction solvent.12,13 However, to allow for the extraction of polar compounds such as flavonoids, polar solvents (like methanol) have to be added as modifiers. There is consequently a substantial reduction in selectivity. This explains why there are relatively few applications to polyphenols in the literature. Even with pressures of up to 689 bar and 20% modifier (usually methanol) in the extraction fluid, yields of polyphenolic compounds remain low, as shown for marigold (Calendula officinalis, Asteraceae) and chamomile (Matricaria recutita, Asteraceae).14 Ultrasound-assisted extraction is a rapid technique that can also be used with mixtures of immiscible solvents: hexane with methanol–water (9:1), for example, is a system used for the Brazilian plant Lychnophora ericoides (Asteraceae). The hexane phase concentrated less polar sesquiterpene lactones and hydrocarbons, while the aqueous alcohol phase concentrated flavonoids and more polar sesquiterpene lactones.15 Microwave-assisted extraction (MAE) has been described for the extraction of various compounds from different matrices.16 It is a simple technique that can be completed in a few minutes. Microwave energy is applied to the sample suspended in solvent, either in a closed vessel or in an open cell. The latter allows larger amounts of sample to be extracted. A certain degree of heating is involved.17

1.3 PREPARATIVE SEPARATION 1.3.1 PRELIMINARY PURIFICATION Once a suitably polar plant extract is obtained, a preliminary cleanup is advantageous. The classical method of separating phenolics from plant extracts is to precipitate with lead acetate or extract into alkali or carbonate, followed by acidification. The lead acetate procedure is often unsatisfactory since some phenolics do not precipitate; other compounds may coprecipitate and it is not always easy to remove the lead salts. Alternatively, solvent partition or countercurrent techniques may be applied. In order to obtain an isoflavonoid-rich fraction from Erythrina species (Leguminosae) for further purification work, an organic solvent extract was dissolved in 90% methanol and first partitioned with hexane. The residual methanol part was adjusted with water to 30% and partitioned with t-butyl methyl ether–hexane (9:1). This latter mixture was then chromatographed to obtain pure compounds.18 A short polyamide column, a Sephadex LH-20 column, or an ion exchange resin can be used. Absorption of crude extracts onto Diaion HP-20 or Amberlite XAD-2 (or XAD-7) columns, followed by elution with a methanol–water gradient, is an excellent way of preparing flavonoid-rich fractions.

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1.3.2 PREPARATIVE METHODS One of the major problems with the preparative separation of flavonoids is their sparing solubility in solvents employed in chromatography. Moreover, the flavonoids become less soluble as their purification proceeds. Poor solubility in the mobile phase used for a chromatographic separation can induce precipitation at the head of the column, leading to poor resolution, decrease in solvent flow, or even blockage of the column. Other complications can also arise. For example, in the separation of anthocyanins and anthocyanin-rich fractions, it is advisable to avoid acetonitrile and formic acid — acetonitrile is difficult to evaporate and there is a risk of ester formation with formic acid. There is no single isolation strategy for the separation of flavonoids and one or many steps may be necessary for their isolation. The choice of method depends on the polarity of the compounds and the quantity of sample available. Most of the preparative methods available are described in a volume by Hostettmann et al.7 Conventional open-column chromatography is still widely used because of its simplicity and its value as an initial separation step. Preparative work on large quantities of flavonoids from crude plant extracts is also possible. Support materials include polyamide, cellulose, silica gel, Sephadex LH-20, and Sephadex G-10, G-25, and G-50. Sephadex LH-20 is recommended for the separation of proanthocyanidins. For Sephadex gels, as well as size exclusion, adsorption and partition mechanisms operate in the presence of organic solvents. Although methanol and ethanol can be used as eluents for proanthocyanidins, acetone is better for displacing the high molecular weight polyphenols. Slow flow rates are also recommended. Open-column chromatography with certain supports (silica gel, polyamide) suffers from a certain degree of irreversible adsorption of the solute on the column. Modifications of the method (dry-column chromatography, vacuum liquid chromatography, VLC, for example) are also of practical use for the rapid fractionation of plant extracts. VLC with a polyamide support has been reported for the separation of flavonol glycosides.19 Preparative TLC is a separation method that requires the least financial outlay and the most basic equipment. It is normally employed for milligram quantities of sample, although gram quantities are also handled if the mixture is not too complex. Preparative TLC in conjunction with open-column chromatography remains a straightforward means of purifying natural products, although variants of planar chromatography, such as centrifugal TLC,7 have found application in the separation of flavonoids. Other combinations are, of course, possible, depending on the particular separation problem. Combining gel filtration or liquid–liquid partition with liquid chromatography (LC) is one solution. Inclusion of chromatography on polymeric supports7 can also provide additional means of solving a difficult separation. Several preparative pressure liquid chromatographic methods are available. These can be classified according to the pressure employed for the separation: . . . .

High-pressure (or high-performance) LC (>20 bar/300 psi) Medium-pressure LC (5 to 20 bar/75 to 300 psi) Low-pressure LC (97% identities are assumed to be allelic variants unless otherwise demonstrated.

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P450 amino acid sequences contain several well-conserved regions, such as the heme binding domain (generally FxxGxxxCxG) and the proline rich region (PPxP) that forms a hinge between the membrane anchored N terminal and the rest of the protein. Rupasinghe et al.25 have modeled the structure of C4H and three other A. thaliana P450s involved in phenylpropanoid biosynthesis, based on the amino acid sequences and crystal structures of other P450s. In addition to C4H these were the flavonoid 3’-hydroxylase (F3’H) and two enzymes involved in the monolignol pathway. The analysis showed that, despite low amino acid sequence identities in some cases, the enzymes displayed significant conservation in terms of structure and substrate recognition. Linear furanocoumarins (psoralens) inhibit P450s as mechanism-based inactivators (suicide inhibitors). Thus, species that produce psoralens may have evolved C4H enzymes with enhanced tolerance to these compounds.18,19 Recombinant C4H from the psoralen-producing species R. graveolens showed markedly slower inhibition kinetics with psoralens, and possibly biologically significant tolerance, compared to C4H from a species that does not produce the compounds (H. tuberosus).19

3.3.4 4-COUMARATE:COA LIGASE 4CL activates the HCAs for entry into the later branches of phenylpropanoid biosynthesis through formation of the corresponding CoA thiol esters. 4-Coumarate, the product of C4H, is key for flavonoid biosynthesis, but 4CL will commonly accept other HCAs as substrates. Generally, 4-coumarate and caffeate are the preferred substrates, followed by ferulate and 5-hydroxyferulate, with low activity against cinnamate and none with sinapate. However, different isoenzymes have been identified that exhibit distinct substrate specificities, including within the same species. These include isoforms with a variant substrate-binding pocket that will accept sinapate,26,27 those that will not accept ferulate,28 and isoforms that differ in their ability to accept 5-hydroxyferulate.29 It is thought that the different isoenzymes may have distinct roles in metabolic channeling in flavonoid or lignin biosynthesis (see, e.g., Refs. 26, 30). Supporting an important role for the variant isoforms is the observation that 4CL is encoded by gene families in all species examined to date.31 The evolution of the 4CL gene family of plants is discussed extensively in Refs. 27, 31. The formation of the HCA-CoA esters proceeds through a two-step reaction, with Mg2þ as a cofactor. In the first step, 4-coumarate and ATP form a coumaroyl–adenylate intermediate, with the simultaneous release of pyrophosphate. In the second step, the coumaroyl group is transferred to the sulfhydryl group of CoA, with the release of AMP. The reaction mechanism of 4CL is discussed in detail in Pietrowska-Borek et al.,32 including the newly discovered ability of recombinant A. thaliana 4CL2 (At4CL2) to synthesize mono- and diadenosine polyphosphates. Based on the presence of a highly conserved peptide motif, 4CL has been placed in the adenylate-forming superfamily that also includes acetyl-CoA synthetases, long-chain fatty acyl-CoA synthetases, luciferases, and peptide synthetases.28,31,33 4CL contains amino acid motifs conserved either among the superfamily or just among 4CL sequences. Mutagenesis, domain swapping, and homology modeling analyses have shown the functional importance of some of these regions and identified amino acids important in the specificity shown toward the different substrates.28,34,35 This information has been used to modify the At4CL2 isoform to accept ferulate and sinapate,34,35 and to change the substrate specificities of the Glycine max (soybean) Gm4CL2 and Gm4CL3 isoforms.33 The route to formation of flavonoids lacking 4’-hydroxylation of the B-ring has not been elucidated. However, one possible route is the direct use of cinnamate as a substrate by 4CL. Activity on cinnamate has been shown at low levels for some of the recombinant 4CL

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proteins, and a separate cinnamoyl:CoA ligase with specific activity on cinnamate and not 4coumarate has been characterized in some species.36 Data with regard to subsequent enzymes accepting the alternative substrates are limited, but cinnamoyl-CoA is used by recombinant chalcone synthase (CHS) from several species, as well as CHS-like enzymes such as pinosylvin synthase (EC 2.3.1.146) (see, e.g., Refs. 37, 38). Indeed, the recombinant CHS from Cassia alata (ringworm bush) can use a wide range of substrates to make various products, including 4-deoxychalcones.39 However, definitive evidence showing this route to 4’-deoxyflavonoids in vivo, from plant studies for example, has not been published.

3.3.5 MODIFICATION

OF

HYDROXYCINNAMIC ACID-COA ESTERS

4-Coumaroyl-CoA is the major substrate for entry into flavonoid biosynthesis through the action of CHS. However, some CHS enzymes may also use caffeoyl-CoA or feruloyl-CoA;2 and various HCA-CoA esters are used by the aromatic acyltransferases that modify the flavonoid glycosides. Although it might be expected that caffeoyl-CoA would be formed by direct 3-hydroxylation of 4-coumaroyl-CoA, and feruloyl-CoA by subsequent 3-Omethylation, varying biosynthetic routes may exist.3,40 In particular, recombinant CYP98A3 of A. thaliana, which encodes an enzyme that can add a hydroxyl at the C-3 position of 4-cinnamate derivatives, shows no activity toward 4-coumaroyl-CoA, and only low-level activity toward 4-coumarate, the preferred substrates being the 5-O-shikimate and 5-O-quinate esters.41–43 However, analysis of the corresponding mutant ref8 supports an in vivo role for CYP98A3 in phenylpropanoid 3-hydroxylation. Similarly, the ferulate 5-hydroxylase (F5H, CYP84A1 of A. thaliana) shows greater preference toward coniferaldehyde and coniferyl alcohol than ferulate or feruloyl-CoA. In addition, O-methylation can occur both on caffeoyl-CoA and 5-hydroxyferuloyl-CoA and their respective aldehyde forms. Thus, a metabolic grid seems to prevail generally for the reactions on the HCAs, particularly with respect to formation of the monolignols. Some of the downstream flavonoid biosynthesis enzymes have been studied for acceptance of O-methylated substrates, in particular CHS (see Section 3.4.1), and some of the oxidoreductases (see Section 3.4.5).

3.4 FORMATION OF ANTHOCYANINS The flavonoid pathway starts with the formation of the C15 backbone by CHS. Chalcones are then generally directly or indirectly converted to a range of other flavonoids in a pathway of intersecting branches, with intermediate compounds being involved in the formation of more than one type of end product (Figure 3.2). This section discusses the genes and enzymes involved in the formation of the simplest common anthocyanins, 3-hydroxyanthocyanidin 3O-glycosides, which require a minimum of five enzymatic steps subsequent to the formation of chalcone (Figure 3.2).

3.4.1 CHALCONE SYNTHASE CHS carries out a series of sequential decarboxylation and condensation reactions, using 4courmaroyl-CoA (in most species) and three molecules of malonyl-CoA, to produce a polyketide intermediate that then undergoes cyclization and aromatization reactions that form the A-ring and the resultant chalcone structure. The chalcone formed from 4-courmaroyl-CoA is naringenin chalcone. However, enzyme preparations and recombinant CHS proteins from some species have been shown to accept other HCA-CoA esters as substrates, such as cinnamoyl-CoA (see, e.g., Ref. 37). In particular, the Hordeum vulgare (barley) CHS2 cDNA encodes a CHS protein that converts feruloyl-CoA and caffeoyl-CoA at the highest rate, and cinnamoyl-CoA and 4-courmaroyl-CoA at lower rates.38

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The key role of CHS in flavonoid biosynthesis has made it a focus of research for many years, and it is now very well characterized. The isolation of a cDNA for CHS represented the first gene cloned for a flavonoid enzyme.44,45 CHS sequences, and a series of CHS-like sequences, have now been characterized from many species, and Austin and Noel46 have identified close to 650 CHS-like sequences in public databases. Native CHS is a homodimer with subunits of 40 to 44 kDa. The structure of the protein produced from the CHS2 cDNA of M. sativa has been determined and the residues of the active site defined.47 It belongs to the polyketide synthase (PKS) group of enzymes that occur in bacteria, fungi, and plants, and is a type III PKS. All the reactions are carried out at a single active site without the need for cofactors.47–49 PKSs are characterized by their ability to catalyze the formation of polyketide chains from the sequential condensation of acetate units from malonate thioesters. In plants they produce a range of natural products with varied in vivo and pharmacological properties. PKSs of particular note include acridone synthase, bibenzyl synthase, 2-pyrone synthase, and stilbene synthase (STS).46 STS forms resveratrol, a plant defense compound of much interest with regard to human health. STS shares high sequence identity with CHS, and is considered to have evolved from CHS more than once.50 Knowledge of the molecular structure of the CHSlike enzymes has allowed direct engineering of CHS and STS to alter their catalytic activities, including the number of condensations carried out (reviewed in Refs. 46, 51, 52). These reviews also present extensive, and superbly illustrated, discussions of CHS enzyme structure and reaction mechanism.

3.4.2 CHALCONE ISOMERASE In a reaction that establishes the flavonoid heterocyclic C-ring, chalcone isomerase (CHI) catalyzes the stereospecific isomerization of chalcones to their corresponding (2S)-flavanones, via an acid base catalysis mechanism.53,54 Almost 40 years ago, the first flavonoid enzyme to be described was CHI (in the adopted hometown of the authors of this chapter).55 Since then CHI has been analyzed in great detail, and surprisingly, it shows little similarity to other known protein sequences,54 although CHI-like sequences have recently been reported from plants and other organisms.56 CHI has a deduced molecular weight (MW) of 27 to 29 kDa, although possible in vivo modifications have been reported.57 Two types of CHI have been identified, the more common CHI-I type, which can use only 6’-hydroxychalcone substrates, and the CHI-II type, which can catalyze isomerization of both 6’-hydroxy- and 6’-deoxychalcones. CHI-II is prevalent in legumes, although sequence analysis and recent transgenic results58 suggest the activity also occurs in nonlegumes. Sequences from different species for the same type of CHI show amino acid identities of >70%, while between type I and type II identities of about 50% are found. Genes for both types of CHI occur as a cluster in Lotus japonicus,59 and the presence of tandem gene copies suggests an origin for CHI-II by gene duplication and divergence from CHI-I. ˚ The structure of the recombinant M. sativa CHI-II protein has been determined to 1.85 A resolution. The progress of the reaction in the reactive site cleft has been elucidated, and a full reaction sequence proposed.52–54 However, the basis for the specificities toward 6’-hydroxyand 6’-deoxychalcones was not resolved, although potentially key amino acid residues were identified. With 6’-hydroxychalcones, such as naringenin chalcone, the isomerization reaction can readily occur nonenzymically to form racemic (2R,2S) flavanone. This occurs easily in vitro and has been reported to occur in vivo to the extent that moderate levels of anthocyanin can be formed.3 However, 6’-deoxychalcones are stable under physiological conditions, due to an

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intramolecular hydrogen bond between the 2’-hydroxyl and the carbonyl group, and CHI-II is required to convert them to flavanones. CHI accelerates ring closure to a 107-fold acceleration over the spontaneous reaction rate, but with significantly slower kinetics for the 6’deoxychalcones than 6’-hydroxychalcones; and ensures formation of the biosynthetically required (2S)-flavanones.53,54,60 The requirement for CHI for significant flavonoid biosynthesis in some plants is well illustrated by the acyanic phenotype of the transparent testa5 (tt5) CHI mutation of A. thaliana, and the increased levels of flavonols in CaMV35S:CHI transgenic plants of Lycopersicon esculentum (tomato).61

3.4.3 FLAVANONE 3b-HYDROXYLASE (2S)-Flavanones are converted stereospecifically to the respective (2R,3R)-dihydroflavonols (DHFs) by flavanone 3b-hydroxylase. Stereospecificity for (2S)-flavanones has been confirmed by analysis of the recombinant protein.62 Flavanone 3b-hydroxylase is commonly abbreviated to F3H, which is what has been used in this chapter, but FHT is also used in the literature, which agrees with the nomenclature for phenylpropanoid biosynthesis proposed in Heller and Forkmann.3 F3H is a soluble nonheme dioxygenase dependent on Fe2þ, O2, and 2-oxoglutarate (2OG), and thus belongs to the family of 2OG-dependent dioxygenases (2OGDs). 2OGDs have been characterized from mammalian, microbial, and plant sources, and they all use four electrons generated from oxoglutarate decarboxylation to split di-oxygen and create reactive enzyme–iron species. The protein family is well represented in flavonoid biosynthesis, as can be seen from Table 3.1, and this will be discussed later. Further details on the 2OGD family are given in Refs. 62, 63. A cDNA for F3H was first isolated from Antirrhinum majus (snapdragon),64 and since then genes and cDNAs have been isolated from over a dozen other species.5,65 The native protein is a monomer of 41 to 42 kDa, although proteolysis during purification gave values of 34 to 39 kDa in early studies of the enzyme. Using sequence comparison and analysis of recombinant proteins good progress has been made in elucidating the tertiary structure of the enzyme, the nature of the active site, and the binding of 2OG and Fe2þ. Britsch et al.65 identified 14 amino acids strictly conserved among F3H sequences from several species, including histidines with a putative role in Fe2þ binding. Mutation analysis of recombinant P. hybrida F3H showed that His220, Asp222, and His278 are indeed involved in Fe2þ binding in the active site, and that Arg288 and Ser290 are required for 2OG binding.66,67 Full characterization awaits determination of the crystal structure for the enzyme.

3.4.4 DIHYDROFLAVONOL 4-REDUCTASE Dihydroflavonol 4-reductase (DFR) catalyzes the stereospecific conversion of (2R,3R)-transDHFs to the respective (2R,3S,4S)-flavan-2,3-trans-3,4-cis-diols (leucoanthocyanidins) through a NADPH-dependent reduction at the 4-carbonyl. DNA sequences for DFR were first identified from A. majus and Z. mays,68,69 and the identity of the Z. mays sequence confirmed by in vitro transcription and translation of the cDNA and assay of the resultant protein.70 DNA sequences have now been cloned from many species, with the size of the predicted protein averaging about 38 kDa. Stereospecificity to (2R,3R)-dihydroquercetin (DHQ) has been shown for some recombinant DFR proteins.71 DFR belongs to the single-domain-reductase/epimerase/dehydrogenase (RED) protein family, which has also been termed the short chain dehydrogenase/reductase (SDR) superfamily. This contains other flavonoid biosynthetic enzymes, in particular the anthocyanidin reductase (ANR), leucoanthocyanidin reductase (LAR), isoflavone reductase (IFR), and vestitone reductase (VR), as well as mammalian, bacterial, and other plant enzymes.72,73

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The preference shown by DFR toward the three common DHFs varies markedly between species, with some enzymes showing little or no activity against dihydrokaempferol (DHK) and others showing preference toward dihydromyricetin (DHM). In particular, DFR in Cymbidium hybrida (cymbidium orchids), L. esculentum, Petunia, and Vaccinium macrocarpon (cranberry) cannot efficiently reduce DHK,3,74,75 so that pelargonidin-based anthocyanins rarely accumulate in these species. However, DFR enzymes of many species accept all three DHFs, and DHM can be used by Dendranthema (chrysanthemum), Dahlia variabilis, Dianthus caryophyllus (carnation), Matthiola, and Nicotiana (tobacco) flowers even though delphinidin derivatives do not naturally occur in these ornamentals.3,76 Some species contain a closely related enzyme activity to DFR that can act on flavanones, termed the flavanone 4-reductase (FNR), which may represent a variant DFR form. This is discussed in more detail in Section 3.4.7. 5-Deoxyleucoanthocyanidin compounds are known to occur in legumes, and analysis of two recombinant DFR proteins (MtDFR1 and MtDFR2) from Medicago truncatula (barrel medic) has found activity on the 5-deoxyDHF substrates fustin and dihydrorobinetin.71 Indeed, fustin was the preferred substrate of both recombinant enzymes. MtDFR1 and MtDFR2 showed distinct enzyme characteristics, and overexpression of MtDFR1 but not MtDFR2 promoted anthocyanin biosynthesis in flowers of N. tabacum. Substrate specificity between DHK, DHQ, and DHM appears, based on chimeric DFR proteins formed using the P. hybrida and Gerbera hybrida sequences, to locate to a 26 amino acid region that may be the binding pocket for the B-ring, and as little as one amino acid change in this region can alter the specificity of the enzyme.73

3.4.5 ANTHOCYANIDIN SYNTHASE The role of anthocyanidin synthase (ANS) in the biosynthetic pathway is to catalyze reduction of the leucoanthocyanidins to the corresponding anthocyanidins. However, in vivo it is anthocyanidins in pseudobase form that are formed, as is described below. In this chapter, use of anthocyanidin should be taken to include the pseudobase form. Furthermore, although the name ANS is commonly used, the enzyme is also referred to in the literature as leucoanthocyanidin dioxygenase (LDOX), reflecting the reaction type. Much of the information on ANS has come not from studies on enzyme extracts but from analysis of DNA sequences and recombinant proteins. Sequences for the ANS were first isolated using transposon generated mutant lines of A. majus and Z. mays.64,77 They encoded proteins of 40 to 41 kDa that were found to have similarity to 2OGDs, during a study on a nonflavonoid enzyme.78 This sequence-based identification was confirmed by the in vitro assay of the recombinant Perilla frutescens protein,79 and subsequent assays on recombinant ANS from a range of species that confirmed the requirement for Fe2þ, 2OG, and ascorbate.80,81 Sequence comparisons show that ANS is more closely related to flavonol synthase (FLS), another 2OGD, than to F3H. From extensive analysis of recombinant proteins, and the crystal structure of A. thaliana protein, detailed reaction mechanisms have been proposed.80–85 The ANS reaction likely proceeds via stereospecific hydroxylation of the leucoanthocyanidin (flavan-3,4-cis-diol) at the C-3 to give a flavan-3,3,4-triol, which spontaneously 2,3-dehydrates and isomerizes to 2flaven-3,4-diol, which then spontaneously isomerizes to a thermodynamically more stable anthocyanidin pseudobase, 3-flaven-2,3-diol (Figure 3.2). The formation of 3-flaven-2,3-diol via the 2-flaven-3,4-diol was previously hypothesized by Heller and Forkmann.3 The reaction sequence, and the subsequent formation of the anthocyanidin 3-O-glycoside, does not require activity of a separate dehydratase, which was once postulated. Recombinant ANS and uridine diphosphate (UDP)-glucose:flavonoid 3-O-glucosyltransferase (F3GT, sometimes

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abbreviated in the literature as UF3GT, UFGT, or 3GT) are sufficient for the formation of cyanidin 3-O-glucoside from leucocyanidin, at least under mildly acid conditions, that are to be expected in a vacuole.80 Turnbull et al.81,83,86 used a range of substrates to study recombinant A. thaliana ANS activity. Trans-DHQ, a potential substrate that would occur in vivo, was converted to quercetin in a reaction equivalent to that of the FLS. Incubation with the physiological substrate (2R,3S,4S)-3,4-cis-leucocyanidin resulted in the formation of cis-DHQ, transDHQ, quercetin, and cyanidin, with cyanidin being a minor product. The acceptance of multiple substrates and generation of a variety of products fits with the proposed 3-hydroxylation mechanism of ANS and the suggested relatively large active site cavity.85 The overlapping in vitro activities of 2OGDs of flavonoid biosynthesis are discussed further in Sections 3.6 and 3.14. Some of the 2OGDs of flavonoid biosynthesis (F3H, FNSI, FLS, and ANS) have been studied for acceptance of O-methylated substrates.87 Substrates methylated at the 3’-hydroxyl were accepted, while methylation at the 4’- or 7-hydroxyls reduced activities to varying degrees. Multiple methylation or methylation at other positions prevented acceptance of the substrate. For 3-deoxyanthocyanin biosynthesis the 3-hydroxyl is, of course, lacking from the ANS substrates (e.g., apiforol). Whether a specific ANS is thus involved in 3-deoxyanthocyanin biosynthesis is not clear. However, it has been postulated that the reaction may still proceed through 3-hydroxylation, and initial results suggest recombinant ANS from species that do not produce 3-deoxyanthocyanins may still use apiforol as a substrate to produce apigeninidin (results of J-I. Nakajima and K. Saito of Chiba University, Japan, with the authors’ coworkers in New Zealand).

3.4.6 FORMATION

OF

ANTHOCYANIDIN 3-O-GLYCOSIDE

The anthocyanidin pseudobases are thought to be too unstable to accumulate in the cell, and are converted to the stable anthocyanins in what might be regarded as the final essential biosynthetic step, O-glycosylation. In the majority of plants, the initial reaction is the transfer of a glucose residue from the energy-rich nucleotide sugar (UDP-glucose) to the 3-hydroxyl of the proposed pseudobase by F3GT. As mentioned in Section 3.4.5, the action of ANS and F3GT has been demonstrated to be sufficient to convert the leucoanthocyanidins to colored anthocyanins (in an acidic environment).80 Although the addition of glucose at the 3-hydroxyl is the most common initial activity, 3-O-galactosylation is the first reaction in some species. No cDNAs for anthocyanidin 3-O-galactosyltransferases have been published, although such sequences have been lodged with the GenBank database (accession BAD06514). 3-O-Glycosylation is often only the first of multiple sugar additions, either at other positions of the anthocyanin core structure (both A- and B-rings) or on to previously added sugars, and other glycosylations are discussed in Section 3.4.9.1. Commonly, the F3GT is designated a flavonoid GT, as enzyme preparations from several species,2 the recombinant Forsythia  intermedia and P. hybrida enzymes,88,89 and the A. majus cDNA expressed in vivo,90 can conjugate both anthocyanidin and flavonol substrates with high efficiency. However, F3GTs of some species, such as Gentiana trifolia and Vitis vinifera (grape),91–93 may specifically or primarily act on anthocyanidin substrate, and should be termed UDP-glucose:anthocyanidin 3-O-glucosyltransferases (A3GTs) in reflection of this. Indeed, within the EC system separate classifications are given for A3GT (EC 2.4.1.115) and UDP-glucose:flavonol 3-O-glucosyltransferase (EC 2.4.1.91). The F3GT is part of the UDPG-glycosyltransferase (UGT) family, which is family 1 of the glycosyltransferase superfamily (EC 2.4.1.X).94,95 UGTs have a central role in detoxifying or

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regulating the bioactivities of a wide range of endogenous and exogenous low molecular weight compounds in both plants and mammals. In plants, they are generally monomeric, soluble enzymes of 50 to 60 kDa catalyzing O-glycoside formation, although cases of C-glycoside formation are known. Affinity for the sugar acceptor is usually high and that for the sugar donor typically lower. Conserved amino acids occur across the UGT family, in particular several histidine residues, and significantly conserved regions are illustrated in the alignment of the Plant Secondary Product Glycosyltransferase motif (PSPG-box) of 44 sequences in Ref. 95. The PSPG-box is thought to be common to UGTs involved in plant secondary metabolism, and may define a monophyletic group of genes. A nomenclature system for the UGTs has been suggested, similar to that for P450s, with groups of plant origin sharing >45% amino acid sequence identity numbered 71 to 100, subgroups with >60% identity given a letter, and the individual gene a number; e.g., the F3GT of G. trifolia is named UGT78B1 under this system (for details, see Refs. 95, 96). In general, the catalytic mechanism of UGTs is not well characterized, and no crystal structure of a plant enzyme has been published. There are few reports of specific F3GT mutations, and none giving a phenotype in petal tissue, perhaps reflecting common redundancy in UGT activity. However, the first reported cloning of a plant UGT DNA sequence was based on the F3GT bronze1 (bz1) mutation of Z. mays, in which glycosylation does not occur and a brown pigment is formed in the kernels by the condensation of the anthocyanidins in the cytosol.4

3.4.7 FORMATION

OF

3-DEOXYANTHOCYANIN

The biosynthesis of 3-deoxyanthocyanins has only been studied in any detail for two grass species, Z. mays and Sorghum bicolor, and one member of the Gesneriaceae, S. cardinalis. It is thought that 3-deoxyanthocyanin biosynthesis occurs through the activity of FNR, so that flavan-4-ols are formed. The flavan-4-ols are then converted to anthocyanins through the action of ANS and a A5GT. The evidence to date is that, in addition to FNR activity, 3-deoxyanthocyanin biosynthesis also requires a marked reduction in the potentially competitive F3H activity. FNR is most likely a variant form of DFR that has dual DFR/FNR activity. The recombinant DFR enzymes of Malus domestica (apple), Pyrus communis (pear), and Z. mays, all species that can produce 3-deoxyflavonoids under some circumstances, show both DFR and FNR activity.97,98 In all three cases, DHFs were preferred as substrates over flavanones, supporting the need for a mechanism promoting flavanone production, i.e., a reduction in F3H activity. Enzymology studies for 3-deoxyanthocyanin-producing flower silks of Z. mays also show FNR activity occurs with only low levels of F3H activity.98 The FNR was initially characterized in detail from the flowers of the Gesneriads S. cardinalis and Columnea hybrida, in which 3-deoxyanthocyanins are found in great excess to 3-hydroxyanthocyanins.3 Recent studies on the recombinant S. cardinalis FNR show that this also has both DFR and FNR activity.99 Gene expression studies in relation to 3-deoxyflavonoid biosynthesis are limited to S. cardinalis, S. bicolor, and Z. mays, but all are in general agreement with the proposed biosynthetic mechanism. In petals of S. cardinalis transcript abundance is very high for the FNR and very low for F3H, with that for ANS intermediate between the two.99 A similar pattern is found for phlobaphene production in Z. mays kernels, but without expression of ANS (see Section 3.15.3). In S. bicolor a similar pattern of DFR/FNR and ANS expression coincident with low F3H transcript levels is seen during production of 3-deoxyflavonoids in response to fungal inoculation,100 although it has been suggested that some biosynthetic variations occur.101

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The 3-deoxyanthocyanidins are initially glucosylated at the 5-hydroxyl. Clones for UDPglucose:anthocyanin 5-O-glucosyltransferases (A5GT) have been isolated from a range of species.88,102 However, all of these were found to require, at a minimum, prior 3-O-glucosylation of the substrate (see Section 3.4.9.1). This suggests that for 3-deoxyanthocyanin formation a specific A5GT may have evolved to accept the aglycone.

3.4.8 FLAVONOID 3’-HYDROXYLASE

AND

FLAVONOID 3’,5’-HYDROXYLASE

In a few species, the B-ring hydroxylation pattern is thought to be fully or partially determined through the HCA-CoA ester used by CHS (see Section 3.4.1). However, most commonly hydroxylation at the C-3’ and C-5’ positions is determined at the C15 level by the activity of two P450s, the F3’H and F3’,5’H. Genes and cDNAs for both enzymes, sometimes informally referred to as the red and blue genes because of their impact on flower color, were first cloned and characterized from Petunia103–105 and subsequently from several other species (listed in Ref. 5). Based on sequence analysis, the F3’H and F3’,5’H proteins are 56 to 58 kDa in size. The F3’H recombinant proteins of A. thaliana, P. hybrida, and P. frutescens accept flavanones, flavones, and DHFs as substrates,105–107 as do enzyme preparations from plant tissues.3 Indeed, recombinant P. frutescens F3’H showed a similar Km (about 20 mM) for naringenin, apigenin, and DHK.107 The A. thaliana F3’H amino acid sequence has been used to generate a model of the enzyme and examine the active site architecture and substrate recognition, as discussed in Section 3.3.3.25 Recombinant F3’,5’H also accepts a range of substrates to carry out stepwise 3’- and 5’-hydroxylation, in particular converting naringenin or eriodictyol to pentahydroxyflavanone, DHK or DHQ to DHM, apigenin or luteolin to tricetin, and kaempferol or quercetin to myricetin.91,103,108,109 Recombinant F3’,5’H from P. hybrida and Catharanthus roseus (Madagascar periwinkle) showed greatest activity with naringenin (Km 7 mM) and apigenin, and decreasing activity against kaempferol and DHQ, with a preference for the 4’-hydroxylated substrates over the 3’4’-hydroxylated ones.108,109 F3’,5’H has been shown to be able to use the alternative electron donor Cyt b5, based on analysis of a knockout line of P. hybrida for the Cytb5 gene (difF), which showed it is required for full activity of F3’,5’H but not F3’H in flowers.110

3.4.9 ANTHOCYANIN MODIFICATION ENZYMES Knowledge of the genetics and molecular biology of the genes encoding the enzymes that carry out modifications of the core anthocyanin structure has advanced greatly in recent years, based on research involving a wide variety of plant species. Of the classic model species, anthocyanin modification enzymes have been studied in detail only for P. hybrida, regarding the production of methylated and acylated anthocyanidin 3,5-O-glycosides. However, 99 UGT-like sequences have been identified in the genome of A. thaliana, and the research currently underway to characterize them by transgenic approaches and expression in vitro may identify other flavonoid GTs.96 3.4.9.1

Anthocyanin Glycosyltransferases

Glycosylation at the 3-hydroxyl, or for 3-deoxyanthocyanidins at the 5-hydroxyl, has been discussed earlier as part of the core anthocyanin biosynthetic pathway. In this section, molecular data on the genes encoding enzymes that carry out subsequent glycosylations is reviewed. A great variety of anthocyanin glycosides occur, but at the time of the review by Heller and Forkmann3 only a few anthocyanin GTs had been characterized biochemically, and DNA sequences were only available for the F3GT. Since then genes or cDNAs have been

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isolated for the UDP-rhamnose:anthocyanidin 3-O-glucoside O-rhamnosyltransferase (A3RT) from P. hybrida,111,112 A5GTs,88,102 and a UDP-glucose:anthocyanin 3’-O-glucosyltransferase (A3’GT).113 The recombinant A5GT from P. hybrida accepts only delphinidin 3-O-(4-coumaroyl)rutinoside, consistent with the prior biochemical data.88 In contrast, the recombinant A5GTs from P. frutescens and Verbena hybrida accept a range of 3-O-glycosides and acyl-glycosides, although prior 3-O-glycosylation is required.102 Phylogenetic alignment of UGT sequences with proven functionality shows that the A3GT and A5GT sequences form two distinct groups, with the A3RT falling well separated from either group.88,114 The separation of the A3RT is due to a distinctive PSPG-box, for the binding of UDP-rhamnose rather than UDPglucose. 3.4.9.2 Anthocyanin Methyltransferases There is a wide range of methylated flavonoids that is formed through the action of members of the S-adenosyl-L-methionine (SAM)-dependent methyltransferase (MT) family (EC 2.1.1.X). This large family includes enzymes targeting O, C, N, and S atoms in the methyl acceptor molecule. Those characterized to date for flavonoid biosynthesis are generally class II O-MTs (OMTs), which do not require Mg2þ and have MWs typically of 38 to 43 kDa, although one of the smaller MW class I Mg2þ-dependent OMT types has also been reported.115 Although C-methylated flavonoids are known, there are no reports on the characterization of the enzymes. Excellent reviews of the plant OMT family are available in Refs. 116 and 117, which include presentations of molecular phylogenies, as does the review of Schro¨der et al.87 Structural information on plant OMTs has been gathered from amino acid sequence analysis and the crystal structures for various animal OMTs and ˚ resolution.118 one plant OMT, whose crystal structure was solved to a 1.8 A Significant conserved regions include motifs for SAM (LExGxGxG) and Mg2þ binding (KGTVL).117 The well-characterized anthocyanin-related OMTs are those acting at the 3’- and 5’hydroxyls, encoded by the genes Mt1, Mt2, Mf1, and Mf2 in P. hybrida.1 Anthocyanins with methylation at the 5- or 7-hydroxyls are also known. The isolation of cDNAs for anthocyanin OMTs has been reported only in the patent literature to date (International Patent Application WO03/062428), although some cDNAs were mentioned in brief in Ref. 119. The patent describes P. hybrida, Fuchsia, Plumbago, and Torenia cDNAs encoding OMTs that act on the 3’- or 3’,5’-hydroxyls. The recombinant proteins act on delphinidin 3-Oglucoside or delphinidin 3-O-rutinoside to produce the 3’- or 3’,5’-O-methylated derivatives. Interestingly, the sequences are closer to those of class I OMTs than class II. 3.4.9.3 Anthocyanin Acyltransferases Anthocyanin acyltransferases (AATs) catalyze transfer of either aromatic or aliphatic acyl groups from a CoA-donor molecule to hydroxyl residues of anthocyanin sugar moieties; and are part of the general group of acyltransferase enzymes (EC 2.3.1.X). A wide range of activities have been characterized, including enzymes using acetyl-CoA, caffeoyl-CoA, 4-coumaroyl-CoA, malonyl-CoA, and succinyl-CoA. Nakayama et al.120 list six aromatic and 14 aliphatic AATs, and others, such as those of Dendranthema  morifolium, have been reported since. Following the publication of the first AAT cDNA in 1998,121 cDNA clones for two aromatic and six aliphatic AATs have been characterized at the molecular level (Table 3.1). Examples of reactions carried out by these enzymes are shown in Figure 3.3.

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OH OH HO

O OHOH

OH

HO O

HO

O

OH

OH HO O

O

OH

OH

O

OH

OH

HO HO

OH

Malonyl-CoA

Caffeoyl-CoA Dv3MaT

Gt5AT

OH

CoA-SH

CoA-SH

HO

OH OH

OH HO

OH

O

O

HO

O

O OHOH

OH HO

HO O

O

OH

O

O

OH HO

O

O O

OH

O

O

O

OH OH

O HO HO

OH

OH

OH

OH

O HO

HO

O

O

OH HO O

OH

2x Malonyl-CoA CoA-SH

OH OH

OH

HO

Dm3MaT2 O

O

O

O

OH

O

OH HO

O O

O

FIGURE 3.3 Examples of aliphatic and aromatic acylation of anthocyanins, as carried out by the malonyl-CoA:anthocyanidin 3-O-glucoside-6’’-O-malonyltransferase (Dv3MaT from D. variabilis), malonyl-CoA:anthocyanidin 3-O-glucoside-3’’,6’’-O-dimalonyltransferase (Dm3MaT2 from D. Xmorifolium), and hydroxycinnamoyl-CoA:anthocyanin 5-O-glucoside-6’’’-O-hydroxycinnamoyltransferase (Gt5AT from G. triflora).

Aromatic AAT cDNAs have been isolated from G. triflora121 and P. frutescens.122 The recombinant G. triflora protein (Gt5AT) can use either caffeoyl-CoA or 4-coumaroyl-CoA to introduce the HCA group to the glucose at the C-5 position of anthocyanidin 3,5-di-Oglucoside. Although specificity is shown with regard to the anthocyanin glycosylation and acylation pattern, the enzyme can accept pelargonidin, cyanidin, or delphinidin derivatives. That the number of hydroxyl groups on the B-ring does not affect reactivity is typical of AATs studied to date. The P. frutescens recombinant product (Pf3AT) was identified as a hydroxycinnamoyl-CoA:anthocyanidin 3-O-glucoside-6’’-O-hydroxycinnamoyltransferase, utilizing cyanidin 3-O-glucoside and cyanidin 3,5-di-O-glucoside (the putative substrates in vivo) as well as other anthocyanins. Km values of 6 to 227 and 113 to 777 mM have been

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reported for various anthocyanin substrates for the Pf3AT and Gt5AT, respectively, and 24 to 190 mM toward the HCA-CoA esters for a range of aromatic AATs.120 The isolation and analysis of aromatic AAT cDNAs from additional species, including P. hybrida and Lavandula angustifolia, has been reported in the patent literature (International Patent Application WO96/25500). Of the aliphatic AAT cDNAs characterized, three encode malonyl-CoA:anthocyanidin 3O-glucoside-6’’-O-malonyltransferases (A3MT) from D. variabilis, Senecio cruentus (cineraria), and D.  morifolium.123–125 The D. variabilis and S. cruentus recombinant proteins (Dv3MaT and Sc3MaT) accept pelargonidin-, cyanidin-, or delphinidin 3-O-glucosides, but do not use anthocyanidin diglycosides. The D.  morifolium recombinant protein (Dm3MaT1) also does not accept diglycosides as substrates, but will use a wide range of flavonoid monoglucosides, including anthocyanidin 3-O-glucosides and quercetin 3-O-glucoside. With regard to acyl donors, Dm3MaT1 has highest activity with malonyl-CoA but also shows significant activity with succinyl-CoA. Other acyl-CoA compounds are either accepted weakly or not at all. Km values of 19 to 57 mM toward malonyl-CoA have been reported for the aliphatic AATs.120 Other aliphatic AAT cDNAs characterized include ones encoding a malonyl-CoA:anthocyanin 5-O-glucoside-6’’’-O-malonyltransferase (Ss5MaT) from Salvia splendens (scarlet sage) and a malonyl-CoA:anthocyanidin 3-O-glucoside-3’’,6’’-O-dimalonyltransferase (Dm3MaT2) from D.  morifolium.125,126 Ss5MaT shows high specificity, accepting only ‘‘bisdemalonylsalvianin’’ (a pelargonidin 3,5-di-O-glucoside derivative), the endogenous substrate. Recombinant Dm3MaT2 produced two products from cyanidin 3-O-glucoside, cyanidin 3-O-(6’’-Omalonylglucoside) and cyanidin 3-O-(3’’,6’’-O-dimalonylglucoside), suggesting it carries out sequential acylations at the glucose 6’’- and 3’’-hydroxyl groups. Both Dm3MaT2 and Ss5MaT show strong preference for malonyl-CoA as the acyl donor, but Ss5MaT also shows significant usage of succinyl-CoA. All AATs characterized to date are monomers of approximately 50 to 52 kDa in size, and are members of the large versatile acyltransferase (VAT or VPAT) family of enzymes (also known as the BAHD superfamily) involved in many primary and secondary metabolite pathways of plants and fungi.120,127 Nakayama et al.120 present detailed sequence comparisons among AATs and a molecular phylogeny for the VAT family. The three A3MT amino acid sequences share >70% amino acid identity. However, although the other AATs, both aliphatic and aromatic, show significant amino acid sequence identity, it is at a relatively low level. For example, Dm3MaT1 has 40% identity to Ss5MaT1, 38% to Gt5AT, and 37% to Pf3AT. Of three significant amino acid motifs identified for VATs, Motifs 1 (HxxxD) and 3 (DFGWG) are thought to be key for catalytic activity, while Motif 2 (YxGNC) might relate to recognition of the anthocyanin, as it is present only in AATs to date. The putative reaction mechanism and the possible role of conserved amino acids, based principally on mutagenesis of recombinant Ss5MaT1, are discussed in detail in Refs. 120, 126, 128. No three-dimensional structure has been published for a member of the VAT family. The evidence suggests that AATs characterized to date are likely to be localized to the cytosol, with their deduced amino acid sequences lacking known vacuolar targeting sequences. However, it cannot be ruled out that some flavonoid ATs occur in the vacuole. Some serine carboxypeptidase-like (SCPL) enzymes, which use 1-O-acylglucosides as acyl group donors and catalyze acylation reactions in plant secondary metabolism, are located in the vacuole, e.g., sinapoylglucose:malate sinapoyltransferase.129,130 It has previously been proposed that anthocyanin malonylation may occur in the vacuole, and that an SCPL-like activity is involved in the acylation of cyanidin O-glycosides in Daucus carota (wild carrot) (discussed in Ref. 131).

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3.5 FORMATION OF PROANTHOCYANIDINS AND PHLOBAPHENES The PAs, or condensed tannins, are polymers synthesized from flavan-3-ol monomer units. The phlobaphenes are 3-deoxy-PAs formed from flavan-4-ol monomers. The biosynthesis of both types of PAs follows the biosynthetic route of anthocyanins from chalcones through to the branch points to flavan-3-ol and flavan-4-ol formation. In this section, the specific enzymes forming the monomers are discussed, along with a discussion on the polymerization process. Although the chemistry of tannins is described in detail elsewhere in this book, it is useful to briefly mention the nature of the monomer subunit types and the polymer forms. Although many variant polymer forms have been reported, the most common ones consist of linear C-4 to C-8 linkages, with the linking bond at the C-4 being trans with respect to the 3-hydroxyl. The subunits are usually flavan-3-ol epimers for the 3-hydroxyl, being either 2,3trans or 2,3-cis, with the latter being prefixed with ‘‘epi.’’ Most commonly these are (2R,3S)trans or (2R,3R)-cis, although 2S-enantisomers do occur, being indicated by the ‘‘ent’’ prefix. Intermediates in the flavonoid pathway up to and including leucoanthocyanidins are 2,3-trans in stereochemistry. Flavan-3-ols may be formed by two biosynthetic routes, from either leucoanthocyanidins or anthocyanidins (Figure 3.4). The 2,3-trans-flavan-3-ols are produced from the leucoanthocyanidins by LAR, while the 2,3-cis-flavan-3-ols are produced from the anthocyanidins by ANR. The common subunits are those with 3’,4’-dihydroxylation of the B-ring (catechin and, most commonly, epicatechin) or 3’,4’,5’-trihydroxylation (gallocatechin and epigallocatechin). Monohydroxylation of the B-ring (at C-4’), producing the subunits of propelargonidin, is rare, as is the occurrence of subunits with hydroxyl patterns on the A- and C-rings varying from the common one of 3,5,7-hydroxylation. As the subunits for PA biosynthesis are formed

R1 OH HO

O

R2 OH

R1

OH

LAR

Flavan-3-ol R1=R2=H Afzelechin R1=OH, R2=H Catechin R1=R2=OH Gallocatechin

OH HO

O

Formation of dimers,trimers and polymers yielding: Propelargonidin Procyanidin Prodelphinidin Mixed polymers

R2 ? OH

OH OH Leucoanthocyanidin R1=R2=H Leucopelargonidin R1=OH, R2=H Leucocyanidin R1=R2=OH Leucodelphinidin HO

ANS

R1

R2 OH

O

R2 OH

OH Anthocyanidin R1=R2=H Pelargonidin R1=OH, R2=H Cyanidin R1=R2=OH Delphinidin

OH HO

O

R2

ANR OH OH epi-Flavan-3-ol R1=R2=H Epiafzelechin R1=OH, R2=H Epicatechin R1=R2=OH Epigallocatechin

FIGURE 3.4 Biosynthetic route to proanthocyanidins from leucoanthocyanidins. The product of the ANS is given in the flavylium cation form. Enzyme abbreviations are defined in the text and in Table 3.1.

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later in the pathway than flavanones, the hydroxylation status of the B-ring of the flavan3-ols is likely to be determined by the action of the F3’H and F3’,5’H on the precursors.

3.5.1 LEUCOANTHOCYANIDIN REDUCTASE LAR removes the 4-hydroxyl from leucoanthocyanidins to produce the corresponding 2,3trans-flavan-3-ols, e.g., catechin from leucocyanidin.5,132 Despite early biochemical characterization, it is only recently that a LAR cDNA was isolated and the encoded activity characterized in detail. Tanner et al.133 purified LAR to homogeneity from Desmodium uncinatum (silverleaf desmodium), and used a partial amino acid sequence to isolate a LAR cDNA. The cDNA was expressed in E. coli, N. tabacum, and Trifolium repens (white clover), with the transgenic plants showing significantly higher levels of LAR activity than nontransformed plants. LAR of D. uncinatum is a NAPDH-dependent reductase with closest similarity to IFR (a reductase involved in isoflavonoid biosynthesis), and like IFR, DFR, and VR (another isoflavonoid reductase), LAR belongs to the RED protein family. It shares several conserved amino acid sequence motifs with other RED proteins, but has a C terminal extension of approximately 65 amino acids of unknown function. The protein is a monomer with a predicted MW of 42.7 kDa. The preferred substrate is 3,4-cis-leucocyanidin, although 3,4cis-leucodelphinidin and 3,4-cis-leucopelargonidin are also accepted. Although 2,3-cis-3,4trans-leucoanthocyanidins have not been shown to exist as substrates in vivo, if LAR accepted them it would raise the possibility of a route to the 2,3-cis-flavan-3-ols in addition to the route through ANR. The difficulty in synthesizing 2,3-cis-3,4-trans-leucoanthocyanidins in vitro has prevented a definitive test of LAR activity on these substrates. However, product inhibition is about 100 times greater with catechin than epicatechin, supporting ANR as the main route. There appears to be no LAR sequence or enzyme activity in A. thaliana, consistent with the lack of catechin derivatives in that species.134

3.5.2 ANTHOCYANIDIN REDUCTASE ANR converts anthocyanidins (presumably the pseudobase forms) to the corresponding 2,3cis-flavan-3-ols, e.g., cyanidin to epicatechin. For many years little information was available on the formation of 2,3-cis-flavan-3-ols. However, the solution emerged from studies on the banyuls mutant of A. thaliana, which displays precocious accumulation of anthocyanins in the seed coat endothelium.135 Initially thought to represent an anthocyanin regulatory gene, it was found that the locus encoded a DFR-like protein of 38 kDa, and as banyuls mutant plants also lack accumulation of PAs in the seed coat endothelium, it was suggested that the gene might encode LAR.136 However, recombinant BANYULS from A. thaliana and M. truncatula did not show LAR activity, but rather reduced pelargonidin, cyanidin, and delphinidin to the corresponding 2,3-cis-flavan-3-ols.137 Low-level production of ent-epiafzelechin, ent-epicatechin, and ent-epigallocatechin was also seen, although these were suspected to be artifacts of the analysis generated by chemical epimerization.138 Like LAR, ANR is a member of the RED protein family. Full details of the protein structure and reaction mechanism are yet to be published. However, Xie et al.138 compared the A. thaliana (AtANR) and M. truncatula (MtANR) ANR amino acid sequences and recombinant protein activities, and made suggestions on the possible reaction series. The two recombinant proteins showed significantly different kinetic properties, substrate specificities, and cofactor requirements. Although AtANR and MtANR share only 60% sequence identity, some well-conserved domains are evident, in particular the Rossmann dinucleotidebinding domain (GxxGxxG) near the N-termini. However, two amino acid variations did

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occur in this domain, and this may account for the ability of MtANR to use either NADH or NAPDH, while AtANR will use only NAPDH. Both reduce pelargonidin, cyanidin, and delphinidin, with MtANR preferring cyanidin > pelargonidin > delphinidin and AtANR showing the reverse preference. With regard to in vivo activities, the low level of PAs (6% of wild-type levels) in the F3’H mutant of A. thaliana (tt7) suggests that AtANR, or other PA biosynthetic enzymes of A. thaliana, have a limited activity against pelargonidin.134 The ANR reaction involves a double reduction at the C-2 and C-3 of the anthocyanidin, allowing the inversion of C-3 stereochemistry. Xie et al.138 postulate four possible reaction mechanisms, proceeding via either flav-3-en-ol or flav-2-en-ol intermediates. The proposed reaction mechanisms are based on anthocyanidins (the flavylium cation forms) as the starting molecules; however, as the authors acknowledge, other forms of the anthocyanidin may exist in vivo. In particular, the 3-flaven-2,3-diol pseudobase is thought to be the more likely in vivo product of the ANS.

3.5.3 PROANTHOCYANIDIN POLYMERIZATION Nonenzymatic studies of polymerization in vitro suggest that it starts by the attack of the C-4 of an electrophilic leucoanthocyanidin on the C-8 of the nucleophilic flavan-3-ol initiating subunit to form the initial dimer (the chemistry of the polymerization is reviewed in Refs. 4, 5, 132). Polymerization then continues by addition of leucoanthocyanidin extension subunits in the same C4–C8 route. This suggests that the great majority of the substrate for polymerization in planta may not need to pass through either the LAR or ANR biosynthetic steps. However, in most cases, the extension units are 2,3-cis, and leucoanthocyanins are 2,3-trans. Thus, it may not be leucoanthocyanidins that are the extension units in planta, but leucoanthocyanidin derivatives. Thus, intermediates proposed for polymerization include reactive (2R,3S) compounds derived from leucoanthocyanidins, such as quinone methide and carbocation products. Another, perhaps more likely, source for the common 2,3-cis extension units is intermediates of the ANS and ANR biosynthetic route, possibly also as quinone methide and carbocation products. Indeed, the tannin-deficient seed4 (tds4) mutant of A. thaliana, which is for the ANS gene, accumulates unidentified possible PA intermediate compounds in the developing seed.139 These seem to fail to be transported into the vacuole as usual and accumulate in the cytoplasm, triggering the formation of multiple small vacuoles. These studies and those of Grotewold et al.140 on Z. mays cell lines suggest that the final steps of PA biosynthesis may be linked to developmental changes in the cell structure. Any enzymatic polymerization process would need to evolve a mechanism for avoidance of inhibitory protein–PA interactions. A membrane-bound biosynthetic complex associated directly with the accumulation of the polymers in the vacuole might achieve this. The recent molecular characterization of the LAR and ANR has been a major advance in the understanding of PA biosynthesis. However, it is still not known whether the polymerization of PAs occurs spontaneously in all tissues or is enzyme catalyzed in some or all cases. Flavan-3-ols and leucoanthocyanidins will polymerize spontaneously in vitro (reviewed in Ref. 5), and no activities responsible for the formation of PA polymers have been described. Differences in PA composition and polymer length do occur between different tissues and during tissue development, and variations from the C4–C8 linkage pattern also occur. However, these variations are not necessarily evidence of an enzymatic mechanism of polymerization, as changes in the availability or reactivity of initiating and extension units might also generate such differences. Nevertheless, a nonenzymatic polymerization process seems unlikely, given that PAs occur in some species with specific arrangements of catechin and epicatechin units. Perhaps the best evidence for biosynthetic steps after LAR and ANR are the mutant lines that have been identified that prevent PA accumulation and appear to occur

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after monomer formation. At least four PA mutations of H. vulgare (ant25, ant26, ant27, and ant28) appear to act after LAR, with evidence for ant26 encoding a polymerization enzyme.141 In A. thaliana, TDS1, TDS2, TDS3 TDS5, and TDS6 act after Banyuls,139 and TT9, TT10, TT11, TT13, and TT14 act after TT12, which encodes a vacuolar transporter for PAs.142 Although some of the TDS mutants may be allelic to the TT mutants, this still indicates a number of genetic steps postmonomer formation, which may include polymerization enzymes, regulatory factors, transport activities, and dirigent proteins that control stereospecificity of polymerization. One other line of evidence supporting enzymatic polymerization comes from recent studies overexpressing ANR in transgenic plants. N. tabacum ANR transgenics are reported to have increased levels of at least four compounds that react with the PA stain dimethylaminocinnamaldehyde (DMACA) but no PA polymers, supporting the requirement for further enzymatic steps.5,133 However, lack of PA polymers may also be due to conditions in the transgenic tissues studied being unsuitable for spontaneous polymerization. Also, Xie et al.137 reported results differing to these, as they found PA polymer-like DMACA staining compounds in leaves or petals of A. thaliana or N. tabacum CaMV35S:ANR transgenics, respectively, although it has been commented that more extensive analysis than what was presented is often required to confirm the PA polymer status.132

3.6 FORMATION OF FLAVONES AND FLAVONOLS A desaturation reaction forming a double bond between C-2 and C-3 of the C-ring is involved in the formation of both flavones and flavonols, and the respective substrates involved, (2S)flavanones and (2R,3R)-DHFs, differ only in the presence or absence of the 3-hydroxyl (Figure 3.2). Two distinct FNS activities have been characterized that convert flavanones to flavones. In most plants FNS is a P450 enzyme (FNSII), but species in the Apiaceae have been found to contain the 2OGD FNSI. FNSII cDNAs were first isolated from G. hybrida, based on a differential display technique focusing on the conserved P450 heme-binding site,143 and from A. majus and T. fournieri using another P450 cDNA as a probe.144 Isolation of a cDNA for FNSI was first reported from P. crispum.145 Although FNSI and FLS catalyze the equivalent 2,3-desaturation reaction, it is thought that FNSI is most likely to have evolved from the F3H in the Apiaceae. Flavonols are formed from DHFs by the FLS. A cDNA for FLS was first isolated from P. hybrida using degenerate PCR primers for conserved 2OGD sequences,146 and indeed all FLS cDNAs identified to date encode 2OGD enzymes. However, the Torenia FNSII shows FLS activity, raising the suggestion that, analogous to flavone formation, there are two types of FLS.144 The recombinant Citrus unshiu (Satsuma mandarin) FLS had Km values of 45 and 272 mM for DHK and DHQ, respectively. A similar reaction mechanism has been proposed for F3H, ANS, FLS, and FNSI, involving cis-hydroxylation at C-3 followed by dehydration, with (2R,3S)-cis-DHFs as possible intermediates.81,84 Akashi et al.144 have suggested that the FNSII reaction likewise involves a C-2 hydroxylation step followed by dehydration. However, the studies of Martens et al.143,145,147 suggest direct 2,3-desaturation of flavanones by FNSI and FNSII, as previously proposed from biochemical studies of FNSI.148 A comparison of 59 2OGD amino acid sequences, including those for ANS, F3H, and FLS, identified three regions of high similarity and eight absolutely conserved amino acids.62 These include residues with proposed functions in Fe2þ and 2OG binding, and two others of unknown function that are required for enzyme activity.62,67 Recent studies of members of the flavonoid 2OGD family show overlapping substrate and product selectivities in vitro. For example, the C. unshiu FLS has been termed a bifunctional

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enzyme, as the recombinant protein has both FLS and F3H activity.62 Two groupings of flavonoid 2OGDs have been proposed, FLS/ANS and F3H/FNSI, with the former having wider substrate selectivity than the latter.62,81,147 The overlapping activities are discussed further in Section 3.14.

3.7 FLAVONE AND FLAVONOL MODIFICATION ENZYMES Flavones and flavonols are the substrates for a range of modification reactions, including glycosylation, methylation, acylation, and sulfation. To date, genes and cDNAs have been cloned that represent activities specific to flavones or flavonols for all of these modifications except acylation. There are also several cDNAs isolated, the encoded proteins of which accept a range of flavonoid, and even nonflavonoid, substrates. However, in vitro activities of recombinant proteins may not reflect their in vivo role. Factors such as the abundance of the protein (temporally or spatially) in relation to the potential substrate, and the involvement of metabolic channeling (see also Section 3.14), affect in vivo activity. However, in various transgenic experiments endogenous flavonoid GTs have been shown to accept substrates that are not normally present in the recipient species, such as 6’-deoxychalcones and isoflavonoids,149–151 supporting broad substrate acceptance of some modification enzymes.

3.7.1 FLAVONE

AND

FLAVONOL GLYCOSYLTRANSFERASES

Clones have now been isolated for several types of UGT with O-glycosylation activity on flavones and flavonols. The recombinant proteins show wide substrate acceptance, including some that will accept both flavonoids and some of the biosynthetically unrelated betalain pigments. In general, the UGTs characterized in flavonoid biosynthesis show high regiospecificity but broad substrate acceptance, although there are exceptions. A number of cDNAs encoding UGT activities against the 7-hydroxyl have been identified. NtGT2 from N. tabacum showed activity against several types of phenolic compounds.152 Despite having closest sequence identity with A5GT sequences, no significant activity with anthocyanins was found but it catalyzed the transfer of glucose to the 7-hydroxyl of flavonols, with a Km of 6.5 mM for the aglycone kaempferol. The recombinant protein from the UGT73C6 gene of A. thaliana also transfers glucose to the 7-hydroxyl of a range of flavonols and flavones, as well as the 6-hydroxyl of the unnatural 6-hydroxyflavone substrate. However, its in vivo activity is likely as a UDP-Glc:flavonol-3-O-glycoside-7-O-glucosyltransferase.153 The recombinant Allium cepa (onion) UGT73G1 protein also showed wide regiospecificity, adding glucose to the 3-, 7-, and 4’-hydroxyls of a wide range of flavonoids, including chalcones, flavanones, flavones, flavonols, and isoflavones, producing both monoand diglucosides.154 The lack of triglucoside products suggests UGT73G1 accepts only aglycone or monoglucoside substrates. Recombinant protein from a UGT cDNA from the Chinese medicinal herb Scutellaria baicalensis also showed activity toward the 7-hydroxyl of flavonoids, among other substrates.155 In contrast to these activities, recombinant protein from A. cepa UGT73J1 showed both high regiospecificity and tight substrate specificity, adding glucose at the 7-hydroxyl of only quercetin 3-O-glucoside (a flavonol) and genistein (an isoflavonoid) out of many flavonoid substrates tested.154 A cDNA from Vigna mungo (black gram) seedlings encodes a protein with UDPgalactose:flavonoid 3-O-galactosyltransferase (F3GalT) activity.156 A 20-fold preference for UDP-galactose over UDP-glucose was found with kaempferol as a substrate. It would accept DHFs and flavones at a lower efficiency (anthocyanins were not tested). Average amino acid sequence identity is around 35 to 45% with F3GTs and 23% to the A3RT of P. hybrida.

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The UGT78D1 gene of A. thaliana encodes a specific UDP-rhamnose:flavonol-3-O-rhamnosyltransferase with activity only on kaempferol and quercetin, out of various flavonoids tested.153 Like many flavonoid UGTs, the UGTs reported to be involved in betalain biosynthesis in Dorotheanthus bellidiformis (Livingstone daisy) show precise regiospecificity but surprisingly wide substrate acceptance. Recombinant betanidin 5-O-glucosyltransferase will add a glucose to the 4’- and 7-hydroxyls of luteolin (a flavone) or quercetin, and the 4’-hydroxyl of cyanidin with lower efficiency;157 betanidin 6-O-glucosyltransferase (B6GT) will add a glucose to the 3-hydroxyl of quercetin and cyanidin.114 B6GT shows marked divergence at the amino acid level from the previously characterized F3GTs (for a molecular phylogeny, see Ref. 114). P. hybrida pollen accumulates kaempferol and quercetin 3-O-(2’’-O-glucopyranosyl)galactopyranosides, which are not prevalent elsewhere in the plant, by the action of flavonol 3-O-galactosyltransferase (PhF3GalT) and flavonol 3-O-galactoside-2’’-O-glucosyltransferase (F2’’GT). Miller et al.158 isolated a cDNA for a pollen-specific gene from P. hybrida whose recombinant protein showed the same activity profile as the previously characterized PhF3GalT.159 Unlike most of the GTs discussed previously, the PhF3GalT showed strong preference and high catalytic efficiency to kaempferol and quercetin, with other lower activities being limited to a range of flavonol aglycones. Notably, the PhF3GalT also catalyzed the reverse reaction, a deglycosylation. The enzyme, therefore, could be involved in modulating the abundance of a biologically active aglycone.

3.7.2 FLAVONE

AND

FLAVONOL METHYLTRANSFERASES

Methylation has been reported at all available hydroxyls of flavones and flavonols (the C-5, -6, -7, -8, -2’, -3’, -4’, and -5’ positions), and it can occur on both aglycone and glycoside substrates. Many of the corresponding enzyme activities have been described in detail, and typically show strong preferences with regard to substrate type and the position methylated.3 Recently, cDNA sequences have been identified for several flavonoid OMTs, allowing sequence-based analysis and examination of recombinant protein activities. All are members of the SAM-MT family described in Section 3.4.9.2. Induced in leaves of H. vulgare in response to pathogen attack is an mRNA encoding a flavonoid 7-OMT with activity against flavanone, flavone, and flavonol aglycones, with the flavone apigenin the preferred substrate.160 Caffeic acid or glycosylated flavonoids were not accepted as substrates. Gauthier et al.161,162 have characterized cDNA clones for two distinct enzyme activities of the semiaquatic freshwater plant Chrysosplenium americanum that methylate the 3’ and 5’ hydroxyls of flavonoids. Recombinant F3’OMT specifically methylated the 3’ or 5’-hydroxyls of 3,7,4’-trimethoxyquercetin, accepting neither quercetin nor mono- or dimethylquercetin as substrates.161 However, in contrast, recombinant proteins from the two highly similar clones CaOMT1 and CaOMT2 showed 3’-OMT activity against luteolin and quercetin, and lower 3- or 5-OMT activities on caffeic and 5-hydroxyferulic acids, respectively.162 An A. thaliana cDNA, AtOMT1, was originally identified as encoding a HCA OMT,163 and the deduced amino acid sequences from CaOMT1, CaOMT2, and AtOMT1 show high sequence identity (around 85%), and even higher identity across putative sequence motifs relating to substrate specificity and binding.117. Recombinant protein from AtOMT1 showed flavonol 3’-OMT activity, using quercetin and myricetin (flavonol aglycones) efficiently; however, it had much lower activity with luteolin and did not accept HCAs.164 The initial identification of AtOMT1 as a HCA OMT based on sequence similarity illustrates the potential problems in using sequence alone to predict function (discussed in detail for OMTs in Ref. 165). A cDNA for an OMT (PFOMT) with wide substrate acceptance that includes flavonols and HCA derivatives has been identified from Mesembryanthemum crystallinum (ice plant).115

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In contrast to the other flavonol OMTs reported, the deduced amino acid sequence of PFOMT has most similarity to caffeoyl-CoA OMTs (CCoAOMTs), and it is a class I OMT with a MW of 27 kDa and a requirement for a bivalent cation such as Mg2þ. A wide range of flavonols, including 6-hydroxykaempferol, quercetin, 6-hydroxyquercetin (quercetagetin), 8-hydroxyquercetin (gossypetin), myricetin, and quercetin 3-O-glucoside, were accepted as substrates by the recombinant protein, as were some flavones, flavanones, and HCA-CoA esters and glucosides. Generally, potential substrates with two free hydroxyls were accepted while those with a single free hydroxyl were not. The reaction product for quercetin was shown to be isorhamnetin (3’-methoxyquercetin), while with quercetagetin five different products with 5-O-, 6-O-, 3’-O-, 5,3’-O-, or 6,3’-O-methylation were generated. This range of substrate choice and products with the recombinant protein is wider than for the purified native enzyme, the major products of which are only the 6-O- and 6,3’-O-methyl ethers. This difference has been shown to be due to the N terminal region of the protein, as a recombinant protein with the first 11 N terminal amino acids removed shows the same enzyme characteristics as the native enzyme.166 The dual methylation reaction suggests a large and flexible active site, which is rare for the OMTs characterized to date. Ibdah et al.115 also examined the wider substrate acceptance of four recombinant CCoAOMTs; one each from Stellaria longipes (chickweed) and A. thaliana with high sequence similarity to PFOMT, and one each from N. tabacum and V. vinifera with lower sequence similarity. The CCoAOMT from S. longipes showed the same range of substrate acceptance as PFOMT, and the same range of products from quercetagetin. The A. thaliana protein efficiently accepted a similar wide range of substrates, but produced only the 6-O- and 6,3’-O-methyl ethers of quercetagetin. In contrast, the N. tabacum and V. vinifera enzymes showed strong preference for caffeoyl-CoA, although they would accept other flavonoids with much lower efficiencies. The in vitro activity pattern is reflected by phylogenetic analysis, which groups the M. crystallinum and S. longipes sequences separately to a large group of class I CCoAOMTs (which include the N. tabacum and V. vinifera sequences). A cDNA, CrOMT2, encoding a flavonoid 3’,5’-OMT has been identified from C. roseus (during a study of alkaloid biosynthesis). The encoded protein could sequentially methylate the 3’- and 5’-hydroxyls of both myricetin and DHM, and showed weaker activity against the 3’-hydroxyl of DHQ.167 Recombinant F3H, FNS, FLS, and ANS were all able to use the 3’-O-methylated substrates.87 3’,5’ O-methylation is characteristic of both flavonol and anthocyanin glycosides of C. roseus (hirsutidin and malvidin glycosides occur), so it is possible that this represents the in vivo activity. Whether a separate anthocyanin 3’,5’-OMT exists in C. roseus, or whether the CrOMT2-derived enzyme also methylates anthocyanins is not known. Schro¨der et al.87 attempted to isolate a cDNA for anthocyanin 7-OMT from C. roseus, and in the process identified a clone (CrOMT6) encoding an OMT that specifically accepted 3’-O-methylated flavonoids as substrates, in particular flavanones, flavones, and flavonols, to produce the 3’,4’-O-methylated derivatives. In a molecular phylogeny the flavonoid-related CrOMT sequences form a separate cluster from the CaOMT and AtOMT1 sequences.

3.7.3 FLAVONE

AND

FLAVONOL SULFOTRANSFERASES

Flavonoids esterified with sulfate groups have been reported to occur in many plant species, in particular mono- to tetrasulfate esters of flavonols and flavones, and their methylated or glycosylated derivatives. These are likely generated by soluble sulfotransferases (STs), which transfer a sulfonate group from 3’-phosphoadenosine 5’-phosphosulfate (PAPS).168 Two subgroups of STs have been reported. The first contains enzymes with generally wide substrate acceptance that are typically involved in detoxification of small metabolites. Enzymes of the second subgroup, which includes the flavonoid STs, show high specificity,

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and in animals are involved in processes such as steroid transport and inactivation. The first plant STs characterized at the molecular level were the flavonol 3-O- and 4’-O-STs (F3ST and F4’ST) from Flaveria chloraefolia,169 followed by a second F3ST, BFST3, from Flaveria bidentis.170 These enzymes form part of a group of flavonol STs that act sequentially to generate the range of flavonol polysulfates found in this genus. Strict specificities are shown to the 3-hydroxyl of flavonol aglycones (F3ST), or the 3’-, 4’- (F4’ST), or 7-hydroxyls of flavonol 3,3’ or 3,4’-disulfates.171 Analysis of the recombinant proteins found the F. chloraefolia F3ST used only flavonol aglycones as substrates (both kaempferol and quercetin, and the methylated rhamnetin and isorhamnetin), and the F4’ST used only the flavonol 3-O-sulfates. BFST3 recombinant protein showed similar activity to the F. chloraefolia F3ST, except that kaempferol was not accepted as a substrate. A range of ST cDNAs has been identified from functional genomics studies of A. thaliana,169 including one (AtST3) that has been shown to encode a flavonoid 7-ST. Unlike BFST3, AtST3 recombinant protein accepts a number of flavonol and flavone aglycones, as well as their 3-O-monosulfated derivatives.169 However, strict specificity to the 7-hydroxyl was found. The plant soluble STs have around 25 to 30% amino acid identity with mammalian soluble STs, and are of a similar size.169 Comparisons between F. chloraefolia F3ST and F4’ST, combined with mutational analysis and data from the crystal structure of mouse estrogen ST, have defined amino acid residues important for PAPS binding, substrate binding and catalysis, and the mechanism of sulfonate transfer.172–175 Sequence relatedness has been used to divide the STs into families and subfamilies in a similar manner as for P450s.169

3.8 BIOSYNTHESIS OF 5-DEOXYFLAVONOIDS A characteristic of legumes is the biosynthesis of 6’-deoxychalcones (chalcones lacking a hydroxyl at the C-6’ position), which are the substrates for the production of 5-deoxyflavonoids. The formation of 6’-deoxychalcones requires the activity of polyketide reductase (PKR) (also known as chalcone reductase or chalcone ketide reductase) in conjunction with CHS. It is thought that CoA-linked polyketide intermediates diffuse in and out of the CHS active site, and while unbound are reduced to alcohols by PKR.46 The resultant hydroxyl groups are then removed from the PKR products in the final cyclization and aromatization steps catalyzed by CHS. PKR is a NADPH-dependent monomeric enzyme of 34 to 35 kDa belonging to the aldoand keto-reductase superfamily.176 The first isolation and characterization of a PKR cDNA was from G. max.177 The G. max cDNA, and cDNAs from other species, have been used to confirm the PKR activity of the recombinant protein, and to produce larger protein amounts for structural analysis.177–179 Studies of the recombinant protein, and analysis of 35SCaMV:PKR transgenic plants,58,149 have also shown that PKR is able to function with CHS proteins from nonlegume species that synthesize only the common 5-hydroxyflavonoids.

3.9 BIOSYNTHESIS OF ISOFLAVONOIDS AND THEIR DERIVATIVES Principally found in legumes, isoflavonoids are a group of compounds that originate from flavanones. The factor differentiating isoflavonoids from other flavonoids is the linking of the B-ring to the C-3 rather than the C-2 position of the C-ring. Subsequent modifications can result in a wide range of structural variation, including the formation of additional heterocyclic rings. The additional rings are principally methylenedioxy or dimethylchromene types, formed from cyclization between vicinal hydroxyl and methoxyl or monoprenyl groups, respectively. The initial steps of isoflavonoid biosynthesis are now well characterized at the

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molecular level, but there is limited progress on the later enzymatic steps that produce the wide range of complex derivatives found in different legume species. A general scheme for their biosynthesis is presented in Figure 3.5 and Figure 3.6.

3.9.1 2-HYDROXYISOFLAVANONE SYNTHASE The entry into the isoflavonoid branch of the pathway occurs through the action of 2hydroxyisoflavanone synthase (2HIS, also known as isoflavone synthase, IFS). 2HIS catalyzes both C-2 to C-3 aryl migration and hydroxylation of the C-2 of (2S)-flavanones to yield (2R,3S)-2-hydroxyisoflavanones. Dehydration of the 2-hydroxyisoflavanones, either spontaneously or through the action of the isoflavone dehydratase (IFD), then forms the isoflavones. The isoflavones formed will be either 5-hydroxy or 5-deoxy compounds, depending on whether they originate from the 6’-hydroxy- or the 6’-deoxychalcone pathways, respectively (e.g., genistein from naringenin and daidzein from liquiritigenin). 2HIS cDNAs were first isolated from G. echinata and G. max by a variety of functional genomics approaches.180–182 These cDNAs were used to identify additional sequences from many legumes and some nonlegume species (see, e.g., Ref. 181), and at the time of this review there were 2HIS sequences from 14 species in public databases. The cDNAs encode P450s that have been classified as part of the CYP93 family (CYP93C) that includes FNSII (CYP93B), flavanone 2-hydroxylase (F2H, CYP93B1), and pterocarpan 6a-hydroxylase (P6aH, CYP93A). Recombinant G. max 2HIS expressed in insect cells was able to form isoflavones without measurable accumulation of 2-hydroxyisoflavanone intermediates.182 This suggests that the dehydration either occurs spontaneously or as part of the 2HIS reaction, without the need for the previously proposed, and partially characterized,183 IFD activity. However, when G. echinata, G. max, or L. japonicus cDNAs were expressed in yeast, 2-hydroxyisoflavanones could be identified.180,181 Liquiritigenin was converted at a greater efficiency than naringenin, although the extent of the variation in efficiency was different for recombinant 2HIS prepared from insect or yeast systems. 2HIS sequences from different species generally show high amino acid identity scores. Some of the amino acid sequences key to the reaction have been identified by computer analysis and mutational analysis of recombinant proteins.184 Changing Ser310 of CYP93C2 to Thr gave increased formation of 3-hydroxyflavanone (i.e., DHF), usually a minor product of the 2HIS reaction. Furthermore, replacing Lys375 with Thr gave F3H-like activity producing only DHFs. Other residues are also important for the reaction, as introduction of the defined Ser and Lys residues into the F2H sequence did not confer the ability to carry out aryl migration or 3-hydroxylation. The results support the suggestion of Hashim et al.185 that the reaction proceeds by a radical generation at C-3 followed by migration of the aryl group from C-2 to C-3, leaving the hydroxyl at C-2.

3.9.2 4’-O-METHYLATION Subsequent to the 2HIS step, a series of reactions lead to a range of plant defense compounds whose exact structures vary between species, in particular pterocarpans — such as glyceollins in G. max and phaseollins in P. vulgaris (Figure 3.5–Figure 3.7). The glyceollins and phaseollins have a free 4’-hydroxyl, but in some legume species, such as Cicer arietinum (chickpea), the 4’-O-methylated versions of daidzein and genistein occur, named formononetin and biochanin A, respectively. Akashi et al.186 suggested that the 2-hydroxyisoflavanone product of 2HIS (e.g., 2,7,4’-trihydroxyisoflavanone that dehydrates to daidzein) might be the substrate for the 4’-O-methylation reaction in vivo, rather than daidzein itself. This biosynthetic route is

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OH

HO

O

OH

HO

OCH3

O O Licodione

O Liquiritigenin 5-Deoxyflavanone

H

O Echinatin Retrochalcone

2HIS HO

O

O

O

H

OH

HO

H

O

HI4'OMT OH

2,7,4'-Trihydroxyisoflavanone

H

O

O

OH H O Rotenone Rotenoid

O

OCH3 2,7-Dihydroxy-4'-methoxyisoflavanone

OCH3 OCH3

(IFD)

(IFD) HO

OH

C2'OMT

F2H

O

HO

O

HO

O OH

I3'H O

O

OH

Daidzein

O

OCH3

Formononetin

OCH3

Calycosin P450

D7OMT HO

O

Isoformononetin O

I2'H

I2'H

O Pseudobaptigenin

O

I2'H HO

O

HO

O

HO

O O

O

HO 2'-Hydroxydaidzein IFR HO

O

OH

O

HO 2'-Hydroxyformononetin IFR HO

O

OCH3

O

O HO 2'-Hydroxypseudobaptigenin IFR

HO

H(R)

O

H(R)

H(S) O

O

O

HO OH (−)-2'-Hydroxydihydrodaidzein

HO (−)-Vestitone

PTS

DMID H(R)

H(R)

DMID HO

H

Pterocarpans O OH

O

HO

O OH(R)

(−)-Medicarpin (e.g., in Medicago and Cicer species)

O H

O

O

(+)-6a-Hydroxymaackiain P3OMT

P2CP or P4CP

(e.g., in Glycine species)

O

OCH3

(−)-Glycinol

Glyceollins

O

(+)-Maackiain P6aH

H(R) OH(S)

O H

O

O

H

O H(S)

OH

(−)-3,9-Dihydroxypterocarpan P6aH HO

HO

H

OH HO OCH3 (−)-7,2'-Dihydroxy-4'-methoxyisoflavanol

O

O

PTS

O

O

H

HO (+)-Sophorol

VR HO

DMID HO

OCH3

O

Phaseollins (e.g., in Phaseolus species)

H3CO

O OH O H

O (+)-Pisatin (e.g., in Pisum species)

O

FIGURE 3.5 Biosynthetic route to isoflavonoids (and some derivatives) from the 5-deoxyflavanone liquiritigenin. A possible route to the retrochalcone echinatin is also shown. Unlabelled arrows indicate biosynthetic steps for which the enzyme(s) have not been characterized. Enzyme abbreviations are defined in the text and in Table 3.1, except for P2CP, pterocarpan 2-C-prenyltransferase; P4CP, pterocarpan 4-C-prenyltransferase.

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O

OH

O Naringenin 2HIS

HO

O

H

HO

OH

O

HI4ⴕOMT OH

O

H

O

OH

OH 2,5,7,4⬘−Tetrahydroxyisoflavanone

Biochanin A I3ⴕH

(IFD) HO

OCH3

O

HO

O OH

OH

O Genistein

OH

OH

O

Pratensein

OCH3

FIGURE 3.6 Biosynthetic route to isoflavones from the 5-hydroxyflavanone naringenin. Enzyme abbreviations are defined in the text.

supported by the isolation of a cDNA from G. echinata whose recombinant protein has 4’-OMT activity against 2,7,4’-trihydroxyisoflavanone but not daidzein, thus indicating it is a hydroxyisoflavanone 4’-OMT (HI4’OMT).187 An alternative biosynthetic route for the introduction of the 4’-methoxyl has been suggested from studies of M. sativa. Initial studies of one of the four isoflavone OMTs (IOMTs) of M. sativa showed it had 7-O-methylation activity to the A-ring of daidzein, thus forming isoformononetin from daidzein. However, overexpression of this IOMT in transgenic M. sativa plants enhanced the biosynthesis of 4’-O-methylated isoflavonoids.188–190 The crystal structure of the IOMT118 indicates the enzyme could accept 2,7,4’-trihydroxyisoflavanone in addition to daidzein, with the SAM methyl donor arranged close to the 7- or 4’-hydroxyl of the respective possible substrates, supporting the observed in vitro and in vivo reactions. Furthermore, IOMT8 (one of the other M. sativa IOMTs) was shown to localize to the endomembranes, with which 2HIS is associated, after induction of isoflavonoid biosynthesis in transgenic M. sativa plants.191 Liu and Dixon191 have proposed that close physical association of 2HIS and the IOMT causes metabolic channeling of 2,7,4’-trihydroxyisoflavanone, ensuring its 4’-O-methylation and the subsequent formation of formononetin, rather than its dehydration to daidzein and subsequent 7-O-methylation. HI4’OMT from G. echinata is thought to be distinct from the M. sativa IOMT, because a separate daidzein 7-OMT is present in G. echinata, prompting the suggestion that the IOMT be renamed D7OMT.187 The HI4’OMT amino acid sequence is closely related to that of the SAM:(þ)-6a-hydroxymaackiain 3-O-methyltransferase (HM3OMT), which carries out a similar reaction in (þ)-pisatin biosynthesis in Pisum sativum (pea) (see Section 3.9.7). The

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O OH H

O

OH

(-) Glycinol P4CP HO

P2CP

O

HO

O

OH H

OH H

O

OH

Glyceollidin I

2PPCI

O

O

O

Glyceollin I

2PPCII

O

O

O

OH H

OH

Glyceollidin II

4PPCI O

O

OH H OH

O

Glyceollin II

OH H OH

O

OH

Glyceollin III

FIGURE 3.7 Biosynthetic route to complex glyceollin phytoalexins from glycinol. Enzyme abbreviations are P2CP, pterocarpan 2-C-prenyltransferase; P4CP, pterocarpan 4-C-prenyltransferase; 2PPCI/ 2PPCII, prenylpterocarpan cyclases acting at the C-2 prenyl group; 4PPCI, prenylpterocarpan cyclase acting at the C-4 prenyl group.

HI4’OMT protein showed activity against the 3-hydroxyl of a compound related to (þ)-6ahydroxymaackiain, (+)-medicarpin, suggesting HI4’OMT may be functionally identical to HM3OMT. However, the HM3OMT substrate is only found in species making (þ)-pisatin. The G. echinata HI4’OMT cDNA was used to isolate HI4’OMT cDNAs from L. japonicus, M. truncatula, and other legumes. Both HI4’OMT and IOMT may be involved in formononetin biosynthesis, perhaps in the same tissues, and the formation of heterodimers of similar OMTs has been reported.192

3.9.3 ISOFLAVONE 2’- AND 3’-HYDROXYLASE Two P450s of the CYP81E subfamily, isoflavone 2’-hydroxylase (I2’H) and isoflavone 3’-hydroxylase (I3’H), catalyze key steps in the formation of the more complex isoflavonoids. Hydroxylation of formononetin at the C-3’ position produces calycosin, a precursor for subsequent methylenedioxy bridge formation (yielding pseudobaptigenin) as part of the branches leading to maackiain- and pisatin-type phytoalexin end products, as well as to the rotenoids and other complex derivatives. Hydroxylation at the C-2’ position of daidzein, formononetin, or pseudobaptigenin provides the hydroxyl required for C–O–C bridge formation that defines the pterocarpans (e.g., glycinol). A cDNA encoding the I2’H was first identified among a group of cDNAs from G. echinata cell lines representing elicitor-induced mRNAs for P450s.193 The recombinant protein catalyzed the 2’-hydroxylation of formononetin and daidzein, and had no activity with HCAs or flavanones. Subsequently, cDNA clones have been isolated from M. truncatula (CYP81E7) and other species.194 CYP81E7 expressed in transgenic A. thaliana conferred the

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ability to form 2’-hydroxyformononetin when formononetin was supplied. A closely related cDNA to CYP81E7, CYP81E9, was found to encode the I3’H from M. truncatula.194 Recombinant MtI2’H and MtI3’H showed preference to the 5-hydroxylated substrate biochanin A over the 5-deoxy equivalent, formononetin. MtI2’H also showed the expected activity with pseudobaptigenin, daidzein, and genistein, but with reducing preference in each case. For daidzein and genistein, a lesser 3’-hydroxylase activity was also found. The preferred substrates for recombinant MtI3’H were, in descending order, biochanin A, formononetin, and 2’-hydroxyformononetin. Km values of 67 and 50 mM toward formononetin were found for MtI2’H and MtI3’H, respectively. The I2’H and I3’H genes are differentially expressed in M. truncatula, in terms of spatial patterns and response to biotic and abiotic stresses.194 The data suggest a role for I3’H in the formation of compounds such as rotenoids in response to insect attack, and I2’H in biosynthesis of antimicrobial isoflavonoids.

3.9.4 ISOFLAVONE REDUCTASE The 2’-hydroxyisoflavones are reduced to the corresponding isoflavanones by a NADPHdependent isoflavone reductase (IFR). The isoflavanones are the final isoflavonoid intermediates of pterocarpan biosynthesis. Variant IFR activities between species are thought to contribute to the stereochemistry of the pterocarpans produced, in particular, (þ)-maackiain in P. sativum, ()-maackiain in C. arietinum, ()-3,9-dihydroxypterocarpan in G. max, and ()-medicarpin in M. sativa. The () indicates 6aR11aR stereochemistry. Clones corresponding to IFR were first isolated from M. sativa, using an antibody raised against the P. sativum protein to screen an expression cDNA library,195 from C. arietinum based on protein purification and sequencing,196 and subsequently from P. sativum.197 IFR has a calculated MW of 34 to 35 kDa, and is a member of the RED protein family. The recombinant M. sativa enzyme converted 2’-hydroxyformononetin to the expected (3R) isomer of vestitone, and would accept 2’-hydroxypseudobaptigenin, but not formononetin, pseudobaptigenin, or several other flavonoids tested. These are similar substrate preferences to those of the purified C. arietinum enzyme. Surprisingly, the recombinant P. sativum enzyme produced a (3R)-isoflavanone product, ()-sophorol, from 2’-hydroxypseudobaptigenin, rather than the (3S)-stereoisomer, (þ)-sophorol, that would be expected from the accumulation of (þ)-maackiain in this species (Figure 3.5). Thus, it is possible that an epimerase is also involved in the biosynthetic pathway to the (þ)-isoflavonoids, at least in P. sativum. Using the crystal structures of two related RED enzymes of lignan biosynthesis, a provisional molecular model has been produced for the M. sativa IFR.198 A smaller binding pocket in the protein, in comparison to the other enzymes, is suggested to account for the specific enantiomer binding and processing of IFR.

3.9.5 VESTITONE REDUCTASE Based on analysis of enzyme preparations, the conversion of isoflavanones to pterocarpans was thought initially to be catalyzed by a single NADPH-dependent enzyme, termed the pterocarpan synthase (PTS). However, it was subsequently shown that in M. sativa the conversion of vestitone to medicarpin involves two enzymes, VR and 7,2’-dihydroxy-4’methoxyisoflavanol (DMI) dehydratase (DMID).199 The reaction series from vestitone to the pterocarpan is thought to proceed by the VR-catalyzed reduction of vestitone to DMI, followed by the loss of water and formation of the C–O–C bridge between the heterocycle and the B-ring, catalyzed by DMID. Guo and Paiva200 used the amino acid sequence of purified VR to isolate a cDNA clone from M. sativa, which was then analyzed by expression in E. coli. VR, a monomeric 38 kDa

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protein, is another member of the RED family. It converts (3R)-vestitone, but not (3S)vestitone, to DMI in vitro, although the stereospecificity may vary with VR enzymes from other species.200 Little has been published on other VR cDNAs, although the G. max VR sequence is available in US patent #6,617,493. The isolation of DNA sequences for DMID has not been reported. In some species, such as C. arietinum and M. sativa, the products of VR and DMID (maackiain and medicarpin) are the main pterocarpan phytoalexins. They are typically glucosylated and malonylated and stored in the vacuole.201 In species such as G. max, P. sativum, and P. vulgaris, the pterocarpans are further converted by a series of reactions to species-specific compounds. For G. max and P. sativum, the initial reaction is a hydroxylation catalyzed by P6aH.

3.9.6 PTEROCARPAN 6A-HYDROXYLASE The main phytoalexins in G. max (glyceollins) and P. sativum (pisatin) are pterocarpans hydroxylated at position C-6a, in a reaction carried out by the P450 P6aH (at least in G. max). Recombinant CYP93A1, from a cDNA isolated from elicitor-induced G. max cells, carries out the stereospecific and regioselective hydroxylation at the 6a position of (6aR,11aR)-3,9-dihydroxypterocarpan, with a Km of 0.1 mM, to yield 3,6a,9-trihydroxypterocarpan.202 Given the specificity of the reaction, the encoded protein was termed the dihydroxypterocarpan 6a-hydroxylase (D6aH). P6aH activities are present in other species, but analysis of cDNA clones has not been published.

3.9.7 SAM:6A-HYDROXYMAACKIAIN 3-O-METHYLTRANSFERASE Methylation of the 3-hydroxyl of (þ)-6a-hydroxymaackiain by HM3OMT produces the major phytoalexin of P. sativum, (þ)-pisatin. Two closely related cDNAs for HM3OMT were isolated from a cDNA library prepared from pathogen-induced P. sativum mRNA using antibodies prepared to the purified enzyme.203 The recombinant proteins had highest activity with (þ)-6a-hydroxymaackiain, a lower activity with (þ)-medicarpin, and low or no activity with ()-6a-hydroxymaackian, ()-medicarpin, ()-maackiain, isoliquiritigenin, daidzein, or formononetin. One of the HM3OMT proteins also had significant activity with (þ)-maackiain although this is unlikely to be an in vivo substrate, as 3-O-methylmaackiain is not observed in P. sativum tissues.

3.9.8 PTEROCARPAN PRENYLTRANSFERASES The formation of phytoalexins such as glyceollins and phaseollins requires C-prenylation by a range of pterocarpan prenyltransferase (PTP) activities, with dimethylallyl pyrophosphate (DMAPP) as the prenyl donor. For glyceollins and phaseollins, prenylation occurs at position C-2 or C-4 of glycinol or C-10 of 3,9-dihydroxypterocarpan.204,205 However, there are differing activities in other species. For example, in Lupinus albus (white lupin) a prenyltransferase acting at the C-6, -8, and -3’ positions of isoflavones has been identified.206 PTPs have also been characterized in detail for the formation of prenylated flavanones in Sophora flavescens (see, e.g., Ref. 207). However, no cDNA clones for flavonoid-related prenyltransferases have been published to date.

3.9.9 PRENYLPTEROCARPAN CYCLASES The final step of glyceollin and phaseollin formation is the cyclization of the prenyl residues of glyceollidins and phaseollidins, carried out by P450 prenylcyclases (Figure 3.7). These

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activities have been studied in detail for the formation of three glyceollins (I, II, and III) from glyceollidin I and II, and it is thought that specific activities are involved in each reaction.208 However, no corresponding cDNA sequences have been published to date.

3.9.10 ISOFLAVONOID GLUCOSYLTRANSFERASES

AND

MALONYLTRANSFERASES

As mentioned previously, in some species the major phytoalexins are glycosylated and acylated. The final product of the isoflavonoid phytoalexin pathway in M. sativa is medicarpin 3-O-glucoside-6’’-O-malonate, and a range of isoflavone 7-O-glucosides and their malonylated versions accumulate in G. max. There are few reports on molecular characterization of DNA sequences for the enzymes carrying out glycosylation or acylation of isoflavonoids, although some cloned GTs with wide substrate acceptance have been shown to act on isoflavones (see Section 3.7.1). However, a cDNA for one isoflavonoid-specific GT has been isolated from G. echinata using the S. baicalensis F7GT cDNA as a probe.209 The UGT73F1 cDNA encodes a putative UDP-glucose:formononetin 7-O-glucosyltransferase. The recombinant protein accepted both formononetin and daidzein efficiently, and had little activity on other flavonoids tested. Glycosylation occurred at only one, as yet unassigned, position of daidzein, which is hydroxylated at C-7 and C-4’. Since the likely in vivo substrate is formononetin, which has only the 7-hydroxyl free, the enzyme was termed a formononetin 7GT. In a molecular phylogeny the UGT73F1 sequence is located in a cluster with other stress-induced GTs.

3.9.11 FLAVONOID 6-HYDROXYLASE The hydroxyl groups at C-5 and C-7 of the A-ring are introduced during the formation of chalcones by CHS (or at the C-7 alone if PKR is coactive). However, flavonoids also occur with C-6 and C-8 hydroxylation, including 6- and 8-hydroxyanthocyanins, flavonols, and isoflavonoids. Latunde-Dada et al.210 have identified a cDNA representing an elicitorinduced P450 (CYP71D9) with flavonoid 6-hydroxylase (F6H) activity, which may be involved in the biosynthesis of isoflavonoids with 6,7-dihydroxylation of the A-ring. The recombinant protein did not act on the isoflavonoids or pterocarpans directly, but rather accepted flavanone and DHF substrates, including liquiritigenin, suggesting hydroxylation occurs prior to aryl migration of the B-ring. In support of this route, 2HIS was found to be able to use 6,7,4’-trihydroxyflavanone. The F6H showed low activity against flavones and little action on the flavonol kaempferol. Nevertheless, it is possible that a similar biosynthetic route through hydroxylation of precursors, perhaps by the same F6H, is involved in the production of other 6-hydroxyflavonoids. However, an alternative activity of the 2OGD type has been characterized at the biochemical level from C. americanum that catalyzes the 6-hydroxylation of partially methylated flavonoids.211

3.10 FORMATION OF AURONES Although it has long been thought, based on genetic mutant and biochemical evidence, that aurones are derived from chalcones, the biosynthetic mechanism has only recently been clarified, and some aspects of the enzymatic process still await in vivo proof. An mRNA from A. majus, specifically expressed in the petal epidermal cells, has been shown to encode a recombinant protein with aureusidin synthase (AUS) activity.212–214 AUS is a variant polyphenol oxidase (PPO) that can catalyze conversion of either 2’,4’,6’, 4-etrahydroxychalcone (naringenin chalcone) or 2’,4’,6’,3,4-pentahydroxychalcone to

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aureusidin (3’,4’-hydroxylated) or bracteatin (3’,4’,5’-hydroxylated), respectively212 (note that carbon numbering differs between chalcones and aurones — Figure 3.1). Thus, it carries out both B-ring hydroxylation and formation of the C-ring, and, indeed, the enzyme studies suggest 3,4,2’-hydroxylation of the chalcone substrate may be a requirement for the formation of the aurone.214 How this observation relates to the biosynthesis of those aurones with no B-ring hydroxylation is not clear. The only studies to date published on the enzymology of B-ring deoxyaurone formation, in cell cultures of Cephalocereus senilis (old man cactus), did not address this step.215 For 4-deoxyaurones, it is likely the 6’-deoxychalcones are acted on by AUS, as the compounds commonly co-occur and AUS preparations show significant activity on the 6’-deoxychalcones.214 PPOs are typically plastid located copper-containing glycoproteins that have activity on a wide range of phenylpropanoids. It has been known for many years that PPOs can form aurones from chalcones, and this has been demonstrated recently with a recombinant tyrosinase from Neurospora crassa.212 However, AUS represents a specific variant to previously defined PPOs. In particular, it lacks a typical N terminal plastid localization signal, and it has been suggested that it may be located to the vacuole.212 How AUS would then compete with CHI for chalcone substrate, as may happen in species such as A. majus that can produce aurones and anthocyanins in the same petal cells, is not clear. However, recombinant AUS can use chalcone 4’-O-glucosides as substrates,214 raising the possibility that aurone formation in vivo occurs in the vacoule from glucosylated substrates. Confirmation of the role of AUS awaits characterization of specific mutants, or the production of knockout or gain of function transgenic plants, and determination of the protein localization. Bifunctional PPOs may also be involved in the biosynthesis of betalains.216 Aurones are commonly glycosylated at the 4- or 6-hydroxyl. International Patent Application WO00/49155 reports that the recombinant S. baicalensis F7GT155 can glucosylate aureusidin at the equivalent 6-hydroxyl, and also details the cloning of similar 7-O-glucosyltransferase cDNAs from A. majus and P. hybrida. However, it is not clear how these activities relate to the aurone or chalcone 6-O-glucosyltransferase activity characterized from Coreopsis grandiflora that accepts both 4-deoxyaurones and 6’-deoxychalcones.217 To date, in addition to CHS mutants, no mutants have been fully characterized that abolish aurone biosynthesis, although a commercial white-flowered line of A. majus was shown to lack AUS transcript in Nakayama et al.212 and there is a preliminary report of an EMS-generated aurone-specific mutant of A. majus.218

3.11 OTHER ACTIVITIES OF FLAVONOID BIOSYNTHESIS There are a few well-characterized modification enzyme activities that have not been detailed in the preceding sections on flavonols, flavones, anthocyanins, and isoflavonoids, and these are discussed here. Chalcones may be modified by hydroxylation, glycosylation, or methylation. The common 6’-deoxychalcone butein is hydroxylated at the C-3’ position by a P450 enzyme thought to be distinct to the F3’H.219 Methylation of the 2’-hydroxyl of isoliquiritigenin in legumes such as M. sativa and P. sativum forms one of the most active flavonoids for signaling to Rhizobium symbiots.220 As methylation prevents formation of the flavonoid C-ring, the OMT activity will help determine the balance between nodulation-related and defense-related flavonoids. Maxwell et al.221 isolated a cDNA from M. sativa for a SAM:isoliquiritigenin 2’-OMT and demonstrated the encoded activity by assaying recombinant protein from E. coli. As would be expected from the symbiosis function, the gene is expressed primarily in developing roots. Haga et al.222 have presented a short report on a cDNA for a similar OMT from G. echinata, which in addition to acting on isoliquiritigenin, may be involved in the methylation of licodione to form the retrochalcone echinatin (Figure 3.5).

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F2H was postulated to be involved in the formation of the common flavones upon its identification from G. echinata, as the recombinant F2H catalyzed the formation of 2-hydroxynaringenin from (2S)-naringenin, which yielded apigenin upon acid treatment.180,223 Based on the subsequent identification of FNS sequences from G. echinata and other species, it now seems unlikely that F2H is involved in the formation of the common flavones. Rather, its in vivo role in G. echinata may be the 2-hydroxylation of liquiritigenin, which can then yield licodione upon hemiacetal opening, as part of the biosynthetic route to echinatin (see Figure 3.5). Thus, F2H could be the licodione synthase. The pathway to echinatin may continue by the methylation of licodione by the OMT described by Haga et al.222 Alternatively, the F2H may be part of the biosynthetic pathway to flavone C-glycosides. 2-Hydroxyflavanones have been proposed to be direct precursors for flavone C-glycosides and the substrates for C-UGTs, thus giving a biosynthetic scheme in which glycosylation occurs prior to the formation of the flavone structure.143,224 The flavonoid modification enzymes for which DNA sequences are available, and which we have already discussed in this chapter, represent only a few of the expected activities. Heller and Forkmann3 tabulated 20 to 30 characterized enzymes, and given the variety of flavonoid structures identified, this must still be only a small portion of the existing activities.

3.12 VACUOLAR IMPORTATION OF FLAVONOIDS Although flavonoids are found in many cellular compartments, it is only the mechanisms for vacuolar import that have been characterized in any detail. Alternative import mechanisms have been found that involve direct uptake, carrier proteins, or secondary modifications triggering importation. While commonalities are found for the import of anthocyanins, flavones, flavonols, and PAs, differences have also been observed for the different types of flavonoid. The best-characterized mechanism shares elements with general xenobiotic detoxification processes, which typically involve the addition of glycosyl, malonyl, or glutathione residues to form stable water-soluble conjugates, and the sequestration of these conjugates by ATPbinding cassette (ABC) transmembrane transporters.225,226 In particular, glutathione-S-transferase (GST, EC 2.5.1.18) activities have been shown to be required for the transport of anthocyanins and PAs in some species, mostly based on studies of mutants affected in GST genes. In the bronze2 (bz2) mutant of Z. mays anthocyanins undergo oxidation and condensation in the cytosol, causing bronze kernel pigmentation.227 The an9 mutant of P. hybrida has acyanic petals,228 while the tt19 mutant of A. thaliana has reduced anthocyanin and PA accumulation in seedlings and seed, respectively.229 Although AN9 and BZ2 only share 12% amino acid identity and belong to different classes of GST (type-I and type-III, respectively), they show functional homology, being able to reciprocally complement the mutations and, furthermore, complement the mutant floral phenotype of the flavonoid3 mutant of D. caryophyllus.230 AN9 also complemented the anthocyanin phenotype of tt19, but it did not overcome the loss of PA production. Another indication that anthocyanin sequestration is linked to general detoxification processes is that alternatively spliced Bz2 mRNAs accumulate in response to various stresses.231 Interestingly, recombinant AN9 does not glutathionate cyanidin 3-O-glucoside or other flavonoids in vitro, and no anthocyanin–glutathione conjugates have been observed in vivo.232 It has been suggested, therefore, that GST directly binds anthocyanins and escorts them to the vacuole, without glutathione addition being required.232 However, the recombinant proteins of the A. thaliana ABC transporter proteins AtMRP1 and AtMRP2 can transport glutathionated anthocyanin in vitro, as well as other glutathione S-conjugates and chlorophyll

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catabolites, supporting a role for glutathionation and subsequent import by ABC transporters.233 Vacuolar transport of PAs differs from that of anthocyanins in some species. In A. thaliana, the TT12 locus encodes a transporter of the multidrug and toxic compound extrusion (MATE) type with 12 membrane-spanning domains, and mutations preventing TT12 function prevent accumulation of PAs.142 Interestingly, a transcript with high sequence identity to TT12, MTP77, is upregulated in L. esculentum transgenics over-producing anthocyanin due to activation of an anthocyanin regulatory gene, suggesting a link between MATE transporters and anthocyanins in this species.234 There is also a preliminary report of a P. frutescens cDNA encoding a membrane protein of unknown function (8R6) that promotes anthocyanin uptake into protoplasts and anthocyanin accumulation when overexpressed in A. thaliana transgenics.235 Within the vacuole of some plants (but not A. thaliana) the anthocyanins may occur in protein containing bodies, termed anthocyanic vacuolar inclusions (AVIs), whose function is as yet unknown but may relate to transport activities.236,237 An additional aspect of flavonoid transport to the vacuole is the coordination of the localization process with vacuole biogenesis. The major vacuole in a cell may grow by small pro-vacuolar vesicles that have budded off the plasma membrane, endoplasmic reticulum, or Golgi fusing with the tonoplast. Interestingly, the tds4 mutation of A. thaliana (for ANS, preventing epicatechin production) prevents normal vacuole development and causes accumulation of small vesicles.139 Other tt mutations that prevent PA accumulation but not epicatechin formation do not interfere with vacuole development, implying a link between epicatechin biosynthesis and vacuole development.139 There are few studies on vacuolar importation of flavonoids other than anthocyanins and PAs. Klein et al. reported uptake of flavone glycosides by isolated H. vulgare primary leaf vacuoles via a vacuolar Hþ-ATPase linked mechanism,238 and by vacuoles from Secale cereale (rye) mesophyll via a possible ABC transporter mechanism.239 Li et al.240 found medicarpin conjugated to glutathione was also sequestered by an ABC transporter mechanism.

3.13 ENZYME COMPLEXES AND METABOLIC CHANNELING It has long been thought that biosynthetic enzymes of plants are organized into macromolecular complexes in specific subcellular locations. It was suggested in the 1970s and 1980s that for flavonoid biosynthesis a multienzyme complex might exist, loosely associated with the endoplasmic reticulum and perhaps anchored through P450 enzymes such as C4H or F3’H (for coverage of the earlier literature, see Refs. 14, 57). This proposal has received support from more recent research, in particular affinity chromatography with flavonoid enzymes, yeast two-hybrid analysis, subcellular localization studies, and transgenic plants lacking individual phenylpropanoid enzymes.14,57,241,242 Activity studies also support direct enzyme association. For example, PKR is thought to act on an intermediate of the CHS reaction, suggesting close association of the two enzymes in the cell.46,57 Additionally, data from transgenic experiments support the occurrence of metabolic channeling and feedback loops in the early steps of phenylpropanoid biosynthesis, in particular for PAL and C4H.14,243,244 A role for enzyme complexes in the metabolic channeling of substrate has been proposed, so that competition between alternate enzyme pathways can be managed and the production of a specific product from a range of possibilities is favored. Furthermore, isoforms of the different enzymes may assemble in particular complexes dedicated to specific classes of flavonoid.

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3.14 ASSIGNING ENZYME FUNCTION FROM DNA SEQUENCE OR RECOMBINANT PROTEINS As molecular studies of flavonoid biosynthesis have progressed, particular issues in assigning enzyme function from DNA sequence or recombinant protein activity have arisen that are worth commenting on briefly. Recent studies with recombinant flavonoid 2OGDs have shown overlapping substrate usage and product formation in vitro. For example, recombinant ANS shows overlapping activities with F3H and FLS, and recombinant FLS shows F3H and FNS activity.62,63,84–86 However, genetic mutants suggest that these in vitro activities may be less prevalent in vivo. For example, the still active ANS or FLS genes do not complement the acyanic phenotypes of F3H mutants of A. majus or A. thaliana, although it is possible (but unlikely) that the genes do not have the appropriate expression patterns either temporally or spatially. The UGT enzymes also may display broader in vitro activities than those in vivo.95,153 The reasons for the differences between the in vitro and in vivo observations are not clear. The in vitro assay conditions may not accurately replicate the in vivo environment, so that differential efficiencies with regard to the alternative substrates and isomers might not be correctly represented. Also, recombinant proteins may have small but important structural differences to the native enzyme, as well illustrated by studies of PFOMT166 (see Section 3.7.2). Alternatively, the formation of the enzymes into complexes and the effects of metabolic channeling may control the different activities. For example, the action of F3GT on an intermediate of the ANS reaction may direct anthocyanin formation over flavonol formation, even though flavonols are the favored ANS product in vitro. The second area worthy of comment is with regard to assignment of enzyme function based on amino acid sequence alone. In some cases sequence comparisons can be used to determine if a new cDNA encodes one of the well-known flavonoid biosynthetic enzymes. However, in some cases, sequence similarity is insufficient for reliable prediction of the encoded function. For example, the OMTs may have amino acid identities of above 85% but different activities.165 For transcription factors such sequence-based assignments of function are significantly more difficult, as specific roles for a given factor may have arisen in particular species. Thus, analysis of genetic mutants and transgenic overexpression or ‘‘knockout’’ lines is still preferable for confirmation of the encoded activities.

3.15 REGULATION OF FLAVONOID GENE TRANSCRIPTION The phenylpropanoid pathway involves many biosynthetic genes and several alternative branches from common precursors leading to different flavonoid types and other compounds. Such complexity requires fine-tuned control, allowing the alteration of flux as conditions vary. This control is often achieved by the coordinate regulation of multiple genes, with the groupings varying with not only the end product that is to be made, but also with respect to the species and the type and developmental stage of a tissue. Furthermore, individual biosynthetic genes may be regulated in response to a number of developmental and environmental signals. For example, in flowers the biosynthetic genes change their activities as a consequence of light and spatio-temporal developmental factors for the production of anthocyanins in the petal epidermal cells, coincident with flower fertility. Studies to date have shown that increases in gene transcription rates generally precede flavonoid production. This observation, in conjunction with studies on flavonoid-related transcription factors (TFs), suggests that gene transcription is the key point for biosynthetic gene regulation, rather than translation or post-translational steps. Post-transcriptional regulation has been reported for flavonoid biosynthesis (reviewed in Ref. 14 and recently

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featured in Ref. 245), and the extent of its role in controlling the pathway may come to light as methods for studying these aspects improve. In combination with metabolic channeling, posttranscriptional regulation would provide a means of fine control on the metabolic flux through the pathway to the accumulation of end products. Nevertheless, the overall data support the idea that it is changes in biosynthetic gene transcription rate that underpin major changes in flavonoid biosynthetic activity in most situations. The transcription rate of a given gene is principally determined by interactions of TFs specific for that gene with the RNA polymerase II-containing holoenzyme and other components of the basal transcription machinery. Gene-specific TFs bind in a sequence-specific manner to motifs (cis-elements) within genes, usually in gene promoters, and increase (as activators) or decrease (as repressors) the rate of transcriptional initiation.246–248 TF activity may be modulated by a range of mechanisms, in particular competition with other TFs, direct interaction with coactivator or corepressor proteins (which themselves do not bind DNA), and reversible phosphorylation. Research on the regulation of the flavonoid biosynthetic genes is at the forefront of general plant transcriptional regulation studies. There are data from a number of different plant species concerning the specific cis-elements and TFs involved, and some of the functional interactions between the different types of TF have been elucidated. In this section, the literature on regulation of flavonoid biosynthesis is reviewed in brief only, and the reader is referred to more detailed review articles where possible. For additional information on the aspects covered, as well as detailed discussion of the TF families, the reader is referred to other reviews, including a comprehensive review of the genomics of transcriptional regulation in A. thaliana.52,248–255

3.15.1 ENVIRONMENTAL REGULATION

OF

EARLY BIOSYNTHETIC STEPS

Studies have predominantly focused on the regulation of CHS, presumably because CHS activity is a key flux point for flavonoid biosynthesis. CHS is commonly regulated coordinately with general phenylpropanoid genes in response to abiotic and biotic stresses. Much data are available for the cis-regulatory elements and associated TFs for regulation of PAL, C4H, 4CL, and CHS in response to UV light and pathogen-related elicitors, and cross-talk between the different stress signaling pathways is being uncovered. Furthermore, the control of flavonoid gene expression during general photomorphogenesis is being characterized as part of studies in A. thaliana on the constitutive photomorphogenic (COP) regulatory system. The COP system is composed of the COP9 signalosome, a multiprotein complex encoded by several COP, De-etiolated (DET), and Fusca genes, and at least four related proteins that act outside the COP9 complex — COP1, COP10, COP1 Interacting Protein (CIP), and DET1 (reviewed in Refs. 256–258). It is thought to act via ubiquitin-mediated, light-dependent degradation of downstream signaling components of many photoreceptors, as COP1 is a putative E3 ubiquitin ligase that interacts directly with several TFs. Affected proteins encoding phenylpropanoid regulators include AtMYB21 and HY5.259,260 COP10 and CIP probably encode other components of the ubiquitin degradation pathway. From promoter analysis and transgenic studies the light-responsive unit (LRU) of the CHS genes of P. crispum and A. thaliana has been shown to be necessary and sufficient for induction of gene expression in response to UV-A and blue light or UV-B (see, e.g., Refs. 261–264). The LRU contains an ACGT-containing element (ACE) and an MYB-recognition element (MRE). A variety of ACEs have been identified that are named from the last nucleotide in the recognition motif, including the A-box (TACGTA)-, C-box (GACGTC)-, G-box (CACGTG)-, and T-box (AACGTT)-type elements. Many basic region/leucine

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zipper (bZIP) proteins have been shown to recognize and bind ACEs present in a range of promoters (reviewed in Refs. 265, 266). In P. crispum, at least seven bZIP proteins (referred to as common plant regulatory factors — CPRFs) bind the LRU ACE with varying affinities. In particular, PcCPRF1 is likely to be vital to the UV-induction process, as PcCPRF1 transcript levels increase in abundance in response to UV light and precede the increase in CHS transcript abundance. In A. thaliana, the bZIP HY5 regulates a number of pathways, including that of the phenylpropanoids, and interacts directly with the ACE of light-responsive promoters.267 Homo- and heterodimers of CPRFs occur, and dimerization, along with phosphorylation, may be important to the subcellular localization and function of bZIP proteins.268,269 A number of two-repeat R2R3 MYB proteins (including AmMYB305 or AmMYB340 described in Section 3.15.4) and an unusual single-repeat MYB from P. crispum, PcMYB1,263 have been shown to activate phenylpropanoid gene promoters through interaction with the LRU MRE or related MREs (e.g., the P-box). The MREs are often not only involved in the response to environmental stimuli but also in the developmental and spatial control of gene expression. MYB proteins with a repressive function are involved in the regulation of phenylpropanoid biosynthetic genes. The first indication of such a role came from overexpression of A. majus AmMYB308 or AmMYB330 in N. tabacum, which caused dramatic reductions in the levels of lignin.270 Analysis of an A. thaliana mutant for the orthologous gene AtMYB4 showed increased C4H transcript levels, elevated levels of sinapate esters (HCA derivatives), and enhanced tolerance to UV-B exposure.271 In CaMV35S:AtMyb4 plants, the C4H, 4CL, and CHS genes were all downregulated. Although white light is required for AtMyb4 gene expression, transcript levels fall markedly within 24 h of exposure to UV-B. Deletion analysis and creation of fusion proteins indicate a role for the C terminal domain of the AtMYB4 protein in the repression function, perhaps through an ‘‘active’’ repressive effect on the basal transcription machinery.271 The response to pathogen infection involves not only some of the cis-elements characterized for the UV-light response but also additional regulatory elements related to pathogenassociated stimuli. These include the H-box and a TGAC (W-box) sequence that interacts specifically with a WRKY TF.249,272,273 H-boxes have been associated with stress induction and tissue specificity of PAL, 4CL, and CHS genes of a number of species. For example, the multiple H-boxes of the P. vulgaris CHS15 gene promoter, along with the neighboring G-box and ACE, contribute to both tissue specificity of gene expression and induction in response to pathogen elicitation.272,273 Although the H-box (CCTACC) closely resembles MREs such as the P-box (e.g., CCACCTACCCC), the interacting TFs characterized to date are not MYB proteins. The KAP-1 and KAP-2 proteins of P. vulgaris, which interact specifically with this sequence in the CHS15 promoter, have sequence similarity to the mammalian Ku autoantigen protein involved in control of DNA recombination and transcription.274 KAP-2 cDNAs have been isolated from P. vulgaris and M. truncatula, and the recombinant protein has been shown to activate H-box-containing promoters in vitro. KAP-2 transcript is constitutively present in P. vulgaris tissues, suggesting post-translational control of its activity, perhaps related to the previously observed elicitor-induced phosphorylation of the protein.275 Pathogen elicitation can also downregulate gene transcription, as evidenced by studies on the UV-light-inducible CHS and ACC genes of P. crispum.276 When plants are placed under both pathogen and UV-light stresses, the pathogen repression signal to these genes is dominant to the UV-light induction signal. For ACC, both signals converge on two very similar ACEs, suggesting the switch from activation to repression might be achieved through replacement of activating TFs with a repressor protein. UV-induced increases in PcCPRF1 transcript levels are prevented by elicitor treatment, while PcCPRF2 transcript levels are decreased by UV light and increased by elicitation, indicating such a regulatory system.

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3.15.2 REGULATION

OF

185

ANTHOCYANIN BIOSYNTHESIS

Regulation of anthocyanin production involves transcriptional activators of the R2R3 MYB and the basic helix–loop–helix (bHLH) (or MYC) types (Table 3.2). This was first revealed by studies of the monocot Z. mays. It was found that the anthocyanin pathway is turned on in this species through the combined action of one member of the COLORED ALEURONE1 (C1)/PURPLE PLANT (PL) MYB family and one member of the RED1 (R)/BOOSTER1 (B) bHLH family.14,52 The members of the MYB and bHLH families are functionally redundant, and their specific expression patterns enable spatial and temporal control of anthocyanin biosynthesis. Activation of the biosynthetic genes is dependent on direct interaction between the MYB and bHLH TFs within the transcriptional activation complex.14,52 The complex binds DNA through discrete cis-elements in the target gene promoters, one that is recognized specifically by the MYB member and one (the ARE) that is recognized by an as yet unidentified protein.277,278 The bHLH member functions in part through the ARE, and may be the protein that binds directly to it, or alternatively, interacts with a different protein that binds to it.278 Other species for which the elucidation of regulatory mechanisms controlling anthocyanin pigmentation is well underway are the eudicotyledon (dicot) species A. majus and P. hybrida (primarily for floral pigmentation) and A. thaliana (for vegetative pigmentation) (see Table 3.2). While TF genes equivalent to those in Z. mays are involved, the mechanism of regulation varies. Based on mutant analyses, the encoded TFs in these species control a subset of the anthocyanin biosynthetic genes, the late biosynthetic genes (LBGs). The early biosynthetic genes (EBGs) are under independent control, by as yet unidentified TFs. Partitioning of the pathway into separately regulated units allows for independent control of the production of other flavonoid types. In insect pollinated flowers, flavonoids have roles beyond pigmentation, e.g., flavones and flavonols are frequently the basis of nectar guides. For the floral models studied, the step in the pathway at which control by the defined TFs starts is at F3H or DFR, depending on whether there is predominate coproduction with anthocyanins of flavones or flavonols, respectively.64,89,119,279 In one of the few studies on fruit, the A regulatory gene of Capsicum annuum (bell pepper) was found to affect only transcript levels of LBGs.280 In A. thaliana, the LBGs are coregulated during induction of anthocyanins in seedlings exposed to white light and for PA production.281–283 Modular control of the pathway is not a universal trait in dicot species. For anthocyanin production in vegetative tissues of P. frutescens, the biosynthetic genes are regulated as a single group, from CHS to GSTs, as occurs in Z. mays.235,284,285 Furthermore, single genes may be important points of control. In Viola cornuta ANS may be the main regulatory target,286 and in V. vinifera berries A3GT is regulated separately and may be the key step for triggering anthocyanin production in berries during ripening.287,288 Modular control has also been found in the monocot Anthurium andraeanum; in both spathe and spadix DFR is regulated separately from the other genes.289 As in Z. mays, families of MYB and bHLH TFs regulating anthocyanin production have been commonly found in the other species investigated to date. Through studies of these families it has become apparent that highly similar family members may vary subtly in their regulatory activity or act at different points in a regulatory hierarchy. In A. majus, differential activities of the family members give variations in floral pigmentation patterns, including a striking venation pattern determined by the Myb gene Venosa.250 Within the MYB and bHLH families in P. hybrida, there are indications that some exert transcriptional control over others,290 a complexity that has not been found in Z. mays291 or reported for related TFs in other species. It remains to be determined whether these P. hybrida TFs also function as direct regulators of the anthocyanin biosynthetic genes.

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TABLE 3.2 Transcription Factors that Regulate Flavonoid Biosynthetic Genes Species Antirrhinum majus

Metabolite Phenylpropanoids (including flavonoids)

Anthocyanins

Arabidopsis thaliana

Phenylpropanoids Anthocyanins and proanthocyanidins

Capsicum annuum Fragaria  ananasa Gerbera hybrida

Anthocyanins Anthocyanins and flavonols Anthocyanins

Ipomoea tricolor Lycopersicon esculentum Perilla frutescens

Anthocyanins Anthocyanins Anthocyanins

Petunia

Anthocyanins

Sorghum bicolor Vitis vinifera Zea mays

Phlobaphenes Anthocyanins Anthocyanins

Protein Type MYB MYB MYB MYB MYB MYB MYB bHLH bHLH MYB MYB MYB MYB bHLH bHLH WD40a WRKY MADS box WIP HD-GLABRA2 VP1-like MYB MYB MYB bHLH bHLH MYB MYB bHLH WD40 MYB MYB bHLH bHLH WD40 MYB MYB MYB MYB bHLH bHLH bHLH bHLH bHLH VP1 WD40

Name

Ref.

AmMYB305 AmMYB308 AmMYB330 AmMYB340 ROSEA1 ROSEA2 VENOSA DELILA MUTABILIS AtMYB4 (repressor) PAP1 (AtMYB75) PAP2 (AtMYB90) TT2 (AtMYB123) TT8 GL3/EGL3 (AtMYC-2, AtMYC-146) TTG1 TTG2 TT16 TT1 ANL2 ABI3 A FaMYB1 (repressor) GMYB10 GMYC1 IVORY SEED ANT1 MYB-P1 MYC-RP/GP PFWD AN2 AN4 AN1 JAF13 AN11 Y MYBA C1 PL B LC R SN IN (repressor) VP1 PAC1

319 270 270 319 250 250 250 363 250 271 364 364 283 282 365, 366, 295, 367 293 308 310 311 300 303 280 297 368 369 408 234 370 371 294 372, 373 372, 373 290 290 292 314 288 374, 375 376 377 378 379 380 299 301, 302 291

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TABLE 3.2 Transcription Factors that Regulate Flavonoid Biosynthetic Genes — continued Species

Metabolite

Protein Type

Name

Ref.

Phlobaphenes/flavone C-glycosides

MYB MYB

P1 (P) P2

312, 317, 381 317

Note: The functions of the transcription factors have been confirmed (or indicated) by genetic mutant or plant transgenic studies. They are activators of transcription unless stated otherwise. Some are direct activators of the flavonoid biosynthetic genes, while others may encode factors upstream in a regulatory cascade. a These WD40 proteins interact with the TFs for the regulation of the biosynthetic genes.

Another type of protein shown to be involved in the regulation of anthocyanin (and PA) synthesis is the WD repeat (WD40) protein.291–293 The WD40 proteins confirmed to date as being involved in flavonoid biosynthesis (Table 3.2) have relatively high sequence identity of around 60%, and form a distinct group within the WD40 family (a molecular phylogeny of WD40 sequences is presented in Ref. 291). Based on gene expression or genetic interaction studies, the WD40 proteins do not function through direct transcriptional control of the MYB and bHLH genes, even though overproduction of MYB or bHLH factors can partially overcome some of the phenotypes of lines mutated in the WD40 gene.291,292 Rather, they likely function as part of the MYB-bHLH transcriptional complex, perhaps providing a stabilizing influence.285,294–296 It remains to be determined whether other types of TFs or regulatory proteins are also directly involved in the control of anthocyanin pigmentation. As mentioned previously, the TF binding the ARE cis-element has not been identified, although it potentially is the bHLH factor. Furthermore, although some R2R3 MYB and bHLH TFs with a repressive effect on transcription have been identified for anthocyanin biosynthesis, their role in the overall regulatory system, as well as that of repressor TFs in general, needs further characterization. FaMYB1 likely plays a role in the regulation of anthocyanin and flavonol production in Fragaria Xananasa (strawberry) fruit, and has structural features in common with the repressor TF AtMYB4, suggesting it operates through a direct repression mechanism.297 C1-I is a dominant negative allele of C1 that lacks the C-terminal activation domain normally present, and probably represses anthocyanin biosynthetic genes ‘‘passively’’ through competition with activators for target promoter binding sites.298 Also in Z. mays is Intensifier1 (In1), which encodes a bHLH protein similar to R.299 IN1 is suggested to have a repressive activity, as recessive mutations in the gene increase anthocyanin levels. It is worth noting that one of the suggested roles of the bHLH TFs is to relieve the MYB coactivators from the effect of an inhibitory factor, which is perhaps of the protein types described above.278 With regard to the regulation of the anthocyanin regulatory genes, progress has been made in dissecting signaling to phenylpropanoid-related TF genes during photomorphogenesis and flavonoid production in vegetative tissues and seeds. ANTHOCYANINLESS2 (Anl2) of A. thaliana encodes a homeobox protein of the HD-GLABRA2 group that is required for anthocyanin production in the subepidermal cells of vegetative tissues.300 Unlike the tt mutants, the anl2 mutant is not altered in pigmentation of the seed coat, but it does have aberrant cellular organization in the roots. Given that homeodomain proteins are often involved in cell specification and pattern formation, anl2 may encode an upstream regulator rather than a direct activator of the flavonoid-related MYB and bHLH genes. Viviparous 1 (Vp1) of Z. mays encodes a distinct type of TF that has been identified subsequently in a

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number of species, including A. thaliana (ABI3).301–303 In Z. mays Vp1 has multiple regulatory roles in seed development, including both up- and downregulation of gene expression. It is required for production of anthocyanins in the aleurone and upregulates the C1 gene directly.304 Regulation of C1 occurs through the Sph cis-element in the promoter, which is recognized by the B3 domain of VP1. VP1 likely acts as part of a complex of TFs, which may include 14-3-3 proteins.305 On a final note, it is being increasingly found that the anthocyanin-related factors regulate other processes. In this regard, the best characterized is the WD40 protein TRANSPARENT TESTA GLABRA1 (TTG1) of A. thaliana. In addition to anthocyanin pigmentation, a number of other processes occurring in epidermal cells are also dependent on TTG1, including trichome, seed mucilage, and PA production.293,306 In a similar vein, the WD40 ANTHOCYANIN11 (AN11) of P. hybrida also influences seed coat development, in conjunction with the activity of the bHLH anthocyanin regulator ANTHOCYANIN1 (AN1).307 These P. hybrida regulators, along with the MYB factor ANTHOCYANIN2 (AN2), also regulate vacuolar pH in the petal cells,307 a role that appears to be played by some of the anthocyanin MYB TFs of A. majus as well (K. Schwinn, unpublished data).

3.15.3 REGULATION

OF

PROANTHOCYANIDIN BIOSYNTHESIS

Although initial progress in understanding regulation of PA biosynthesis was made with Z. mays, it is now best characterized in A. thaliana, in which PAs accumulate in the testa of the seeds. There are at least six classes of regulatory proteins that have been shown to control transcription of the genes for the PA pathway: bHLH, MADS box, R2R3 MYB, WD40, WIP, and WRKY (Table 3.3). The bHLH and MYB factors are thought to be direct activators of PA production. Knockout and gain of function experiments have demonstrated that TT2 (MYB) and TT8 (bHLH) interact to upregulate LBGs, but not EBGs such as CHS.137,282,283 TT2 may be a key determinant of the pattern of PA biosynthesis, as its transcript abundance shows much greater spatial and temporal variation than that of TT8. TT2 is also involved in regulating anthocyanin production during seedling development. The WD40 protein is TTG1 (described in the previous section). The WRKY TF is TTG2, which may function downstream of TTG1. Mutant lines for ttg2 have reduced production of PAs and mucilage, and have fewer, less branched trichomes, although they are wild type for anthocyanin production in vegetative tissues.308 However, ttg2 does not affect ANR gene expression, suggesting a late role in PA biosynthesis or a post-transcriptional regulatory role.309 TT1, encoding a member of the WIP subfamily of zinc finger proteins, is required for endothelium development, as tt1 mutants have reduced PA production and altered seed coat morphology.310 The MADS box protein TT16 (identical to BSISTER) also may be involved in endothelium development. Lines mutant for tt16 have altered cell shape and reduced PA production and expression of ANR, but only in a specific region of the seed coat, and ectopic expression of TT16 leads to ectopic PA accumulation.311 Overexpression of TT2 can partially complement the tt16 phenotype, restoring PA biosynthesis, suggesting TT2 acts parallel or downstream of TT16. The production of 3-deoxyflavonoids, in particular the 3-deoxy-PAs, in Z. mays, also involves R2R3 MYB transcription factors.312–315 In Z. mays, for the production of phlobaphenes, the MYB protein P1 activates CHS and DFR, and, presumably, the gene for the flavan-3-ol biosynthetic enzyme, but does not upregulate F3H.312,313 The regulatory activity of P1 does not require a bHLH coactivator, even though P1 recognizes the same promoter elements of the DFR gene as C1, the MYB TF regulating anthocyanin synthesis. Grotewold et al.316 compared the amino acid sequence of P1 and C1 and were

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TABLE 3.3 Genetic Loci of A. thaliana Involved in Flavonoid Biosynthesis for which Genetic Mutants and the Encoded Product Have Been Characterized Locus

Gene Product

Ref.a

Biosynthetic enzymes TT3 TT4 TT5 TT6 TT7 TDS4/TT18 Banyuls

DFR CHS CHI F3H F3’H ANS ANR

382 383 382 384 106 134 136, 137

Transporter activities TT12 TT19

MATE transporter GST

142 229

Regulatory factors TT1 TT2 TT8 TT16 TTG1 TTG2 ANL2

WIP MYB bHLH MADS box WD40 WRKY HD-GLABRA2

311 259 258 310 293 308 300

a

Reference to the first publication reporting detailed characterization of the corresponding cDNA or gene.

able to identify which amino acid residues in the C1 protein defined the interaction with the Z. mays bHLH proteins.

3.15.4 REGULATION

OF THE

PRODUCTION

OF

OTHER FLAVONOIDS

There are much less data on the regulation of flavonoids such as the isoflavonoids, flavones, and flavonols. Some of the genes regulating the EBGs in response to environmental stimuli, as discussed in Section 3.15.1, may be involved in controlling flavonol or flavone production. However, their specific role in relation to these compounds, and the regulation of genes encoding FLS and FNS in general, has not been studied widely. The P1 gene of Z. mays, which controls phlobaphene production, along with a closely related second gene P2, controls production of flavone C-glycosides in Z. mays flower silks by upregulating genes required for flavanone, and possibly flavone, biosynthesis but not the subsequent genes that are required for anthocyanin production.317 Furthermore, P1 or P2 driven by the CaMV35S promoter induces production of flavone C-glycosides in transgenic cell lines of Z. mays.140,317 Flavonol production in Z. mays may be under separate regulatory control to anthocyanins or flavones.317,318 Two A. majus MYB proteins with relatively high sequence identity, AmMYB305 and AmMYB340, may be involved in regulation of the EBGs required for flavonol biosynthesis.319 AmMYB305 has been shown to activate the promoters of CHI and F3H, and AmMYB340 to regulate CHI and bind the ‘‘P-box’’ MYB recognition element that is linked to petal-enhanced expression of phenylpropanoid genes.319,320 Like P1 of Z. mays, the proteins did not require a bHLH partner for their binding or activating activities.

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In P. hybrida, genetic and biochemical evidence suggests that An1 and An2, which regulate the LBGs for anthocyanin production, also positively regulate F3’,5’H and Cytb5, but do not affect F3’H expression.105,110 However, in leaves of CaMV35S:Lc transgenic P. hybrida both F3’H and F3’,5’H are upregulated, but not FLS.321 The an4 mutation, which lacks activity of an anthocyanin regulator related to An2 and results in acyanic pollen, does not effect the expression of F3GalT.322 In A. thaliana, some of the genes for PA biosynthesis, such as TTG1, that are required for LBG expression do not affect expression of FLS or F3’H.283 The induction of isoflavonoid production in response to biotic signals is extensively characterized,323 and analysis of gene promoter cis-elements is well advanced for both the EBGs (see Section 3.15.1 and Ref. 323) and isoflavonoid-specific genes (see, e.g., Ref. 324). However, there is no information on the TFs factors involved specifically in isoflavonoid gene regulation. Introduction of a transgene (CRC) for a chimeric protein with activity of both the C1 and R Z. mays anthocyanin-related TFs into G. max did not alter the transcript levels for the isoflavonoid-specific genes 2HIS, IFR, and IOMT, although PKR, FLS, and other phenylpropanoid genes were upregulated.325

3.16 GENETIC MODIFICATION OF FLAVONOID BIOSYNTHESIS In addition to being carried out as part of fundamental studies, genetic modification (GM) of flavonoid production has been used to extend existing flower color ranges or induce vegetative anthocyanin pigmentation in ornamental crops, to modify production of plant-defense flavonoids, and to increase levels of flavonoids related to human and animal health. Indeed, the flavonoid pathway has been the target of more biotechnology research than probably any other plant secondary metabolite pathway. The major approaches have been to prevent or inhibit flavonoid production, redirect substrate within the pathway, introduce new flavonoid biosynthetic activities, and modulate pathway regulation. There are numerous examples of the GM of flavonoid biosynthesis using these approaches, and due to space limitations we discuss only some of them here. An extensive listing of published examples is provided in Table 3.4–Table 3.6. An emerging area in flavonoid biotechnology is the introduction of flavonoid biosynthesis into microorganisms (see, e.g., Ref. 326), but the focus of the following sections will be on GM approaches in plants.

3.16.1 PREVENTING FLAVONOID PRODUCTION A reduction in, or the prevention of, flavonoid biosynthesis has been demonstrated many times, and in several species, by inhibiting production of a single flavonoid biosynthetic enzyme. This approach is reviewed in Refs. 76, 327, and examples are listed in Table 3.4. It is worth noting that the first published accounts of antisense or sense RNA inhibition of plant gene expression involved CHS in P. hybrida.328–330 Commonly the target phenotype has been flower color. In addition to the expected whiteflower phenotypes, in some species both ordered and erratic pigmentation patterns have been obtained (Table 3.4). Patterning only seems to occur in species that naturally have patterned varieties. Furthermore, some of the patterns show instability, not only within a particular plant but also in their inheritance (see, e.g., Ref. 331), which may limit the commercial usefulness of some of the more dramatic phenotypes.332 Approaches to inhibit anthocyanin production that target CHS can cause plant sterility, as flavonols play a role in fertility in some species.333–335 It is possible to inhibit anthocyanin production by targeting an enzyme such as DFR, which still allows the formation of flavonols and flavones. Sense or antisense DFR transgenes have been used to reduce or prevent anthocyanin production in several species (Table 3.4), with results similar to those for CHS

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TABLE 3.4 Genetic Modification of Flavonoid Production Using Inhibition of Flavonoid Biosynthetic Gene Activity by Sense or Antisense RNA Transgene

Species Modified

Phenotype Change

Ref.

CHSa Sense and antisense Sense Antisense Antisense Antisense Antisense

Dendranthema Dianthus caryophyllus Eustoma grandiflorum Gerbera hybrida Juglans nigra  J. regia Lotus corniculatus

Antisense Antisense

Petunia hybrida Petunia hybrida

Sense Sense Sense and antisense Sense

Petunia hybrida Rosa hybrida Torenia fournieri Torenia hybrida

Flower color changed from pink to white Flower color changed from pink to white Flower color changed from purple to white or patterns Flower color changed from red to pink or cream Enhanced adventitious root formation Decreased flavonoids, enhanced PA production in root cultures Flower color changed from red to white or patterns Flower color changed from purple to pale purple or white Flower color changed from purple to white or patterns Flower color changed from red to pale red Flower color changed from blue to pale blue or patterns Flower color changed from blue to white or patterns

329, 330 390 391, 392 393

F3H Antisense

Dianthus caryophyllus

Flower color changed from orange to white

394

DFR Sense Antisense Sense or antisense Sense and antisense Sense

Petunia hybrida Solanum tuberosum Lotus corniculatus Torenia fournieri Torenia hybrida

Flower color changed from purple to white or patterns Decreased anthocyanin levels Decreased PA levels Flower color changed from blue to pale blue or patterns Flower color changed from blue to white or patterns

335 343 337–339 391, 392 393

F3’,5’H Sense

Petunia hybrida

335, 395

Sense

Torenia hybrida

Flower color changed from dark blue to pale blue or pink Flower color changed from blue to pink

393

FLS Antisense Antisense Antisense

Eustoma grandiflorum Petunia Petunia

Reddening effect on flower color Flower color changed from purple to red Flower color changed from white to pale pink

341 146 342

FNSII Antisense

Torenia

Paler flower color

350

3RT Antisense

Petunia hybrida

Flower color changed from purple to pink or patterns

111

IFR Sense or antisense

Pisum sativum

Reduced pisatin production

396

HM3OMT Sense or antisense

Pisum sativum

Reduced pisatin production and reduced pathogen resistance

396

385 386 387 388 389 336 328 327

a Many examples of antisense or sense suppression of CHS gene activity in P. hybrida have been published, many using it as a phenotypic marker for studying the silencing process rather than through an interest in the effect on flavonoid biosynthesis or function. Only the first reports are referenced here.

F3GT

F3’,5’H

DFR and ANS DFR and F3’,5’H F3’H

Nicotiana tabacum Petunia Nicotiana tabacum Arabidopsis thaliana Arabidopsis thaliana Lycopersicon esculentum Forsythia Xintermedia Lotus corniculatus Nicotiana tabacum Petunia Petunia Solanum tuberosum Forsythia Xintermedia Dianthus caryophyllus Petunia Torenia Dianthus caryophyllus Nicotiana tabacum Petunia Eustoma grandiflorum

Species Modified

Ref. 58 149 334 213 151 61 344 338 71, 75 342 73, 345, 397, 398 343 89 348 105 350 348 109, 349 146, 395, 399 90

Phenotypea Flower color changed from pink to pale pink Flower color changed from white to pale yellow Flower color changed from pink to pale pink Seed color changedb Increased flavonol levels Increased flavonol levels Vegetative anthocyanin pigmentation increased PA types altered in cell cultures Flower color changed from pink to dark pink Flower color changed from white to pink Flower color changed from pale pink to orange or red Increased anthocyanin levels Vegetative and flower anthocyanin pigmentation increased or induced Flower color changed from pink or white to blue-purple Flower color changed from lilac to pink Reddening effect on flower color Flower color changed from pink to blue-purple Change in pink shade of flowers Flower color changed from pale pink-red to magenta-deep red or patterns No change in visible phenotypec

192

DFR

STS AUS CHI

CHR

Transgene

TABLE 3.5 Genetic Modification of Flavonoid Production in Plants by the Introduction of Novel Flavonoid Biosynthetic Activities or by Increasing Endogenous Activities (All ‘‘Sense’’ Transgenes). Examples of Complementation of Genetic Mutants Are Not Featured

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113 123 137 151, 182, 346 347 346 346 346 346 151 151 151 150 194 189

No change in visible phenotyped No change in visible phenotypee Flower color changed from pink to white; PA-like compounds produced Genistein produced Isoflavone levels changed Genistein produced No change in phenotype Genistein produced in cell lines Daidzein and genistein produced in cell lines Genistein produced Genistein produced Genistein produced No change in visible phenotypef No change in visible phenotypeg Enhanced production 4’-O-methylated isoflavonoid

Petunia Petunia Nicotiana tabacum Arabidopsis thaliana Glycine max Nicotiana tabacum Zea mays Zea mays Zea mays Arabidopsis thaliana Arabidopsis thaliana (tt6/tt3) Arabidopsis thaliana

Nicotiana tabacum Arabidopsis thaliana Medicago sativa

b

Only a general indication of the phenotype is given. Seed color was restored in the tt5 mutant. c A change in flavonoid glycosylation and acylation occurred. d One new anthocyanin type, delphinidin 3,5,3’-tri-O-glucoside, was found. e Anthocyanins with novel malonylation were formed. f Cell lines were able to biotransform exogenously supplied isoflavonoids. g Transgenic plants were able to convert exogenously supplied formononetin to 2’-hydroxyformononetin.

a

2HIS, CHI, and Pap1 IFR I2’H I7OMT

2HIS and R/C1 2HIS CHR, and R/C1 2HIS and CHI

A3’GT and F5GT Dv3MaT ANR 2HIS

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bHLH, Delila

bHLH, B-Peru

MYB, Rosea1

MYB, Pap1 with EARmotif repression domain MYB, P1 or P2

3-Deoxyflavonoids, C-glycosylflavones, other phenylpropanoids and fluorescent compounds increased Anthocyanins increased Anthocyanins increased No change in visible phenotype Anthocyanins increased Anthocyanins increased Anthocyanins increased

Zea mays cell lines Eustoma grandiflorum Petunia Medicago sativa Trifolium repens Lycopersicon esculentum Nicotiana tabacum

Anthocyanins increased Anthocyanins increased No change in visible phenotype No change in visible phenotype No change in visible phenotype Anthocyanins increased Anthocyanins increased under high light conditions Anthocyanins increased Anthocyanins and other phenylpropanoids increased Anthocyanins increased Anthocyanin and PA production inhibited

Effect on Flavonoid Productionb

Lycopersicon esculentum Nicotiana tabacum Arabidopsis thaliana Medicago sativa Nicotiana tabacum Trifolium repens Nicotiana tabacum Trifolium repens Arabidopsis thaliana Nicotiana tabacum Arabidopsis thaliana

Species Modified

401 401 360 400 402 402

140, 317

234 234 355 360 355 400 369 400 364 364 357, 358

Ref.

194

MYB, Gmyb10 MYB, Myb.Ph2 MYB, Pap1 or Pap2

MYB, C1

MYB, Ant1

TF Type and Transgenea

TABLE 3.6 Genetic Modification of Flavonoid Production in Stably Transformed Plants or Cell Lines by Introduction of Genes Encoding Transcription Factors that Regulate Flavonoid Biosynthetic Genes (All ‘‘Sense’’ Transgenes)

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Arabidopsis thaliana

Nicotiana tabacum Arabidopsis thaliana Glycine max Zea mays cell lines Glycine max

Lycopersicon esculentum Nicotiana tabacum Pelargonium Petunia Lycopersicon esculentum Nicotiana tabacum Lotus corniculatus

Arabidopsis thaliana Eustoma grandiflorum Medicago sativa

403 355 359 321 371 371 356 354 404 402 325 140, 405 325 355

Anthocyanins increased

355 359 360

Anthocyanins increased No change in visible phenotype Anthocyanins and PAs increased and flavones decreased under stress conditions Increased under high light levels Anthocyanins increased No change in visible phenotype Anthocyanins increased Anthocyanins increased Anthocyanins increased Anthocyanins and proanthocyanidins increased. PAs increased in roots (and decreased in leaves of some lines) Anthocyanins increased (variegated patterns) No change in visible phenotype Ratio of genistein to daidzein reduced Anthocyanins, phlobaphenes, and C-glycosylflavones increased Isoflavonoids increased

b

Except for MYB.Ph2, P1, and P2, the other TFs normally function as regulators of anthocyanin biosynthesis. Only a general indication of phenotype is given, and the full changes identified may include production of anthocyanin earlier in flower development than normal, increased anthocyanin production only under stress conditions, small increases in flavonoid levels in tissues already producing flavonoids, ectopic flavonoid production, changes in levels of nonflavonoid phenylpropanoids.

a

bHLH and MYB, C1 and R and suppressed F3H bHLH and MYB, Lc and C1

bHLH and transposon, R and Tag1 bHLH and MYB, C1 and Delila bHLH and MYB, C1 and R

bHLH, Sn

bHLH, Myc-rp and Myc-gp

bHLH, Lc

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inhibition. Sense or antisense transgenes for CHS or DFR have also been used to reduce PA levels in transgenic root cultures of Lotus corniculatus (bird’s foot trefoil).336–339 An alternative approach to RNA suppression for controlled reduction of flavonoid enzyme activity is the expression of single-chain antibody fragments targeted to a key enzyme or TF. Early attempts with enzymes such as DFR have been inconclusive as to the effectiveness of the technology.340

3.16.2 REDIRECTING SUBSTRATE

IN THE

FLAVONOID PATHWAY

The flavonoid pathway contains many branch points at which enzymes may compete for substrate, depending on the spatial and temporal occurrences of the enzymes and any metabolite channeling effects. Altering the balance of the competing activities may alter the levels of the different enzyme products and their derivatives. Alternatively, when a potential substrate is accumulating in tissues, a rate-limiting step may be overcome by increasing levels of the required enzyme. Changes in the production rates of different branches of the pathway have been achieved by altering the competing activities of FLS and DFR, CHS and STS or PKR, and ANR and F3GT. Introduction of an antisense FLS transgene into E. grandiflorum,341 N. tabacum,146 or specific Petunia lines342 reduced flavonol production and increased anthocyanin levels. CaMV35S:DFR transgenes increased anthocyanin content in flowers of N. tabacum and Petunia and tubers of S. tuberosum, and altered the type of PAs in L. corniculatus cell cultures.75,338,342,343 In Forsythia, anthocyanins accumulate in some vegetative tissues, but only flavonol glycosides are found in petals. Introduction of a CaMV35S:DFR transgene into F.  intermedia increased levels of anthocyanins in tissues which normally produce them, demonstrating that DFR is rate limiting for anthocyanin biosynthesis in these cells.344 The addition of a second sense transgene, for M. incana ANS, extended anthocyanin pigmentation to the flowers of the double transgenic lines.89 2HIS and F3H also potentially compete for substrate, and reduction of F3H transcript levels in transgenic G. max lines enhanced isoflavonoid accumulation (see Section 3.16.3.3). STS from V. vinifera uses the same substrates as CHS, so that a CaMV35S:STS transgene introduced into N. tabacum reduced anthocyanin levels in the flowers of the transgenics, so that flowers were near white rather than the usual dark pink.334 Similarly, the introduction of CaMV35S:PKR transgenes diverted substrate into 6’-deoxychalcone production in transgenic N. tabacum and Petunia, significantly reducing floral anthocyanin biosynthesis and resulting in pale flower colors.58,149 A CaMV35S:ANR transgene introduced into N. tabacum changed the flower color of some transgenic lines from pink to white, presumably through competition with F3GT (see also Section 3.5.3).137 Thus, the introduction of STS, PKR, or ANR transgenes offers a route for reduction of flavonoid biosynthesis, and may produce transgenics with more stable phenotypes than antisense RNA or sense-inhibition approaches. The overproduction of an enzyme at a rate-limiting step to increase levels of specific flavonoids is well illustrated by the Forsythia ANS example described earlier, and also by the use of CaMV35S:CHI to increase flavonol levels in A. thaliana and L. esculentum.61,151 In particular, fruit of L. esculentum plants expressing P. hybrida CHI had up to a 78-fold increase in flavonol content, principally rutin, in fruit peel.

3.16.3 INTRODUCING NOVEL FLAVONOID COMPOUNDS 3.16.3.1

Chalcones, Aurones, and Flavonols

The biosynthesis of the yellow flavonoids has been targeted for biotechnology applications in commercial ornamental crops, such as Cyclamen, E. grandiflorum, Impatiens, and Pelargonium, which currently lack yellow-flowered varieties. The compounds targeted to date are the

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aurones, which provide strong yellow colors, and the chalcones, which can provide yellow colors in certain circumstances. Aurones should offer excellent biotechnology prospects for generating yellow colors, as their direct precursors, chalcones, are ubiquitous intermediates in flavonoid biosynthesis, and cDNAs are available for the key biosynthetic activity, AUS. However, no experiments showing the use of the AUS cDNA to introduce aurone production in transgenic plants have been published. A successful biotechnology route for directing chalcone accumulation has been the use of PKR to generate 6’-deoxychalcones, which are not accepted as substrates by CHI of many species. Introducing CaMV35S:PKR into a white-flowered line of Petunia generated transgenic lines that accumulated up to 50% of their petal (and pollen) flavonoids as 6’-deoxychalcones, changing the flower color from white to pale yellow.149 Hydroxylation and glucosylation of the novel chalcones occurred at the C-3 and C-3’ positions. In N. tabacum, the same approach resulted in the accumulation of the flavanone liquiritigenin in the petals at the expense of anthocyanin accumulation, indicating the endogenous CHI could accept the 6’deoxychalcone substrate.58 3.16.3.2

Altering Dihydroflavonol 4-Reductase Activity

As discussed in Section 3.4.4, in some species DFR can show strong preference to DHF substrate with di- or trihydroxylated B-rings, limiting the production of pelargonidin-based anthocyanins. Meyer et al.,345 in the first published case of GM of flower color, introduced a Z. mays CaMV35S:DFR transgene into a P. hybrida mutant that accumulated DHK, enabling reduction of DHK, and production of pelargonidin-based anthocyanins in the petals. Subsequent crosses of the transgenics to commercial P. hybrida cultivars led to F2 lines with flower colors, including orange, novel to this species. Similar results have been obtained with other DFR transgenes in P. hybrida (Table 3.5). DFR transgenes have also been used to alter the type of PA accumulated338 and to encourage accumulation of delphinidin-derived anthocyanins (see Section 3.16.3.4). 3.16.3.3

Isoflavonoids

Modification of isoflavonoid biosynthesis may have a wide range of applications for improving not only plant defense characters but also the health benefits of food for humans. With the exception of IFD (which may not be required in vivo), cDNA clones are available for all of the enzymes needed for the production of the isoflavonoid vestitone. Furthermore, as VR cDNAs have been cloned, only clones for the DMID are lacking for the biosynthetic branch of the antifungal pterocarpans. To date, experiments have focused on 2HIS, but there has also been success using IFR, I2’H, and I7OMT. Overexpression of 2HIS genes has not only successfully introduced isoflavonoid production into species that lack this branch of the flavonoid pathway, but also altered levels of these compounds in isoflavonoid-producing species (Table 3.5). The first reported GM experiment used CaMV35S:G.max2HIS to produce genistein in A. thaliana, although only at levels of around 2 to 4 mg g1 fresh weight.182 The level of genistein could be raised approximately threefold in the transgenics by UV-B induction of the general phenylpropanoid pathway,346 or up to 30-fold (50 mg g1) by using a mutant line (tt3 or tt6) lacking DFR and F3H gene activity as the recipient of CaMV35S:2HIS and CaMV35S:CHI-II transgenes.151 However, these levels are still low compared to, for example, isoflavonoid levels of >4 mg g1 fresh weight of G. max seeds.325 The experiments of Liu et al.151 suggest competing activities within flavonoid biosynthesis and the effects of metabolic channeling may significantly affect the ability to engineer isoflavonoid biosynthesis in nonlegumes. Several enzymes may use

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flavanones as substrates in addition to the 2HIS, including F2H, F3H, F6H, FNR, FNS, F3’H, F3’,5’H, and various GTs and OMTs. Thus, understanding the relationship between these activities will be important for future biotechnology approaches. The CaMV35S:G.max2HIS transgene was also introduced into N. tabacum transgenic plants, resulting in genistein being produced in the petals (at 2 mg g1 fresh weight) but not leaves.346 Cell lines of Z. mays only produced genistein when the 2HIS transgene was cointroduced with the chimeric CRC transgene, which induced general flavonoid biosynthesis.346 CRC encodes a fusion protein comprised of two Z. mays TFs that regulate anthocyanin biosynthesis. By introducing a third transgene, CaMV35S:G.maxPKR, low levels of daidzein could be produced along with genistein. Analysis in most experiments has included a hydrolysis to yield the aglycone (genistein or daidzein). However, when extraction without hydrolysis was performed, it was found that most isoflavonoids in A. thaliana, N. tabacum, and Z. mays transgenics were conjugated forms. Genistin and malonyl-genistin were found in N. tabacum petals346 and genistin, genistin-O-glucoside, genistin-O-rhamnoside, and a genistin glucose, rhamnose di-O-glycoside, in A. thaliana.151 A CaMV35S:M.sativaIFR transgene was used to generate transgenic N. tabacum cell lines, which were then analyzed for their ability to metabolize exogenously supplied isoflavonoids.150 The transgenic cells could take up 2’-hydroxyformononetin and convert it to vestitone. Both 2’-hydroxyformononetin and vestitone accumulated as 2’- or 7-O-glucosides, demonstrating the activity of endogenous GTs on these compounds. There are fewer publications on changing levels of isoflavonoids in isoflavonoid-producing species. Yu et al.325 introduced a CRC transgene into G. max, under the control of a seedspecific promoter. Overall levels of seed isoflavonoids were slightly raised, and there was a reduction in the ratio of genistein to daidzein. Accompanying the changes in isoflavonoid levels was an accumulation of isoliquiritigenin and liquiritigenin malonyl-glucose conjugates, as well as flavonols and PA-like compounds. There was also an association of the strong phenotypes with a visual color change in some seed. Suppression of F3H gene activity further raised isoflavonoid levels in the CRC transgenics. There is also a preliminary report that the introduction of a CaMV35S:G.max2HIS transgene into G. max resulted in plants with either reduced or enhanced levels of isoflavones.347 In addition, the role of the D7OMT in isoflavonoid biosynthesis has been studied by expression of a CaMV35S:D7OMT transgene in M. sativa.189 Some transgenics showed higher transcript abundance for flavonoid biosynthesis enzymes after infection with Phoma medicaginis, as well as increased isoflavonoid levels and improved pathogen resistance. 3.16.3.4

Altering B-Ring Hydroxylation

An obvious approach for flavonoid biotechnology is to direct the accumulation of pelargonidin- or delphinidin-derived anthocyanins in species that may lack them by inhibiting the activity of the F3’H and/or F3’5’H or introducing the F3’,5’H. Thus, it is no surprise that F3’,5’H transgenes have been introduced into several species that lack the activity, including the leading ornamental crops Dendranthema, Dianthus, and Rosa hybrida (Table 3.5). Indeed, transgenic Dianthus with novel colors based on delphinidin-derived anthocyanins are now commercially available in Australia, Japan, and the United States.348 The amount of delphinidin produced in some of the first F3’,5’H transgenics was relatively low, due to competition from the F3’H and the substrate preference of the endogenous DFR for DHK or DHQ. Much higher levels of delphinidin-derived anthocyanins were produced by introducing both a F3’,5’H transgene and a transgene for a DFR that prefers DHM to DHK as substrate (such as that from P. hybrida) into a plant background that accumulates DHK (a DFR-F3’H double mutant) (International Patent Application WO96/36716). An alternative approach has been

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demonstrated by Okinaka et al.,349 who generated transgenic Nicotiana in which over 99% of the anthocyanins accumulated were delphinidin based by using a Campanula medium cDNA for a F3’,5’H that seems particularly efficient at generating delphinidin precursors. However, formation of blue flower colors involves many factors in addition to production of delphinidin-derived anthocyanins, and many of these are still out of reach of the current gene technology. In a similar approach to that for increasing delphinidin-derived anthocyanin levels, a F3’H transgene has been used to increase the amount of cyanidin-based anthocyanins in T. hybrida.350 Inhibition of the activities of F3’H or F3’,5’H should enable production of pelargonidinbased anthocyanins in species that lack them. Dendranthema is one candidate for such an approach.351 Of course, the subsequent enzymes would need to be able to use the substrates with only monohydroxylation of the B-ring, and in particular, DFR specificity would be a consideration for some species (e.g., Cymbidium). Reports of transgenic plants demonstrating this approach have yet to be published. 3.16.3.5

Secondary Modifications

Although there is a wide range of cDNAs available for secondary modifications of flavonoids, biotechnology applications to date have primarily focused on modifying anthocyanin production. Glycosylation can affect the anthocyanin-based color of flowers through both direct effects on anthocyanin chemistry and indirect effects in which the change in glycosylation has ramifications on other modifications. This later effect is nicely illustrated by experiments with the A3RT and F3GT. Inhibition of A3RT gene activity in P. hybrida produced transgenics with altered flower color. The flowers had reduced levels of malvidin derivatives and increased levels of pigments based on delphinidin and petunidin, presumably due to the anthocyanin OMT being unable to use the nonrhamnosylated substrate.111 Introduction of a CaMV35S:A.majusF3GT transgene into E. grandiflorum resulted in a change from flavonoid 3-O-galactosylation to 3-O-glucosylation, and an associated reduction in acylation of the flavonols, but no change in flower color.90 Much of the focus on glycosylation activities for biotechnology has been with regard to generating blue flower colors in leading ornamental species, although published transgenic experiments to date have concentrated on model species. The A3’GT is involved in the formation of the blue anthocyanin gentiodelphin in the source species G. triflora,113 and thus is a good prospect for generating anthocyanins more suited to blue flower colors. Expression of CaMV35S:A3’GT and CaMV35S:A5GT transgenes together in P. hybrida resulted in the formation of a new anthocyanin type, delphinidin 3,5,3’-tri-O-glucoside, but only at low levels (2 to 6% of total anthocyanins). No change in flower color occurred.113 To date, published results are available for only one of the AAT cDNAs, the Dv3MaT, which was overexpressed in P. hybrida. Although the transgenics produced malonylated anthocyanins in the petals that were novel to P. hybrida, no change in flower color occurred.123 Modification of the activity of anthocyanin OMTs has been reported only in the patent literature (International Patent Application WO03/062428).

3.16.4 MODULATING PATHWAY REGULATION TFs have been used to modify not only the amount of flavonoids in transgenic plants and cell lines of several species but also their temporal and spatial distributions, including effective use in heterologous species. A key advantage of targeting TF activity is that several biosynthetic genes may be coordinately regulated, overcoming the need to introduce multiple transgenes for biosynthetic enzymes or to identify a rate-limiting step.

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Anthocyanin production has been increased in transgenic plants of several species by introduction of anthocyanin-related Myb or bHLH cDNAs under the control of the CaMV35S promoter. Most experiments to date have used C1 and R/B family transgenes from Z. mays; however, increasingly TF genes from other species are proving effective (Table 3.6). The Z. mays TF transgenes also increased the levels of flavonols in L. esculentum, PAs in L. corniculatus and various flavonoids, and other metabolites in Z. mays cell lines.140,352–354 Cointroducing transgenes for MYB and bHLH TFs that normally interact can enable higher levels of anthocyanin production, or novel spatial distribution, compared to the introduction of either transgene alone. The first example of this was for A. thaliana, in which plants with both CaMV35S:C1 and CaMV35S:Lc transgenes had increased anthocyanin levels and novel distribution patterns not seen in plants with either transgene on its own.355 As would be expected from the role of some TFs in repressing gene expression, appropriate transgenes can also be used to downregulate sections of the phenylpropanoid pathway.270,271,297,356 Furthermore, TFs that normally increase transcription can be altered so that they repress it, through the addition of repression domains from other proteins, such as the ERFassociated amphiphilic repression motif.357,358 For reasons that are not clear, the overexpression of anthocyanin-related TFs can enhance production of other flavonoids in addition to anthocyanins. It may be that the TFs have an uncharacterized role in regulating the other pathways as part of their usual function. Alternatively, they may increase flux into, or alter flux within, the flavonoid pathway so that substrate is fed into production of the nonanthocyanin end products. A further possibility is that the effects seen are due to the nonphysiological levels of TF protein produced through the use of strong promoters, such as CaMV35S. Excess levels of TF protein may promote activity on gene promoter sites additional to the usual targets, as demonstrated in CaMV35S:AtMYB4 transgenic A. thaliana,271 or interfere with the endogenous regulatory environment. Although there has been much success with flavonoid-related TF transgenes, the technology has also proven unpredictable. This is well illustrated by the fact that different bHLH TFs, despite all being regulators of anthocyanin production, generate distinct phenotypes in recipient species (Table 3.6). Thus, one transgene may produce a phenotype in a given species while one with a similar sequence may not (see, e.g., Ref. 354), or one recipient species may develop a strong phenotype while the same transgene gives no increased pigmentation in other species (see, e.g., Refs. 321, 359). Such diverse responses likely reflect differences in the binding or activation characteristics of the introduced TFs, combined with variation in the type and activity of interacting endogenous TFs and the presence or absence of target promoter cis-sequences in the recipient species. The role of endogenous factors is demonstrated by the markedly different phenotypes of M. sativa and P. hybrida CaMV35S:Lc transgenics under varying environmental conditions.254,360

3.17 CONCLUDING COMMENTS Since 1994, remarkable progress has been made in our understanding of flavonoid biosynthesis. DNA sequences are now available for most of the biosynthetic enzymes required to form the common flavonoid types, such as anthocyanins, flavonols, flavones, PAs, isoflavonoids, and pterocarpans. These have allowed three-dimensional structures to be established for some of the enzymes using homology modeling or x-ray crystallography. Furthermore, significant progress has been made in understanding some of the activities involved in transport of anthocyanins and PAs to the vacuole. The magnitude of the advances in molecular knowledge of the pathway is illustrated by the listing in Table 3.1 of over 50 flavonoid biosynthetic enzymes for which cDNAs or genes are available, compared to the

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eight that were listed in the review by Forkmann,1 which covered the literature up to 1991. Likewise, the same review listed cloned regulatory genes from only two species, A. majus and Z. mays, while Table 3.2 lists cloned genes from 12 species. Biotechnology of the flavonoid pathway was in its infancy at the start of the 1990s, but is currently being widely applied to develop improved cultivars of ornamental, pasture, and food crops. In particular, the recent identification of the PA monomer biosynthetic genes should be of significant benefit to agriculture in the coming decade. As knowledge of flavonoids and human health progresses, one may anticipate that gene technology will be increasingly applied to improve the health characteristics of crop plants. Important factors in the future success of flavonoid biotechnology in achieving precision engineering of the pathway will be not only continuing advances in the identification of regulatory and biosynthetic genes, but also an improved understanding of metabolic channeling. This may apply particularly to the introduction of new branches of the pathway, such as that for the pterocarpans, to target crops.

3.18 ACKNOWLEDGMENTS It is a pleasure to thank Dr Rick Dixon and Dr Bettina Deavours for commenting on the isoflavonoid section, and Associate Professor Kevin Gould for general reviewing of the manuscript.

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385. Courtney-Gutterson, N. et al., Modification of flower color in florists chrysanthemum-production of a white-flowering variety through molecular-genetics. Biotechnology, 12, 268, 1994. 386. Gutterson, N., Anthocyanin biosynthetic genes and their application to flower colour modification through sense suppression. Hort. Sci., 30, 964, 1995. 387. Deroles, S.C. et al., An antisense chalcone synthase gene leads to novel flower patterns in lisianthus (Eustoma grandiflorum). Mol Breed., 4, 59, 1998. 388. Elomaa, P. et al., Agrobacterium-mediated transfer of antisense chalcone synthase cDNA to Gerbera hybrida inhibits flower pigmentation. Biotechnology, 11, 508, 1993. 389. El Euch, C. et al., Expression of antisense chalcone synthase RNA in transgenic hybrid walnut microcuttings. Effect on flavonoid content and rooting ability. Plant Mol. Biol., 38, 467, 1998. 390. Firoozabady, E. et al., Regeneration of transgenic rose (Rosa hybrida) plants from embryogenic tissue. Biotechnology, 12, 609, 1994. 391. Aida, R. et al., Modification of flower colour in torenia (Torenia fournieri Lind.) by genetic transformation. Plant Sci., 153, 33, 2000. 392. Aida, R. et al., Copigmentation gives bluer flowers on transgenic torenia plants with the antisense dihydroflavonol-4-reductase gene. Plant Sci., 160, 49, 2000. 393. Suzuki, K. et al., Flower color modifications of Torenia hybrida by cosuppression of anthocyanin biosynthesis genes. Mol. Breed., 6, 239, 2000. 394. Zuker, A. et al., Modification of flower colour and fragrance by antisense suppression of the flavanone 3-hydroxylase gene. Mol. Breed., 9, 33, 2002. 395. Shimada, Y. et al., Genetic engineering of the anthocyanin biosynthetic pathway with flavonoid3’,5’-hydroxylase: specific switching of the pathway in petunia. Plant Cell Rep., 20, 456, 2001. 396. Wu, Q. and VanEtten, H.D., Introduction of plant and fungal genes into pea (Pisum sativum L.) hairy roots reduces their ability to produce pisatin and affects their response to a fungal pathogen. Mol. Plant Microbe Interact., 17, 798, 2004. 397. Helariutta, Y. et al., Cloning of a cDNA coding for dihydroflavonol-4-reductase (DFR) and characterization of dfr expression in corrollas of Gerbera hybrida var. Regina (Compositae). Plant Mol. Biol., 22, 183, 1993. 398. Tanaka, Y. et al., Molecular cloning and characterization of Rosa hybrida dihydroflavonol 4-reductase gene. Plant Cell Physiol., 36, 1023, 1995. 399. Mori, S. et al., Heterologous expression of the flavonoid 3’,5’-hydroxylase gene of Vinca major alters flower color in transgenic Petunia hybrida. Plant Cell Rep., 22, 415, 2004. 400. de Majnik, J. et al., Anthocyanin regulatory gene expression in transgenic white clover can result in an altered pattern of pigmentation. Aus. J. Plant Physiol., 27, 659, 2000. 401. Schwinn, K. et al., Regulation of anthocyanin biosynthesis in Antirrhinum. Acta Hort., 560, 201, 2001. 402. Mooney, M. et al., Altered regulation of tomato and tobacco pigmentation genes caused by the delila gene of Antirrhinum. Plant J., 7, 333, 1995. 403. Goldsbrough, A.P., Tong, Y., and Yodder, J.I., Lc as a non-destructive visual reporter and transposon excision marker gene for tomato. Plant J., 9, 927, 1996. 404. Liu, D., Galli, M., and Crawford, N.M., Engineering variegated floral patterns in tobacco plants using the arabidopsis transposable element Tag1. Plant Cell Physiol., 42, 419, 2001. 405. Bruce, W. et al., Expression profiling of the maize flavonoid pathway genes controlled by estradiolinducible transcription factors CRC and P. Plant Cell, 12, 65, 2000. 406. Suzuki, H. et al., Identification and characterization of a novel anthocyanin malonyltransferase from scarlet sage (Salvia splendens) flowers: an enzyme that is phylogenetically separated from other anthocyanin acyltransferases. Plant J., 38, 994, 2004. 407. Frydman, A. et al., Citrus fruit bitter flavours: isolation and functional characterization of the gene Cm1,2RhaT encoding a 1,2 rhamnosyltransferase, a key enzyme in the biosynthesis of the bitter flavonoids of citrus. Plant J., 40, 88, 2004. 408. Park, K.-I. et al., An intragenic tandem duplication in a transcriptional regulatory gene for anthocyanin biosynthesis confers pale-colored flowers and seeds with fine spots in Ipomoea tricolor. Plant J., 38, 840, 2004.

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Flavonoids in Foods Janet A.M. Kyle and Garry G. Duthie

CONTENTS 4.1 4.2

Introduction ............................................................................................................... 219 Database Development .............................................................................................. 222 4.2.1 Database Development................................................................................... 222 4.2.2 Selection of Foods and Flavonoid Classes ..................................................... 223 4.2.3 Collation and Evaluation of Literature Sources ............................................. 224 4.3 Database of Flavonoids in Foods.............................................................................. 228 4.3.1 Fruits .............................................................................................................. 238 4.3.2 Vegetables ....................................................................................................... 238 4.3.3 Beverages ........................................................................................................ 239 4.3.4 Miscellaneous Foods....................................................................................... 239 4.4 Quality and Completeness of Flavonoid Content Data............................................. 240 4.4.1 Factors Affecting Flavonoid Content of Food............................................... 240 4.4.1.1 Analytical Variations ........................................................................ 240 4.4.1.2 Environmental Factors ..................................................................... 241 4.4.1.3 Species Characteristics ...................................................................... 241 4.4.1.4 Processing and Storage ..................................................................... 242 4.5 Estimated Dietary Flavonoid Intake ......................................................................... 242 4.5.1 Estimation of Dietary Flavonoid Intake ........................................................ 242 4.5.2 Previous Estimations of Dietary Flavonoid Intake ........................................ 242 4.5.3 Estimation of Scottish Dietary Flavonoid Intake Using the New Comprehensive Flavonoid Database .............................................................. 244 4.5.4 Comparison with Other Estimates of Dietary Flavonoid Intake.................... 245 4.5.5 Future Requirements to Improve Database ................................................... 246 4.6 Conclusions................................................................................................................ 246 4.7 Acknowledgments ...................................................................................................... 246 References .......................................................................................................................... 248 Appendix 1 ......................................................................................................................... 256 Botanical Names of Fruits.............................................................................................. 256 Botanical Names of Vegetables ...................................................................................... 257 Botanical Names of Herbs and Spices............................................................................ 258 Botanical Names of Legumes ......................................................................................... 258 Appendix 2: References Used for Database Compilation .................................................. 259

4.1 INTRODUCTION A ‘‘poor’’ diet is a major contributing factor to the etiology of chronic diseases such as heart disease and cancer.1,2 However, defining what constitutes a ‘‘healthy’’ diet remains contentious, as it is difficult to definitively ascribe beneficial and detrimental properties to the 219

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diverse components of the many foods we consume. Nevertheless, considerable evidence indicates that adequate fruit and vegetable consumption has a role in maintaining health and preventing disease.3–9 Some of these protective effects may be due to flavonoids, which are widely distributed in plant-based foods at varying levels.10–13 For example, numerous in vitro investigations have demonstrated potent effects of flavonoids in mammalian systems that are potentially anticarcinogenic and antiatherogenic.14–16 These include antioxidant protection of DNA and low-density lipoprotein, modulation of inflammation, inhibition of platelet aggregation, estrogenic effects, and modulation of adhesion receptor expression.14–18 The role of flavonoids in health is extensively covered in Chapter 6. From a nutritional perspective, the actual importance of flavonoids to health and disease remains unclear. Unlike the recognized micronutrients that can be obtained from plantbased diets, such as vitamin E and vitamin C, a lack of dietary flavonoids does not result in obvious deficiency syndromes. Consequently, the initial classification of some citrus flavonoids as ‘‘vitamin P’’19 was later revoked.10 In addition, epidemiological studies relating intake of flavonoids to disease incidence or risk do not give consistent results. For example, the average combined intake of flavonols and flavones in a cross-cultural correlation study composed of 16 cohorts followed up for 25 years after initial baseline measurements collected around 196020 was found to be inversely associated with coronary heart disease mortality, statistically explaining 25% of the variability in rates across the cohorts. In contrast, increased risk with increasing flavonoid intake has also been observed (Table 4.1). Similarly, although some studies have found positive inverse relationships between flavonoid intake and several cancers, others have failed to demonstrate significant statistical associations (Table 4.2). Early analysis and identification of flavonoids in plant materials and products led to estimated intakes of up to 1 g/day in the United States.10 This approximation included flavanones, flavonols, and flavones (160 to 175 mg/day), anthocyanins (180 to 215 mg/day), catechins (220 mg/day), and biflavans (460 mg/day). More recent estimates focusing on flavonol and flavone intake indicate that these early intake levels may be too high. One explanation for this is that flavonoid analysis initially employed semiquantitative spectrophotometric measurement.21–24 Analytical methodology has since progressed with the development of more sensitive and specific techniques. Optimized and better-validated sample preparation and hydrolysis techniques are now commonly used.25–30 For example, Hertog et al.25 optimized and tested the completeness of acid hydrolysis and solvent extraction of flavonol glycosides to their free (aglycone) form before quantifying flavonol and flavone concentrations of freeze-dried fruit and vegetable samples. Reversed-phase high-pressure liquid chromatography (RP-HPLC) with ultraviolet (UV) detection31 has improved isolation and separation of compounds superseding thin layer chromatography isolation and quantification by measurement of UV spectral shifts in response to addition of colorimetric reagents. Implementing such improved methodology on a selection of nine fruits, 28 vegetables, and several different beverages commonly consumed in the Netherlands32 generally provided lower values compared with earlier determinations.3,33 When flavonol and flavone intake was recalculated, levels of intake in the United States fell to 13 mg/day for this subgroup of flavonoids, which is about one tenth that of earlier estimates.20 These Dutch compositional data, with the addition of local food preferences such as berries, have since been used in several studies to assess dietary intake and potential associations with disease incidence.34–38 Application of this limited dataset to epidemiological studies relating flavonoid intake to disease incidence has produced conflicting results (Table 4.1 and Table 4.2), probably reflecting, in part, the paucity of composition data for many foods.17,39 In addition,

26

10 10 13

Flavonols/flavones Flavonols/flavones Flavonols Flavonols Flavonols/flavanonesd [Quercetin]

Flavonols/flavones Catechinse Catechins Catechin/epicatechin Gallated catechinsf

US, 34,789 men

Welsh, 1,900 men

Dutch, 4,807 men and women

Finnish, 9,131 men and women

US, 34,492 women Dutch, 693 men Dutch, 805 men USA, 34,492 women

Note: Values in bold indicate statistical significance. a Multivariate adjusted relative risk (95% confidence intervals) highest vs. lowest quintile of intake. b Quercetin, kaempferol, and myricetin. c Apigenin and luteolin. d Hesperetin and naringenin. e Catechin, epicatechin, gallocatechin, epigallocatechin, epicatechingallate, and epigallocatechingallate. f Gallocatechin, epigallocatechin, epicatechingallate, epigallocatechingallate.

15

5.6

14

6

5

Follow-up (Years)

Flavonolsb/flavonesc

Flavonoid Class

Cohort Dutch, 693 men 805 men Finnish, 2,748 men and 2,385 women

Study

Mortality (n ¼ 438) Incidence (n ¼ 90) Mortality (n ¼ 90) Mortality (n ¼ 767)

Mortality (n ¼ 681)

Incidence (n ¼ 38) Mortality (n ¼ 43) Mortality, men (n ¼ 324) Mortality, women (n ¼ 149) Incidence (n ¼ 486) Mortality (n ¼ 105) Incidence (n ¼ 186) Mortality (n ¼ 131) Incidence (n ¼ 146) Mortality (n ¼ 30) Incidence (n ¼ 806)

No. of Cases

0.52 (0.22–1.23) 0.32 (0.15–0.71) 0.73 (0.41–1.32) 0.67 (0.44–1.00) 1.08 (0.81–1.43) 0.63 (0.33–1.20) 1.0 (0.9–2.9) 1.6 (0.9–2.9) 0.76 (0.49–1.18) 0.35 (0.13–0.98) 0.79 (0.64–0.98) [0.86 (0.70–1.05)] 0.93 (0.74–1.17) [0.79 (0.63–0.99)] 0.62 (0.44–0.87) 0.70 (0.39–1.26) 0.49 (0.27–0.88) 0.85 (0.67–1.07) 0.76 (0.58–1.03) 1.00 (0.77–1.29)

RR (95% CI)a

TABLE 4.1 Epidemiological Studies Investigating Dietary Flavonoid Intake and Coronary Heart Disease Incidence and Mortality

138

36 137

129

136

135

35

34

134

Ref.

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TABLE 4.2 Epidemiological Studies Investigating Dietary Flavonoid Intake and Cancer Incidence Study

Flavonoid Class

Follow-up (Years)

Cohort US, 34,651 women

Catechins

13

Dutch, 728 men

Catechins

10

Dutch, 246 men

Flavonol/flavone

5

Finnish, 27,110 male Smokers

Flavonols/flavones

6

Finnish, 9,959 men and women

Flavonols/flavones

20

Site of Cancer

RR (95% CI)

Ref.

All causes Bronchus and lung (n ¼ 549) Colon (n ¼ 635) Lung (n ¼ 12) Epithelial (n ¼ 30) All causes (n ¼ 27) Alimentary and respiratory (n ¼ 19) Lung (n ¼ 791) Urothelial (n ¼ 156) Renal cell (n ¼ 92) Prostate (n ¼ 226) Stomach (n ¼ 111) Colorectal (n ¼ 133) All sites (n ¼ 997) Lung (n ¼ 151)

0.97 (0.88–1.06) 0.94 (0.72–1.23)

139

1.10 (0.85–1.44) 0.92 (0.41–2.07) 0.94 (0.56–1.59) 1.21 (0.66–2.21) 1.02 (0.51–2.04) 0.6 (0.4–0.7) 1.2 (0.7–1.8) 0.6 (0.4–1.1) 1.3 (0.9–1.8) 1.2 (0.7–1.9) 1.7 (1.0–2.7) 0.87 (0.70–1.09) 0.53 (0.29–0.97)

140 140

141

142

Case–control Hawaii, men and women Spanish, women

Flavonols/flavanones [Quercetin] Flavonols

Lung (582 cases and 582 controls) Lung (103 cases and 206 controls)

OR (95% CI) 0.8 (0.5–1.4) [0.7 (0.4–1.1)] 0.98 (0.44–2.19)

143 144

concentrations of flavonoids in foods can vary by many orders of magnitude due to the influence of numerous factors such as species, variety, climate, degree of ripeness, and postharvest storage.10,12,40 Consequently, the aims in this chapter are to critically examine the available literature on the flavonoid composition of foods and to establish a food flavonoid database, which can be continually expanded as more information becomes available. By using predetermined selection criteria to ensure critical assessment of data quality, the intention is to provide researchers with an improved resource for use in studies exploring the relationships between flavonoid intake and health as well as highlighting important food groups where flavonoid content data are currently lacking.

4.2 DATABASE DEVELOPMENT 4.2.1 DATABASE DEVELOPMENT To ensure comprehensive coverage of foods and relevant flavonoids, compilation of the flavonoid composition database followed a preset development profile (Figure 4.1). This was a multistage process that evolved from a review of two major food composition databases41–43 and from other early stage nutrient bases such as those for vitamin K44 and

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Select flavonoids and identify foods

↓ Collate literature sources

↓ Classify literature

↓ Qualitative literature

Quantitative literature (Food content)

↓

↓

Flavonoids characteristics file

Evaluate quality

Sample identity Sampling protocol Food sample preparation Analytical sample preparation Analytical procedure Unit of expression

↓ Working flavonoid database

Accept

Reject

↓ ↓ Archive Calculate single value

↓

Final flavonoid content database FIGURE 4.1 Schematic of selection and evaluation processes used to compile the flavonoid database.

carotenoids.42,45 Essentially, the database development profile consists of the selection of commonly consumed flavonoid-rich foods, collation and evaluation of available literature, and, finally, acceptance or rejection of flavonoid content values (Figure 4.1).

4.2.2 SELECTION OF FOODS

AND

FLAVONOID CLASSES

As all foods of plant origin potentially contain flavonoids3,10 and over 4000 individual compounds have previously been identified,11 the development of a comprehensive flavonoid database is a huge task to undertake. Therefore, in the first instance, it was decided to focus on foods commonly available and eaten in Britain and to initially consider those flavonoid classes that have attracted most attention in relation to potential health benefits namely flavonols, flavones, catechins, flavanones, and anthocyan(id)ins.17 Table 4.3 outlines the compounds selected to represent the five main subclasses of flavonoids. Consumer dietary surveys of the UK population were initially consulted.46,47 Although a general indication of commonly consumed foods was found in these surveys, fruits and vegetables were presented as generalized groups such as ‘‘other fresh fruit.’’ The fruits assigned to this group were not clearly identified. Visiting local British supermarkets proved to be the most informative method of identifying products readily available to the consumer and proved a good starting point for the literature search for flavonoid composition data (Table 4.4).

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TABLE 4.3 Compounds Included in Flavonoid Database Flavonoid Subclass

Compound

Flavonols

R1

Quercetin (R1 ¼ OH, R2 ¼ H) Kaempferol (R1 ¼ R2 ¼ H) Myricetin (R1 ¼ R2 ¼ OH)

OH O R1

HO

OH O OH

OH

R2

O OH

OH

O

Apigenin (R1 ¼ H) Luteolin (R1 ¼ OH) (þ)-Catechin (C) (R1 ¼ H, R2 ¼ OH) (
)-Epicatechin (EC) (R1 ¼ H, R2 ¼ H) (
)-Epigallocatechin (EGC) (R1 ¼ OH, R2 ¼ OH) (
)-Epicatechingallate (ECG) (R1 ¼ H, R2 ¼
OC
Ph(OH)3) (
)-Epigallocatechingallate (EGCG) (R1 ¼ OH, R2 ¼
OC
Ph(OH)3) (
)-Gallocatechin (GC) (R1 ¼
OC
Ph(OH)3, R2 ¼ H)

Flavones OH

Catechins

OH O

OH

R1 R2 OH R1

Flavanones

R2

O H

OH

OH

Hesperetin (R1 ¼ OH, R2 ¼ OMe) Naringenin (R1 ¼ H, R2 ¼ OH)

O

Delphinidin (R1 ¼ R2 ¼ OH) Cyanidin (R1 ¼ OH, R2 ¼ H) Pelargonidin (R1 ¼ R2 ¼ H) Petunidin (R1 ¼ OMe, R2 ¼ OH) Peonidin (R1 ¼ OMe, R2 ¼ H) Malvidin (R1 ¼ R2 ¼ OMe)

Anthocyanidins R2 OH O+

HO

R1 OH OH

Procyanidin B-type dimers OH OH O

HO

OH

H R1 R2 OH HO

OH

B1: R1 ¼ OH; R2 ¼ H; R3 ¼ H; R4 ¼ OH B2: R1 ¼ OH; R2 ¼ H; R3 ¼ OH; R4 ¼ H B3: R1 ¼ H; R2 ¼ OH; R3 ¼ H; R4 ¼ OH B4: R1 ¼ H; R2 ¼ OH; R3 ¼ OH; R4 ¼ H

O R3 OH

R4

4.2.3 COLLATION

AND

EVALUATION

OF

LITERATURE SOURCES

To ensure coverage of a broad spectrum of journals containing both original and review articles, bibliography databases, such as CAB abstracts, BIDS ISI and Embase, Medline and Current Contents Agriculture and Food Citation index, were searched. Terms used for all database searches were kept simple to limit the risk of missing any original publications (Table 4.5). Initially, each flavonoid subclass was entered and then cross-searched with the

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TABLE 4.4 Foods of Plant Origin Commonly Consumed in the United Kingdom and Available in Local Supermarketsa,b Food Type

Food Item

Beverages

Tea, coffee, fruit and herbal drinks Cocoa or drinking chocolate, malted drinks Fruit juice concentrates, ready to drink fruit juices (still and carbonated) Beer, lager, wine, spirits, liqueurs, alco pops

Fresh fruits Normally available Seasonal Exotic fruit section Fresh vegetables Normally available

Seasonal

Specialist Fresh herbs Normally available

Apples, bananas, oranges, grapefruit, pears, melons, grapes, lemon, strawberries Satsumas, tangerines, clementines, peaches, pineapples, nectarines, plums, mangoes, raspberries, blueberries, blackcurrants, blackberries, rhubarbs Custard apple, passion fruit, pomegranate, sharon fruit, lychee, figs, cranberry, gooseberry Broccoli, carrots, onions, potatoes, courgette, mushrooms Lettuce (different varieties), tomatoes (different types), celery, cucumber, sweet pepper (red and green) Spinach, winter greens, leeks, suede, turnip, Brussels sprouts, red cabbage, parsnips, corn-on-cob, red radish, mange tout, French beans, sweet potatoes, shallots, asparagus, chives Artichoke, squash, yam, celeric, fennel bulb, okra, oyster mushrooms Oregano, basil, thyme, mint, coriander, rosemary, sage, dill

a

Supermarkets were visited at least once per month over 4 years. Also from Gregory et al.46 and the National Household Consumption Survey.47 b Processed food stuffs not included.

terms ‘‘composition’’ or ‘‘content.’’ Common and botanical names of foods (Appendix 1) were then individually added to the search profile. Food Science and Nutrition Journal Archives were also hand searched to ensure complete coverage of journals dating back to 1976. Pre-1976 literature was referred to for flavonoid characterization purposes only. To ensure compatibility with the Royal Society of Chemistry’s food composition tables, predetermined screening procedures were used (Table 4.6), which were derived from those outlined for the nutrient tables.41 All publications and reports on flavonoid content of foods were subsequently evaluated employing the screening procedures (Table 4.6). In brief, inclusion criteria were (a) randomly selected food items purchased from various commercial outlets during different seasons of the year, (b) food samples prepared using normal domestic TABLE 4.5 Search Strategy for Locating Flavonoid Publications Search Term

Publications Medline Web of Science

(Flavonols or flavones or catechins or flavanols or anthocyanins or flavanones) and (composition or content) and (Malus or apple or apples) and (Prunus or apricot or apricots) and (Allium or onion or onions) and (repeated for all foods outlined in Table 4.4)

13,315 833 17 2 14

4,373 711 44 17 19

CAB 6,617 4,061 190 158 43

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TABLE 4.6 Selection Criteria for Addition to Database Criteria

Outlined in Manuscript

Sample identity

Foods common or varietal name Country of origin and locality with details of growing conditions if possible; e.g., British tomatoes grown in greenhouses Place and time of sample collection; e.g., purchased from local market or commercial grower in September 1999 Number of samples collected and how these were obtained; e.g., 1 kg of fruit purchased from three shops State of sample; e.g., raw, cooked, processed (canned or frozen), pickled Preparative treatment outlined; e.g., chopping or shredding Storage conditions before analysis outlined; e.g., freeze dried and stored at
208C Nature of sample analyzed; e.g., edible portion only Sample extraction and hydrolysis details; e.g., solvent extraction after freeze drying, with optimized acid or enzymatic hydrolysis Preparation of flavonoid standards and use of internal standards Chromatographic separation and detection method used, ideally RP-HPLC with UV or fluorescent detection Outline of quality assurance procedures employed Method of calculating content value; e.g., based on retention time of standards, mean of duplicate samples, adjustment to recovery of internal standard Presentation of final value; e.g., mean + SD as fresh weight or dry weight with original moisture content

Sampling protocol

Food sample preparation Analytical sample preparation

Analytical procedure

Unit of expression

practices such as discarding nonedible portions of onions, (c) optimized sample extraction and hydrolysis conditions clearly outlined or cited, and (d) flavonoid separation and determination conducted using standard modern techniques with validation and quality assurance measures summarized.25,31 A worked example of the selection criteria as applied to four different onion composition studies is presented in Table 4.7. Acceptable papers were included into the working database (see Appendix 2), while manuscripts not meeting the criteria were archived and reasons for the exclusion noted. The evaluation criteria applied during database development highlighted a lack of acceptable anthocyanin food content literature. Values were often presented as percentage of the total anthocyanin content.48,49 In addition, test samples were frequently gathered from noncommercial sources, such as horticultural research stations.50,51 Moreover, analytical procedures often employed spectral pH differential methodology rather than HPLC to estimate anthocyanin content.52,53 Consequently, although there is a substantial amount of characterization information with crude estimates of total anthocyanin content (Table 4.8), anthocyanins had to be excluded from the final database. Similarly, the flavanone eriodictyol was also excluded from the final database due to a lack of rigorously analyzed quantitative information. The evaluation process also illustrated that food content data are increasingly presented as total glycosides of flavonoids such as quercetin-3-glucoside. If a study met all the criteria except presenting aglycone data, the values were converted to aglycone format using molecular weights, an approach validated by Price et al.54 Additionally, values expressed in parts per million or milligrams per kilogram were converted to mg/100 g. Content levels presented as dry weight were only adjusted to fresh weight concentrations if the original moisture content was available. During the process of finalizing the database, to ensure all available flavonoid composition data had been gathered, literature determining proanthocyanidin content of foods was identified. Subsequently, content values for B-type procyanidin dimers

C18 column RP-HPLC UV–visible Spiked standards recovery reported, identification on aglycone RP-HPLC retention times mg/kg fresh weight Accept

Freeze dried, stored at
208C for 70% of the fresh weight, does not. Consequently, when analyzed as normally eaten only trace levels are present. Often termed the citrus flavonoids, flavanones are only found in citrus fruits such as oranges, grapefruit, and lemons. Although naringenin is present at greater concentrations than hesperetin in grapefruit (39.2 and 1.4 mg/100 g, respectively), the latter is the dominant form in oranges, lemons, and limes. Although citrus fruit also contains low levels of flavones, the olive is by far the richest source of luteolin and apigenin (12.4 and 4.6 mg/100 g, respectively).

4.3.2 VEGETABLES Allium (e.g., onions), Brassica (e.g., broccoli and kale), and Lactuca (e.g., lettuce) varieties of vegetables and tomatoes (Lycopersicon species) are abundant sources of flavonols, primarily quercetin and kaempferol (Table 4.10). Flavones are also found in some vegetables such as celery, sweet peppers, and lettuce. Catechins and type B procyanidins, however, have not been found in leafy green or root vegetables but have been detected in legumes such as broad and green beans. The tomato is the only vegetable (although taxonomically a fruit) to possibly contain the flavanones naringenin and hesperetin.

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Of the Allium species, shallots and red onions represent the richest potential source of quercetin containing 95 and 64 mg/100 g, respectively. Brassica vegetables including broccoli, kale, cabbage, and brussels sprouts tend to contain complex mixtures of flavonols, with significant quantities of kaempferol and myricetin glycosides present in addition to quercetin conjugates. Kale is a good example of this with mean levels of 11.5 mg quercetin/100 g and 34.1 mg kaempferol/100 g. Legumes such as green and broad beans also contain complex mixtures, mainly of flavonols and catechins. For example, broad beans contain (
)-epicatechin (30.0 mg/100 g), (þ)-catechin (14.5 mg/100 g), (
)-gallocatechin (4.8 mg/100 g), and quercetin, myricetin, and kaempferol at concentrations below 3.0 mg/100 g. Green chilli pepper is one of the few vegetables to contain both flavonols (quercetin, 11.39 mg/100 g) and flavones (luteolin, 2.7 mg/100 g) at detectable levels. Celery and sweet ball peppers are the main food sources of flavones independent of flavonols.

4.3.3 BEVERAGES Catechins are often the most common flavonoids in beverages such as fruit juice, tea, and wine (Table 4.11). These tend to contain complex mixtures of simple catechins and their gallated esters. Type B procyanidins have frequently been characterized in beverages such as fruit juices; however, reliable quantitative data are limited. Flavonols are also present in most beverages while flavanones are again restricted to citrus juices such as grapefruit and orange. The presence of flavones in beverages is not well described with only some characterization information available in the literature. Fruit juice contains both catechins and flavonols. Apple juice is one of the richest juice sources of catechins (containing 6.3 mg (
)-epicatechin/100 ml and 0.8 mg (þ)-catechin/ 100 ml) whereas cranberry juice contains the most flavonols, mainly in the form of quercetin and myricetin (17.5 mg/100 ml and 4.7 mg/100 ml, respectively). Tea is the only analyzed beverage to contain (
)-epigallocatechingallate (EGCG) in quantifiable amounts. EGCG and (
)-epicatechingallate (ECG) are the most abundant forms, each contributing 27% to the total catechin content (22.2 mg/100 ml) of black tea. Three flavonols (quercetin, kaempferol, and myricetin) are also found in tea. For example, 100 g of decaffeinated tea contains 5.2 mg quercetin, 2.4 mg kaempferol, and 0.1 mg myricetin. Wine also contains a complex mix of catechins, flavonols, procyanidins, and flavanones. Red wine contains higher flavonoid levels than white or rose´ wines. Procyanidins usually represent 50% of the flavonoids found in red wine, followed by catechins (37%). A similar profile is observed with beer where again procyanidins dominate accounting for 42% of total flavonoid content.

4.3.4 MISCELLANEOUS FOODS Jam, confectionery, and herb compositional data are presented in Table 4.12. Honey contains low levels of both flavonols and flavones, and the presence of the flavanone naringenin has also been documented. Fruit jams also contain low levels of flavonols and catechins, which generally reflect the flavonoid profile of the whole fruit. Quantitative data for chocolate are limited, but the available literature demonstrates that it is a good potential source of (þ)-catechin, (
)-epicatechin, and type B procyanidins. Dark chocolate, for example, contains 6.6 mg, 21.8 mg, and 2.1 mg/100 g of catechin epicatechin, and procyanidins, respectively. Compositional analysis data for herbs are also limited; however, these plants may be rich sources of flavones. For example, parsley is the major source of apigenin (217.9 mg/100 g) in the whole database, while sage and thyme are rich in luteolin (33.4 and 39.5 mg/100 g, respectively).

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4.4 QUALITY AND COMPLETENESS OF FLAVONOID CONTENT DATA The data in Table 4.9–Table 4.12 are comprehensive estimates of five classes of flavonoids in commonly available foods in the United Kingdom. Moreover, these estimates are derived from critically assessed published sources and the evaluation procedures adopted ensured the inclusion of content values for edible parts of plant materials available to the UK consumer. A USDA compiled database (http://www.nal.usda.gov/fnic/foodcomp/Data/Flav/flav.pdf) aimed primarily at the North American diet is also available. These databases are in contrast to another literature-derived database that is available for flavonoids55 where data quality was not formally assessed and flavonoid values determined using semiquantitative methods were also included. Nevertheless, the current database also has unavoidable limitations as the selection of appropriate food items and flavonoid values still required an element of operator judgment. For example, potentially useful information was excluded because (a) only experimental plants rather than commercially available varieties were analyzed (e.g., Ref. 56), (b) the country of origin did not supply the UK market (e.g., Ref. 57), (c) values were expressed only on a dry weight basis (e.g., Ref. 58), (d) final figures were presented as percentage of the total content (e.g., Ref. 59), and (e) the flavonoid contribution from the edible portions were difficult to separate from the whole fruit (e.g., Ref. 60). In addition, flavonoid data for several commonly consumed items are likely to be missing. For example, no flavanone data are available for satsumas, tangerines, and clementines, although these are seasonally abundant in UK supermarkets. There is also an overall lack of information on commonly consumed items such as herbs, fruit tea, and beer.61 Additionally, bias may be introduced due to the relative number of compositional studies relating to each of the different flavonoid subclasses. For example, there are five large studies comprehensively identifying flavonols and flavones in several foods and beverages,25,29,32,62–66 but fewer for catechins,67–69 procyanidins,69 and flavanones.29

4.4.1 FACTORS AFFECTING FLAVONOID CONTENT

OF

FOOD

Another potential source of error in the database relates to the possibility that the flavonoid content of fruits and vegetables analyzed in a particular study do not reflect ‘‘normal’’ levels in the products. Such regional differences are frequently cited in order to explain the apparent lack of association between dietary components and disease.2,70 The present database attempts to minimize this effect by including flavonoid values of products from countries known to export to the United Kingdom as over 50% of fresh produce consumed in this country is imported from the global market to ensure a year round supply.71 Apples, for example, are imported from 24 different countries including France, Argentina, New Zealand, and Canada with British varieties being available for 9 months of the year (freshinfo. com). However, other factors affecting flavonoid levels such as analytical variations, environmental factors, species characteristics, and the effects of processing and storage are more difficult to take into account when compiling the database. 4.4.1.1

Analytical Variations

The methods of extraction and analysis can markedly affect the determination of flavonoids in foods.12,13,31,72–76 Rigorous application of the selection criteria (Table 4.6) may minimize this confounding effect. Overall, sample preparation and extraction techniques along the lines described by Merken and Beecher31 were considered acceptable. These included freezedrying, extraction either with aqueous methanol containing an antioxidant such as BHT or

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by solid-phase columns, filtration and the reduction of flavonol conjugates to the ‘‘free’’ aglycone by acid hydrolysis, enzyme digestion, or alkaline hydrolysis. Acceptable separation methodology normally involved RP-HPLC with UV, diode array, or electrochemical detection. Fluorescence detection, capillary zone electrophoresis, and micellar electrokinetic capillary chromatography were also included if identification and confirmation of eluted peaks was based on comparison with external standards, or if mass spectroscopy or nuclear magnetic resonance was used to confirm structural identity. 4.4.1.2 Environmental Factors The flavonoid content of plant foods may be affected by growing conditions.3,10 For example, red wine produced in the warm, dry, and sunny conditions prevalent in the New World tend to contain more quercetin and myricetin (but less catechin) than the wines produced in the cooler and damper regions of Northern Europe.77,78 Similar regional and climatic effects on flavonoid content have been observed for many different fruits and vegetables.65,79–81 Concentrations of flavonol and flavanone monoglycosides, for example, are greatest on the surface of plants grown in or originating from arid and semiarid habitats.11,79,82 However, flavonoid profiles are also influenced by irrigation, which, for example, modifies concentrations and types of anthocyanins and catechins in berries.82,83 Marked differences in flavonoid content can even occur within a single variety depending on numerous factors such as maturity at harvesting, storage, use of glass and polythene, and organic cultivation methods.32,65,68,84–86 This latter factor may be one reason why the flavonoid content of foods from Hungary are much higher than those from Western Europe, the enhanced levels reflecting the role of flavonoids in plants as insecticides and antimicrobial and antifungal agents.11,85 Interestingly, Hungary is one of the main suppliers of organic vegetables to UK supermarkets. Such environmental influences may account for why, for example, quercetin levels in Spanish cherry tomatoes range from 3.8 mg/100 g to 20.0 mg/100 g during a single year80 and why produce grown in polythene tunnels with reduced UV exposure contain 98% less flavonoid glycosides than when grown in the open air.10,11,40,82 The degree to which such environmental factors decrease the accuracy of the database is impossible to quantify but is likely to be minimized by the computation of average content values from a wide range of sources. This, in turn, is likely to reflect the average intake of a population exposed to a diverse range of products over the longer term. 4.4.1.3 Species Characteristics Computation of a single value from a wide range of sources will also minimize analogous confounding effects of varietal differences as flavonoid subclasses can vary widely between different cultivars of fruits and vegetables.11,32,87,88 Examples of such differences include flavonols in berries,89 flavones in honey90 and olives,91 catechins in pears92 and apples,86 procyanidins in apples93 and blueberries,94 and flavanones in citrus fruit95 and grapefruit juice.96 Typically, for example, the flavonol content of 12 chilli-pepper varieties ranges from 0 to 85 mg/100 g.97 Such differences can be ascribed to: (a) genetic mutations influencing the synthesis and accumulation of flavonoids in tissue11,79; (b) the degree of pigmentation,56,79,89,98–100 particularly in berries101 and onions3 (although this has been recently disputed54,56,79,80 as original determinations may have included the nonedible and anthocyanin-rich skin of the onion); (c) the stage of maturity,13,102 quercetin levels, for example, tending to decline as fresh peppers ripen103 whereas fresh young tea leafs contain more catechin derivatives than older ones.104

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In addition, there are varietal effects on the degree and type of glycolsylation of flavonoids.105 For example, quercetin rhamnoside is the most abundant glycoside in Jonagold and Golden Delicious apples whereas in Cox’s orange and Elstar varieties, quercetin galactoside and arabinoside dominate.86 As the nature of the sugar attachment may influence the bioavailability of a particular flavonoid,106,107 it may ultimately be preferable for the database to show flavonoid content data as glycosides. At present, such information is lacking as the majority of studies employ hydrolysis to liberate the aglycone from the food matrix. Alternatively, once the biological significance of different glycosides have been determined, it may be possible to calculate conversion factors for flavonoids that are analogous to the current means of expressing tocopherol homologs as vitamin E equivalents.41 4.4.1.4

Processing and Storage

In general, industrially produced products such as tea, red wine, and fruit juice have significantly different flavonoid levels and profiles than the original fresh product.108–112 Processing and preservation can expose fresh products to increased risk of oxidative damage and the activation of oxidative enzymes such as polyphenol oxidase.92,113 In addition, procedures such as solvent extraction, sulfur dioxide treatment, pasteurization, enzymic clarification, heating, canning, irradiation, drying, and fermentation have been reported to affect procyanidin and catechin concentrations in fruit juice,108–110,114–117 quercetin glucosides, catechins, and procyanidins in grapes,118 procyanidin and flavonol levels in tomatoes and related sauces,119 and quercetin concentrations in berries.81 Domestic preparation procedures such as chopping, shredding, peeling, and cooking may also affect flavonoid content accounting, for example, for 21 to 54% losses of flavonols in onions54,120,121 as well as inducing glucosidase-mediated formation of monoglucosides and free quercetin from diglucosides.56 Boiling is reported to lead to reduced flavonol contents of onions,54,80,120 broccoli,122 tomatoes,80 asparagus, and green beans120 although the effects of microwave cooking and frying may be less marked80,120 due to decreased leaching of flavonoids from the foods during these cooking procedures.54 Therefore, to minimize the confounding effects of such procedures, where possible values obtained from cooked and processed products were also included in the database.

4.5 ESTIMATED DIETARY FLAVONOID INTAKE 4.5.1 ESTIMATION

OF

DIETARY FLAVONOID INTAKE

Investigation of the relationship between diet and the development of chronic diseases requires an assessment tool that provides a valid estimate of ‘‘usual intake.’’123 There is a wide variety of techniques available to assess dietary intake either prospectively or retrospectively. These range from those that provide relatively precise measurements of individual diet such as weighed intake records or duplicate diets to those that broadly rank intake in large cohort studies into high, medium, and low categories such as diet history or food frequency questionnaires. The advantages and disadvantages of these measurements have been extensively discussed and reviewed by several key workers in the field of dietary assessment.2,123–125 Dietary assessment workers consistently agree that after selection of the most appropriate measurement tool, accurate and representative nutrient data on food composition are required.

4.5.2 PREVIOUS ESTIMATIONS OF DIETARY FLAVONOID INTAKE An initial estimate of flavonoid intake of 1000 mg/day was calculated in the United States during the 1970s using semiquantitative food composition data (Table 4.13).10 This estimate was not questioned until the 1990s with the calculation of dietary flavonol and flavone

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TABLE 4.13 Average Daily Flavonoid Intake in the United States During 1971 Flavonoid

mg/day

Flavanones, flavones, flavonols Anthocyanins Catechins Biflavans Total flavonoids

160–175 (110–121)a 180–215 (124–148) 220 (152) 460 (317) 1020–1070 (703–738)

a

Expressed as quercetin-3-rhamnoside (converted to quercetin aglycone). Source: Reproduced from Kuhnau, J., World Rev. Nutr. Diet., 24, 117, 1976. With permission.

aglycone (including glycosides hydrolyzed to their free form) intake from Dutch composition data for 28 vegetables, nine fruits, and several beverages.32,126 Intake estimates for cohorts from seven countries ranged from 3 mg/day in Finland to 65 mg/day in Japan.20 When the data of Kuhnau,10 originally expressed as quercetin-3-rhamnoside equivalents, are converted to quercetin aglycones (703 to 738 mg/day), flavanones, flavonols, and flavones contribute 110 to 121 mg/day (Table 4.13). This suggests that the earlier study somewhat overestimated dietary flavonoid intake. Several dietary flavonoid intake studies have now been completed using the Dutch composition data often with additional estimates of flavonoid content of local food preferences such as berries (Table 4.14). Comparison of these intake studies indicates that quercetin is consistently the main contributor to flavonol and flavone intake. In the Netherlands, for example, quercetin accounts for 70% of the 23 mg/day total flavonol and flavone intake followed by kaempferol (17%), myricetin (6%), luteolin (4%), and apigenin (3%).127

TABLE 4.14 Estimated Daily Dietary Flavonoid Intakes by Different Countries Country

mg/daya

Netherlands United States United Kingdom (Wales) Finland Spain Japan

23 20–24 26 4 5 16

Tea (48%), onions (29%), apples (7%) Tea (26%), onions (24%), apples (8%) Tea (82%), onions (10%) Apples and onions Tea (26%), onions (23%), apples (8%) Onions (46%), molokheya (10%), apples (7%), green tea (5%)

27 145 135 34 144 146

Netherlands United States

50 25

Tea (83%), chocolate (6%), apples and pears (6%) Tea (59%), apples and pears (26%)

130 139

Finland

20

Orange and grapefruit

129

Flavonoid

Main Dietary Sources

Ref.

Flavonols/flavones

Catechins

Flavanones

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Different countries obtain flavonoids from differing sources with, for example, green tea being the main contributor to intake in Japan, red wine in Italy, and apples in Finland.20 However, the original dietary data for these investigations were collected during the early 1960s and may be outdated, as dietary patterns have changed during the last 40 years. For example, green tea consumption in Japan accounted for 80% of flavonol intake in 1960 but only 5% in 1997.57 Table 4.14 outlines recent dietary flavonoid estimates and main dietary sources using data gathered after 1985. Interestingly, Japanese flavonol and flavone intake is reported to have fallen from 65 to 17 mg/day with onions, not green tea, now being the main dietary source. This may reflect increasing westernization of the Japanese diet.128

4.5.3 ESTIMATION OF SCOTTISH DIETARY FLAVONOID INTAKE USING THE NEW COMPREHENSIVE FLAVONOID DATABASE The flavonoid database described in this chapter was applied to 4-day weighed food records obtained from healthy Scottish men (n ¼ 41) and women (n ¼ 52) to provide a provisional estimate of flavonoid intake in Scotland. All subjects consumed foods containing flavonols, procyanidins, and catechins, dietary intakes of which are given in Table 4.15. The main flavonol consumed was quercetin, accounting for 66 and 63% of the total flavonol intake of 18.8 mg/day. Primary sources of flavonols were from black tea (42.7%), onions (14.3%), apples (10.2%), and lager (7.2%) (Table 4.16). Procyanidins and catechins were primarily obtained from black tea (procyanidins >47.6% and catechins >57.6%) and apples (procyanidins >15.8% and catechins >7.5%) (Table 4.16). The main catechins consumed were EGCG (23%), ECG (22%), and EC (25%). Flavones and flavanones were less frequently consumed during the 4-day collection period. Flavones were not consumed at all by 38 participants, while 29 people did not consume any citrus flavonoids — flavanones. The interquartile range of intake of flavones was relatively limited, ranging from 0.0 to 2.0 mg/day. Flavone consumption was not normally distributed and was negatively skewed toward a lack of consumption of foods rich in flavones such as olives and lettuce. Likewise, flavanone intake was also not normally distributed with a mean flavanone intake of 1 mg/day compared to the median intake of 1.2 mg/day. This is accounted for by the fact that the range of flavanone intakes was very wide (0 to 239 mg/day), 36% of participants not consuming any flavanone-rich foods. The main dietary

TABLE 4.15 Estimated Dietary Flavonoid Intake by UK (Scottish) Population (n 5 81) Flavonoid Subclass Anthocyanins Flavonols (quercetin þ kaempferol þ myricetin) Flavones (apigenin þ luteolin) Proanthocyanidins (procyanidin B1 þ B2 þ B3 þ B4) Catechins (C þ EC þ EGC þ ECG þ EGCG þ GC)a Flavanones (hesperidin þ naringenin) a

Daily intake (mg) (Median [Range])

18.8 (1.9–51.3) 0.1 (0–6.7) 22.5 (0–144.5) 59.0 (1.8–263.3) 1.2 (0–238.6)

C, catechin; EC, epicatechin; EGC, epigallocatechin; ECG, epicatechin gallate; EGCG, epigallocatechin gallate; GC, gallocatechin.

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TABLE 4.16 Main Dietary Sources of Flavonoids from UK (Scottish) Dieta Flavonols Food Item Black tea Onion Apples Lager Tomato Baked beans Red wine Orange Juice

Flavones %b

Food Item

Procyanidins %

Food Item

%

Catechins Food Item

Flavanones %

c

Food Item

24.4 Black tea 49.5 Black tea 63.6 Orange juice Sweet peppers Lettuce 18.1 Apples 20.6 Apples 11.2 White wine Cheese and tom. pizza 11.9 Red wine 8.9 Red wine 4.9 Red wine Vegetable soup 7.6 Lager 8.0 White wine 4.9 Orange Honey 5.7 Chocolate 4.4 Chocolate 4.1 Vegetable milk milk samosas 2.1 Scotch broth 3.7 Strawberries 0.9 Lager 3.9 Grapefruit juice 2.8 Chilli cone carne 3.6 Peaches 0.7 Apple juice 2.7 Lemon juice 2.0 Celery 2.8 Grapes 0.4 Grapes 1.8 Lemon sorbet

42.7 14.3 10.2 7.2 2.4

% 37.8 19.2 19.0 11.6 4.8 3.4 2.4 0.9

a

Data collected from 40 males and 41 females using 4-day weighed intake records. Percentage contribution of the top eight dietary flavonoid sources. c Sweet peppers — total contribution of red, green, and yellow peppers. b

sources of flavanones were orange juice (37.8%) and wine (red wine 19.0% and white wine 19.2%) (Table 4.16).

4.5.4 COMPARISON

WITH

OTHER ESTIMATES

OF

DIETARY FLAVONOID INTAKE

Several dietary flavonoid intake studies have now been completed using the Dutch composition data often with additional estimates of flavonoid content of local food preferences such as berries (Table 4.14). The intake data reported above are the first estimation of dietary intake of different types of flavonoids by a UK population. Flavonol, flavone, and catechin intakes were comparable with Dutch literature127,130 and the only other UK dietary flavonol investigation131 (Table 4.14). The proportional contribution by individual flavonols and catechins to total flavonol and total catechin intakes, respectively, were analogous with Dutch intake and tea was their main dietary source. The flavanone intake of 1.2 mg/day is less than Finnish estimates of 20.2 + 27.6 mg/day (mean + SD) for men and women combined.129 This may reflect differences in dietary preferences although it should also be noted that the Finnish data were calculated from a food frequency questionnaire, a dietary assessment method known to overestimate intake compared with weighed records. Procyanidin intake has not previously been estimated, as there has been a lack of reliable content values. However, Santo-Buelga and Scalbert75 noted that a rough estimated intake of proanthocyanidins in Spain might range from 10 to >100 mg. If this estimate is correct, then the procyanidins type B1-4 measured here represents a small fraction of the total. Identification of black tea as the primary source of flavonols (42.7%), procyanidins (49.5%), and catechins (63.6%) is again consistent with published literature for tea-drinking nations.130,131 For example, a study of 1900 Welsh men also observed that tea was the main dietary source of flavonols.131 Interestingly, 5.4 + 3.0 cups of tea were consumed by these subjects per day between 1979 and 1983 whereas the Scottish participants reported consuming only 2.8 + 2.4 cups of tea per day. This may reflect the current downward trend in tea consumption in the United Kingdom especially by adults under 50 years61 and also suggests that flavonols are obtained from other food sources in the Scottish diet. Hertog,131 for

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example, did not report lager as a major source of flavonols in the Welsh population despite its widespread consumption.46 This is possibly because lager was not included in the Dutch database.25,32,126

4.5.5 FUTURE REQUIREMENTS TO IMPROVE DATABASE The compilation of the database has further emphasized the diversity of potential dietary sources of flavonoids. It has also been used to give the first estimation of dietary intake of different types of flavonoids by a UK population. However, continual update is required to accommodate the increasingly varied purchasing patterns of foods in the United Kingdom61 as well as for use in countries with markedly different dietary habits. There is a current lack of directly analyzed flavonoid measurements for composite meals. Therefore, recipe calculations would have to include assumptions for cooking losses or gains, which could subsequently introduce bias when calculating dietary intake.132 Moreover, it is also important to confirm the flavonoid profile of composite dishes as they may contain unusual complex mixtures. For example, bolognaise sauce contains all five flavonoid subclasses (Table 4.17) whereas no individual food in the database exhibits such a profile. Despite these reservations, calculating the flavonoid content of recipes may be reasonably robust. Fjelkner-Modig et al.,133 found close agreement between the directly analyzed and calculated quercetin levels in moussaka. However, it is possible that flavonoid values for retail products such as canned soups and preprepared meals may be underestimated as recipes and proportions of ingredients for such products are usually unavailable. Similarly, there is only limited compositional analysis for fruit juices and herbal tea despite their growing popularity.61 Also, currently lacking are data on flavonoid contents of satsumas, tangerines, and clementines (which were consumed by 25% of subjects during the 4-day record collection period) and herbs commonly added to recipe dishes. Both are potentially good sources of flavonoids. Despite these caveats, the database constructed in the present study is a comprehensive assessment of the currently available data on the flavonoid contents of foods.

4.6 CONCLUSIONS A comprehensive and critical review of food flavonoid literature has led to the development of a food composition database for flavonols, flavones, procyanidins, catechins, and flavanones. This database can now be used and continuously updated to estimate flavonoid intake of populations, to identify dietary sources of flavonoids, and to assess associations between flavonoid intake and disease. However, there is a need for better food composition data for flavones, procyanidins, and flavanones as current literature is sparse particularly for citrus fruits, fruit juices, and herbs. In addition, anthocyanin food composition data are lacking although validated methods of determination are becoming available.

4.7 ACKNOWLEDGMENTS Compilation of this flavonoid database could not have taken place without funding from the Scottish Executive Environment and Rural Affairs Department (SEERAD), the Ministry of Agriculture Fisheries and Food, UK, and the EU Framework V Programme. We are also grateful to Dr Geraldine McNeil for much needed help and advice.

0.8 60.0 500.0 10.0 40.0 30.0 10.0 397.0 125.0 125.0 2.5 1.8 1.8 1303.8 886.6c

Clove garlic, crushed Onions chopped Minced beef Vegetable oil Carrots, chopped Celery chopped Tomato puree Canned tomatoes Stock Red wine Salt Pepper Dried mixed herbs Total raw Cooked dish Flavonoid content (mg/cooked dish)d Flavonoid content (mg/100 g)

— 0.1 — — C Tr Tr Tr — 0.1 — — — 0.2 0.1 Tr

13.6 1.5

K

Tr 24.4 — — C Trb 0.4 1.2 — 1.2 — — — 27.2

Qu

Flavonols

0.4 Tr

— Ca — — — Tr — — — 0.7 — — — 0.7

Myr

0.9 0.1

— — — 1.8

— — — 0.5 0.2 Tr

— C — — — 1.8 — — —

Apig

— — — — — 0.5 — — —

Lut

Flavones

9.4 1.1

— — — — — — — — — 18.8 — — — 18.8

B1–4

Procyanidin

0.2 Tr

— — — — — — — — — 0.4 — — — 0.4

EGC

4.1 0.5

— — — — — — — — — 8.2 — — — 8.2

C

2.4 0.3

— — — — — — — — — 4.8 — — — 4.8

EC

0.0 —

— — — — — — — — — Tr — — — 0.0

EGCG

Catechins

0.0 —

— — — — — — — — — Tr — — — 0.0

ECG

0.3 Tr

— — — — — — — — — 0.5 — — — 0.5

GC

1.1 0.1

— — — — — — — — — 2.2 — — — 2.2

Nar

0.3 Tr

— — — — — — — — — 0.7 — — — 0.7

Hesp

Flavanones

Source: Ingredients — recipe taken from Holland, B. et al. The composition of foods, In: McCance and Widdowson’s The Composition of Foods. Cambridge: Royal Society of Chemistry & MAFF, 1991. With permission. a C — Characterized but not quantified. b Tr — below limit of detection ( 20) were shown to be present in a red wine and selectively precipitated by proteins used as fining agents,270,271 meaning that they were soluble and presumably astringent. Assessment of taste is achieved by sensory analysis, from very simple experiments such as triangular tests aiming at determining detection thresholds to complex descriptive analysis approaches. A method referred to as time–intensity that consists in recording continuously the intensity of a given sensation over time under standardized conditions has been applied to study flavonoid bitterness and astringency properties.247,272–279 Recent studies performed using this method have shown that flavanol bitterness decreases from monomer to trimer.242 Epicatechin was perceived more bitter than catechin and the C4– C6-linked catechin dimer more bitter than other procyanidin dimers with C4–C6 linkages. This may be due to the higher lipophilic character of these molecules facilitating their diffusion to the gustatory receptor.21 Bitterness of procyanidin fractions in 5% ethanol decreased with their

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mean degree of polymerization (3, 10, 70).280 No bitterness was detected when tasting the same fractions in a wine-like solution containing 13% ethanol and acidified with tartaric acid.20 Astringency was classically considered to increase with flavanol chain length and decrease beyond the octamer level,21,281 but, to our knowledge, this had never been confirmed experimentally as higher molecular weight fractions were not available. In fact, recent sensory studies performed on a series of proanthocyanidin fractions isolated from grape or apple and differing in chain length, galloylation rate, and content of epigallocatechin units showed that polymeric fractions (mDP 30, 70) were by far the most astringent.20 Larger molecular weight proanthocyanidins extracted from apple (mDP 70), grape seeds (mDP 10, 20% galloylated units), and grape skins (mDP 20, 5% galloylated units, 20% prodelphinidin units) exhibited similar astringency when tasted at the same concentration (0.5 g/l) in a model wine medium, in spite of their large composition differences determined by thiolysis.20 This confirmed earlier results obtained in citric acid solutions and in white wine.282 The higher percentage of galloylation in the seed proanthocyanidins actually compensated for their lower molecular weight since the same fraction after degalloylation with tannase was scored similar to the mDP12 fraction from grape skins. The decrease of astringency occurring during wine aging is usually ascribed to the conversion of proanthocyanidins to less astringent and eventually insoluble derivatives through polymerization reactions. However, the recent findings developed above suggest that this assumption has to be at least partly revised. On the one hand, astringency of flavonoid derivatives increases with their molecular weight so that reactions leading to higher molecular weight species may result in enhanced rather than decreased astringency. On the other hand, flavonoid reactions in wine yield not only larger molecules, through acetaldehyde-induced polymerization and formation of anthocyanin–flavanol adducts, but also lower molecular weight compounds through acid-catalyzed cleavage, especially if large amounts of monomeric flavonoids such as anthocyanins, are present. An average size reduction of wine molecules might be regarded as a possible alternative explanation for the loss of astringency associated with wine aging. Very little is known of the sensory properties of the various tannin and anthocyaninderived species identified. Conversion of proanthocyanidins to methylmethine-linked oligomers has been shown to occur during persimon ripening and postulated to participate in astringency reduction.85,283 However, a mDP5 methylmethine-linked catechin fraction obtained by acetaldehyde-mediated polymerization of catechin was equally astringent as equivalent chain length procyanidins.284 The astringency of wine tannin fractions appears to be correlated to the content of flavanol units released after thiolysis regardless of their environment in the original molecules.282 Anthocyanins contributed neither bitterness nor astringency.285 Whether incorporation of anthocyanin moieties in tannin-derived structures affects their interactions with proteins and taste properties remains to be investigated. Taste perception of flavanols is also greatly affected by other constituents of the medium. In particular, lowering of pH leads to a significant increase in astringency whereas increasing the level of ethanol enhances bitterness.286,287 The gustatory perception of tannins may also be altered by the presence of polysaccharides and proteins. A mechanism involving interaction of tannins with soluble pectins released during ripening, impeding their binding to salivary protein, has been proposed to explain changes occurring during fruit maturation.249,288,289 The formation of soluble and colloidal polysaccharide–tannin complexes in wine-like model systems was demonstrated by light scattering.264 Polysaccharides isolated from wine inhibited aggregation of flavanols, except type II rhamnogalaturoanan dimer, which enhanced it.264 Carbohydrates of different origins also solubilized flavanol–protein complexes, ionic polysaccharides being more effective.290 Similarly, analyses of the wines

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before and after protein fining suggested that the reduction of astringency induced by fining was due to the presence of soluble tannin–protein complexes, along with removal of highly polymerized and highly galloylated tannins.271,291 A sensory study based on an incomplete factorial design allowed to demonstrate that astringency of procyanidins was reduced in the presence of rhamnogalaturonan II added at levels encountered in wine but was modified neither by anthocyanins nor by the other wine polysaccharides (mannoproteins and arabinogalactan proteins).292 Increase in ethanol level resulted in higher bitterness perception but had no effect on astringency. The role of colloidal phenomena in astringency perception cannot be easily inferred from the available data. Aggregation kinetics and particle size as well as astringency intensity increased with the concentration of flavanols and with their chain length. Factors decreasing flavanol particle size such as presence of ethanol or of manoproteins and arabinogalactan proteins had no effect on astringency perception. In contrast, the presence of RGII and proteins, both of which increase particle size, reduced astringency perception, possibly because the flavanol involved in these aggregates could no longer interact with salivary or mouth proteins.

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214. Es-Safi, N.E., Cheynier, V., and Moutounet, M., Study of the reactions between (þ)-catechin and furfural derivatives in the presence or absence of anthocyanins and their implication in food color change. J. Agric. Food Chem. 48, 5946, 2000. 215. Pissara, J. et al., Reaction between malvidin 3-glucoside and (þ)-catechin in model solutions containing different aldehydes. J. Food Sci. 68, 476, 2003. 216. Oszmianski, J., Cheynier, C., and Moutounet, M., Iron-catalyzed oxidation of (þ)-catechin in wine-like model solutions. J. Agric. Food Chem. 44, 1972, 1996. 217. Es-Safi, N.E. et al., Structure of a new xanthylium salt derivative. Tetrahedron Lett. 40, 5869, 1999. 218. Es-Safi, N.E. et al., New phenolic compounds formed by evolution of (þ)-catechin and glyoxylic acid in hydroalcoholic solution and their implication in color changes of grape-derived food. J. Agric. Food Chem. 48, 4233, 2000. 219. Romero, C. and Bakker, J., Interactions between grape anthocyanins and pyruvic acid, with effects of pH and acid concentration on anthocyanin composition and color in model solutions. J. Agric. Food Chem. 47, 3130, 1999. 220. Romero, C. and Bakker, J., Effect of storage temperature and pyruvate on kinetics of anthocyanin degradation, vitisin A formation and color characteristics of model solution. J. Agric. Food Chem. 48, 2135, 2000. 221. Brouillard, R. and Lang, J., The hemiacetal-cis-chalcone equilibrium of malvin, a natural anthocyanin. Can. J. Chem. 68, 755, 1990. 222. Es-Safi, N.E. et al., New polyphenolic compounds with xanthylium skeletons formed through reaction between (þ)-catechin and glyoxylic acid. J. Agric. Food Chem. 47, 5211, 1999. 223. Bradshaw, M.P., Prenzler, P.D., and Scollary, G.R., Ascorbic acid-induced browning of (þ)-catechin in a model wine system. J. Agric. Food Chem. 49, 934, 2001. 224. Bradshaw, M.P. et al., Defining the ascorbic acid crossover from anti-oxidant to pro-oxidant in a model wine matrix containing (þ)-catechin. J. Agric. Food Chem. 51, 4126, 2003. 225. Piffaut, B. et al., Comparative degradation pathways of malvidin3,5-diglucoside after enzymatic and thermal treatments. Food Chem. 50, 115, 1994. 226. Brouillard, R. and Dangles, O., Anthocyanin molecular interactions: the first step in the formation of new pigments during wine aging. Food Chem. 51, 365, 1994. 227. Goto, T. and Kondo, T., Structure and molecular stacking of anthocyanins. Flower color variation. Angew. Chem. Int. Ed. Engl. 30, 17, 1991. 228. Brouillard, R. and Dangles, O., Flavonoids and flower colour. In The Flavonoids. Advances in Research Since 1986 (ed. J.B. Harborne), Chapman & Hall, London, 1993, p. 565. 229. Boulton, R., The copigmentation of anthocyanins and its role in the color of red wine: a critical review. Am. J. Enol. Vitic. 52, 67, 2001. 230. Timberlake, C.F. and Bridle, P., Flavylium salts resistant to sulphur dioxide. Chem. Ind. 1489, 1968. 231. Brouillard, R., Iabucci, G.A., and Sweeny, J.G., Chemistry of anthocyanin pigments. 9. UV–visible spectrophotometric determination of the acidity constants of apigeninidin and three related 3-deoxyflavylium salts. J. Am. Chem. Soc. 104, 7585, 1982. 232. Mazza, G. and Brouillard, R., Color stability and structural transformations of cyanidin 3,5-diglucoside and four deoxyanthocyanins in aqueous solutions. J. Agric. Food Chem. 35, 1987. 233. Roehri-Stoeckel, C. et al., Synthetic dyes: simple and original ways to 4-substituted flavylium salts and their corresponding vitisin derivatives. Can. J. Chem. 79, 1173, 2001. 234. Heredia, F.J. et al., Chromatic characterization of anthocyanins from red grapes — I. pH effect. Food Chem. 63, 491, 1998. 235. Escribano-Bailon, M., Dangles, O., and Brouillard, R., Coupling reactions between flavylium ions and catechin. Phytochemistry 41, 1583, 1996. 236. Atanosova, V. et al., First evidence of acetaldehyde-induced anthocyanin polymerisation. In Polyphenol Communications 2002 (ed. I. Hadrami), Marrakech, 2002, p. 417. 237. Salas, E. et al., Structure determination and color properties of a newly synthesized direct-linked flavanol–anthocyanin dimer. Tetrahedron Lett. 45, 8725, 2004. 238. Simpson, R.F., Factors affecting oxidative browning of white wine. Vitis 21, 233, 1982.

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239. Simpson, R.F., Pinking in Australian white table wines. Aust. Wine Brew. Spirit Rev. 56, 1977. 240. Simpson, R.F., Oxidative pinking in white wines. Vitis 16, 286, 1977. 241. Noble, A., Bitterness and astringency in wine. In Bitterness in Foods and Beverages (ed. R. Rousseff), Elsevier, Amsterdam, 1990, p. 145. 242. Gacon, K., Peleg, H., and Noble, A.C., Bitterness and astringency of flavan-3-ol monomers, dimers and trimers. Food Qual. Prefer. 7, 343, 1996. 243. Bate-Smith, E., Astringency in foods. Food 23, 124, 1954. 244. Breslin, P.A. et al., Psychophysical evidence that oral astringency is a tactile sensation. Chem. Senses 18, 405, 1993. 245. Green, B.G., Oral astringency: a tactile component of flavor. Acta Psychol. 84, 119, 1993. 246. Clifford, M.N., Astringency. In Phytochemistry of Fruits and Vegetables (eds F. Tomas-Barberan and R. Robins), Clarendon Press, Oxford, 1997, p. 87. 247. Lee, C.B. and Lawless, H.T., Time-course of astringent sensations. Chem. Senses 16, 225, 1991. 248. Haslam, E., Polyphenol–protein interactions. Biochem. J. 139, 285, 1974. 249. Haslam, E. and Lilley, T.H., Natural astringency in foodstuffs. A molecular interpretation. Crit. Rev. Food Sci. Nutr. 27, 1, 1988. 250. McManus, J.P. et al., Polyphenol interactions. Part 1. Introduction; some observations on the reversible complexation of polyphenols with proteins and polysaccharides. J. Chem. Soc. Perkin Trans. II 1429, 1985. 251. Baxter, N.J. et al., Multiple interactions between polyphenols and a salivary proline-rich protein repeat result in complexation and precipitation. Biochemistry 36, 5566, 1997. 252. Okuda, T., Mori, K., and Hatano, T., Relationships of the structures of tannins to the binding activities with hemoglobin and methylene blue. Chem. Pharm. Bull. 33, 1424, 1985. 253. Porter, L.J. and Woodruffe, J., Haemanalysis: the relative astringency of proanthocyanidin polymers. Phytochemistry 23, 1255, 1984. 254. Ricardo da Silva, J.M. et al., Interaction of grape seed procyanidins with various proteins in relation to wine fining. J. Sci. Food Agric. 57, 111, 1991. 255. Sarni-Manchado, P., Cheynier, V., and Moutounet, M., Interactions of grape seed tannins with salivary proteins. J. Agric. Food Chem. 47, 42, 1999. 256. Maury, C. et al., Influence of fining with different molecular weight gelatins on proanthocyanidin composition and perception of wines. Am. J. Enol. Vitic. 52, 140, 2001. 257. Bate-Smith, E.C., Haemanalysis of tannins: the concept of relative astringency. Phytochemistry 12, 907, 1973. 258. Hatano, T. and Hemingway, R.W., Association of (þ)-catechin and catechin-(4a ! 8)-catechin with oligopeptides. J. Chem. Soc. Chem. Commun. 2537, 1996. 259. Hatano, T., Yoshida, T., and Hemingway, R.W., Interaction of flavonoids with peptides and proteins and conformations of dimeric flavonoids in solution. In Plant Polyphenols 2. Chemistry, Biology, Pharmacology, Ecology (eds G.G. Gross, R.W. Hemingway, T. Yoshida, and S.J. Branham), Kluwer Academic/Plenum Publisher, New York, 1999, p. 509. 260. Luck, G. et al., Polyphenols, astringency and prolin-rich proteins. Phytochemistry 37, 357, 1994. 261. Charlton, A.J., Haslam, E., and Williamson, M.P., Multiple conformations of the proline-richprotein/epigallocatechin gallate complex determined by time-averaged nuclear Overhauser effects. J. Am. Chem. Soc. 124, 9899, 2002. 262. Charlton, A. et al., Polyphenol/peptide binding and precipitation. J. Agric. Food Chem. 50, 1593, 2002. 263. Sarni-Manchado, P. and Cheynier, V., Study of noncovalent complexation between catechin derivatives and peptide by electrospray ionization-mass spectrometry (ESI-MS). J. Mass Spectrom. 37, 609, 2002. 264. Riou, V. et al., Aggregation of grape seed tannins in model — effect of wine polysaccharides. Food Hydrocoll. 16, 17, 2002. 265. Poncet-Legrand, C. et al., Flavan-3-ol aggregation in model ethanolic solutions: incidence of polyphenol structure, concentration, ethanol content and ionic strength. Langmuir 19, 10563, 2003.

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266. Edelmann, A. et al., Dynamic light scattering study of the complexation between proline rich proteins and flavan-3-ols: influence of molecular structure, polyphenol/protein ratio and ionic strength. In Oenologie 2003 (eds A. Lonvaud-Funel, G. De Revel, and P. Darriet), Tec et Doc, Arcachon, 2003, p. 408. 267. Saucier, C., Glories, Y., and Roux, D., Interactions tanins-colloides: nouvelles avance´es concernant la notion de ‘‘bons’’ et de ‘‘mauvais’’ tanins. Rev. Oenol. 94, 9, 2000. 268. Saucier, C. et al., Characterization of (þ)-catechin-acetaldehyde polymers: a model for colloidal state of wine polyphenols. J. Agric. Food Chem. 45, 1045, 1997. 269. Maury, C., Etude des phe´nome`nes implique´s dans les collages prote´iques en oenologie, The`se Doctorat Montpellier II-ENSAM, Montpellier, 2001. 270. Sarni-Manchado, P. et al., Analysis and characterization of wine condensed tannins precipitated by protein used as fining agent in enology. Am. J. Enol. Vitic. 50, 81, 1999. 271. Maury, C. et al., Influence of fining with different molecular weight gelatins on proanthocyanidin composition and perception of wines. Am. J. Enol. Vitic. 52, 140, 2001. 272. Fischer, U. and Noble, A.C., The effect of ethanol, catechin concentration, and pH on sourness and bitterness of wine. Am. J. Enol. Vitic. 45, 6, 1994. 273. Guinard, J.-X., Pangborn, R.M., and Lewis, M.J., The time-course of astringency in wine upon repeated ingestion. Am. J. Enol. Vitic. 37, 184, 1986. 274. Kallithraka, S., Bakker, J., and Clifford, M.N., Red wine and model wine astringency as affected by malic and lactic acid. J. Food Sci. 62, 416, 1997. 275. Kallithraka, S., Bakker, J., and Clifford, M.N., Effect of pH on astringency in model solutions and wines. J. Agric. Food Chem. 45, 2211, 1997. 276. Kallithraka, S., Bakker, J., and Clifford, M.N., Evaluation of bitterness and astringency of (þ)-catechin and (
)-epicatechin in red wine and in model solutions. J. Sens. Stud. 12, 25, 1997. 277. Naish, M., Clifford, M.N., and Birch, G.G., Sensory astringency of 5-O-caffeoylquinic acid, tannic acid and grape seed tannin by a time-intensity procedure. J. Sci. Food Agric. 61, 57, 1993. 278. Robichaud, J.L. and Noble, A.C., Astringency and bitterness of selected phenolics in wine. J. Sci. Food Agric. 53, 343, 1990. 279. Valentova, H. et al., Time-intensity studies of astringent taste. Food Chem. 78, 29, 2002. 280. Vidal, S. et al., Effect of tannin composition and wine carbohydrates on astringency and bitterness. In 5th Pangborn Sensory Science Symposium, Boston, 2003. 281. Goldstein, J.L. and Swain, T., The inhibition of enzymes by tannins. Phytochemistry 4, 185, 1965. 282. Brossaud, F., Cheynier, V., and Noble, A., Bitterness and astringency of grape and wine polyphenols. Aust. J. Grape Wine Res. 7, 33, 2001. 283. Matsuo, T. and Itoo, S., A model experiment for de-astringency of persimmon fruit with high carbon dioxide treatment: in vitro gelation of kaki-tannin by reacting with acetaldehyde. Agric. Biol. Chem. 46, 683, 1982. 284. Vidal, S. et al., Taste and mouth-feel properties of different types of tannin-like polyphenolic compounds and anthocyanins in wine. Anal. Chim. Acta 513, 57, 2004. 285. Vidal, S. et al., The mouth feel properties of polysaccharides and anthocyanins in a wine-like medium. Food Chem. 85, 519, 2004. 286. Noble, A., Why do wines taste bitter and feel astringent? In Wine Flavor (eds A.L. Waterhouse and S. Eberler), American Chemical Society, Washington, DC, 1998, p. 156. 287. Noble, A.C., Astringency and bitterness of flavonoid phenols. In Chemistry of Taste: Mechanisms, Behaviors, and Mimics (eds P. Given and D. Paredes), American Chemical Society, Washington, DC, 2002, p. 192. 288. Ozawa, T., Lilley, T.H., and Haslam, E., Polyphenol interactions: astringency and the loss of astringency in ripening fruit. Phytochemistry 26, 2937, 1987. 289. Taira, S., Ono, M., and Matsumoto, N., Reduction of persimmon astringency by complex formation between pectin and tannins. Postharvest Biol. Technol. 12, 265, 1998. 290. de Freitas, V., Carvalho, E., and Mateus, N., Study of carbohydrate influence on protein–tannin aggregation by nephelometry. Food Chem. 81, 503, 2003.

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291. Maury, C. et al., Influence of fining with plant proteins on proanthocyanidin composition of red wines. Am. J. Enol. Vitic. 54, 105, 2003. 292. Vidal, S. et al., Use of an experimental design approach for evaluation of key wine components on mouth-feel perception. Food Qual. Prefer. 15, 209, 2004. 293. Mateus, N. et al., Occurrence of anthocyanin-derived pigments in red wines. J. Agric. Food Chem. 49, 4836, 2001. 294. Es-Safi, N.E., Cheynier, V., and Moutounet, M., Implication of phenolic reactions in food organoleptic properties. J. Food Compost. Anal. 16, 535, 2003.

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Dietary Flavonoids and Health — Broadening the Perspective Mike Clifford and J.E. Brown

CONTENTS 6.1 6.2 6.3 6.4

Introduction ............................................................................................................... 320 The Diversity of Dietary PPT .................................................................................... 321 The Intake of PPT ..................................................................................................... 322 Absorption of PPT and the Nature of the Plasma Metabolites................................. 324 6.4.1 Introduction .................................................................................................. 324 6.4.2 Flavanols, Flavanol Gallates, and Proanthocyanidins ................................. 326 6.4.3 Flavonol Glycosides...................................................................................... 326 6.4.4 Flavones and Polymethylflavones................................................................. 327 6.4.5 Isoflavones .................................................................................................... 327 6.4.6 Flavanones .................................................................................................... 328 6.4.7 Chalcones, Dihdyrochalcones, and Retrochalcones...................................... 328 6.4.8 Anthocyanins ................................................................................................ 328 6.4.9 Stilbenes ........................................................................................................ 329 6.4.10 Hydroxybenzoic Acids, Hydroxycinnamic Acids, and Associated Conjugates .................................................................................................... 329 6.4.11 Oleuropein, Tyrosol, and Hydroxytyrosol .................................................... 330 6.4.12 Hydrolyzable Tannins................................................................................... 330 6.4.13 Lignins and Lignans...................................................................................... 330 6.4.14 Derived Polyphenols ..................................................................................... 330 6.4.15 Person-to-Person Variation........................................................................... 331 6.5 PPT Metabolites in Tissues........................................................................................ 331 6.5.1 Pseudo-Pharmacokinetic and Redox Properties ........................................... 331 6.5.2 Binding to Plasma Proteins........................................................................... 334 6.5.3 Effects on the Vascular System ..................................................................... 334 6.5.4 Transformation of PPT Metabolites after Absorption ................................. 338 6.6 PPT Prior to Absorption ........................................................................................... 339 6.6.1 Interaction with Tissues and Nutrients Prior to Absorption ........................ 339 6.6.2 Modulation of the Gut Microflora — Prebiotic Effects ............................... 340 6.6.3 Modulation of the Postprandial Surge in Plasma Glucose — Glycemic Index........................................................................... 341 6.7 Safety Assessment of Dietary PPT............................................................................. 341 6.8 Conclusions and Future Research Requirements ...................................................... 343 References .......................................................................................................................... 344

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6.1 INTRODUCTION Toward the end of the 20th century, epidemiological studies and associated meta-analyses suggested strongly that long-term consumption of diets rich in plant foods offered some protection against chronic diseases, especially cancer.1–7 Because uncontrolled production of free radicals was thought to be significantly implicated in the etiology of cancer,8–11 these observations focused attention on the possible role of radical scavenging and radical suppressing nutrients and nonnutrients in explaining the apparent benefit of such diets.12–15 The realization that free radicals were similarly implicated in the etiology of many other chronic diseases,16,17 along with the recognition of the ‘‘French Paradox’’18 and the seminal papers from Hertog et al.,19,20 immediately focused attention on flavonoids and the foods and beverages rich therein. An unfortunate, but unintended side effect of these papers was the tendency of many investigators to think of dietary phenols, polyphenols, and tannins (PPT) as encompassing only the flavonoids, and the flavonoids per se to encompass only the three flavonols and two flavones that featured in those studies,19,20 but this is misleading and was never intended. This particular combination of events almost certainly resulted in many subsequent investigations adopting a too narrow focus.21 Subsequent epidemiological studies have supported the association between better health and long-term consumption of diets rich in foods of plant origin.22–29 However, whether this is because such diets minimize exposure to deleterious substances (e.g., oxidized cholesterol, pyrolysis mutagens, salt, saturated fat, etc.), or maximize intake of certain beneficial nutrients (e.g., isothiocyanates and other sulfur-containing plant constituents, mono-unsaturated fatty acids, and poly-unsaturated fatty acids, PPT, polyacetylenes, selenium, terpenes, etc.) or some combination as advocated in the ‘‘Polymeal’’ concept, remains unknown.30,31 An in vitro study indicates that there may be mechanistic basis for true synergy between PPT and isothiocyanates.32 In contrast, more recent studies seeking to assess the suggested link between the consumption of flavonols and flavones, or other flavonoids, have given much less consistent results. Some studies have suggested a possible protective effect of flavonoids against vascular diseases33–37 or certain (but not all) cancers,38–43 whereas other studies have suggested no protective effect or even an increased risk in certain populations.44–50 Interestingly, an investigation of the relationship between the consumption of broccoli and other cruciferous vegetables and the risk of breast cancer in premenopausal women attributed the beneficial effects to isothiocyanates and not to the phenolic components,51 although these crops are good sources of dietary phenols52,53 including flavonoids,54–56 and a potential for synergy in vivo has been demonstrated.32,57 In the same time period, various studies have suggested beneficial effects associated with raised consumption of other classes of dietary phenols. For example, increased coffee consumption has been linked with reduced incidence of type II diabetes.58–63 Similarly, increased consumption of lignans (or at least greater plasma concentrations of their metabolites) has been linked with reduced incidence of estrogen-related cancers in some64–66 but not all studies,67,68 and a prospective study was equivocal.69 It has been suggested that this inconsistency might have a genetic basis.70 Increased consumption of isoflavones has also been associated with decreased risk of estrogen-related cancers and vascular diseases.40,71 This brief introduction demonstrates that the relationships between diet and health are far from simple and most certainly far from fully understood, but for a critical and detailed review of epidemiological data the reader is referred to an excellent paper by Arts and Hollman.72 The objective of the review that follows is to record recent changes in the perceived role of flavonoids as health-promoting dietary antioxidants and place these

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observations in a broader context embracing other dietary phenols, and mechanisms other than simple radical scavenging and radical suppression.

6.2 THE DIVERSITY OF DIETARY PPT PPT may be classified in several ways; for example, by biosynthetic origin, occurrence, function or effect, or structure.73–75 A classification based on structure and function will be used in this chapter.76 Simple phenols are substances containing only one aromatic ring and bearing at least one phenolic hydroxyl group and possibly other substituents, whereas polyphenols contain more than one such aromatic ring. Phenols and polyphenols may occur as unconjugated aglycones or, as conjugates, frequently with sugars or organic acids, but also with amino acids, lipids, etc.77 The commonest simple phenols are cinnamates that have a C6–C3 structure78,79 accompanied by C6–C2 and C6–C1 compounds, and a few unsubstituted phenols.80–82 In general, these occur as conjugates. Flavonoids are the most extensively studied polyphenols, all characterized by a C6–C3–C6 structure, subdivided by the nature of the C3 element into anthocyanins, chalcones, dihydrochalcones, flavanols, flavanones, flavones, flavonols, isoflavones, and proanthocyanidins. The flavanols and proanthocyanidins generally occur unconjugated but the others normally occur as glycosides. Since the seminal paper of Hertog et al.,83 there has been a tendency to think of dietary PPT as encompassing only the flavonoids, and the flavonoids per se to consist only of the three flavonols and two flavones that featured in that study, but this is misleading and was never intended. It is not possible to say with precision just how many individual PPT occur regularly in human diets, but on present evidence a figure in excess of 200 seems reasonable.77 The term ‘‘tannin’’ refers historically to crude plant preparations that are capable of converting hides to leather84 and such preparations are not consumed as human food. However, the functional polyphenols contained therein at high concentration may also occur in certain foods and beverages but at comparatively low concentrations that would render them totally ineffective for producing leather. These polyphenols may be subdivided into the flavonoid-derived proanthocyanidins (condensed tannins)85,86 and the gallic acidderived and ellagic acid-derived hydrolyzable tannins, this latter subgroup of more restricted occurrence in human food (but commoner in some animal feeds).87 The phloroglucinolderived phlorotannins, while never used for preparing leather, also have a limited occurrence in human food.80 The more recent term ‘‘phytoestrogen’’ refers to substances with estrogenic or antiandrogenic activity at least in vitro, and encompasses some isoflavones, some stilbenes, some lignans, and some coumarins.88 The lignans are not estrogen-active until transformed by the gut microflora.88,89 ‘‘Antioxidants’’ is a third function-based term much used to describe PPT, but individual compounds differ markedly in their ability to scavenge reactive oxygen species and reactive nitrogen species, and inhibit oxidative enzymes. Mammalian metabolites of PPT do not necessarily retain fully the antioxidant ability of the PPT found in plants and especially not that of their aglycones as commonly tested in vitro.90,91 The PPT discussed above are substances found in healthy and intact plant tissues, and mainly have known structures. However, many traditional foods and beverages as consumed have been produced by more or less extensive processing of such plant tissues, resulting in biochemical or chemical transformations of the naturally occurring PPT. In some cases, for example, black tea, matured red wines, and coffee beverage, these transformations may be substantial, generating large quantities of substances not found in the original plant material. There have been significant advances in the last decade in the chemistry of both red wine92–97 and black tea.98–106 This includes the characterization of the first large-mass thearubigin derived from four flavanol monomers and containing three benztropolone moieties,107 and evidence that peroxidase-like reactions are involved in their production.101 The derived

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polyphenols of matured wines are discussed eloquently by Cheynier in Chapter 5. However, the structures of the majority of these novel compounds have yet to be elucidated. Although often described as tannins, the beverages containing these substances are not functional tanning agents, and these substances should be referred to collectively as derived polyphenols (rather than tannins) until such time as their full structural characterization permits a more precise nomenclature.76

6.3 THE INTAKE OF PPT There have been several attempts to estimate the quantities of PPT consumed, either by using diet diaries or food frequency questionnaires and data on the typical composition of individual commodities33,36,41,47,50,86,108–113 or by diet analysis.42,46,83 In comparison with the comprehensive databases providing the content in the diet of the established micro- and macronutrients, data for the contents of PPT are much more limited. Those data that are available for PPT content have been obtained by many different methods of analysis, rarely take account of the effects of agricultural practice, season, cooking, or commercial processing, are not necessarily just for the edible portion, and may be for varieties of fruits and vegetables different from those consumed in a particular diet under investigation.71,110,111 These are potentially serious limitations since quantitatively cultivars may differ substantially in composition, and the nonedible parts of fruits and vegetables may differ greatly both quantitatively and qualitatively, compared with the flesh or juice.114 Thermal processing of tea beverages results in significant flavanol epimerization and some food products present the consumer with epimers that do not occur naturally.115,116 In addition, domestic cooking and commercial processing may, in some cases, cause extensive leaching and destruction,56,117–122 although such data as are available sometimes are not completely in agreement56,122 and much remains to be investigated.123 Data based on analysis of particular diets avoid these limitations but are usually restricted to a few PPT because of the difficulties and cost associated with quantifying so many individual compounds of known structure, to say nothing of the serious difficulties associated with quantifying the uncharacterized derived polyphenols.124 When such data are available, they are usually for PPT as aglycones released by hydrolysis (to simplify the analysis still further) and generally for the flavonols and flavones first studied by Hertog et al.83 since these are amongst the easiest to determine.33,34,36,38,39,41,46,47,71,125–127 There are more limited data for flavanones47,126 and isoflavones after hydrolysis,47,71 and flavanols, and proanthocyanidins86,128–130 (which occur as aglycones). The lack of comprehensive and reliable food composition tables that encompass the PPT (and other nonnutrients) in commodities as consumed seriously inhibits the demonstration of statistical relationships between intake and health or disease and may be a factor contributing to the apparent inconsistency in the outcome of epidemiological studies (discussed above). This lack also impedes proper risk assessment of botanicals,131 as discussed below. A significant development is the creation of three online free-access databases. One provides data for contents in 205 commodities for most classes of flavonoids including the flavanol-derived theaflavins and thearubigins of black tea, but excluding isoflavones and dihydrochalcones.132 The second provides data for isoflavones in 128 commodities,133 and the third for flavanols and proanthocyanidins in 225 commodities.134 A similar development at the University of Surrey in the United Kingdom covers an even wider range of dietary phenols (including chlorogenic acids, benzoic acids, phenyl alcohols, lignans, and derived polyphenols) in some 80 commodities, but is not yet available online. Developed as part of an EU research program, the Vegetal Estrogens in Nutrition and the Skeleton (VENUS) database constructed in Microsoft Access 2000 contains the daidzein and genistein contents of 791

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foods, more limited data for coumestrol, formomonetin, and biochanin A, plus levels for the lignans matairesinol and secoisolariciresinol in 158 foods.135 A commercial database covers cinnamates, flavonoids, isoflavones, and lignans plus many nonphenolic plant constituents.136 Chapter 4 in this volume describes the development of a UK-focused database covering primarily anthocyanidins, flavanols, flavanones, flavones, and flavonols. While recognizing the limitations (discussed above) of such an approach to estimating diet composition and the intake of PPT, using the University of Surrey database in conjunction with diet diaries available from their other studies137–139 has produced interesting data (Table 6.1) and insights. From Table 6.1 it is clear that PPT intakes may vary substantially, and that the flavones and flavonols, upon which most emphasis has so far been placed,33,34,36,38,39,41,46,47,71,83,125–127 form a comparatively small part of the total intake for the populations studied. The relatively low consumption of chalcones and dihydrochalcones, isoflavones, anthocyanins, and stilbenes reflects the comparatively low consumption of apples and ciders, soya products, dark berries, and red wines by these populations. The significant contributions made by the hydroxycinnamates (in these populations primarily reflecting coffee consumption78,79) and derived polyphenols (in these populations primarily reflecting black tea consumption140–142) are striking. In this context, ‘‘black tea’’ refers to the beverage prepared from the fermented leaf (as distinct from green tea) and not to the addition

TABLE 6.1 Mean Dietary Intakes of 14 Classes of PPT as Determined from Diet-Diaries and a Food Composition Database PPT

103 UK Females Aged 20–30 Yearsa Estimated as Conjugates

Total, range Total, mean Hydroxybenzoates Hydroxycinnamates Total flavonoids Anthocyanins Chalcones and dihydrochalcones Flavanols Flavanones Flavones Flavonols Isoflavones Proanthocyanidins Ellagitannins Derived polyphenols Stilbenes Lignans a

100–2300 780 15 353 210 5 0.7 64 22 72 35 9 7 23 170 9 0.04

Estimated as Aglyconesc

451 176 105

50 UK Males Aged 27–57 Yearsb Estimated as Conjugates 30–2200 1058 23 670 205 9

Estimated as Aglyconesc

598 335 103

58 89 17 26 0.13 6 170

160

160

From Ref. 108. From Ref. 113. c Aglycones are estimated approximately by taking rutin as a representative flavonoid and 5-caffeoylquinic acid as a representative hydroxycinnamate and adjusting for the relevant molecular masses. Source: Reprinted from Clifford, M.N., Planta Med., 12, 1103, 2004. With permission. b

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or otherwise of milk to the beverage prior to consumption. This domination by PPT from black tea and coffee indicates the importance also of considering the hydroxycinnamates and derived polyphenols whenever assessing the dietary significance of PPT, and clearly shows the limitations of looking only at flavonols and flavones after hydrolysis no matter how precise per se the data for these aglycones might be. It is important to stress that data for the composition of black tea and coffee beverage reflect exactly what is consumed (with the exception of the dregs left in the cup) since all transformations associated with processing and domestic preparation have already taken place. Moreover, NEODIET publications77 are replete with analytical data from numerous sources for the composition of these beverages (thus better avoiding extreme values associated with any peculiarity of the material analyzed or method of analysis) compared with data for many fruits and vegetables. Accordingly, the estimated consumption figures obtained using this University of Surrey database are likely to be more accurate than would have been the case if solid foods were the major sources of PPT, and data were for raw foods rather than after cooking or processing. This argument applies also to the data for PPT delivered by wines and juices. Using this approach has led us to estimate typical mean intakes of PPT for the two populations so far studied to be in the range 450 to 600 mg calculated as aglycones.

6.4 ABSORPTION OF PPT AND THE NATURE OF THE PLASMA METABOLITES 6.4.1 INTRODUCTION There have been comparatively few human studies using synthetic labeled forms of dietary PPT. In the absence of the comprehensive data that such studies provide, it is difficult to estimate the precise levels of absorption. Generally, estimates have been based on the urinary excretion of recognizable aglycones released after deconjugation with commercial sulfatase/bglucuronidase. A review of 97 bioavailability studies where original data have been recalculated to 50 mg aglycone equivalents found that excretion in urine ranged from 0.3 to 43% of the dose.143 In some but not all studies this would include measurement also of the methylated forms, but data on amino acid conjugates are generally conspicuous by their absence. Generally, there would be no account of material that had been absorbed and excreted in bile, or absorbed after transformation to phenolic acids by the gut microflora, and even when phenolic acids have been fed there has rarely been any attempt to quantify the excretion of glycine or glutamine conjugates. Accordingly such data as are available, and hence used by Manach et al.,143 will be underestimates of the true absorption, but it is impossible to judge by what amount. On present data,143 gallic acid and isoflavones are the most well absorbed dietary PPT, though neither are major components of the European diet. Flavanols, flavanones, and flavonol glycosides are intermediate, whereas proanthocyanidins, flavanol gallates, and anthocyanins are least well absorbed. Data for other classes are either nonexistent or inadequate — lack of data for chlorogenic acids and derived polyphenols, major contributors to total PPT intake, is a serious gap in our knowledge. The number of volunteers studied has generally been small (rarely more than ten), thus giving little insight into the between-person variation (whether phenotypic or genotypic), and very few studies have investigated the effects of repeat dosing at typical dietary levels which is how many PPT-rich commodities are consumed. All of these shortcomings must be addressed in future studies. Although little studied, it is clear that the absorption of dietary PPT may be influenced by the matrix in which they are consumed, with enhanced excretion in urine of easily recognized mammalian conjugates observed when presented in foods with a higher fat content.144–148 In contrast, addition of milk to tea does not significantly affect absorption of either flavanols149 or flavonols150 despite suggestions that it might.46 Alcohol seems not to affect the

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absorption of (þ)-catechin,151–153 resveratrol or quercetin aglycones,152,153 or malvidin-3glucoside from red wine,152 but hastens (þ)-catechin clearance from the plasma compartment either by more rapid excretion or more extensive methylation.151 Extensive studies in humans and animals have indicated that some PPT can be absorbed in the small intestine, for example, certain cinnamate conjugates,154,155 flavanols156 (that occur naturally as aglycones), and quercetin-3-glucoside and quercetin-4’-glucoside.157–159 In contrast, quercetin, quercetin-3-galactoside, quercetin-3-rutinoside (rutin), naringenin-7glucoside, genistein-7-glucoside, and cyanidin-3,5-diglucoside seem not to be.159,160 Mechanisms of absorption have not been completely elucidated but involve inter alia interaction of certain glucosides with the active sugar transporter (SGLT1) and lumenal lactase–phloridzin hydrolase, passive diffusion of the more hydrophobic aglycones, or absorption of the glucoside and interaction with cytosolic b-glucosidase. Although varying with PPT subclass and matrix, when expressed relative to the total intake of PPT, only some 5 to 10% of the amount consumed is absorbed at this site. The major part of that absorbed in the duodenum (not less than 90 to 95% for every substance so far studied) enters the circulation as mammalian conjugates produced by a combination of methylation, sulfate conjugation, glucuronide conjugation plus glycine conjugation in the case of phenolic acids.91 Only a very small amount of the total PPT consumed, maximally 5 to 10%, enters the plasma as unchanged plant phenols. The 90 to 95% of the total PPT ingested, plus any mammalian glucuronides excreted through the bile, pass to the colon where they are metabolized by the gut microflora. Transformations may be extensive, and include the removal of sugars, removal of phenolic hydroxyls, fission of aromatic rings, hydrogenation, and metabolism to carbon dioxide, possibly via oxaloacetate.161 A substantial range of microbial metabolites has been identified, including phenols and aromatic acids, phenolic acids, or lactones possessing 0, 1, or 2 phenolic hydroxyls and up to five carbons in the side chain.162–189 Many of these metabolites arise from flavonoids and nonflavonoids, requiring a broader approach. Certain Eubacterium spp. and Peptostreptococcus spp. are able to convert plant lignans to mammalian lignans.190 Eubacterium is of particular interest since this species not only metabolizes dietary (poly)phenols,183–185,187,190–194 but also produces butyrate,195 a preferred energy source for colonic epithelial cells thought to play an important role in maintaining colon health in humans. Butyrate encourages differentiation of cultured colon cells and through PPARg activation decreases absorption by the paracellular route.196 Clostridium orbiscindens, a somewhat atypical member of the genus, is also of interest for its ability to metabolize flavonoids.186,197 The yield of phenolic or aromatic acids is variable (up to ten times) between individuals, and for some individuals can vary with substrate,198 but can be substantial (up to 50%) relative to the intake of PPT substrates.167,169,177–180,188,199,200 There is evidence from cell culture studies that some of the aromatic or phenolic acids, e.g., benzoic, salicylic, m-coumaric, p-coumaric, ferulic, 3-hydroxyphenylpropionic, and 3,4dihydroxyphenylpropionic, are transported actively by the monocarboxylate transporter MCT1,201–206 but gallic acid and intact 5-caffeoylquinic acid are not. These latter acids may enter by the paracellular route,207,208 but absorption by this route is thought to be inhibited by butyrate enhancing PPARg activation.196 In vitro, green tea flavanols inhibit the active transport of phenolic acids by MCT1, but the significance in vivo of this observation is uncertain.209 Although these acids occur in the plasma primarily as mammalian conjugates some reports suggest that a variable portion may be present in the free form.155,210 Table 6.2 summarizes in a semiquantitative manner, so far as current knowledge allows, the fate of a ‘‘typical’’ daily consumption of some 450 to 600 mg of PPT (calculated as aglycones) previously defined in Table 6.1. There have been significant advances in our knowledge of the PPT-derived metabolites that occur in plasma, i.e., identity of conjugating species, position(s) of conjugation, and

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TABLE 6.2 Fate of Ingested PPT Aglycones (mg) Estimated mean daily consumption (mg/day)(from Table 6.1) . ~5 to 10% of intake absorbed in duodenum and excreted in urine. Of this . 5 to 10% unchanged plant (poly)phenols, and . 90 to 95% mammalian conjugates . ~90 to 95% fermented in colon (unabsorbed PPT þ enteric and entero-hepatic cycling of glucuronides, etc.) .  Poorly defined and very variable portion (5 to 50%?) absorbed depending on individual’s flora and substrates. Mainly mammalian conjugates of microbial metabolites

450–600 22–60 60%) by more than one flavanol at the concentration of 10 mM. In addition, whereas the b-adrenoceptor is inhibited by epicatechin and its 3’-deoxy analog, 5HT1 appears more sensitive to 4,8procyanidin dimers. The origin of specific flavonoid–protein interactions may be traced to the structural resemblance between some properly substituted flavonoids and a variety of bioactive compounds including coenzymes (e.g., nucleotides), steroid hormones, and neurotransmitters (e.g., catecholamines) (Figure 9.5). An unexpected case of specific flavonoid–protein binding occurring in vivo can be found in the vacuoles of some flower OH OH C

A

D

HO

NHCH3

B HO

HO

(R)-Epinephrine (adrenalin)

Estradiol

NH2 N

O

O − O

P O

O −

O

P O

N

O

−

P O

O

N

N

O

−

Adenosine-5⬘-triphosphate (ATP)

OH

OH

FIGURE 9.5 Structures of biologically important molecules with a formal structural resemblance to flavonoids.

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petals (e.g., lisianthus and carnation) where specific anthocyanins are sequestered within protein matrices.16 In purple lisianthus, for instance, four minor acylated anthocyanin-3,5diglycosides are tightly bound (noncovalent association) to a protein aggregate including three major components (MW 34 to 50 kDa) whereas their more abundant triglycoside analogs remain in solution.

9.2 EXAMPLES OF FLAVONOID–PROTEIN INTERACTIONS IN MAN 9.2.1 INTERACTIONS PRIOR

TO INTESTINAL

ABSORPTION

9.2.1.1 Interactions with Salivary Proteins and Astringency The interaction of tannins (oligomeric procyanidins) with salivary proteins is a key step in the development of the oral sensation of dryness and roughness called astringency, which is typical of tannin-rich food. Basic salivary proteins are proline-rich proteins (25 to 42%) that can bind and precipitate polyphenols. They comprise a typical 19-residue sequence that is essentially constituted of proline, glutamine, and glycine residues. This sequence is repeated 5 to 15 times to form proteins of ~150 residues that display extended conformations with multiple binding sites for polyphenols.10 Polyphenol–salivary protein interactions are especially significant with procyanidins (condensed tannins) and galloylated derivatives of Dglucose (hydrolyzable tannins) that possess several 1,2-dihydroxy- or 1,2,3-trihydroxybenzene nuclei allowing multiple interactions with the protein. When the polyphenol concentration is increased to provide sufficient coating of the protein, interactions of the polyphenol molecules (probably under their self-associated form) with a second protein molecule lead to extensive aggregation to form colloidal particles of different sizes. Ultimately, precipitation occurs. Detailed investigations by nuclear magnetic resonance4,5,10,11,17 using the typical prolinerich sequences (~20 residues including seven to eight Pro residues) have provided an outline of the main characteristics of the binding: – The proline residues themselves are privileged sites for interactions with the phenolic nuclei. For instance, b-1,2,3,4,6-penta-O-galloyl-D-glucose (PGG) is able to stack one of its galloyl units on the most accessible face of the pyrrolidine heterocycle (that presenting the Ca–H group). The interaction is essentially driven by dispersion forces and the hydrophobic effect with the possible participation of H bonds between some phenolic OH groups (donors) and the O atom of the tertiary amide group linking the Pro residue to the preceding residue. – The size of the binding site is restricted to a proline residue for small polyphenols (propylgallate, flavanol monomers) only. As the polyphenol size increases, the number of binding sites is reduced. For instance, up to seven to eight epigallocatechin-3O-gallate (EGCG) molecules (one per Pro residue) can be simultaneously bound to the 19-mer peptide (pH 3.8, 278C, 10% DMSO). By contrast, the stoichiometry of the peptide–PGG complex is 1:2. – Multidentate binding of the polyphenol is important for the formation of stable complexes. Indeed, taking into account polyphenol self-association and assuming identical peptide binding sites (probably, a crude approximation), dissociation constants can be estimated from binding isotherms expressing the chemical shift changes of sensitive peptide proton signals as a function of the polyphenol concentration. Kd values are 0.05, 2.4, 5.0, and 0.05 mM for PGG, EGCG, epicatechin, and its 4,8-b dimer (procyanidin B2), respectively (pH 3.8, 38C, 10% dimethyl sulfoxide [DMSO], except for epicatechin [no DMSO]).

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– Cooperativity between peptide binding sites may be important. Thus, the affinity of EGCG for the 19-mer peptide (eight Pro residues) is ~50 times as strong as for a 7-mer peptide with only one to two binding site(s) for EGCG. Similarly, complexation with a full-length basic salivary protein is also much stronger than with the peptide models.18 Hence, it may be proposed that salivary proteins wrap around the polyphenol molecules to allow multiple interactions. However, since proline residues provide rigidity to the protein backbone, this process is expected to take place with little loss in rotational freedom and little change in the extended conformation of the peptide. – From the concentration dependence of the polyphenol chemical shifts as a function of the polyphenol concentration in the absence and presence of peptide, it is clear that polyphenol self-association is only weakly affected by the peptide. Thus, peptide– polyphenol binding probably involves noncovalent polyphenol oligomers that are more effective than the corresponding monomers at developing interactions with a second peptide molecule to trigger precipitation. – Polyphenol–salivary protein interaction is essentially pH independent in the range 3.8 to 6.0 whereas the extent of precipitation is higher and the particle sizes larger at higher pH. Indeed, at higher pH, the net charge of the peptide moieties must be lower, thus favoring aggregation. On the other hand, at the highest pH values, partial autoxidation of EGCG may take place during the 24-h incubation of the polyphenol with the protein, thus providing electrophilic o-quinone intermediates that may couple to the nucleophilic residues of the protein. Hence, it cannot be excluded that the formation of covalent polyphenol–protein linkages is partially responsible for the increased aggregation at higher pH. The influence of procyanidin structure on the extent of salivary protein precipitation has also been studied by light scattering techniques.19 Factors favoring precipitation are: catechin moieties rather than epicatechin moieties; the presence of 3-O-galloyl residues; a higher degree of polymerization; and 4,8-interflavan linkages rather than 4,6-interflavan linkages. However, it must be kept in mind that the extent of precipitation may not be a faithful reflection of the polyphenol–protein affinity in solution (see above). Despite their very short sequence (7 to 38 amino acid residues for the 12 histatins identified so far), the histidine-rich salivary protein histatins have also been reported to precipitate tannins, eventually more efficiently than proline-rich proteins, especially at neutral pH and high tannin concentration.20,21 A detailed NMR analysis of the binding between EGCG and histatin 5, a 24-mer that is very rich in basic His, Lys, and Arg residues (~60%) and devoid of secondary structure, has revealed noncooperative binding of six to seven flavanol molecules with a dissociation constant of 1 mM (pH 3.0, 258C).22 9.2.1.2

Interactions in the Gastrointestinal Tract

The formation of insoluble tannin–dietary protein complexes and inhibition of digestive enzymes by tannins have been investigated for a long time for their implications in the low digestibility of nutrients in animals.23 However, data on the structure and stability of the corresponding complexes seem scarce. In addition, the interactions of flavonoids other than tannins with dietary proteins and their possible consequences on flavonoid bioavailability and antioxidant activity in the gastrointestinal tract are essentially not documented. Regarding digestive enzymes, some properly hydroxylated flavone and flavonol aglycones (e.g., quercetin) have been reported to inhibit the protease trypsin with IC50 values in the range 10 to 60 mM.24

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9.2.2 INTERACTIONS INVOLVED

IN

FLAVONOID BIOAVAILABILITY

9.2.2.1 Intestinal Absorption After tannins, flavonoid glycosides are by far the most common dietary sources of flavonoids. However, intestinal absorption requires prior deglycosylation. This step, which does not take place in the gastric compartment, occurs in the large intestine as a result of microbial metabolism.25 In addition, some flavonoid glucosides can be absorbed directly from the small intestine upon deglucosylation by the enzyme lactase phlorizin hydrolase (LPH) and subsequent passive diffusion of the aglycones through the enterocyte layer (route 1). However, a minor route (route 2) could also consist in active transport of the glucosides through the sodium-dependent intestinal D-glucose carrier SGLT1 and subsequent deglucosylation by cytosolic b-glucosidase. Using inhibitors of LPH and SGLT1, it was demonstrated that route 1 is the sole absorption mechanism for quercetin-3-glucoside (Q3Glc) whereas route 2 could contribute to the absorption of quercetin-4’-glucoside (Q4’Glc).26 Hydrolysis of flavonoid glucosides by LPH has been studied in detail. This enzyme, which is present on the luminal side of the brush border of the small intestine, primarily catalyzes the hydrolysis of lactose. However, LPH also displays a second site for the hydrolysis of more lipophilic substrates such as the dihydrochalcone glucoside phlorizin. Selective inhibition of the phlorizin site only marginally affects the efficiency of LPH at hydrolyzing Q3Glc and Q4’Glc, thus demonstrating that deglucosylation mainly occurs at the lactase site.27 Q3Glc and Q4’Glc have similar Km (40 to 50 mM) and kcat values and are more rapidly hydrolyzed than isoflavone glucosides. The ability of extracts of human small intestine and liver to hydrolyze flavonoid glucosides (likely due to the cytosolic broad-specificity b-glucoside) was also investigated.28 The flavonol Q4’Glc and the isoflavone genistein 7-glucoside are hydrolyzed with similar efficiencies by both tissues with apparent Km values of 32 and 14 mM, respectively. By contrast, Q3Glc, quercetin-3,4’-diglucoside, kaempferol-3-glucoside, and rutin (Q-3-b-D-Glc-1,6-a-L-Rha) are not hydrolyzed (with the exception of a small proportion of Q3Glc with the small intestine extract). Hence, in the flavonol family, a Glc moiety at the 4’ position and a free OH group at the 3 position seem required for activity. The fraction of flavonoids that reaches the colon can be extensively metabolized by microflora enzymes. This may be an important step in flavonoid bioavailability, especially for flavonoids that are essentially not absorbed from the small intestine such as the oligomeric procyanidins.29 Flavonoid glycosides (native forms) and glucuronides (excreted in the bile) can be hydrolyzed to the corresponding aglycones and further processed into phenolic acids.25,30,31 Both the flavonoid aglycones and their phenolic acid derivatives can then be absorbed from the colon. In fact, phenolic acids and their glucuronides are detected in much larger concentration in blood and urine than the conjugates of the flavonoid aglycones themselves, thus raising the possibility that the cleavage products are relevant active forms in vivo.31,32 However, no detailed biochemical information (enzyme identification and isolation for the determination of structure–activity relationships, Km values, etc.) is currently available about the degradation of flavonoids by microflora enzymes. 9.2.2.2 Conjugation Enzymes The detection of sulfates and glucuronides of quercetin and 3’-O-methylquercetin in the plasma of volunteers having absorbed a flavonol-rich meal33 has prompted detailed investigations of quercetin metabolism in the enterocyte and liver. By recording the formation of the different quercetin glucuronides (QGlcU) from quercetin and UDP-glucuronic acid in the presence of human liver cell-free extract, it was shown that conjugation on the B ring (positions 3’ and 4’) takes place with low Km values (0.5 to 1 mM), which suggest a high

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affinity of quercetin for the corresponding isoforms of liver UDP-glucuronyl transferase.34 Although quercetin has a lower affinity for isoforms catalyzing conjugation at the 7 position (together with marginal conjugation at the 3 position), the Vmax value is higher. Hence, at high quercetin concentration, glucuronidation at the 7 position may be predominant. Alternatively, quercetin and other flavonols have been shown to be substrates of purified isoforms of UDP-glucuronyl transferase.35,36 Using human liver cell-free extracts, it was also possible to demonstrate that quercetin glucuronides undergo further metabolism in the liver.37 For instance, deconjugation to free quercetin takes place rapidly and is as efficient for each of the four glucuronides tested (positions 3, 3’, 4’, and 7). These results are in agreement with a preliminary investigation with human cell extracts from liver, small intestine, and neutrophils.38 In addition, a detailed kinetic analysis with pure b-glucuronidase showed that Q4’GlcU (Km ¼ 48 mM) displays more affinity for the enzyme than its 3 and 7 regioisomers (Km ¼ 167 and 237 mM, respectively) although deconjugation at the 3 position is faster based on the kcat/Km values. Hence, net glucuronidation of dietary flavonols in the liver could be the result of a balance between the activity of UDP-glucuronyl transferase and b-glucuronidase that would be normally shifted toward the former. Since conjugation dramatically alters the antioxidant activity of flavonoids and their interactions with proteins,33,34 their eventual deconjugation could be of great importance in the development of flavonoid-mediated health effects. Using intact hepatocytes, methylation of Q3GlcU and Q7GlcU at the 3’ and 4’ positions as a result of catalysis by catechol O-methyltransferase and formation of quercetin 3’-sulfate (following initial deglucuronidation) were also observed.37 By contrast, Q4’GlcU is not metabolized under the same conditions. 9.2.2.3

Plasma Proteins

The absorption bands of flavonol conjugates detected in the plasma of rats fed quercetin or rutin are bathochromically shifted in comparison to typical flavonol absorption bands.39 A similar phenomenon can be reproduced by adding serum albumin (SA) to flavonol solutions, thus suggesting that the circulating flavonols are bound to SA. Since then, several studies have investigated flavonol–albumin complexation. For instance, the human SA (HSA)–quercetin binding constant (high-affinity site) has been evaluated at physiological pH by circular dichroism (14.6 + 2.1
103 M1, 378C), ultracentrifugation (267 + 33
103 M1, 208C), and fluorescence (50 + 8
103 M1, 258C).40–43 These values reflect the moderate affinity of quercetin for albumin in line with similar observations for a variety of drugs and xenobiotics.44 On the other hand, the sole flavonols that can be detected in plasma after a meal rich in quercetin or rutin are glucuronides and sulfoglucuronides of quercetin and 3’-O-methylquercetin.33 Hence, investigating the binding of quercetin conjugates (or models of quercetin conjugates), rather than that of quercetin itself, is more biologically relevant. To that purpose, the influence of quercetin methylation, glycosidation, and sulfation on albumin binding has been assessed.42,43 (Table 9.1). Quercetin-7-O-sulfate retains a high affinity for BSA and HSA whereas additional sulfation of 4’-OH markedly weakens the binding to both albumins. Glycosidation and sulfation of 3-OH, methylation of 3’-OH (isorhamnetin), and deletion of 3’-OH (kaempferol) all significantly lower the affinity to BSA, the binding to HSA being much less affected. These observations outline the importance of a free OH at position 3’ for a strong binding to BSA. Luteolin (no 3-OH) is as efficient as quercetin in binding BSA but not HSA. The influence of glycosyl and acyl substituents is also reflected in the large differences in affinity to BSA displayed by chrysin (strong binding competitively to quercetin), chrysin-7-O-b-D-glucoside and p-methoxycinnamic acid methyl ester (weak binding), and chrysin-7-O-(6-O-p-methoxycinnamoyl)-b-D-glucoside (strong binding noncompetitively to quercetin).45

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TABLE 9.1 Binding Constants (K) for Flavonoid–Serum Albumin Complexes (1:1 Stoichiometry), pH 7.4 Phosphate–NaCl Buffer, 258C K + SD (3103 M21)

Flavonoida BSA

HSA

Quercetin Quercetin-7-O-sulfate Quercetin-3-O-sulfate Quercetin-4’,7-O-disulfate 3’-O-Methylquercetin Quercetin-3-O-b-D-Glc Rutin Kaempferol Luteolin Luteolin-7-O-b-D-Glc

134 + 6b 143 + 29 21 + 2 25 + 2 24 + 1d 13 + 4d 11 + 7d 12 + 1d 143 + 35 N/A

50 + 8c 87 + 23 58 + 5 6 + 1d N/A 16 + 1 — 129 + 13d 14 + 3 N/A

Flavonoide 4’-O-Methylquercetin Diosmetin Baicalein Baicalein-7-O-b-D-GlcU Genistein Naringenin Catechin

51 + 2d 66 + 2 148 + 2d 78 + 1d 30 + 1 49 + 1 N/A

75 + 3d 53 + 1 74 + 4 117 + 4 11 + 1 3+1 N/A

a

Flavonoids forming fluorescent complexes. SD: standard deviation from four experiments. c From triplicates. d From duplicates. Otherwise SD from curve fitting. e Assuming competitive binding with quercetin (fluorescent indicator). N/A, not applicable. b

While nonfluorescent in its free state, SA-bound quercetin is strongly fluorescent in the visible range. Hence, quercetin can be used as a fluorescent probe for investigating the binding of flavonoids that are nonfluorescent in both their free and SA-bound states such as flavones and flavonols lacking a free 4’-OH, flavanones, and isoflavones42,43 (Table 9.1). Assuming competitive binding, it can be noticed that methylation of 4’-OH (quercetin vs. tamarixetin, luteolin vs. diosmetin) decreases the BSA binding constants by a factor 2 to 3. By contrast, the affinity for HSA of tamarixetin (4’-O-methylquercetin), identified as a quercetin metabolite in bile and urine, remains high. Baicalein (5,6,7-trihydroxyflavone) and its 7-O-b-D-glucuronide (baicalin) are tightly bound to both albumins. Thus, the relatively bulky glucuronyl moiety that is typical of most flavonoid conjugates does not hamper the binding in this case. The isoflavone genistein appears as a poor albumin ligand. The lack of conjugation or a nonplanar C ring in the flavanone naringenin may be responsible for its relatively low affinity for both albumins, especially HSA. These structural characteristics are even more pronounced in the flavanol catechin, which actually does not affect the fluorescence of albumin-bound quercetin, thus suggesting either no affinity for albumin or binding to a totally independent site. Despite its moderate intensity (binding constants K in the range 104 to 105 M1), the interaction between albumin and flavones and flavonols is strong enough to ensure a

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quasi-total complexation of the circulating forms, owing to the respective concentrations of the partners (0.1 to 1 mM for the circulating forms, 0.6 mM for serum albumin). Hence, it may be reasonably proposed that flavonols and flavones circulate as albumin complexes rather than in their free form. Additional investigations aimed at demonstrating specific binding to a particular SA site have been carried out. Displacement studies with known site markers (dansylasparagine and warfarin for subdomain IIA, ibuprofen and diazepam for subdomain IIIA)43 are in agreement with preliminary results41: the quercetin high-affinity binding site appears to be located in subdomain IIA for both HSA and BSA. In the case of HSA, the quercetin binding cavity in subdomain IIA is large enough to accommodate additional ligands such as salicylate40 and warfarin.41,43 Furthermore, this site, which is known to bind a large variety of xenobiotics, is lined by positively charged basic residues (Lys, Arg) and nonpolar residues (Tyr, Trp, Leu), in agreement with a complexation driven by dispersion interactions, the hydrophobic effect, and, possibly, attractive coulombic interactions involving partially dissociated flavonol molecules. Finally, flavonoid–albumin binding is noncompetitive to that of fatty acids.40 Interactions with other plasma proteins are still poorly documented. Weak binding of quercetin with a1-glycoprotein has been reported.41 Moreover, when a sample of human plasma is eluted on an EGCG-linked sepharose column, the sole proteins that are retained are fibronectin, fibrinogen, and histidine-rich glycoprotein.46 Binding of EGCG to each of these plasma proteins was confirmed using dot binding assays on nitrocellulose sheets. In addition, the binding was shown to be restricted to flavanols having a 3-O-galloyl moiety. Interaction of catechin with the protein component (Apo A-1) of high-density lipoproteins has also been proposed from gel electrophoresis experiments and comparison with molecular mass markers.47

9.2.3 INTERACTIONS POTENTIALLY INVOLVED 9.2.3.1

IN

CELLULAR HEALTH EFFECTS

ATP-Binding Proteins

Flavonoids are known to inhibit the function of many ATP-binding proteins,6,7 such as mitochondrial ATPase, myosin, Na/K and Ca plasma membrane ATPases, protein kinases, topoisomerase II, and multidrug resistance (MDR) proteins. In general, inhibition takes place through binding of the flavonoids to the ATP-binding site. Only two cases relevant to the inhibition of carcinogenesis by flavonoids48,49 will be discussed in detail. 9.2.3.1.1 Kinases Phosphorylation of proteins at OH groups of serine, threonine, and tyrosine residues is an important mechanism of intracellular signal transduction involved in various cellular responses including the regulation of cell growth and proliferation.49,50 The reaction makes use of ATP as a phosphate donor and is catalyzed by protein kinases. For instance, growth factor hormones bind to extracellular domains of large transmembrane receptors that display a tyrosine kinase moiety in their intracellular portion. As a consequence of hormone–receptor binding, the receptor dimerizes and becomes active in the phosphorylation of proteins close to the membrane, thereby triggering a large number of signaling pathways themselves involving other PKs, such as PKC, a Ser/Thr PK, and mitogen-activated PKs (MAPKs). On the other hand, each phase of the cell cycle, during which the DNA is replicated and the chromosomes built and then separated, is characterized by intense bursts of phosphorylation controlled by highly regulated kinases called cyclin-dependent kinases (CDKs). A possible mechanism for the potential anticarcinogenic effects of flavonoids could be their ability to inhibit various PKs (demonstrated with purified enzymes or cell extracts). For

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instance, the isoflavone genistein has been shown to inhibit the epidermal growth factor (EGF) receptor in the submicromolar range by competing with ATP for its binding site.51 Similarly, butein (2’,3,4,4’-tetrahydroxychalcone) appears as a specific inhibitor of tyrosine kinases (IC50 for EGF receptor ¼ 65 mM) acting competitively to ATP and noncompetitively to the phosphate acceptor and having no affinity for Ser/Thr PKs such as PKC and the cAMP-dependent PKA.52 However, structural changes may affect both the selectivity toward different kinases and the binding site. For instance, silymarin, a flavanonol analog, was suggested to bind to the hormone-binding site in competition with EGF.53 Recently, PKC was shown to be efficiently inhibited by flavones and flavonols having a 3’,4’-dihydroxy substitution on the B ring (efficient concentrations 50 in the range 1 to 10 mM).54,55 Hydrogen bonding between these two OH groups and the enzyme seems a key determinant of the complexation that takes place in the ATP-binding site, in competition with the cofactor. Similar structure–activity relationships were also established in the inhibition by flavonoids of phosphoinositide 3-kinase (PI3-K), a lipid kinase catalyzing phosphorylation of inositol lipids at the D3 position of the inositol ring to form new intracellular lipid second messengers.55 Flavonoids were also demonstrated to inhibit CDKs.56 Consistently, studies with intact cells have shown that various flavonoids can cause cell cycle arrest in correlation to their ability to inhibit CDKs.53,57 Flavonoids can also modulate the activity of MAPKs as a possible mechanism for their potential antineurodegenerative action58,59 and protection against autoimmune, allergic, and cardiovascular diseases.60,61 For instance, investigations on intact antigen-presenting dendritic cells have shown that the MAP kinases involved in cell maturation (ERK, p38 kinase, JNK) can be activated by bacterial lipopolysaccharide and that this activation is strongly inhibited by pretreatment of the cells by EGCG.61 However, no evidence is provided that the mechanism actually proceeds via direct EGCG–MAPK inhibition. Interestingly, quercetin3-O-glucuronide (Q3GlcU), a quercetin metabolite, is more specific than quercetin in inhibiting the activity of MAP kinases in vascular smooth muscle cells.60 Indeed, pretreatment of the cells with Q3GlcU selectively prevents the activation of c-Jun N terminal kinase (JNK) by angiotensin II. Since JNK is responsible for c-Jun phosphorylation that produces a component of transcription factor AP-1, its inhibition blocks AP-1-mediated gene expression, which is involved in the growth of vascular smooth muscle cells. Once more, the molecular mechanism underlying the effect of the flavonoid remains unclear. Indeed, angiotensin-II-mediated JNK activation may be due to ROS produced by NADH/NADPH oxidase. Hence, its inhibition may be a combination of antioxidant action (electron transfer to ROS) and flavonoid–protein interaction (e.g., direct inhibition of JNK or NADH/NADPH oxidase). As a recent example of progress made in elucidating the molecular mechanisms by which flavonoids regulate gene expression, it has been shown that the potent inhibition by luteolin of the lipopolysaccharide-activated transcriptional activity of the nuclear factor kB in rat fibroblasts does not proceed by inhibition of the release of NFkB from its cytoplasmic complex with inhibitor IkB nor by its translocation into the nucleus and subsequent binding to DNA.62 In fact, luteolin activates the PKA pathway, thereby stimulating the production of phosphorylated proteins that will compete with NFkB for coactivator CBP. The mechanism of the luteolin-mediated PKA activation is not elucidated yet although modulation of cAMP level via inhibition of cAMP phosphodiesterase by luteolin is suggested. Pretreatment of neurons by flavonoids (epicatechin and its 3’-O-methylether, kaempferol) strongly inhibits cell death induced by oxidized low-density lipoproteins (ox-LDL) without reduction of ox-LDL uptake or intracellular oxidative stress.59 Cell protection is selectively correlated to inactivation of JNK, thus suggesting that, irrespective of their H-atom donating activity, flavonoids can selectively attenuate a pro-apoptotic signaling cascade involving MAPKs.

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9.2.3.1.2 Multidrug Resistance Proteins Cancer cells typically overexpress ATP-dependent transmembrane transporters capable of expelling a wide variety of chemically unrelated drugs used in cancer therapy. This phenomenon is known as multidrug resistance (MDR). Inhibition of MDR proteins, such as the Pglycoprotein (Pgp), to prevent drug efflux during cancer therapy has thus potential clinical value. Quercetin was shown to efficiently inhibit the Pgp-mediated drug efflux by inhibiting the ATPase activity required for transport.63 From investigations using a soluble cytosolic portion of mouse Pgp, which includes the nucleotide- and drug-binding domains, it was possible to monitor flavonoid binding by fluorescence as well as its influence on ATP binding and the efflux of the anticancer steroid drug RU 486.64 Flavones (aglycones) bearing OH groups at positions 3 and 5 come up as efficient mouse Pgp ligands with apparent dissociation constants lower than 10 mM. By contrast, the quercetin glycoside rutin, the flavanone naringenin, and the isoflavone genistein have low affinity for Pgp. Interestingly, flavones and flavonols behave as bifunctional inhibitors whose binding site overlap the vicinal binding sites for both ATP and RU 486. Those trends were confirmed using a cytosolic portion of Pgp from the parasite Leishmania tropica.65 In the presence of the most efficient Pgp inhibitors, the drug daunomycin was shown to accumulate in resistant parasites and inhibit their growth. Interestingly, the presence of a 1,1-dimethylallyl substituent at position 8 of the flavone nucleus markedly increases the affinity for Pgp (a factor ~20 for apigenin and kaempferide) with apparent dissociation constants of ~1 mM. These observations prompted the search for more active amphiphilic flavonoids bearing saturated or unsaturated (prenyl, geranyl) hydrocarbon chains.66,67 For instance, 4-n-octyloxy-2’,4’,6’-trihydroxychalcone displays an optimized affinity for mouse Pgp with a dissociation constant of 20 nM. The interaction of flavonoids with MDR proteins is of interest not only in the field of cancer prevention and therapy but also in the field of flavonoid bioavailability. Indeed, using specific inhibitors of MDR proteins, it was shown that multiresistant protein 2 (MRP2), but not Pgp, is involved in the efflux of quercetin conjugates from human hepatic cells.37 Similar observations were made with the cell line Caco-2 (a popular model for human intestinal absorption) where MRP2 was found responsible for the efficient efflux of chrysin after its conjugation into a mixture of glucuronide and sulfate.68 9.2.3.2

Ligand–Receptor Interactions

9.2.3.2.1 Estrogen Receptors Estrogen hormones influence the growth, differentiation, and functioning of many tissues from the male and female reproductive systems. They also have cardioprotective effects. Some dietary flavonoids, especially the isoflavone genistein, belong to the phytoestrogen family as they tightly bind both estrogen receptors (ER) a and b and trigger gene activation as full agonists.69 This effect could provide a basis for interpreting the inverse relation between the risk of prostate and breast cancers and the intake of isoflavone-rich soy foods that has been put forward by epidemiological studies. The affinity of genistein (4’,5,7-trihydroxyisoflavone) for ERa and ERb is 0.7 and 13% of that for the endogenous ligand 17b-estradiol, respectively.69 Hence, the corresponding dissociation constants can be calculated to be as low as 7 nM (ERa) and 0.6 nM (ERb). The high affinity of isoflavones for ERa and ERb can be interpreted by the isoflavones A and C rings mimicking the estrogen A and B rings. The binding of apigenin (4’,5,7-trihydroxyflavone) and kaempferol (3,4’,5,7-tetrahydroxyflavone) to ERb is six to seven times weaker than that of genistein. Moreover, deletion of the 5-OH phenolic group of genistein to give daidzein weakens the binding by a factor 3 to 4 and 13 for ERa and ERb, respectively. In comparison

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to their aglycones, daidzein and genistein glucuronides have an affinity for the ERb that is reduced by a factor 10 and 40, respectively.70 Nonetheless, given the relatively high peak serum concentrations of total daidzein and genistein (0.5 to 1 mM) reached after consumption of soy food, isoflavone glucuronide–ERb binding appears strong enough to be of biological significance. Like 17b-estradiol binding, genistein binding promotes dimerization of the receptor and subsequent binding to DNA at the estrogen receptor element,71 thereby inducing gene activation. The estrogenic potency of genistein on ERa and ERb is 0.025 and 0.8% that of 17b-estradiol, respectively.69 9.2.3.2.2 GABA-A Receptor g-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. GABA-A receptors are pentameric trans-membrane proteins having a central chloride ion channel. The chloride flux can be regulated by a variety of neuroactive ligands including flavones that are able to bind to the benzodiazepine (BDZ) binding site at the interface between a and g subunits. Flavones typically behave as partial agonists potentiating the GABA-activated ion current in a sub-maximal manner.72 As such, they are potential anxiolytic agents. Naturally occurring flavones typically bind to the BDZ receptor with moderate affinity (Ki in the range 1 to 100 mM) and have been selected as leads for structure–affinity relationship studies including numerous synthetic flavonoid analogs. Hence, the introduction of methyl and nitro groups as well as halogen atoms on the A and B rings has emerged as a powerful way to increase the flavonoid–receptor interaction. For instance, 6-methyl-3’,5-dinitroflavone binds with a record Ki value of 1.9 nM.73 Moreover, recent investigations74 have highlighted that some naturally occurring 2’-hydroxyflavones can approach such an affinity (Ki ¼ 6.1 nM for 5,7,2’-trihydroxy-6,8-dimethoxyflavone extracted from a Chinese medicinal herb). It has been proposed that the critical interactions between a flavonoid ligand and the BDZ receptor include hydrogen bonding at the C ring oxygen atoms and hydrophobic interactions (possibly p-stacking interactions involving aromatic amino acid residues) developed by the A and B rings.72,73 Since flavonoids are able to bind to the BDZ binding site of the GABA-A receptor, they might well interact with the BDZ binding site of the mitochondrial permeability transition protein, thereby modulating oxidative stress-induced apoptosis.58 9.2.3.2.3 Adenosine Receptors Adenosine receptors (subtypes A1, A2A, A2B, and A3) play a role in brain and heart protection as well as in the modulation of the immune and inflammatory systems. Hence, adenosine antagonists have potential pharmacological value. Interestingly, several flavone and flavonol aglycones have rather high affinities for adenosine receptors.75 In addition, varying the substitution of the flavone nucleus by OH and OR groups (R ¼ Me, Et, nPr) can produce fairly selective A3 ligands with Ki values of the order of 1 mM (close to that of the natural ligand adenosine). Alkylation of the OH groups typically increases both the affinity and selectivity.76 In a functional A3 receptor assay, the most potent ligands were also shown to reverse inhibition of adenylyl cyclase, thus demonstrating antagonism. 9.2.3.3 Redox Enzymes Lipoxygenases (LOX), cycloxygenases (COXs), and xanthine oxidase (XO) are metalloenzymes whose catalytic cycle involves ROS such as lipid peroxyl radicals, superoxide, and hydrogen peroxide. LOXs and COXs catalyze important steps in the biosynthesis of leucotrienes and prostaglandins from arachidonic acid, which is an important cascade in the development of inflammatory responses. XO catalyzes the ultimate step in purine biosynthesis, the conversion of xanthine into uric acid. XO inhibition is an important issue in the

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treatment of gout. Flavonoids may exert part of their antioxidant and anti-inflammatory activities via direct inhibition of LOXs, COXs, and XO. Typically, interpretation of the inhibition studies are complicated because of the possible combination of distinct inhibition mechanisms: formation of noncovalent enzyme-inhibitor complexes, direct scavenging by flavonoid antioxidants of ROS inside or outside the catalytic pocket (with simultaneous oxidation of the flavonoids), chelation of the enzyme metal centers by the flavonoids, and enzyme inactivation by reactive aryloxyl radicals, quinones, or quinonoid compounds produced upon flavonoid oxidation that may eventually form covalent adducts with the enzyme. 9.2.3.3.1 Lipoxygenases and Cycloxygenases Mammalian 15-lipoxygenase 1 (15-LOX1) has been proposed as an endogenous pro-oxidant enzyme capable of oxidizing LDLs, an early event in the development of atherosclerosis.77 Hence, its inhibition by flavonoids is a potential mechanism for the prevention of cardiovascular diseases by these antioxidants. Recently, the inhibition by flavonoids of the peroxidation of linoleic acid catalyzed by rabbit reticulocyte 15-LOX1 has been investigated.78 Flavone and flavonol aglycones come up as the most potent inhibitors and affect enzyme activity in three distinct ways: prolongation of the initial lag phase during which the accumulation of lipid hydroperoxides is very slow, lowering of the maximal peroxidation rate during the subsequent phase of hydroperoxide accumulation, and inactivation of the enzyme in a third phase due to the combined action of the flavonoid and intermediates of the catalytic cycle. In addition, the inhibition (assessed as IC50 values from the concentration dependence of the percentage of peroxidation rate decrease during the second phase) is insensitive to the presence of Fe(III) (an observation ruling out iron–flavonoid chelation as a possible inhibition mechanism) and stronger with flavones and flavonols having a catechol group (a critical determinant of radical scavenging efficiency) either on the A ring or on the B ring (most potent inhibitors with IC50 ~1 mM: luteolin, baicalein, fisetin). Overall, a mechanism combining direct inhibition (noncompetitively to linoleic acid) and radical scavenging can be proposed. Interestingly, QGlcU, the main circulating quercetin metabolites, retain the ability to inhibit soybean LOX.34 For instance, Q3’GlcU (Kd ¼ 6.5 mM), Q4’GlcU (Kd ¼ 8.4 mM), and Q7GlcU (Kd ¼ 6.0 mM) display an affinity for the enzyme that is only two to three times as low as that of quercetin (Kd ¼ 2.8 mM), whereas Q3GlcU (Kd ¼ 60 mM) is a much poorer inhibitor. The inhibition of the 15-LOX-induced peroxidation of LDL by quercetin and its 3-, 4’-, and 7-monoglucosides (QGlc) has also been addressed.79 Quercetin, Q7Glc, and Q3Glc, which all possess a catechol group in the B ring, inhibit LDL peroxidation with IC50 values in the range 0.3 to 0.5 mM and efficiently spare endogenous LDL-bound a-tocopherol. By contrast, Q4’Glc, which lacks a free catechol group, is less effective (IC50 ¼ 1.2 mM) and does not spare a-tocopherol. These results suggest that the inhibition of LDL peroxidation by quercetin and its glucosides mainly proceeds via peroxyl radical scavenging and regeneration of a-tocopherol from the corresponding a-tocopheryl radical rather than by direct enzyme inhibition. Interestingly, the percentage of residual flavonol (initial concentration: 1 mM) after 6 h of incubation in the presence of 15-LOX and in the absence of LDL (pH 7.4, 208C) is ~0, 20, 40, and 90% for Q4’Glc, quercetin, Q7Glc, and Q3Glc, respectively. By contrast, in the absence of 15-LOX and in the presence of LDL, only quercetin and Q7Glc are partially consumed (residual flavonol ¼ 60%). This unexpected result shows that 15-LOX can catalyze the autoxidation of quercetin and its monoglucosides in a way that is highly dependent on the site of glucosidation. Finally, in the presence of both 15-LOX and LDL, the flavonols are totally consumed in less than 2 h (with the exception Q3Glc consumed in 4 h) in agreement with an inhibition dominated by redox processes. Quercetin and a selection of naturally occurring prenylated flavonoids used as antiinflammatory agents in Chinese medicine were also tested for their ability to inhibit the

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synthesis of 12- and 5-hydroxyeicosatetraenoic acids from arachidonic acid catalyzed by 12-LOX (from platelets) and 5-LOX (from polymorphonuclear leucocytes), respectively.80 Similarly, quercetin and the prenylated flavonoids were tested for their ability to inhibit the synthesis of thromboxane B2 and prostaglandins E2 and D2 from arachidonic acid catalyzed by COX1 and COX2, respectively. Quercetin appears as a potent inhibitor of 5-LOX (IC50 ¼ 0.8 mM), a more modest inhibitor of 12-LOX (IC50 ¼ 12 mM) and COX1 (IC50 ¼ 8 mM), and a very poor inhibitor of COX2 (IC50 ¼ 76 mM). Interestingly, apigenin is inactive toward all four enzymes. In addition, some chalcones and flavanones having a lavandulyl (5-methyl-2-isopropenyl-hex-4-enyl) group at position 8 (A ring) and a 2’,4’dihydroxy substitution on the B ring are selective inhibitors of 5-LOX and COX1, and inactive toward 12-LOX and COX2. 9.2.3.3.2 Xanthine Oxidase Regarding XO activity and the simultaneous formation of uric acid (from xanthine) and superoxide, flavonoids can act as true enzyme inhibitors (formation of enzyme-inhibitor complexes) thereby quenching both superoxide and uric acid formation or by scavenging superoxide that can be independently recorded using chemiluminescence or colorimetric methods. Hence, it is possible to rank flavonoids in distinct classes81: superoxide scavengers without inhibitory activity on XO, XO inhibitors without additional superoxide scavenging activity (IC50 for uric acid formation  IC50 for superoxide scavenging), XO inhibitors with an additional superoxide scavenging activity (IC50 for uric acid formation > IC50 for superoxide scavenging), XO inhibitors with an additional pro-oxidant effect in superoxide production (IC50 for uric acid formation < IC50 for superoxide scavenging), weak XO inhibitors with an additional pro-oxidant effect in superoxide production, and flavonoids with no effect on XO and superoxide. A planar C ring (flavones, flavonols) seems required for XO inhibition (IC50 in the range 0.5 to 10 mM with the exception of 3-hydroxyflavone, which does not interact with XO). Hence, catechins have pure superoxide scavenging activity and do not interact with XO. Only flavonols with a catechol group on the B ring (quercetin, myricetin, fisetin) display additional superoxide scavenging activity. By contrast, some hydroxylated flavones (chrysin, apigenin, luteolin) show an underlying pro-oxidant activity. Interestingly, glycosidation of the flavonoid nucleus generally abolishes XO inhibition. For instance, the IC50 values of quercetin for XO inhibition and superoxide scavenging are 2.6 and 1.6 mM, respectively. By contrast, quercetin-3-O-rhamnoside (quercitrin) has an IC50 of 8.1 mM for superoxide scavenging but no longer inhibits XO (IC50 > 100 mM). Similarly, Q3GlcU and Q7GlcU are very poor XO inhibitors (Kd  100 mM).34 However, Q3’GlcU (Kd ¼ 1.4 mM) and Q4’GlcU (Kd ¼ 0.25 mM) are strong inhibitors of XO, the latter as potent as quercetin itself. Hence, while glucuronidation at the 3’ or 4’ position suppresses the free catechol moiety of the B ring and thereby most of the radical scavenging activity, the affinity for XO is spared as if flavonol–XO binding took place with marginal participation of the B ring. While epicatechin and its oligomers do not inhibit XO, oligomers of epicatechin-3-Ogallate (4b-8 interflavan linkage) are inhibitors whose potency increases with the number of monomer units (IC50 ¼ 7.2 to 4.4 mM from dimer to tetramer).82 Accordingly, a French maritime pine bark extract (pycnogenol) rich in procyanidins (75% weight, DP 2 to 7) was found to strongly reduce XO activity and retard the electrophoretic mobility of the protein under nondenaturing conditions only.83 In addition, pure low molecular weight components of the extract are without effect. Hence, it can be concluded that XO inhibition proceeds by binding to XO of the high DP procyanidins (DP >3). Moreover, the binding is noncompetitive with respect to the substrate xanthine, abolished by polyethylene glycol or the surfactant Triton X-100 and unaffected by addition of sodium chloride or urea. Hence, it can be proposed that the binding does not take place to the xanthine binding site and primarily

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involves dispersion forces and the hydrophobic effect. In the same work, the activities of catalase (from human erythrocyte), horseradish peroxidase, and soybean lipoxygenase were also shown to be inhibited by the pine bark extract. For catalase at least, this may proceed by procyanidin–protein binding since the electrophoretic mobility of catalase under nondenaturing conditions is also decreased by the extract. Similarly, catechin polymers formed upon horseradish peroxidase-catalyzed oxidation of catechin or polycondensation of catechin with aldehydes prove much more efficient than catechin (at identical monomer concentration) at inhibiting XO and superoxide formation.12,13 A more detailed investigation with the catechin–acetaldehyde polycondensate (which is expected to form in wine because of the microbial oxidation of ethanol to acetaldehyde) shows that inhibition is noncompetitive to xanthine and likely occurs via binding to the FAD or Fe/S redox centers involved in electron transfers from the reduced molybdenum center to dioxygen with simultaneous production of superoxide.13 9.2.3.3.3 Peroxidases and Tyrosinases These enzymes have been used to oxidize flavonoids for investigating the reactivity and potential toxicity of their aryloxyl radicals (one-electron oxidation) and o-quinones (twoelectron oxidation). For instance, 4’-hydroxyflavonoids are quickly converted into aryloxyl radicals that can oxidize glutathione and NADH with concomitant reduction of dioxygen and ROS formation.84–86 This process provides a possible metal-independent mechanism for the pro-oxidant activity of flavonoids. Alternatively, 3’,4’-dihydroxyflavonoids are oxidized into the corresponding semiquinone radicals, which quickly disproportionate. The resulting o-quinones can then be reduced by NADH (hydride ion transfer) or form conjugates with glutathione without dioxygen activation.84,85,87,88 Flavonoid-derived o-quinones can eventually react with Cys residues of proteins to form (reversible) covalent adducts. The latter process provides an original mechanism for the inhibition by quercetin of glutathione S-transferase P1-1,89 an enzyme involved in the defense against electrophiles and in MDR of tumor cells. 9.2.3.3.4 Cytochrome P450 These heme-containing monooxygenases include several isoforms (1A1, 1A2, 1B1, 3A4, etc.) with different tissue distributions and play a key role in the metabolism of endogenous substrates (e.g., steroids) and xenobiotics (food components, drugs, carcinogens, pollutants).8 Although the metabolism of xenobiotics by cytochrome P450 (CYP, phase I enzymes) typically results in more hydrophilic compounds that are more readily excreted after eventual conjugation by phase II enzymes (e.g., UDP glucuronyltransferases, sulfotransferases), toxic reactive intermediates, including free radicals, can be formed. Indeed, CYPs are responsible for the conversion of some procarcinogens (e.g., polyaromatic hydrocarbons or PAHs) into carcinogens (e.g., PAH epoxides). CYP–flavonoid interactions are a good example of the multiple ways flavonoids can affect enzymatic activities, i.e., from the regulation of gene expression to direct binding to the processed enzymes.8 Flavonoids can induce, or eventually inhibit, the biosynthesis of CYP 1A1 via interactions with the aryl hydrocarbon receptor (AhR), a cytosolic protein that, once activated by a ligand, translocates to the nucleus and, in association with the AhR translocator, forms a transcription factor for CYP 1A1. For instance, in human breast cancer cells, quercetin binds to AhR as an agonist (in competition with the typical AhR ligand 2,3,7, 8-tetrachlorodibenzo-p-dioxin) and stimulates gene expression for CYP 1A1 with a parallel increase in CYP 1A1-mediated O-deethylation of 7-ethoxyresorufin.90 This process is strikingly dependent on the hydroxylation pattern of the B ring since kaempferol (3’-deoxyquercetin) binds AhR as an antagonist (no subsequent activation of CYP 1A1). It is also highly dependent on the cell type since, in hepatic cells, quercetin binds to AhR as an antagonist,

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thereby inhibiting gene expression for CYP 1A1 and benzo[a]pyrene activation.91 This provides a possible mechanism for the anticancer activity of quercetin. Flavonoids, especially flavones and flavonols, also directly bind to several CYP isoforms (1A1, 1A2, 1B1, 3A4) involved in xenobiotics metabolism and inhibit enzyme activity. Structure–activity relationships92–95 show rather high isoform selectivities depending on the flavonoid substitution pattern and contrasted inhibition mechanisms. For instance, inhibition by flavonoids of 7-methoxyresorufin O-demethylation in microsomes enriched in CYP 1A1 and 1A2 reveals that galangin (3,5,7-trihydroxyflavone) is a mixed inhibitor of CYP 1A2 (Ki ¼ 8 nM) and a five times less potent inhibitor of CYP 1A1. By contrast, 7-hydroxyflavone is a competitive inhibitor of CYP 1A1 (Ki ¼ 15 nM) and a six times less potent inhibitor of CYP 1A2.95 In addition, fairly selective inhibition of CYP 1B1 (specifically detected in cancer cells) by some flavonoids has been reported. For example, 5,7-dihydroxy-4’-methoxyflavone inhibits 1B1, 1A1, and 1A2 with IC50 values of 7, 80, and 80 nM, respectively.92 Eventually, flavonoids can be hydroxylated or demethylated by CYPs. For instance, hesperetin (4’-methoxy-3’,5,7-trihydroxyflavanone) is specifically demethylated by CYPs 1A1 and 1B1, but not by CYPs 1A2 and 3A4.92 In addition, 3,5,7-trihydroxyflavone undergoes sequential CYP 1A1-catalyzed hydroxylation at C4’ and C3’ to finally yield quercetin.96,97 These reactions may be relevant to flavonoid metabolism and cytotoxicity since the corresponding products are more reducing and thus more prone to autoxidation with simultaneous ROS production. Finally, flavonoids are also able to inhibit CYP19 or aromatase, an enzyme catalyzing a three-step oxidation sequence resulting in aromatization of the A ring of male steroid hormones (androgens) to yield estrogens. Together with flavonoid–estrogen receptor binding, this process could be relevant to the prevention of hormone-dependent cancers by flavonoids. Binding studies98,99 show that flavonoids are more efficient inhibitors than isoflavonoids with the A and C rings of the former possibly mimicking the androgen D and C rings, respectively. The simultaneous presence of a 4-keto group (possibly interacting with the heme iron center as an axial ligand in agreement with the observed high spin–low spin transition upon binding) and a 7-OH group is critical for a high affinity. By contrast, hydroxylation at positions 3 and 6 is strongly destabilizing. Flavanones bind almost as tightly as flavones but isoflavones are only poor ligands99 (Ki ¼ 2.6, 5.1, and 123 mM for 5,7-dihydroxyflavone, (+)-4’,5,7trihydroxyflavanone, and 4’,5,7-trihydroxyisoflavone, respectively) in sharp contrast to the structural requirement for strong flavonoid–estrogen receptor binding (see above). Interestingly, 17b-hydroxysteroid dehydrogenase, another redox enzyme involved in steroid metabolism, is also strongly inhibited by 7-hydroxyflavonoids.100 For instance, the flavone apigenin is more potent at inhibiting 17b-hydroxysteroid dehydrogenase (IC50 ¼ 0.3 mM) than aromatase (IC50 ¼ 2.9 mM) and the isoflavone genistein, which is only a weak aromatase inhibitor, inhibits 17b-hydroxysteroid dehydrogenase with an IC50 of 1 mM. 9.2.3.4 Modulation of Antioxidant Properties and Oxidation Pathways by Binding to Proteins In addition to enzymatic oxidation, flavonoid oxidation can take place via autoxidation (metal-catalyzed oxidation by dioxygen) and ROS scavenging. The former process can be related to flavonoid cytotoxicity (ROS production) while the latter is one of the main antioxidant mechanisms. Both processes may be modulated by flavonoid–protein binding. Although poorly documented so far, these points could be important and, for instance, albumin–flavonoid complexes with an affinity for LDL could act as the true plasma antioxidants participating in the regeneration of a-tocopherol from the a-tocopheryl radical formed

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upon scavenging of LDL-bound lipid peroxyl radicals. In addition, flavonoid–protein complexation can be expected to provide protection to the protein against oxidative degradation. In principle, addition of an oxidizing agent to a mixture of flavonoid and protein can cause degradation of both partners. From the influence of the protein on the kinetics of flavonoid oxidation, it can be decided whether the bound flavonoid molecule is still accessible to the oxidizing agent, i.e., whether it is still antioxidant. On the other hand, a reliable procedure for monitoring protein oxidation (with or without cleavage of peptide bonds) is needed to assess the eventual protection of the protein by the flavonoid. For example, inhibition of the enzymatic activity of butyrylcholine esterase, a contaminant of commercially available serum albumin, is a sensitive marker of protein degradation by peroxyl radicals.101 The influence of serum albumin on quercetin oxidation has been investigated with different one-electron or two-electron oxidizing agents: the peroxyl radicals formed by thermal decomposition of diazo compound AAPH in the presence of dioxygen, sodium periodate, and potassium nitrosodisulfonate. Rather unexpectedly, quercetin–BSA binding does not affect the rate of quercetin oxidation by periodate102 and even accelerates the rate of quercetin oxidation by nitrosodisulfonate (Dufour et al., unpublished results). Hence, SA-bound quercetin remains fully accessible to these small oxidizing agents, thus suggesting that it retains its antioxidant activity. In the first step, the quercetin o-quinone (in fast equilibrium with a p-quinone methide form) that is barely detectable in the absence of BSA because of subsequent fast water addition, is strongly stabilized, a likely consequence of ligand–protein charge transfer interactions and a low local water concentration. Serum albumin was also demonstrated to protect the quercetin p-quinone methide–water adduct from further degradation leading to 3,4-dihydroxybenzoic acid and 2-oxo-2-(2,4,6-trihydroxyphenyl)acetic acid. Investigations with other flavonoids confirm that albumin only weakly affects the kinetics of flavonoid oxidation while leaving the product distribution essentially unchanged. Unlike quercetin and kaempferol, whose oxidation leads to C ring cleavage, oxidation of luteolin, isoquercitrin, and catechin, either in their free or BSA-bound form, preferentially leads to dimers. Under conditions where the protein is not oxidatively degraded, its influence on the radical scavenging activity of flavonoids can be more readily assessed. For example, whereas the reaction of BSA and gelatin with the ABTS radical cation is negligible, sorghum procyanidin (15 to 17 flavanol units) can scavenge up to six ABTS radicals per monomer at pH 7.4.103 Of the two proteins, only gelatin slightly affects the kinetics of radical scavenging. However, the overall stoichiometry remains unaffected. At pH 4.9, the inhibition of ABTS scavenging by both proteins, especially gelatin, is somehow stronger but tends to vanish with time. In the case of BSA at least, these observations could simply point to negligible protein– flavonoid binding. However, covalent coupling between the proteins and procyanidin quinones may take place during radical scavenging. Indeed, although the amount of procyanidin– protein precipitate is not affected by ABTS, procyanidin oxidation by ABTS leads to precipates that cannot be resolubilized. Using the ABTS scavenging test, it was also possible to demonstrate that quercetin and human plasma exert nonadditive antioxidant activities,104 thus suggesting that binding of quercetin to plasma proteins masks part of the electrondonating activity of quercetin. The masking effect decreases in the series quercetin > rutin > catechin. The same trend emerges when plasma is replaced by serum albumin. Interestingly, the binding affinity to serum albumin42,43 parallels the masking effect. However, it must be noted that ABTS is much bulkier than ROS. Hence, its scavenging by polyphenols is expected to be especially sensitive to steric hindrance brought by the protein environment. Since lipid peroxidation is clearly related to the onset of atherosclerosis and the impairment of membrane functions, the influence of proteins on the ability of flavonoids to inhibit

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lipid peroxidation deserves examination. Such investigations have been carried out with BSA and lecithin liposomes.105 Whereas BSA alone already slows down the formation of lipid hydroperoxides and hexanal, its influence on the antiperoxidizing activity of the selected polyphenols is highly dependent on the polyphenolic structure. Hence, BSA lowers the inhibition of hydroperoxide formation by catechins and caffeic acid, enhances inhibition by malvidin and rutin, and leaves essentially unchanged inhibition by quercetin. No clear interpretation based on polyphenol–BSA binding can be given. The influence of a protein environment on the antioxidant activity of flavonoids can be readily evaluated by monitoring the inhibition by flavonoids of the peroxidation of HSAbound linoleic acid in plasma-mimicking conditions.106 The AAPH-initiated peroxidation of linoleic acid leads to four isomeric hydroperoxides that further react to form the corresponding ketodienes and alcohols. As expected, the formation of the lipid peroxidation products is inhibited more efficiently by 3’,4’-dihydroxyflavonoids (quercetin, quercetin-3-b-Dglucoside > catechin) than by flavonoids having a monohydroxylated B ring (kaempferol, 3’-O-methylquercetin, quercetin-3,4’-b-D-diglucoside). More importantly, the strong binding of quercetin to HSA (noncompetitively to linoleic acid) does not alter its antiperoxidizing activity. In contrast, a-tocopherol, although much more potent than flavonoids in the absence of HSA, and ascorbate are only weakly active. Thus, in plasma, the flavonol–albumin complex could be regarded as an antioxidant species with the flavonol molecule efficiently trapping the peroxyl radicals derived from AAPH and eventually from the lipid. Similarly, HSA-bound quercetin efficiently protects the enzyme butyrylcholine esterase (a typical contaminant of commercially available HSA) from oxidative damage by AAPH-derived peroxyl radicals.101 Oxidation of catechols in the presence of a protein may lead to extensive catechol–protein covalent coupling (Figure 9.4) as demonstrated in the case of the chlorogenic acid–BSA couple.107 Autoxidation of EGCG at pH 4.9 in the presence of Zn(II) cations was shown to generate semiquinone radicals (stabilized by Zn(II) binding) mainly on the B ring moiety.108 In the presence of BSA, EGCG autoxidation is accompanied by irreversible protein precipitation suggesting covalent EGCG–BSA coupling that probably involves EGCG o-quinones in fast disproportionation equilibrium with the semiquinone radicals. Finally, incubation of Hep G2 and Caco-2 cells with [14C]quercetin results in quercetin–protein covalent coupling (as much as 10% of the total cellular content of quercetin in the case of Caco-2 cells).109 The process is insensitive to the presence of an excess ascorbate, which rules out significant autoxidation of quercetin in the buffer or cell culture medium. Hence, quercetin oxidation could involve ROS within the cells. The quercetin-derived quinone or quinone methide intermediates thus formed are then proposed to add to specific cell proteins (MW ~55– 80 kDa in the case of Hep G2 cells), the major cell proteins remaining unaltered. More generally, one-electron oxidation of protein-bound phenols to form reactive aryloxyl radicals is a possible pro-oxidant mechanism since these radicals can propagate H-atom or electron transfers within the protein. In addition to phenol–protein covalent coupling, these phenol-mediated oxidative damages to proteins could be detrimental to their function as enzymes, receptors, and membrane transporters. For instance, investigations by capillary electrophoresis have shown that quercetin in concentrations lower than 25 mM potentiates HSA degradation by AAPH-derived peroxyl radicals.110

9.3 CONCLUSION AND PERSPECTIVES Flavonoids, as food components or potential drugs, interact with a wide range of proteins by distinct mechanisms: weak and rather unspecific binding of tannins to proline-rich or histidine-rich random coils leading to protein precipitation, specific enzyme inhibition, and

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ligand–receptor interactions mostly involving flavonoid aglycones with an unsaturated C ring, binding to transport proteins. In addition, flavonoid–protein interactions can modulate the redox properties of flavonoids that underline their antioxidant, and eventually their pro-oxidant, activity. After electrophilic activation by one-electron or two-electron oxidation, flavonoids can also form covalent bonds with proteins. Whether these binding processes are relevant to human health is not clearly demonstrated yet. However, one of the most promising perspectives is the participation of flavonoids in the regulation of gene expression, possibly by direct interactions with specific receptors and nuclear factors. For example, quercetin has been shown to increase the intracellular glutathione level by activating the promoter of the catalytic subunit of g-glutamylcysteine synthetase.111 This effect is fairly specific since myricetin (5’-hydroxyquercetin) and two quercetin 3-glycosides are inactive. As a possible molecular mechanism, quercetin could help release specific nuclear factors (from inert cytosolic complexes), thereby facilitating their translocation into the nucleus. On the other hand, some flavones, isoflavones, and flavonols are also known to activate peroxisome proliferator-activated receptor-g (PPAR-g), thus leading to suppression of inducible COX-2 and NO synthase in mouse macrophages.112 A likely mechanism consists in allosteric binding of the flavonoids to PPAR-g and subsequent modification of the receptor conformation. In conclusion, spectacular advances in the fields of flavonoid bioavailability and flavonoid-mediated cell effects in relation to the development of new biological tools (e.g., proteomic analysis, reporter genes) have been achieved during the last decade. A more coherent picture of the ways flavonoids combine their redox properties and affinity to specific proteins is emerging. This wealth of new chemical and biological information suggests that the elucidation of in vivo molecular mechanisms and receptors involved in flavonoid health effects is at hand.

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10

The Anthocyanins Øyvind M. Andersen and Monica Jordheim

CONTENTS 10.1

Introduction ............................................................................................................. 472 10.1.1 Anthocyanin Structures............................................................................... 472 10.1.2 Nutritional Supplements — Health Aspects ............................................... 473 10.1.3 Food Colorants ........................................................................................... 473 10.1.4 Molecular Biology, Biosynthesis, and Functions ........................................ 474 10.1.5 Analytical Methods and Instrumentation ................................................... 474 10.2 Anthocyanin Chemistry ........................................................................................... 475 10.2.1 General Aspects and Nomenclature ............................................................ 475 10.2.2 Anthocyanidins ........................................................................................... 475 10.2.3 Anthocyanins Not Based on the Common Anthocyanidins ....................... 480 10.2.4 Glycosides ................................................................................................... 480 10.2.4.1 Monosaccharides ......................................................................... 481 10.2.4.2 Disaccharides............................................................................... 481 10.2.4.3 Trisaccharides .............................................................................. 496 10.2.4.4 Glycosidic Linkages..................................................................... 496 10.2.5 Anthocyanins with Acylation ...................................................................... 498 10.2.5.1 Acylation with Phenolic Acids..................................................... 499 10.2.5.2 Acylation with Aliphatic Acids ................................................... 502 10.2.6 Dimeric Flavonoids Including an Anthocyanin Unit.................................. 503 10.2.7 Metalloanthocyanins ................................................................................... 506 10.2.8 Anthocyanin Colors and Stability............................................................... 508 10.3 Anthocyanin Production .......................................................................................... 511 10.3.1 Cell Cultures................................................................................................ 511 10.3.2 Synthesis...................................................................................................... 513 10.4 Anthocyanin Localization in Plant Cells ................................................................. 514 10.5 Chemotaxonomic Patterns ....................................................................................... 515 10.5.1 Alliaceae ...................................................................................................... 516 10.5.2 Convolvulaceae ........................................................................................... 518 10.5.3 Cruciferae .................................................................................................... 518 10.5.4 Gentianaceae ............................................................................................... 518 10.5.5 Geraniaceae ................................................................................................. 519 10.5.6 Labiatae....................................................................................................... 519 10.5.7 Leguminosae................................................................................................ 520 10.5.8 Liliaceae ...................................................................................................... 520 10.5.9 Nymphaeaceae ............................................................................................ 520 10.5.10 Orchidaceae ............................................................................................... 522 10.5.11 Ranunculaceae........................................................................................... 522 10.5.12 Solanaceae ................................................................................................. 522 References .......................................................................................................................... 523 Appendix ............................................................................................................................ 537 471

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10.1 INTRODUCTION The anthocyanins constitute a major flavonoid group that is responsible for cyanic colors ranging from salmon pink through red and violet to dark blue of most flowers, fruits, and leaves of angiosperms. They are sometimes present in other plant tissues such as roots, tubers, stems, bulbils, and are also found in various gymnosperms, ferns, and some bryophytes. As described below, the past decade has witnessed a renaissance in research activities on and general interests in these water-soluble pigments in several areas. When searching Chemical Abstracts/Medline for the word anthocyanin, the number of articles obtained was 790 in 2003 compared to 257 in 1993. This chapter follows on from those of the four previous editions of The Flavonoids,1–4 and the three review articles of Harborne and Williams.5–7 It will confine its attention largely to a detailed account on anthocyanin structures reported after 1992 (Section 10.2 and Table 10.2). Special effort has been made to present a comprehensive overview of all the various anthocyanins with complete structures in the literature (Section 10.2 and Appendix A). Many anthocyanins reported in checklists of previous reviews3,8 have been excluded from Appendix A mainly because of the lack of experimental proofs for proper determination of the linkage point(s) between one or more of the glycosidic units involved. For instance, after careful considerations of the data used as evidence for determination of the linkage position of the monosaccharides in the different anthocyanidin 5-monoglycosides presented in the various reports in the literature, we have excluded these anthocyanins apart from the deoxyanthocyanidin 5-glycosides from Appendix A. Anthocyanin production by cell cultures (Section 10.3.1) and synthesis (Section 10.3.2), and anthocyanin localization in plant cells (Section 10.4) have been treated separately due to important progress in these fields in recent years. Motivated by the many reports on anthocyanins from various sources in the review period (Table 10.2), some chemotaxomic considerations have been included in Section 10.5. This chapter has not dealt with other articles than those written in the English or German language. Thus, this review has most probably not given the right credit, in particular, to the Japanese research groups of Tadeo Kondo and Kumi Yoshida; Norio Sait, Fumi Tatsuzawa, and Toshio Honda; and Norihiko Terahara.

10.1.1 ANTHOCYANIN STRUCTURES The total number of different anthocyanins reported to be isolated from plants in this review is 539 (Appendix A). This number includes 277 anthocyanins that have been identified later than 1992. Several previously reported anthocyanins have for the first time received complete structural elucidation, and some structures have been revised. The majority of anthocyanins with the most complex structures and highest molecular masses have been reported in the period of this review. Two classes of dimeric anthocyanins isolated from plants (section 10.2.6) have been identified in plants for the first time. One class includes pigments where an anthocyanin and a flavone or flavonol are linked to each end of a dicarboxylic acyl unit.9–12 The other class includes four different catechins linked covalently to pelargonidin 3-glucoside.13 During the last decade, seven new desoxyanthocyanidins and a novel type of anthocyanidin called pyranoanthocyanidins have been reported (Section 10.2.2). Toward the end of the 20th century, several color-stable 4-substituted anthocyanins, pyranoanthocyanins, were discovered in small amounts in red wine and grape pomace.14–16 Recently, similar compounds have been isolated from extracts of petals of Rosa hybrida cv. ‘‘M’me Violet,’’17 scales of red onion,18 and strawberries.13,19 About 94% of the new anthocyanins in the period of this review are based on only six anthocyanidins (Table 10.2).

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The first natural C-glycosylanthocyanin has recently been isolated from flowers of Tricyrtis formosana.20 No new monosaccharide units have been identified in anthocyanins during the last decade; however, two new disaccharides21–23 and one new trisaccharide24,25 have been reported connected to anthocyanidins (Section 10.2.4). The two anthocyanins from blue flowers of Nymphae´a caerulea26 and the two minor anthocyanins from red onions18 are, with the exception of the desoxyanthocyanins, the only anthocyanins without a sugar in the 3-positions. Among the new anthocyanins reported after 1992, around 88% contain acyl group(s). The acyl groups, E-3,5-dihydroxycinnamoyl in a triacylatedtetraglucosylated cyanidin derivative from Ipomoea asarifolia,27 and tartaryl in four anthocyanins isolated from flowers of Anemone coronaria,28,29 have, for the first time, been identified as part of an anthocyanins (Section 10.2.5). The first anthocyanins found conjugated with sulfate, malvidin 3-glucoside-5-[2-(sulfato)glucoside] and malvidin 3-glucoside5-[2-(sulfato)-6-(malonyl)glucoside], have been isolated from violet flowers of Babiana stricta.30 Six novel anthocyanins made in transgenic plants31,32 and four novel anthocyanins produced in plant cell cultures33–36 have been included in Appendix A. Some interesting research on the complex metalloanthocyanins is outlined in Section 10.2.6.

10.1.2 NUTRITIONAL SUPPLEMENTS — HEALTH ASPECTS There has been an explosive interest in anthocyanins as potential nutritional supplements for humans. Regular consumption of anthocyanins and other polyphenols in fruits, vegetables, wines, jams, and preserves is associated with probable reduced risks of chronic diseases such as cancer, cardiovascular diseases, virus inhibition, Alzheimer’s disease. Anthocyanins and other flavonoids are regarded as important nutraceuticals mainly due to their antioxidant effects, which give them a potential role in prevention of the various diseases associated with oxidative stress. However, flavonoids have further been recognized to modulate the activity of a wide range of enzymes and cell receptors.37 In spite of the voluminous literature available, Western medicine has, however, not yet used flavonoids therapeutically, even though their safety record is exceptional. Aspects related to the impact of flavonoids on human health are presented in Chapter 6. The literature on the occurrence of anthocyanins and other flavonoids in foods, their possible dietary effects, bioavaiability, metabolism, pharmacokinetic data, and safety has recently been reviewed by several authors.33–51 The current knowledge on various molecular evidences of cancer chemoprevention by anthocyanins has been summarized by Hou.52 He divided the mechanisms into antioxidation, the molecular mechanisms involved in anticarcinogenesis, and the molecular mechanisms involved in the apoptosis induction of tumor cells.

10.1.3 FOOD COLORANTS There is a worldwide interest in further use of food colorants from natural sources as a consequence of perceived consumer preferences as well as legislative action in connection with synthetic dyes. Several excellent overviews of the common anthocyanin food dyes, quantitative and qualitative aspects of anthocyanins used in food products, and physicochemical properties of anthocyanins (color characteristics and stability) have been presented in the period of this review.53–57 An impressive compilation of the anthocyanin content of a variety of fruits, vegetables, and grains has been published by Mazza and Miniati.58 The flavonoid composition of foods is treated in Chapter 4. Different types of anthocyanin-derived pigments, including the pyranoanthocyanins originating by cycloaddition of diverse compounds at C-4 and the 5-hydroxyl of anthocyanidins, and compounds resulting from the condensation between anthocyanins and flavanols, either direct or mediated by acetaldehyde or other compounds, are generated in wine during storage.59–61 This has led to enlightenment of the color changes that take place in red wine (Chapter 5).

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10.1.4 MOLECULAR BIOLOGY, BIOSYNTHESIS, AND FUNCTIONS Advances in molecular biology, coupled with improved knowledge of anthocyanin biosynthesis, have led to increased interests in cultivars and plant mutants with new colors and shapes. A general overview of the biosynthetic pathway leading to flavonoids and recent advances in the molecular biology and biotechnology of flavonoid biosynthesis is presented in Chapter 3. Several reviews in the field of anthocyanins have recently been reported. Springob et al.62 covered the biochemistry, molecular biology, and regulation of anthocyanin biosynthesis, with particular emphasis on mechanistic features and late steps of anthocyanin biosynthesis, including glycosylation and vacuolar sequestration. Irani et al.63 focused on molecular mechanisms of the regulation of anthocyanin biosynthesis, and the factors that influence the pigmentation properties of anthocyanins, while Ben-Meir et al.64 outlined the biochemistry and genetics of the pathway leading to anthocyanin production, and provide an overview on the application of the generated knowledge toward molecular breeding of ornamentals. Other related excellent reviews of Forkmann and coworkers have covered classical versus molecular breeding of ornamentals,65 metabolic engineering and applications of flavonoids,66 and biosynthesis of flavonoids.67 Anthocyanic coloration plays a vital role in the attraction of insects and birds, leading to pollination and seed dispersal, but their appearance in young leaves and seedlings is often transient. There is increasing evidence that anthocyanins, particularly when they are located at the upper surface of the leaf or in the epidermal cells, have a role to play in the physiological survival of plants. It has been outlined that foliar anthocyanins accumulate in young, expanding foliage, in autumnal foliage of deciduous species, in response to nutrient deficiency, temperature changes, or ultraviolet (UV) radiation exposure, and in association with damage or defense against browsing herbivores or pathogenic fungal infection.42,68–70 The functions of anthocyanins have in this context mainly been hypothesized as a compatible solute contributing to osmotic adjustment to drought and frost stress, an antioxidant, and a UV and visible light protectant. The flavonoid functions in plants are treated in Chapter 7.

10.1.5 ANALYTICAL METHODS

AND INSTRUMENTATION

Continual improvements in methods and instrumentation (e.g., high-performance liquid chromatography [HPLC], liquid chromatography–mass spectrometry [LC–MS], and nuclear magnetic resonance [NMR] spectroscopy) used for separation and structural elucidation of anthocyanins (see Chapters 1 and 2) have made it easier to use smaller quantities of material, and to achieve results at increasing levels of precision. New anthocyanins regularly turn up in plant sources that already have been well investigated before (Table 10.2). Most anthocyanins show instability toward a variety of chemical and physical parameters, including oxygen, high temperatures, and most pH values.49 The various anthocyanins have similar structures and may occur in complex mixtures, which makes them rather difficult to isolate. A routine analysis may involve just one HPLC injection (5 ml) of a crude extract of dried petal (0.5 mg). However, a typical structural elucidation of a novel anthocyanin may demand more plant material (above 100 g) subjected to extraction with acidified alcoholic solvent, followed by purification and separation using various chromatographic techniques before structural elucidation by spectroscopy and sometimes chemical degradation.50,51 Recent MS and twodimensional (2D) NMR techniques have, in particular, become important for the determination of many anthocyanin linkage positions and identification of aliphatic acyl groups. Analytical methods for extraction, separation, and characterization of anthocyanins have been treated in a number of recent reviews.72–79

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10.2 ANTHOCYANIN CHEMISTRY 10.2.1 GENERAL ASPECTS AND NOMENCLATURE The anthocyanins consist of an aglycone (anthocyanidin), sugar(s), and, in many cases, acyl group(s). The anthocyanidins are derivatives of 2-phenylbenzopyrylium (flavylium cation) (Table 10.1). The numbering of the left structure in Table 10.1 is used for most anthocyanins. The pyranoanthocyanins are based on the skeleton represented by the structure on the right in Table 10.1. A more systematic name, e.g., 5-carboxypyranopelargonidin, can be 5-carboxy-2(4-hydroxyphenyl)-3,8-dihydroxy-pyrano[4,3,2-de]-1-benzopyrylium. When a given anthocyanin is dissolved in water, a series of secondary structures are formed from the flavylium cation according to different acid–base, hydration, and tautomeric reactions.80 While 31 monomeric anthocyanidins (Table 10.1) have been properly identified, around 90% of all anthocyanins (Appendix A) are based on only six anthocyanidins, pelargonidin (Pg), cyanidin (Cy), peonidin (Pn), delphinidin (Dp), petunidin (Pt), and malvidin (Mv). Among the 539 anthocyanins or anthocyanidins that have been identified, 97% are glycosidated (Figure 10.1). The 3-desoxyanthocyanidins, sphagnorubins and rosacyanin B (Table 10.1, Figure 10.3), are the only anthocyanidins found in their nonglycosidated form in plants. Nearly all reports on anthocyanins specifying the D or L configuration of the anthocyanin sugar moieties (monosaccharides), lack experimental evidence for this type of assignments.

10.2.2 ANTHOCYANIDINS In addition to the 18 anthocyanidins listed previously,4 Table 10.1 contains seven new desoxyanthocyanidins and a novel type of anthocyanidin called pyranoanthocyanidins. While 31 monomeric anthocyanidins have been properly identified, most of the anthocyanins are based on cyanidin (30%), delphinidin (22%), and pelargonidin (18%), respectively (Figure 10.2). Altogether 20% of the anthocyanins are based on the three common anthocyanidins (peonidin, malvidin, and petunidin) that are methylated. Around 3, 3, and 2% of the anthocyanins or anthocyanidins are labeled as 3-desoxyanthocyanidins, rare methylated anthocyanidins, and 6-hydroxyanthocyanidins, respectively. In bryophytes, anthocyanins are usually based on 3-desoxyanthocyanidins located in the cell wall. A new anthocyanidin, riccionidin A (Figure 10.3), has been isolated from the liverwort Ricciocarpos natans.81 It could be derived from 6,7,2’,4’,6’-pentahydroxyflavylium, having undergone ring closure of the 6’-hydroxyl at the 3-position. Its visible spectrum in methanolic HCl is at 494 nm. This pigment was accompanied by riccionidin B, which most probably is based on two molecules of riccionidin A linked via the 3’- or 5’-positions. Both pigments were also detected in the liverworts Marchantia polymorpha, Riccia duplex, and Scapania undulata.81 Somewhat, unexpectedly, riccionidin A has also been isolated from adventitious root cultures of Rhus javanica (Anacardiaceae).82 A new 3-desoxyanthocyanidin, 7-O-methylapigeninidin, has been isolated in low concentration from grains and leaf sheaths of Sorghum caudatum.83 Its UV–vis spectrum recorded in methanol with 0.1% HCl showed absorption maxima at 278.6 and 476.4 nm. The secondaryion MS spectrum showed a strong [M]þ ion at m/z 269, consistent with the C16H13O4 molecular formula. The 1H and 13C NMR spectral data were closely related to those of apigeninidin, except for a singlet at 4.08 ppm (aromatic O-methyl group). This methyl group was located at C-7 after observation of DIFFNOEs between the methyl protons and both the H-8 and H-6 protons. The pigment was found in low concentration both in grains and in leaf sheaths. A similar 3-desoxyanthocyanidin has been detected in grains of Sorghum bicolor after incubation with the fungus Colletotrichum sublineolum.84 In addition to plasma desorption MS data, bathochromic shift analyses indicated that the structure of the compound was

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TABLE 10.1 The Structures of Naturally Occurring Anthocyanidin.a The Numbering of the Structure on the Left is Used for all Anthocyanins; the Numbering for the Pyranoanthocyanins is Given in the Structure on the Right 3ⴕ 4ⴕ 9 8

3ⴕ

9 O

7

1ⴕ

5

10

9b

7 6a

5ⴕ

5ⴕ

3 3a

6O

2

6

1ⴕ 2

4ⴕ 8

9a O

4 5

3 4

O

OH

Substitution Pattern 3

5 (6a)b

Common anthocyanidins Pelargonidin (Pg) Cyanidin (Cy) Delphinidin (Dp) Peonidin (Pn) Petunidin (Pt) Malvidin (Mv)

OH OH OH OH OH OH

OH OH OH OH OH OH

Rare methylated anthocyanidins 5-MethylCy 7-MethylPn (rosinidin) 5-MethylDp (pulchellidin) 5-MethylPt (europinidin) 5-MethylMv (capensinidin) 7-MethylMv (hirsutidin)

OH OH OH OH OH OH

6-Hydroxylated anthocyanidins 6-HydroxyPg 6-HydroxyCy 6-HydroxyDp 3-Desoxyanthocyanidins Apigeninidin (Ap) Luteolinidin (Lt) Tricetinidin (Tr) 7-MethylApc 5-MethylLtc 5-Methyl-6-hydroxyAp (carajurone)c 5,4’-Dimethyl-6-hydroxyAp (carajurin) 5-Methyl-6-hydroxyLtc 5,4’-Dimethyl-6-hydroxyLtc Riccionidin Ac, d

6 (7)b

7 (8)b

3’

H H H H H H

OH OH OH OH OH OH

H H OH OMe OMe OMe

OH OH OH OH OH OH

H H OH H OH OMe

OMe OH OMe OMe OMe OH

H H H H H H

OH OMe OH OH OH OMe

OH OMe OH OMe OMe OMe

OH OH OH OH OH OH

H H OH OH OMe OMe

OH OH OH

OH OH OH

OH OH OH

OH OH OH

H OH OH

OH OH OH

H H OH

H H H H H H H H OH OH

OH OH OH OH OMe OMe OMe OMe OMe H

H H H H H OH OH OH OH OH

OH OH OH OMe OH OH OH OH OH OH

H OH OH H OH H H OH OH H

OH OH OH OH OH OH OMe OH OMe OH

H H OH H H H H H H H

4’

5’

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TABLE 10.1 The Structures of Naturally Occurring Anthocyanidins.a The Numbering of the Structure on the Left is Used for all Anthocyanins; the Numbering for the Pyranoanthocyanins is Given in the Structure on the Right — continued Substitution Pattern

Pyranoanthocyanidins 5-CarboxypyranoPgc 5-CarboxypyranoCyc,e

3

5 (6a)b

6 (7)b

7 (8)b

3’

4’

5’

OH OH

O– O–

H H

OH OH

H OH

OH OH

H H

a

Sphagnorubins A–C from peat moss, Sphagnum, have not been included (Figure 10.3). The numbers in parentheses correspond to the pyranoanthocyanidins. c New anthocyanidins (reported between 1992 and 2004). d Ring closure on the basis of ether linkage between the 3- and 6’-positions. Riccionidin A and its dimer, riccionidin B, have an additional OH-group in the 2’-position (Figure 10.3). e Rosacyanin B (Figure 10.3). b

consistent with that of 5-O-methylluteolinidin. The spectrum of this phytoalexin, which showed greater fungitoxicity than luteolinidin, revealed an absorption maximum at 495 nm. Although a previous synthesis of the desoxyanthocyanidin carajurin, 6,7-dihydroxy-5,4’dimethoxy-flavylium (isolated from leaves of Arrabidaea chica), was published in 1953,85

120

100

80

60

40

20

0 An

1M

1MA

2M

2MA

3M

3MA

>3M

>3MA

FIGURE 10.1 Anthocyanidins (An) and anthocyanins grouped according to their content of monosaccharide units and acylation. The vertical axis represents the number of pigments. The upper dark part of each bar represents the anthocyanins reported later than 1992. 1M, one monosaccharide unit; 1MA, one monosaccharide unit plus acylation; 2M, two monosaccharide units; 2MA, two monosaccharide plus acylation; 3M, three monosaccharide units; 3MA, three monosaccharide units plus acylation; >3M, more than three monosaccharide units; >3MA, more than three monosaccharide units plus acylation.

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180 160 140 120 100 80 60 40 20 0 Pg

Cy

Pn

Dp

Pt

Mv

RMS

6OH

Des

Pyr

Sp

FIGURE 10.2 The number of anthocyanins based on the various anthocyanidins. The upper dark part of each bar represents the anthocyanins reported later than 1992. Pg, pelargonidin; Cy, cyanidin; Pn, peonidin, Dp, delphinidin; Pt, petunidin; Mv, malvidin; RMS, rare methylated structures; 6OH, 6-hydroxy-; Des, desoxy-; Pyr, pyrano-; Sp, sphagnorubins. See Table 10.1 for structures.

some authors have considered the structure of this pigment to be only partially described.1,58 More recently, two groups86,87 have nearly simultaneously confirmed the structure of carajurin — even with a crystal structure.87 The structure of carajurone was also revised to be 6,7,4’-trihydroxy-5-methoxy-flavylium.86 Additionally, two new 3-desoxyanthocyanidins, HO HO

OH OH

OH

O

HO

O

HO

O

O

522 O

O

OR2 OH R1O

OH

O +

526

HO

HO

HO

527: R1 = R2 = H 528: R1 = Me, R2 = H 529: R1 = R2 = Me

FIGURE 10.3 Some anthocyanidins with unusual structures; 522, riccionidin A; 526, rosacyanin B; 527–529, sphagnorubins A–C.

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6,7,3’-trihydroxy-5,4’-dimethoxy-flavylium86 and 6,7,3’,4’-tetrahydroxy-5-methoxy-flavylium,86,87 were isolated from these leaves, which are traditionally used by some indigenous populations of South America for body painting and for dyeing fibers. In recent years, several color-stable 4-substituted anthocyanins have been discovered in small amounts in red wine and grape pomace (see Chapter 5). Vitisin A and acetylvitisin A were identified as the 3-glucoside and the 3-acetylglucoside of malvidin containing an additional C3H2O2 unit linking the C-4 and the C-5 hydroxyl group. Vitisin B and acetylvitisin B were identified as analogous pigments having a CH¼¼CH moiety instead of the C3H2O2 unit.15 The suggested structure for carboxypyranomalvidin (vitisidin A) was later slightly revised by Fulcrand et al.,16 who proved that the C3H2O2 unit was part of a pyran ring having a free acid group. They suggested that vitisin A was formed by cycloaddition of pyruvic acid involving both C-4 and the hydroxyl at C-5 of malvidin. Four reported methylpyranoanthocyanins isolated from blackcurrant seeds88 were later shown to be the oxidative cycloaddition products of the extraction solvent (acetone) and the natural anthocyanins.89 Pyranoanthocyanidins generated from the respective glycosides after hydrolysis were found to undergo rearrangement to form a new type of furoanthocyanidins.90 Recently, four new pyranoanthocyanins, namely pyranocyanin C and D and pyranodelphinidin C and D, were isolated by the same group from an extract of blackcurrant seeds.91 These pigments were absent in fresh extracts, and their levels increased gradually with time. Their formation was likely to be from the reaction of the anthocyanins and p-coumaric acid in the extracts. The first pyranoanthocyanidin isolated from intact plants received the trivial name rosacyanin B (Figure 10.3).17 This violet pigment was isolated in small amounts from the petals of Rosa hybrida cv. ‘‘M’me Violet.’’ Its structure was revealed mainly by high resolution fast atom bombardment MS and NMR (1D and 2D). Rosacyanin B is very stable in acidic alcoholic solutions; however, under neutral or weakly acidic aqueous conditions it is precipitated before forming the colorless pseudobase. This anthocyanidin contains no sugar units. Recently, four anthocyanins with the same aglycone, 5-carboxypyranocyanidin, have been isolated from acidified, methanolic extracts of the edible scales, as well as from the dry outer scales of red onion (Allium cepa).18 Two of the structures were elucidated by 2D NMR spectroscopy and LC–MS as the 3-glucoside and 3-[6-(malonyl)glucoside] (525) of this 4-substituted aglycone. The two analog pigments methylated at either the terminal carboxyl group of the acyl moiety or at the aglycone carboxyl were most probably formed by esterification of 525 with the solvent (acidified methanol) during the isolation process. Another 3-glucoside (523) with the new 4-substituted aglycone, 5-carboxypyranopelargonidin, has been isolated in small amounts from the acidified, methanolic extract of strawberries (Fragaria
ananassa).19 By comparison of UV–vis absorption spectra, 523 showed in contrast to ordinary pelargonidin 3-glucoside (5) a local absorption peak around 360 nm, a hypsochromic shift (8 nm) of the visible absorption maximum, and lack of a distinct UV absorption peak around 280 nm. The similarities between the absorption spectra of 523 in various acidic and neutral buffer solutions implied restricted formation of the instable colorless equilibrium forms, which are typical for most anthocyanins in weakly acidic solutions. The molar absorptivity of 523 varied little with pH contrary to similar values of, for instance, 5. Each anthocyanidin is involved in a series of equilibria giving rise to different forms, which exhibit their own properties including color.80 One- and two-dimensional NMR have been used to characterize the various forms of malvidin 3,5-diglucoside present in aqueous solution in the pH range 0.3 to 4.5 and to determine their molar fractions as a function of pH.92 In addition to the flavylium cation, two hemiacetal forms and both the cis and trans forms of chalcone were firmly identified. In a reexamination, the intricate pH-dependent set of chemical reactions involving synthetic flavylium compounds (e.g., 4’-hydroxyflavylium) was confirmed to be basically identical to those of natural anthocyanins (e.g., malvidin 3,5-diglucoside) in

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acidic and neutral media.94 For each process, a kinetic expression was deduced allowing calculation of all the equilibrium constants and most of the rate constants in the system. In recent years, Pina et al. have performed a systematic investigation of the photochemical and thermal reactions of synthetic flavylium compounds.94 They have shown that 4’,7-dihydroxyflavylium (AHþ) in a water–ionic liquid biphasic system can be used as a write–read–erase system. In acid media, the trans-chalcone form is soluble in ionic liquids and is thermally metastable, but reacts photochemically (write) to give the yellow flavylium salt, which can be optically read without being erased. The system is prepared for a new cycle by two consecutive pH ‘‘jumps.’’95 These results are very interesting since the flavylium compounds represent examples of multistate or multifunctional chemical systems that may be used for information processing at the molecular level according to principles similar to those that govern information transfer in living organisms. In particular, flavylium compounds can behave as optical memories and logic gates systems: a write–read–erase molecular switch.

10.2.3 ANTHOCYANINS NOT BASED

ON THE

COMMON ANTHOCYANIDINS

Although most new anthocyanins discovered during the last decade have been based on the six common anthocyanidins (Figure 10.2), some rare exceptions with limited distribution have been reported. The major 3-deoxyanthocyanin isolated from the fern Blechnum novaezelandiae was determined to be luteolinidin 5-[3-(glucosyl)-2-(acetyl)glucoside] by HPLC, NMR (1D, 2D), and electrospray MS.96 The new 3-[6-(p-coumaryl)glucoside] and 3-glucoside of hirsutidin together with the known corresponding petunidin and malvidin derivatives have been identified in extracts of both cell suspensions and fresh flowers of Catharanthus roseus.97 The extracts were analyzed by positive-ion electrospray ionization MS, and collision experiments were performed on molecular ions by means of ion trap facilities. Purified compounds were also analyzed by thin-layer chromatography and UV–vis spectroscopy. The 3-rutinoside and 3-glucoside of 6-hydroxycyanidin have previously been isolated from red flowers of Alstroemeria cultivars,98 whereas 6-hydroxydelphinidin 3-rutinoside, occurred in pink-purple flowers of five cultivars.99 During the period of this review, the 3-[6-(malonyl)glucoside] of 6-hydroxycyanidin and 6-hydroxydelphinidin in addition to 6-hydroxydelphinidin 3-glucoside have been identified in various Alstroemeria cultivars.100–102 The position of the 6-hydroxyl of these anthocyanidins was unambiguously assigned by homo- and heteronuclear NMR techniques.103 Flower color, hue, and color intensity of fresh tepals of 28 Chilean species and 183 interspecific hybrids have been described by CIELAB parameters.104 Compared with flowers containing exclusively cyanidin 3-glycosides, the hues of flowers with 6-hydroxycyanidin 3-glycosides were more reddish. Substitution of the anthocyanidin A-ring with 6-hydroxyl causes a hypsochromic shift (~15 nm) in the visible spectra, which has diagnostic value.103 The relationship between flower color and anthocyanin content has also been investigated in 45 Alstroemeria cultivars by Tatsuzawa et al.105 The major anthocyanins of outer perianths were cyanidin 3-rutinoside and 6-hydroxycyanidin 3-rutinoside in cultivars with red flowers, 6-hydroxydelphinidin 3-rutinoside in those that were red-purple, and delphinidin 3-rutinoside in purple ones. Recently, the same group has isolated the 3-(glucoside) and 3-[6-(rhamnosyl)glucoside] of 6-hydroxypelargonidin (aurantinidin) from extracts of the orange-red flowers of the Alstroemeria cultivars ‘‘Oreiju,’’ ‘‘Mayprista,’’ and ‘‘Spotty-red.’’106 Aurantinidin has previously been reported to occur in Impatiens aurantiaca (Balsaminaceae).107

10.2.4 GLYCOSIDES Most anthocyanins contain two, three, or just one monosaccharide unit (Figure 10.1); however, as much as seven glucosyl units have been found in ternatin A1 (Clitoria ternatea)108

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and cyanodelphin (Delphinium hybridum).109 Altogether 240 and 24 anthocyanins have been reported to contain a disaccharide and a trisaccharide, respectively, while no tetrasaccharide has been found yet in anthocyanins. The sugar moieties are connected to the anthocyanidins through O-linkages; however, recently Saito et al.20 have isolated 8-C-glucosylcyanidin 3-[6-(malonyl)glucoside] from the purple flowers of Tricyrtis formosana cultivar Fujimusume (Liliaceae). Although C-glycosylation is common in other flavonoids, especially flavones (Chapter 13), this is the first report of a natural C-glycosylanthocyanin. 10.2.4.1

Monosaccharides

The anthocyanin monosaccharides are represented by glucose, galactose, rhamnose, arabinose, xylose, and glucuronic acid. There is no new monosaccharide attached to anthocyanidins reported in the period of this review. Glucosyl moieties have been identified in as much as 90% of the anthocyanins, while the rarest monosaccharide in anthocyanins, glucuronosyl, is limited to 11 anthocyanins (Figure 10.4). This latter monosaccharide has previously been identified in anthocyanins isolated from flowers of Helenium autumnale and Bellis perennis (Compositae),110,111 and tentatively identified as luteolinidin 4’-glucuronide in flower extracts of Holmskioldia sanguinea.112 More recently, three delphinidin and three cyanidin derivatives based on 3-[2-(2-(caffeylglucosyl)galactoside]-7-[6-(caffeyl)glucoside]-3’-glucuronoside have been isolated from flowers of Anemone coronaria.28,29 Glucuronosyl units have also been found in two anthocyanin–flavonol complexes isolated from chive flowers (Allium schoenoprasum), however, linked to the flavonol moieties.11 The acid function of the glucuronosyl of these latter complexes was considerably methylesterified during extraction with methanol containing as little as 1% trifluoroacetic acid. 10.2.4.2

Disaccharides

The following disaccharides have previously4 been found linked to anthocyanidins: 2-glucosylglucose (sophorose), 6-rhamnosylglucose (rutinose), 2-xylosylglucose (sambubiose), 6-g lucosylglucose (gentiobiose), 6-rhamnosylgalactose (robinobiose), 2-xylosylgalactose (lathyrose), 2-rhamnosylglucose (neohesperidose), 3-glucosylglucose (laminariobiose), 6-arabinosylglucose, 2glucuronylglucose, 6-glucosylgalactose, and 4-arabinosylglucose (Figure 10.5). In addition, several anthocyanidin disaccharides have been detected without proper determination of the linkage points between the monosaccharides. During the period of this review, Yoshida et al.21 have isolated delphinidin 3-[6-(E-p-coumaryl)glucoside]-5-[6-(malonyl)-4-(rhamnosyl)glucoside] (muscarinin A) from purplish-blue spicate flower petals of Muscari armeniacum (Liliaceae), which contained an interesting 1 ! 4 linkage between the rhamnose and one of the glucose units. Another new disaccharide, 2-glucosylgalactose, has been found in pelargonidin 3-[2-(2-E-caffeyl)glucosyl)-galactoside] isolated from sepals of Pulsatilla cernua (Ranunculaceae),22 in the major anthocyanin, cyanidin 3-[2-(glucosyl)galactoside], isolated from scarlet fruits of Cornus suecica (Cornaceae),23 and in seven exciting acylated cyanidin and delphinidin derivatives from flowers of Anemone coronaria28,29 (Table 10.2). Among the new anthocyanins, which have been reported after 1992, 47, 22, and 36 contain sophorose, rutinose, and sambubiose, respectively (Figure 10.5). Most of the anthocyanins containing sophorose were first isolated from species belonging to Convolvulaceae (22) and Cruciferae (13) (Table 10.2). This disaccharide has also been identified in new anthocyanins isolated from Ajuga (Labiatae),36,113,114 Consolida (Ranunculaceae),115 Begonia (Begoniaceae),116 and in the flavonol unit of two covalent anthocyanin–flavonol complexes from Allium (Alliaceae).11 Most of the novel anthocyanins containing rutinose (20) have been isolated from species belonging to the genera Petunia and Solanum in Solanaceae (Table 10.2). However,

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500 450 400 350 300 250 200 150 100 50 0 glc

rha

gal

xyl

ara

glu

FIGURE 10.4 Numbers of anthocyanins containing the various monosaccharides identified in anthocyanins. The upper dark part of each bar represents the anthocyanins reported later than 1992. glc, glucose; rha, rhamnose; xyl, xylose; gal, galactose; ara, arabinose; glu, glucuronic acid. Some anthocyanins contain more than one type of monosaccharide.

80 70 60 50 40 30 20 10 0 so

ru

sa

ge

ro

la

2gga

ne

lm

6arg

gugl 6gga 4arg

rhgl

FIGURE 10.5 Numbers of anthocyanins containing the various disaccharides identified in anthocyanins. The upper dark part of each bar represents the anthocyanins reported later than 1992. so, 2-glucosylglucose; ru, 6-rhamnosylglucose; sa, 2-xylosylglucose; ge, 6-glucosylglucose; ro, 6-rhamnosylgalactose; la, 2-xylosylgalactose; 2gga, 2-glucosylgalactose; ne, 2-rhamnosylglucose; lm, 3-glucosylglucose; 6arg, 6-arabinosylglucose; gugl, 2-glucuronylglucose; 6gga, 6-glucosylgalactose; 4arg, 4-arabinosylglucose; rhgl, 4-rhamnosylglucose.

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TABLE 10.2 Occurrence of Anthocyanins Reported after 1992 Taxon BRYOPHYTA BLECHNACEAE Blechnum novae-zelandiae HEPATOPHYTA MARCHANTIACEAE Marchantia polymorpha RICCIACEAE Riccia duplex Ricciocarpus natans SCAPANIACEAE Scapania undulata

Organ

Pigmenta

Referencesb

Tissue

Lt5-[3-(glc)-2-(ace)glc] (514)c

96 (2001)

Cell walls

Riccionidin A (522), riccionidin Bd, e

81 (1994)

Cell walls

Riccionidin A (522), riccionidin Bd, e

81 (1994)

Cell walls

Riccionidin A (522), riccionidin Bd, e

81 (1994)

Cones Needles

Cy3-glc, Dp3-glc, Pn3-glc, Pt3-glc Cy3-glc, Dp3-glc, Pn3-glc, Pt3-glc, Mv3-glc

295 (2003) 338 (2002)

Fruits Fruits

Cy3-glc, Cy3-[6-(rha)glc] Cy3-glc, Cy3-[6-(rha)glc]

339 (1994) 339 (1994)

Leaves

Cy3-[6-(2,5-di-(fer)ara)glc]7,3’-[6(fer)glc] (251)

136 (1995)

Grass

Cy3-[3,6-di-(mal)glc], Cy3-[6(mal)glc], Cy3-[6-(rha)glc], Cy3-glc, Dp3-[6-(mal)glc], Dp3glc, Pn3-[6-(mal)glc], Pn3-[di(mal)glc]e, Pn3-glc

296 (2001)

Flowers

Cy3-[caf-6-(ara)glc], Cy3-[6-(ara)glc]

340 (1992)

Cy3-[6-(rha)glc], Cy3-glc

341 (2004)

Phalaris arundinacea

Leaves and flowers Flower tops

342 (2001)

Phragmites australis

Flowers

Sorghum bicolorg

Grains

Cy3-[3,6-di-(mal)glc], Cy3-[6(mal)glc], Cy3-glc, Pn3-glc Cy3-[6-(mal)glc], Cy3-[6-(suc)glc] (135), Cy3-glc 5MLt (519)

Sorghum caudatum

Grains

7Map (516), Ap,Lt,Lt5-glc

GYMNOSPERMAE Pinaceae Abies, Picea, Pinus, Pseudotsuga, Tsugaf 27 spp. Pinus banksiana ANGIOSPERMAE MONOCOTYLEDONEAE Palmae (5 Arecaceae) Euterpe edulisg Pinanga polymorphag (Asian palm) Commelinaceae Tradescantia pallida Gramineae (5 Poaceae) Alopecurus, Anthoxanthum, Avenula, Bothriochloa, Dactylis, Deschampsia, Elymus, Festuca, Holcus, Hordeum, Mischanthus, Molinia, Oryza, Phalaris, Phleum, Poa, Sinarundinaria, Zea,f 23 spp. Panicum melinisg Pennisetum setaceum (Rubrum Red Riding Hood)

221 (1998) 84 (1996) 83 (1997) 343 (1994) 344 (2003) continued

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TABLE 10.2 Occurrence of Anthocyanins Reported after 1992 — continued Taxon Triticum aestivumg (cv. Katepwa) Triticum aestivumg (cv. Purendo 38) Zea mays

Pigmenta

Organ Grains (purple wheat) Grains (blue wheat) Leaves and flowers

Referencesb

Cy3-gal, Cy3-glc, Pn3-glc Cy3-glc, Pn3-glc

344 (2003)

Cy3-[3,6-di-(mal)glc], Cy3-[6-(mal)glc], Cy3-glc, Pn3-glc

342 (2001)

30 (1994)

Iridaceae Babiana stricta

Violet flowers

Crocus antalyensis

Flowers

Crocus chrysanthus (Skyline)

Flowers

Crocus chrysanthus (Eyecatcher) Crocus sieberi ssp. sublimes (Tricolor) Liliaceae Dianella nigra

Flowers

Mv3-glc-5-[2-(S)-6-(mal)glc] (472), Mv3-glc-5-[2(S)glc] (467), Mv3-glc-5-[6-(mal)glc] (469) Dp3,5-di-glc, Dp3,7-di-glc, Dp3-glc-5-[6(mal)glc] (338), Pt3,5-di-glc, Pt3,7-di-glc (427) Mv3,7-di[6-(mal)glc] (473), Pt3,7-di[6-(mal)glc] (439) Dp3-[6-(rha)glc], Pt3-[6-(rha)glc]

Flowers

Dp3,5-di-glc, Pt3,5-di-glc

346 (1998)

Berries

146 (2001)

Dianella tasmanica

Berries

Hyacinthus orientalis

Red flowers

Hyacinthus orientalis

Blue flowers

Lilium Muscari armeniacum

Flowers Blue flowers

Tricyrtis formosana Tulipa (Queen Wilhelmina)

Flowers Flowers

Tulipa gesneriana

Anthers

Dp3-glc-7,3’,5’-tri[6-(cum)glc] (399), Dp3,7,3’,5’tetra[6-(cum)glc] (403) Dp3-glc-7,3’,5’-tri[6-(cum)glc] (399), Dp3-glc-7glc-3’,5’-di[6-(cum)glc] (391) Pg3-[6-(caf)glc]-5-[6-(mal)glc], Pg3-[6-(caf)glc]-5glc, Pg3-[6-(cum)glc]-5-[4-(mal)glc] (50), Pg3[6-(cum)glc]-5-[6-(ace)glc] (49), Pg3-[6-(fer)glc]5-[6-(mal)glc] (54), Pg3-[6-(fer)glc]-5-glc (46), Pg3-glc-5-[6-(mal)glc] (35), Pg3-[6-(Z-cum)glc]5-glc (42) Cy3-[6-(cum)glc]-5-[6-(mal)glc], Dp3-[6-(caf)glc]5-[6-(mal)glc], Dp3-[6-(cum)glc]-5-[6-(mal)glc], Dp3-[6-(cum)glc]-5-glc, Dp3-[6-(Z-cum)glc]-5[6-(mal)glc], Pg3-[6-(cum)glc]-5-[6-(mal)glc], Pt3-[6-(cum)glc]-5-[6-(mal)glc] (443) Cy3-[6-(rha)glc]-7-glc (124), Cy3-[6-(rha)glc] Dp3-[6-(cum)glc]-5-[6-(mal)-4-(rha)glc] (370), Dp3-glc, Pt3-glc, Mv3-glc Cy3-[6-(mal)glc]8C-glc (151) Cy3-[6-(2-(ace)rha)glc] (144), Cy3-[6-(rha)glc], Pg3-[6-(2-(ace)rha)glc] (29)d, Pg3-[6-(rha)glc] Dp3-[6-(2-(ace)rha)glc] (332), Dp3-[6-(3(ace)rha)glc] (333), Dp3-[6-(rha)glc]

Alliaceae Agapanthus praecox ssp. orientalis

Flowers

Allium cepa

Bulbs

Dp3-[6-(cum)glc]-7-glc]Kae3-glc-7-xyl-4’-glc suc (538), Dp3-[6-(cum)glc]-7-glc]Kae3,7-di-glc-4’glc suc (539) 5-Carboxypyranocyanidin 3-glucoside (524), 5-Carboxypyranocyanidin 3-[6-(malonyl) glucoside] (525)

345 (1999) 346 (1998) 346 (1998)

146 (2001) 201 (1995) 327 (1995)

328 (1995)

120 (1999) 21 (2002) 20 (2003) 122 (1999) 121 (1999)

12 (2000)

18 (2003)

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TABLE 10.2 Occurrence of Anthocyanins Reported after 1992 — continued Taxon

Organ

Allium cepa

Bulbs

Allium sativum Allium schoenoprasum

Inner scale leaves Flowers

Allium victorialis

Stems

Triteleia bridgesii

Flowers

Alstroemeriaceae Alstroemeria (Westland, Tiara)

Pigmenta

Referencesb

Cy3,4’-di-glc (113), Cy3,5-di-glc, Cy3-[3-(glc)-6(mal)glc] (150), Cy3-[3-(glc)-6-(mal)glc]4’-glc (192), Cy3-[3-(glc)-6-(Me-mal)glc], Cy3-[3-(glc)glc], Cy3[6-(mal)glc], Cy3-glc, Cy4’-glc (100), Cy7-[3-(glc)-6(mal)glc]4’-glc (193), Pn3-[6-(mal)glc], Pn3-[6(mal)glc]-5-glc (283) Cy3-[(ace)glc]e, Cy3-[3-(mal)glc], Cy3-[3,6-di-(mal)glc], Cy3-[6-(mal)glc], Cy3-glc (6’’-(Cy3-glc)) (2’’’’-(Kae3-[2’’-(glc)(glc)]-7glu))malonate (536), (6’’-(Cy3-[3’’-(ace)glc])) (2’’’’(Kae3-[2’’-(glc)(glc)]-7-glu))malonate (537), Cy3[3,6-di-(mal)glc], Cy3-[6-(ace)glc], Cy3-[6-(mal)glc], Cy3-glc Cy3-[3-(mal)glc] (133), Cy3-[3,6-di-(mal)glc] (141), Cy3-[6-(mal)glc], Cy3-glc Cy3-[cum-glc-cum-glc]-5-[mal-glc]e, Dp3-[6-(4(glc)cum)glc]-5-[6-(mal)glc] (372), Dp3-[6-(cum)glc]5-[6-(mal)glc], Dp3-[6-(cum)glc]-5-glc, Dp3-[6-(Zcum)glc]-5-[6-(mal)glc]

135 (1994) 147 (2003)

Flowers/ tepals

Cy-6OH-3-[6-(mal)glc] (500), Cy-6OH-3-[6-(rha)glc], Cy-6OH-3-glc, Dp-6OH-3-[6-(mal)glc] (504), Dp6OH-3-[6-(rha)glc], Dp-6OH-3-glc (502), Pg-6OH-3[6-(rha)glc] (496), Pg-6OH-3-glc (495), Cy3-[6(mal)glc], Cy3-[6-(rha)glc], Cy3-glc, Dp3-[6(mal)glc], Dp3-[6-(rha)glc], Dp3-glc, Pg3-[6-(rha)glc]

100 (1996) 101 (2001) 102 (2002) 122 (2003)

Musaceae Musa
paradisiacag

Bracts

Cy3-[6-(rha)glc], Dp3-[6-(rha)glc], Mv3-[6-(rha)glc], Pg3-[6-(rha)glc], Pn3-[6-(rha)glc]

347 (2001)

Orchidaceae Bletilla striata

Flowers

Cy3-[6-(mal)glc]-7-[6-(cum)glc]-3’-[6-(4-(6-(4(glc)cum)glc)cum)glc] (257), Cy3-glc-7-[6-(cum)glc]3’-[6-(4-(6-(4-(glc)cum)glc)cum)glc] (254), Cy3-[6(mal)glc]-7-[6-(caf)glc]-3’-[6-(4-(6-(4(glc)caf)glc)caf)glc] (258), Cy3-glc-7-[6-(caf)glc]-3’[6-(4-(6-(4-(glc)caf)glc)caf)glc] (256) Cy3-[6-(mal)glc]7,3’-di[6-(sin)glc], Cy3-glc-7,3’-di[6(sin)glc] Cy3-[6-(mal)glc]7,3’-di[6-(4-(glc)hba)glc] (253)

157 (1995)

Dendrobium (Pompadour) Dendrobium phalaenopsis (Pramot) Dracula chimaera Dracula cordobae
Laeliocattleya (minipurple)

Purple flowers Red-purple flowers Flowers Flowers

Cy3-[6-(mal)glc], Cy3-[6-(rha)glc], Cy3-glc, Pn3-[6(rha)glc], Pn3-[6-(mal)glc] Cy3-[6-(mal)glc], Cy3-[6-(rha)glc], Cy3-glc, Pn3-[6(rha)glc], Pn3-[6-(mal)glc]

204 (1997) 11 (2000)

202 (1995) 166 (1998)

181 (2002) 189 (1994) 330 (2003) 330 (2003)

continued

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TABLE 10.2 Occurrence of Anthocyanins Reported after 1992 — continued Taxon

Pigmenta

Organ

Referencesb

Laelia pumila Cattleya walkeriana

Flowers

Cy3-[6-(mal)glc]-7-[6-(cum)glc]-3’-[6-(4-(6(caf)glc)cum)glc] (245), Cy3-[6-(mal)glc]-7-[6(cum)glc]-3’-[6-(4-(6-(caf)glc)caf)glc] (247), Cy3-[6(mal)glc]-7-[6-(caf)glc]-3’-[6-(4-(6-(caf)glc)caf)glc] (249), Cy3-[6-(mal)glc]-7-[6-(fer)glc]-3’-[6-(4-(6(fer)glc)caf)glc]e, Cy3-[6-(mal)glc]-7-[6-(cum)glc]-3’-[6(4-(6-(cum)glc)cum)glc] (244)

155 (1994) 156 (1996)

Phalaenopsis equestris P. intermedia P. leucorrhoda P. sanderiana, P. schilleriana

Flowers

180 (1997)

Sophronitis coccinea

Flowers

Vanda

Flowers

Cy3-[6-(mal)glc]7,3’-di[6-(sin)glc] (230), Cy3-glc-7,3’di[6-(sin)glc] (222) cumCy3-[mal-glc]7,3’-di-glce, Cy3,3’-di-glc-7-[6-(caf)glc] (204), Cy3-[6-(mal)glc]-7-[6-(caf)glc]-3’-glc (210), Cy3[6-(mal)glc]-7-[6-(fer)glc]-3’-glc (211), ferCy3,7,3’-triglce Cy3-[6-(mal)glc]7,3’-di[6-(fer)glc]d, Cy3-[6-(mal)glc]7,3’di[6-(sin)glc], Cy3-glc-7,3’-di[6-(sin)glc], Dp3-[malglc]7,3’-di[fer-glc]d, g, Dp3-[6-(mal)glc]7,3’-di[6(sin)glc] (382), Dp3-glc-7,3’-di[6-(sin)glc] (376), sinferCy3-[mal-glc]7,3’-di-glce, sinferDp3-[malglc]7,3’-di-glcd,e

Blue-purple flowers

(6’’’-(Dp3-[6’’-(glc)glc])) (6’’-(Ap7-glc))malonate (534), (6’’’-(Dp3-[6’’-(glc)glc])) (6’’-(Lt 7-glc))malonate (535)

9 (1994) 10 (2004)

Leaves

Cy3-[2-(gao)-6-(rha)glc](161), Cy3-[2-(gao)glc] (139), Cy3-[2,3di(gao)glc] (143), Cy3-[6-(rha)glc], Cy3-glc

Adventitious roots

Riccionidin A

Cultured cells Berries

Pn3-[2-(xyl)gal] (264) Cy3-[2-(xyl)gal]

133 (1994) 134 (1992)

Cell suspension

Hi3-[6-(cum)glc] (493), Hi3-glc (492), Mv3-[6-(cum)glc] (463), Mv3-glc, Pt3-[6-(cum)glc], Pt3-glc

97 (1998) 348 (2003)

Floral tissue

Cy3-glc

339 (1994)

Flowers

Cy3-[2-(xyl)-6-(caf)glc] (158), Cy3-[2-(xyl)-6-(Z-caf)glc] (159)g, Cy3-[2-(glc)-6-(cum)glc] (167)g, Cy3-[2-(glc)-6(Z-cum)glc] (168)g, Cy3-[2-(xyl)-6-(cum)glc] (156)g, Cy3-[2-(xyl)-6-(Z-cum)glc] (157)g

116 (1995)

Pontederiaceae Eichhornia crassipes DICOTYLEDONEAE Aceraceae Acer platanoides Anacardiaceae Rhus javanica Araliaceae Aralia cordata Fatsia japonica Apocyanaceae Catharanthus roseusg Balanophoraceae Cynomorium coccineumg Begoniaceae Begonia

176 (1998)

182 (2004)

193 (1992) 195 (1999) 82 (2000)

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TABLE 10.2 Occurrence of Anthocyanins Reported after 1992 — continued Taxon

Organ

Pigmenta

Referencesb

Bignoniaceae Arrabidaea chica

Leaves

6-OH-5-Me-Ap (517), 6-OH-5-Me-Lt (520), 5,4’-Me-6OH (521)

Boraginaceae Lobostemon

Flowers

Cy3,5-di-glc, Cy3-[6-(rha)glc], Cy3-glc, Dp3,5-di-glc, Dp3-[6-(rha)glc], Dp3-glc

299 (1997)

Skin, pulp

Cy3-glc/gal, Pt3-glc/gal, Pn3-glc/gal

349 (2003)

Flowers

Dp3-[6-(rha)glc]-7-[6-(4-(6-(4-(glc)hba)glc)hba)glc] (404), Dp3-[6-(rha)glc]-7-[6-(4-(6-(hba)glc)hba)glc] (387), Dp3-[6-(rha)glc]-7-glc (318), Dp3-[6-(rha)glc]-7[6-(4-(6-(4-(6-(hba)glc)hba)glc)hba)glc]

117 (1993)

Caprifoliaceae Lonicera caerulea

Fruits

350 (2004)

Sambucus canadensis

Flowers

Cy3,5-di-glc, Cy3-[6-(rha)glc], Cy3-glc, Pg3-glc, Pn3-[6(rha)glc], Pn3-glc Cy3-[6-(Z-cum)-2-(xyl)glc]-5-glc (196), Cy3-[6-(cum)-2(xyl)glc]-5-glc, Cy3-[2-(xyl)glc], Cy3-[2-(xyl)glc]-5-glc, Cy3,5-di-glc, Cy3-glc

Caryophyllaceae Dianthus caryophyllus

Flowers

Cy3,5-glc(6’’,6’’’-mal diester) (152), Cy3-[6-(mly)glc]-5glc, Pg3,5-glc(6’’,6’’’-mal diester) (38), Dp3,5glc(6’’,6’’’-mal diester) (339)h, Dp3-[6-(mly)glc]-5-glc (340)h, Dp3,5-di[6-(mly)glc] (347)h

214 (1998) 215 (2000) 216 (2000) 31 (2003)

Compositae (5Asteraceae) Cichorium intybus

Flowers

351 (2002)

Dendranthema grandiflorum Felicia amelloides Gynura aurantiaca cv.

Purple-red flowers Flowers Leaves

Dp3,5-di[6-(mal)glc] (346), Dp3-[6-(mal)glc]-5-glc (337), Dp3glc5-[6-(mal)glc], Dp3,5-di-glc Cy3-[3,6-di(mal)glc]

139 (1999) 248 (1994)

Helianthus annuusg

Lactuca sativa Senecio cruentus

Purple sunflower seeds Leaves Flowers

Evolvulus pilosus

Blue flowers

Dp3-[2-(rha)glc]-7-[6-(mal)glc] (357) Cy3-[6-(mal)glc]-7-[6-(4-(6-(caf)glc)caf)glc]-3’-[6-(caf)glc] (248) Cy3-ara, Cy3-glc, Cy3-xyl, Cy3-[di(mal)-glc], Cy3[di(mal)-xyl]d, Cy3-[mal-ara], Cy3-[mal-glc], Cy3-[mal-xyl] Cy3-[6-(mal)glc] Cy3-[6-(mal)glc]-3’-[6-(caf)glc] (186), Cy3-glc-3’-[6(caf)glc] (172), Cy3,3’-glc, Pg3-[6-(mal)glc], Pg3-[6(mal)glc]-7-[6-(4-(6-(caf)glc)caf)glc] (85), Pg3-[6(mal)glc]-7-[6-(caf)glc] (53) Dp3-[6-(4-(6-(3-(glc)caf)glc)caf)glc]-5-[6-(mal)glc] (397), Dp3,5-di-glc, Dp3-[6-(4-(6-(3-(glc)caf)glc)caf)glc]-5glc (392)

Burseraceae Dacryodes edulisg Campanulaceae Campanula isophylla C. carpatica C. poskarshyanaf

86 (2001) 87 (2002)

125 (1995)

206 (1997)

197 (1994)

352 (1996) 353 (1993) 354 (1995)

313 (1994) 223 (1996)

continued

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TABLE 10.2 Occurrence of Anthocyanins Reported after 1992 — continued Taxon

Organ

Convolvulaceae Ipomoea asarifolia

Flowers

Ipomoea batatis (batatas)

Purple tubers

Ipomoea purpurea

Brownish-red flowers

Ipomoea purpurea

Violet-blue flowers

Ipomoea purpurea

Red-purple flowers

Pharbitis nil/Ipomoea nil

Flowers

Coriariaceae Coriaria myrtifoliag Cornaceae Cornus suecica Crassulaceae Crassula, Cotyledon, Tylecodon,f, g 22 spp. Cruciferae (Brassicaceae) Brassica campestris

Pigmenta

Referencesb

Cy3-[2-(6-(caf)glc)-6-(4-(6-(hca)glc)caf)glc]-5-glc (243), Cy3-[2-(6-(cum)glc)-6-(4-(6-(cum)glc)caf)glc]-5-glc (241), Cy3-[2-(6-(caf)glc)-6-(caf)glc)]-5-glc, Cy3-[2-(6(cum)glc)-6-(caf)glc]-5-glc (214) Cy3-[2-(glc)glc]-5-glc, Cy3-[2-(6-(cum)glc)glc]-5-glc (199), Cy3-[6-(caf)-2-(glc)glc]-5-glc (205), Pn3-[6(caf)-2-(glc)glc]-5-glc, Cy3-[2-(6-(hba)glc)-6-(caf)glc]5-glc (212), Cy3-[2-(6-(caf)glc)-6-(caf)glc]-5-glc, Cy3[2-(6-(fer)glc)-6-(caf)glc]-5-glc (217), Pn3-[2-(6(fer)glc)-6-(caf)glc]-5-glc, Pn3-[2-(6-(caf)glc)-6(caf)glc]-5-glc, Pn[2-(6-(hba)glc)-6-(caf)glc]-5-glc (291) Cy3-[2-(6-(4-(6-(3-(glc)caf)glc)caf)glc)glc] (236), Cy3-[2(glc)glc], Cy3-[2-(6-(caf)glc)glc] (174), Cy3-[2-(glc)-6(caf)glc] (173) Cy3-[2-(6-(3-(glc)caf)glc)-6-(4-(6-(caf)glc)caf)glc]-5-glc (255), Cy3-[2-(6-(3-(glc)caf)glc)-6-(caf)glc]-5-glc (235), Cy3-[2-(6-(caf)glc)-6-(caf)glc]-5-glc (215), Cy3-[2(glc)glc]-5-glc Pg3-[2-(6-(3-(glc)caf)glc)-6-(4-(6-(caf)glc)caf)glc]-5-glc (93), Pg3-[2-(6-(caf)glc)-6-(4-(6-(caf)glc)caf)glc]-5-glc (91), Pg3-[2-(6-(caf)glc)-6-(caf)glc]-5-glc (76), Pg3-[2(6-(3-(glc)caf)glc)-6-(caf)glc]-5-glc, Pg3-[2-(glc)-6(caf)glc]-5-glc Cy3-[2-(glc)-6-(4-(glc)caf)glc]-5-glc (232), Cy3-[6-(3(glc)caf)glc]-5-glc (206), Pg3,5-di-glc, Pg3-[2-(6-(3(glc)caf)glc)-6-(4-(6-(caf)glc)caf)glc]-5-glc, Pg3-[2-(6(caf)glc)-6-(caf)glc]-5-glc, Pg3-[2-(glc)-6-(caf)glc]-5-glc (64), Pg3-[2-(6-(cum)glc)glc]-5-glc (60), Pg3-[2-(glc)-6(4-(glc)caf)glc]-5-glc (89), Pg3-[6-(3-(glc)caf)glc] (45), Pg3-[6-(3-(glc)caf)glc]-5-glc (65), Pg3-[6-(caf)glc] (28), Pg3-glc, Pn3,5-di-glc, Pn3-[2-(glc)-2-(6-(glc)caf)glc]-5glc, Pn3-[2-(glc)glc]-5-glc, Pn3-[6-(3-(glc)caf)glc] (285), Pn3-[6-(3-(glc)caf)glc]-5-glc (290), Pn3-glc

355 (1998) 27 (2003)

Fruits

Dp-, Cy-, Pt-, Pn-, Mv3-glc, Dp-, Cy-, Pt-, Pn-, Mv3-gal

361 (2002)

Fruits

Cy3-[2-(glc)gal] (114), Cy3-[2-(glc)glc], Cy3-glc, Cy3-gal

23 (1998)

Flower

Cy3-[2-(glc)glc], Cy3-[2-(xyl)glc], Cy3-glc, Dp3-[2(xyl)glc], Pn3-glc

298 (1995)

Stem

Cy[2-(2-(sin)glc)-6-(fer)glc]-5-[6-(mal)glc] (229), Cy[2-(2(sin)glc)-6-(cum)glc]-5-[6-(mal)glc] (227), Cy[2-(2(sin)glc)-6-(fer)glc]-5-glc, Cy[2-(2-(sin)glc)-6(cum)glc]-5-glc

178 (1997)

357 (1992) 356 (1997) 188 (1999) 35 (2000)

358 (1998)

305 (1995)

306 (1996)

312 (1993) 309 (1994) 359 (1996) 310 (2001) 360 (2001)

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The Anthocyanins

TABLE 10.2 Occurrence of Anthocyanins Reported after 1992 — continued Taxon

Organ

Pigmenta

Referencesb

Matthiola incana

Leaves and stems Flowers

Raphanus sativus

Callus

Ericaceae Vaccinium padifolium

Berries

Cy3-[6-(rha)-2-(xyl)glc], Dp3-rha, Mv3-[2-(xyl)glc] (451), Mv3-[6-(rha)glc], Pn3-[2-(xyl)glc], Pn3-[6-(rha)-2-(xyl)glc] (274), Pt3-[2-(xyl)glc] (423), Pt3-[6-(rha)-2-(xyl)glc] (430)

124 (1999) 25 (2000)

Euphorbiaceae Acalypha hispida

Flowers

Cy3-[(2-(gao)-6-(rha)gal] (160)d, Cy3-[2-(gao)gal], Cy3-gal

130 (2003)

Flowers

Cy3-[6-(rha)gal]-5-[6-(cum)glc] (180), Cy3-gal-5-[6(cum)glc] (162), Dp3-[6-(rha)gal]-5-glc (316), Dp3-[6(rha)gal]-5-[6-(cum)glc] (361), Dp3-[6-(rha)gal]-5-[6(Z-cum)glc] (362), Dp3-[6-(rha)glc]-5-[6-(cum)glc] (363), Dp3-[6-(rha)glc]-5-[6-(Z-cum)glc] (364), Dp3[6-(rha)gal]-5-[6-(fer)glc] (367), Dp3-[6-(rha)gal]-5-[6(Z-fer)glc] (368), Dp3-gal-5-[6-(cum)glc] (342), Dp3gal-5-[6-(Z-cum)glc] (343), Dp3-glc-5-[6-(cum)glc] Dp3,3’-di-glc-5-[6-(caf)glc] (369), Dp3,3’-di-glc-5-[6(cum)glc] (366), Dp3-glc-5-,3’-di[6-(caf)glc], Dp3-glc5-[6-(caf)glc]-3’-[6-(cum)glc] (373), Dp3-glc-5-[6(cum)glc] (344), Dp3-glc-5-[6-(cum)glc]-3’-[6-(caf)glc] (374) Cy3-glc, Cy3-glc-5,3’-di[6-(caf)glc] (216), Cy3-glc-5-[6(caf)glc] (171), Cy3-glc-5-[6-(cum)glc] (165)

129 (1993) 123 (1996)

Arabidopsis thaliana

Gentianaceae Eustoma grandiflorum, after genetical transformation

Gentiana

Blue flowers

Gentiana

Pink flowers

Cy3-[6-(4-(glc)cum)-2-(2-(sin)xyl)glc]-5-[6-(mal)glc] (239)d Cy3-[2-(2-(sin)xyl)-6-(caf)glc]-5-[6-(mal)glc] (225), Cy3[2-(2-(sin)xyl)-6-(cum)glc]-5-[6-(mal)glc] (224), Cy3[2-(2-(sin)xyl)-6-(fer)glc]-5-[6-(mal)glc] (226), Cy3-[2(2-(sin)xyl)-6-(fer)glc]-5-glc (218), Pg3-[2-(2-(fer)xyl)6-(fer)glc]-5-[6-(mal)glc] (83), Pg3-[2-(2-(sin)xyl)-6(cum)glc]-5-[6-(mal)glc] (84), Pg3-[2-(2-(sin)xyl)-6(cum)glc]-5-glc (75), Pg3-[2-(xyl)glc]-5-glc, Pg3-[2(xyl)-6-(cum)glc]-5-[6-(mal)glc] (68), Pg3-[2-(2(sin)xyl)-6-(fer)glc]-5-[6-(mal)glc] (86), Pg3-[2-(2(sin)xyl)-6-(fer)glc]-5-glc (81), Pg3-[2-(xyl)-6-(fer)glc]5-[6-(mal)glc] (70), Pg3-glc Cy3-[2-(6-(fer)glc)-6-(caf)glc]-5-glc, Pg3-[2-(2-(fer)glc)6-(fer)glc]-5-glc (80), Pg3-[2-(6-(caf)glc)-6-(caf)glc]-5glc, Pg3-[2-(6-(caf)glc)-6-(cum)glc]-5-glc (73), Pg3-[2(6-(caf)glc)-6-(fer)glc]-5-glc (77), Pg3-[2-(6-(fer)glc)-6(caf)glc]-5-glc (78), Pg3-[2-(6-(fer)glc)-6-(cum)glc]-5glc (74), Pg3-[2-(6-(fer)glc)-6-(fer)glc]-5-glc (79), Pg3[2-(6-(fer)glc)glc]-5-glc (67), Pg3-[2-(glc)-6-(caf)glc]-5glc, Pg3-[2-(glc)-6-(cum)glc]-5-[6-(mal)glc] (71), Pg3[2-(glc)-6-(cum)glc]-5-glc (61), Pg3-[2-(glc)-6-(fer)glc]5-[6-(mal)glc] (72), Pg3-[2-(glc)-6-(fer)glc]-5-glc (66)

167 (2002) 177 (1995) 173 (1996)

315 (1998) 314 (2002)

154 (1997)

153 (1995)

continued

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Flavonoids: Chemistry, Biochemistry, and Applications

TABLE 10.2 Occurrence of Anthocyanins Reported after 1992 — continued Taxon

Organ

Geraniaceae Geranium pratense G. sanguineum G. Johnson’s Blue

Flowers

Geranium sylvaticum

Flowers

Pelargonium domesticum (‘Dubonnet’)

Flowers

Grossulariaceae Ribes nigrum

Labiatae (5Lamiaceae) Ajuga reptans

Berries

Flowers, and cell cultures

Pigmenta

Mv3,5-di-glc, Mv3-glc, Mv3-glc-5-[6-(ace)glc] (466), Mv5-glc Cy3,5-di-glc, Cy3-glc, Dp3-glc, Mv3,5-di-glc, Mv3-[6(ace)glc]-5-glc (465) Cy3-glc-5-[6-(ace)glc] (147), Cy3,5-di-glc, Dp3-glc-5-[6(ace)glc] (334), Dp3,5-di-glc, Mv3,5-di-glc, Mv3-glc5-[6-(ace)glc], Pg3-glc-5-[6-(ace)glc], Pg3,5-di-glc, Pn3-glc-5-[6-(ace)glc] (282), Pn3,5-di-glc, Pt3-glc-5[6-(ace)glc] (437), Pt3,5-di-glc Cy3-[6-(rha)glc], Dp3-glc (pyranocyanidin A, pyranocyanidin B, pyranodelphinin A, and pyranodelphinin B)d, i Cy3-[6-(cum)glc], Cy3-[ara], Cy3-glc, Dp3-[6-(cum)glc], Dp3-[6-(rha)glc], Mv3-[6-(rha)glc], Mv3-glc, Pg3-[6(rha)glc], Pg3-glc, Pn3-[6-(rha)glc], Pn3-glc, Pt3-[6(rha)glc], Pt3-glc (pyranocyanidin C, pyranocyanidin D, pyranodelphinin C, and pyranodelphinin D)d

Referencesb

211 (1997) 210 (1995) 317 (1998)

88 (2000) 89 (2001) 365 (2002) 91 (2002)

Lamium, Salvia, Thymus, 49 spp. Ocimum basilicumg (Dark Opal, Holy Sacred Red, Opal, Osmin Purple, Purple Bush, Purple Ruffles, Red Rubin, Rubin) Salvia patens

Flowers

Dp3-[2-(6-(cum)glc)-6-(cum)glc]-5-[6-(mal)glc] (379), Cy3-[2-(6-(cum)glc)-6-(cum)glc]-5-[6-(mal)glc] (223), Dp3-[2-(glc)glc]-5-glc, Cy3-[2-(glc)glc]-5-glc, Dp3-[2-(6-(fer)glc)-6-(cum)glc]-5-[6-(mal)glc] (380)d, Dp3-[2-(6-(fer)glc)-6-(fer)glc]-5-[6-(mal)glc] (381), Cy3-[2-(6-(cum)glc)-6-(cum)glc]-5-glc (213), Dp3-[di-fer(2glc-glc)]-5-glce, Cy3-[fer-cum(2glc-glc)]-5-[mal-glc]e Cy3-[6-(cum)glc]-5-[4-(mal)-6-(mal)glc] (354)

Flowers and leaves

Cy3,5-di-glc, Cy3-glc, Cy3-[cum-glc], Cy3-[cum-glc]-5glc, Pn3,5-di-glc, Pn3-[cum-glc]-5-glc

320 (1998)

Flowers

226 (1994)

Salvia uliginosa Leguminosae (=Fabaceae) Amphithalea, Coelidium, Hypocalyptus, Liparia,f, g 10 spp.

Flowers

Dp3-[6-(cum)glc]-5-[6-(mal)glc] þ apigenin7,4’-diglc þ Mg (protodelphin) Dp3-[6-(cum)glc]-5-[4-(ace)-6-(mal)glc] (353) Cy3-glc, Cy3-[6-(ace)glc], Cy3-[6-(cum)glc], Mv3-glc, Pn3-glc, Cy3-[2-(glc)glc], Pg3-[2-(glc)glc]

326 (1995)

Flowers

113 (1996) 114 (2001)

200 (1992)

209 (1999)

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The Anthocyanins

TABLE 10.2 Occurrence of Anthocyanins Reported after 1992 — continued Taxon

Organ

Pigmenta

Referencesb

Pg5-gald, e Dp3-[2-(rha)-6-(mal)glc] (337), Dp3-[2-(rha)glc], Dp3-[6-(mal)glc], Dp3-[6-(mal)glc]-3’-[6-(4-(6(cum)glc)cum)glc]5’-[6-(cum)glc] (409), Dp3-[6(mal)glc]-3’-[6-(4-(6-(4-(glc)cum)glc)cum)glc]5’-[6-(4(glc)cum)glc] (415), Dp3-[6-(mal)glc]-3’-[6-(4-(6-(4(glc)cum)glc)cum)glc]5’-glc (407), Dp3-[6-(mal)glc]3’-[6-(4-(6-(cum)glc)cum)glc]5’-[6-(4-(glc)cum)glc] (411), Dp3-[6-(mal)glc]-3’-[6-(4-(6-(4(glc)cum)glc)cum)glc]5’-[6-(cum)glc] (410), Dp3-[6(mal)glc]-3’-[6-(4-(6-(cum)glc)cum)glc]5’-glc (395), Dp3-[6-(mal)glc]-3’-[6-(4-(glc)cum)glc]5’-[6-(cum)glc] (396), Dp3-[6-(mal)glc]-3’-[6-(4-(glc)cum)glc]5’-glc (388), Dp3-[6-(mal)glc]-3’,5’-di-[6-(cum)glc] (378), Dp3-[6-(mal)glc]-3’-[6-(cum)glc]5’-glc (371), Dp3-[6-(mal)glc]-3’,5-di-glc (358), Dp3-glc, Dp3-glc-3’,5’-di-[6-(4-(glc)cum)glc] (405), Dp3-glc-3’-[6-(4-(glc)cum)glc]5’-glc (386) Cy3-glc, Dp3-glc, Pt3-glc (Dp3-[6-(mal)glc]apigenin7-[6-(mal)glc]malonic residue þ Fe)d, (Dp3-[6-(mal)glc]luteolin7-[6(mal)glc]malonic residue þ Fe)d Cy3-[6-(mal)glc], Pg3-[6-(mal)glc]

362 (1994) 144 (1996) 145 (1998) 141 (2003)

Dp3-glc Pn3-glc, Pn3-[6-(rha)glc] Cy3,5-di-glc, Cy3-glc, Dp3-glc, Pg3-glc, Pt3-glc, Pt3,5-di-glc, Mv3-glc, Mv3,5-di-glc Dp3-[2-(xyl)gal]-5-glc (314), Dp3-[2-(xyl)gal]-5-[6(ace)glc] (356) Cy3-glc, Cy3-[6-(cum)glc] Dp3-[6-(rha)glc]-5-glc, Pt3-[6-(rha)glc]-5-glc, Mv3-[6’’rha)glc]-5-glc Cy Cy3-glc, Mv3-glc, Pt3-glc Cy3-glc, Pn3-glc, Cy3-[6-(ace)glc], Pn3-[6-(ace)glc], Cy3-[6-(cum)glc]

322 (1996) 322 (1996) 323 (1997) 363 (2001) 131 (2000)

Cassia auriculata Clitoria ternatea

Heartwood

Glycine max Lupinus (Russell hybrids)

Seed coats Blue flowers

Lupinus (Russell hybrids) Phaseolus coccinesu Phaseolus lunatus Phaseolus vulgaris g

Pink flowers Seed coats Seed coats Seed coats

Pisum spp.

Purple pod

Podalyria,g 7 spp. Vicia villosa

Flowers Blue flowers

Vigna angularis Vigna subterranean Virgilia,g 2 spp.

Grains Grains Flowers

Linaceae Linum grandiflorum

Flowers

Cy3-[6-(rha)glc], Dp3-[2-(xyl)-6-(rha)glc] (312), Dp3-[6-(rha)glc]

24 (1995)

Lobeliaceae Lobelia erinus

Flowers

Cy3-[6-(4-(Z/E-cum)rha)glc]-5-[6-(mal)glc]-3’-[6(caf)glc] (238)

118 (1995) 365 (1996)

Flowers

Mv3-[6-(mal)glc]-5-glc (468), Mv3-[6-(mal)glc] (462)

339 (1994)

Flowers

Mv3-[6-(cum)glc]-5-[2-(ace)xyl] (471)

208 (1993)

Malvaceae Lavatera maritimag Melastomataceae Tibouchina urvilleana

363 (2001) 225 (1993)

225 (1993)

325 (1994) 321 (1998) 322 (1996) 324 (1997) 325 (1994)

continued

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Flavonoids: Chemistry, Biochemistry, and Applications

TABLE 10.2 Occurrence of Anthocyanins Reported after 1992 — continued Taxon Myrtaceae Eugenia umbelliflora g Nymphae´aceae Nymphae´a alba

Nymphae´a caerulea (=N. capensis) Nymphae´a marliacea f

Organ

Papaveraceae Meconopsis grandis,g M. horridula, and M. betonicifolia Passifloraceae Passiflora edulis Passiflora suberosa

Referencesb

Berries

Cy3-glc, Dp3-glc, Mv3-glc, Pg3-glc, Pn3-glc, Pt3-glc

366 (2003)

Leaves

Cy3-[2-(gao)-6-(ace)gal], Cy3-[6-(ace)gal] (129), Cy3-gal, Dp3-[2-(gao)-6-(ace)gal], Dp3-[2-(gao)gal], Dp3-[6(ace)gal], Dp3-gal Dp3’-[2-(gao)gal] (325), Dp3’-[2-(gao)-6-(ace)gal] (331)

192 (2001)

Cy3-[2-(gao)-6-(ace)gal] (142), Dp3-gal, Dp3-[6-(ace)gal] (322), Dp3-[2’’’’(gao)gal] Dp3-[2-(gao)-6-(ace)gal] (330)

367 (1997)

Leaves

Mv3-[6-(rha)glc]-5-glc, Mv3-mal-[6-(rha)glc]-5-glc, Mv3di-mal-[6-(rha)glc]-5-glc

368 (2001)

Flowers

Cy3-[2-(xyl)-6-(mal)glc]-7-glc (190)

127 (1996) 128 (2001)

Fruit Fruit

Cy3-[6-(mal)glc], Cy3-glc, Pg3-glc Cy3-[6-(mal)glc], Cy3-glc, Dp3-[6-(mal)glc], Dp3-glc, Pg3-[6-(mal)glc], Pg3-glc, Pt3-[6-(mal)glc], Pt3-glc

369 (1997) 369 (1997)

Flowers Leaves Flowers

Oxalidaceae Oxalis triangularis g

Pigmenta

26 (1999)

191 (1998)

Primulaceae Cyclamen persicum (Bonfire) Cyclamen persicum (Sierra Rose) Ranunculaceae Aconitum chinense Anemone coronaria

Flowers Flowers

Pn3-[2-(rha)glc] (268)d Pn3,5-di-glc, Cy3,5-di-glc, Mv3,5-di-glc

140 (1999) 140 (1999)

Flowers Flowers

184 (1994) 132 (2001) 28 (2002) 29 (2003)

Consolida armeniaca

Flowers

Delphinium hybridum

Flowers

Dp3-[6-(rha)glc]-7-[6-(4-(6-(hba)glc)hba)glc] Cy3-[2-(2-(caf)glc)-6-(3-(2-tar)mal)gal]-7-[6-(caf)glc]-3’-glu (246), Cy3-[2-(2-(caf)glc)-6-(mal)glc]-7-[6-(caf)glc]-3’-glu (240), Cy3-[2-(2-(caf)glc)glc]-7-[6-(caf)glc]-3’-glu (234), Dp3-[2-(2-(caf)glc)gal-(3-(2-tar)mal)gal]-7-[6-(caf)glc] (383), Dp3-[2-(2-(caf)glc)-6-(3-(2-tar)mal)gal]-7-[6(caf)glc]-3’-glu (401), Dp3-[2-(2-(caf)glc)-6-(mal)gal]-7[6-(caf)glc]-3’-glu (398), Dp3-[2-(2-(caf)glc)gal]-7-[6(caf)glc]-3’-glu (393), Pg3-[2-(xyl)-6-(mal)gal] (32), Pg3[2-(xyl)-6-(Me-mal)gal] (33), Pg3-[2-(xyl)gal], Pg3-[2(xyl)-6-(3-(3-(4-(glc)caf)2-tar)mal)gal] (82) Dp3-[6-(mal)glc]-7-[6-(4-(6-(hba)glc)hba)glc] (377)d, Dp3[6-(mal)glc]-7-[2-(glc)-6-(4-(6-(hba)glc)hba)glc] (394)d, Dp3-[6-(mal)glc]-7-[2-(6-(hba)glc)-6-(4-(6(hba)glc)hba)glc] (400)d, Dp3-[6-(mal)glc]-7-[glc-2-(6(hba)glc)-6-(4-(6-(hba)glc)hba)glc]e Dp3-[6-(rha)glc], Dp3-[6-(rha)glc]-7-glc, Pg3,7-di-glc, Pg3[6-(mal)glc]-7-[6-(4-(glc)hba)glc] (69), Pg3-[6-(mal)glc]7-glc (36), Pg3-[6-(rha)glc]-7-[6-(4-(glc)hba)glc] (87), Pg3-[6-(rha)glc]-7-[6-(hba)glc] (57), Pg3-[6-(rha)glc]-7glc (21), Pg3-glc-7-[6-(4-(glc)hba)glc] (58)

115 (1996)

119 (1998) 331 (1999)

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The Anthocyanins

TABLE 10.2 Occurrence of Anthocyanins Reported after 1992 — continued Taxon

Pigmenta

Organ

Referencesb

Pulsatilla cernua Ranunculus asiaticus

Flowers Flower

Pg3-[2-(2-(caf)glc)gal] (44) Cy3-[2-(xyl)-6-(mal)glc] (148), Cy3-[2-(xyl)glc], Dp3-[2-(xyl)-6-(mal)glc] (335), Dp3-[2-(xyl)glc]

Rhamnaceae Ceanothus papillosus

Flowers

Dp3-[6-(rha)glc]7,3’-di[6-(cum)glc] (389), Dp3-[6-(rha)glc]-7-[6-(cum)glc]-3’-glc (384)

32 (1997)

Rosaceae Fragaria
ananassa

Berries

A5-CarboxypyranoPg3-glc (523), Pg3-glc Afzelechin(4a ! 8)Pg3-glc (530), Epiafzelechin (4a ! 8)Pg3-glc (531), Catechin (4a ! 8)Pg3-glc (532), Epicatechin (4a ! 8)Pg3-glc (533) Cy3-[2-(glc)-6-(rha)glc], Cy3-[6-(rha)glc], Cy3-glc

19 (2004) 13 (2004)

Prunus cerasus (Balaton, Montmorency) Rosa (Cinnamomeae, Chinenses, Gallicanae), 44 spp. Rosa hybrida Rubus iaciniatus Rubiaceae Cephaelis subcoriaceag Rutaceae Citrus sinensis (Florida)g Sapindaceae Litchi chinensis Sonn.

Scrophulariaceae Mimulus cardinalis g Mimulus lewisii g Solanaceae Petunia f (Baccara, Carpet, Celebrity, Fantasy, Fulcon, Madness, Prime Time), 17 spp. Petunia ‘‘Mitchell’’ (P. axillaries
P. hybrida) g Petunia exserta Petunia guarapuavensis Petunia hybrida

Fruit

22 (1998) 126 (1996)

370 (1997) 300 (1995) 301 (2000)

Flower Berries

Cy3,5-di-glc, Cy3-[2-(glc)glc], Cy3-[6-(cum)glc], Cy3-[6-(rha)glc], Cy3-glc, Pg3,5-di-glc, Pg3-glc, Pn3,5-di-glc, Pn3-[6-(cum)glc], Pn3-[6-(rha)glc] Rosacyanin B (526) Cy3-[6-di-(oxa)glc]d, g

Fruits

Cy3-glc

339 (1994)

Juice

Cy3-[6-(mal)glc], Cy3-glc

371 (2002)

Pericarp

Cy3-[6-(rha)glc], Cy3-glc, Cy3-gal, Pg3,7-di-glc

372 (1993) 373 (2000) 374 (2004)

Flowers Flowers

Cy3-glc, Pg3-glc Cy3-glc, Pg3-glc

375 (1997) 375 (1997)

Pink flowers

Pn3-[6-(4-(4-(6-(caf)glc)cum)rha)glc]-5-glc (296), Pn3[6-(4-(4-(glc)cum)rha)glc]-5-glc (295), Pn3-[cum-6(rha)glc]-5-glc, Pn3caf [6-(rha)glc]-5-glc, Pn3-[6(rha)glc]-5-glc Pt3-[cum-6-(rha)glc]-5-glc, Pt3-[6-(rha)glc]-5-glc, Pt3[caf-6-(rha)glc]-5-glc

165 (2004)

Flowers

Leaves

Flowers Flowers Flowers

Cy3-[6-(rha)glc], Cy3-glc, Pg3-[6-(rha)glc], Pg3-glc Mv3-[6-(4-(4-(6-(caf)glc)cum)rha)glc]-5-glc (482), Mv3-[6-(4-(4-(6-(caf)glc)caf)rha)glc]-5-glc (484) Mv3-[6-(4-(4-(6-(caf)glc)caf)rha)glc]-5-glc, Mv3-[6-(4(4-(6-(caf)glc)cum)rha)glc]-5-glc, Mv3-[6-(4-(4-(6(cum)glc)cum)rha)glc]-5-glc (481), Mv3-[6-(4-(4-(6(fer)glc)cum)rha)glc]-5-glc (483), Mv3-[6-(4(caf)rha]-5-glc (478), Mv3-[6-(4-(Z-cum)rha)glc]-5glc (477), Pt3-[6-(4-(4-(6-(caf)glc)cum)rha)glc]-5-glc (445)

17 (2002) 57 (2002)

376 (1998)

377 (1999) 162 (1997) 159 (1998) 168 (1999) 161 (2001)

continued

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TABLE 10.2 Occurrence of Anthocyanins Reported after 1992 — continued Taxon

Organ

Petunia integrifolia subsp. inflata Petunia occidentalis

Strains

Petunia reitzii

Flowers

Solanum melongena

Skin

Solanum stenotomum g

Tubers

Solanum andigena
Solanum tuberosum Solanum tuberosum (Congo) Solanum tuberosum

Tubers

Theaceae Camellia sinensis Visnea mocanerag Umbelliferae (=Apiaceae) Daucus carota (Nentes scarlet-104) Glehnia littoralis Verbenaceae Verbena hybrida

Flowers

Tubers and shoots Tubers

Pigmenta Mv3-[6-(4-(4-(6-(caf)glc)cum)rha)glc] (480), Mv3[6-(4-(caf)rha)glc], Mv3-[6-(4-(cum)rha)glc] Dp3-[6-(4-(caf)rha)glc]-5-glc (365), Mv3-[caf-glcrut]e, Pt3-[6-(4-(4-(glc)cum)rha)glc]-5-glc (444), Pt3-[caf-glc-caf-rut]-5-glce, Pt3-[caf-glc-cumrut]-5-glc (445)e, Pt3-[caf-glc-rut]e, Pt3-[cumglc-rut]-5-glce Dp3-[6-(4-(4-(6-(caf)glc)cum)rha)glc]-5-glc (390), Dp3-[6-(4-(4-(glc)cum)rha)glc]-5-glc (385), Dp3-[6-(rha)-2-(caf)glc]-5-glc, Dp3-[6-(rha)-2(cum)glc]-5-glc, Dp3-[6-(rha)-2-(Z-cum)glc]-5glc, Dp3-[6-(rha)glc], Dp3-[6-(rha)glc]-5-glc, Pt3-[6-(rha)glc]-5-glc, Pt3-[6-(rha)-2-(caf)glc]-5glc, Pt3-[6-(rha)-2-(cum)glc]-5-glc, Pt3-[6-(rha)-2-(Z-cum)glc]-5-glc Dp3-[6-(4-(cum)rha)glc]-5-glc, Dp3-[6-(4-(Z-cum)rha)glc]-5-glcd Dp3-[cum-6-(rha)glc]-5-glc, Mv3-[cum-6(rha)glc]-5-glc, Mv3-[fer-6-(rha)glc]-5-glc, Pn3[caf-6-(rha)glc]-5-glc, Pn3-[cum-6-(rha)glc]-5glc, Pn3-[fer-6-(rha)glc]-5-glc, Pt3-[caf-6(rha)glc]-5-glc, Pt3-[cum-6-(rha)glc], Pt3-[cum6-(rha)glc]-5-glc, Pt3-[Z-cum-6-(rha)glc]-7-glce, Pt3-[fer-6-(rha)glc]-5-glc Pg3-[6-(4-(fer)rha)glc]-5-glc (62), Pg3-[6-(4(cum)rha)glc]-5-glc Mv3-[6-(4-(fer)rha)glc]-5-glc (479), Pt3-[6-(4(fer)rha)glc]-5-glc (443) Pn3-[6-(4-(caf)rha)glc]-5-glc (288), Pn3-[6-(4(cum)rha)glc]-5-glc, Pt3-[6-(4-(caf)rha)glc]-5glc (442), Pt3-[6-(4-(cum)rha)glc]-5-glc (441)

Referencesb 163 (1999) 160 (1999)

164 (2000)

378 (2001) 379 (2003)

171 (1998) 172 (2000) 169 (2003)

Leaves Fruits

Cy3-gal, Dp3-[6-(cum)gal] (326), Dp3-gal Cy3-gal, Cy3-glc, Dp3-glc, Mv3-glc, Pn3-glc, Pt3-glc

158 (2001) 380 (1996)

Cell culture

Cy3-[2-(xyl)gal], Cy3-glc

381 (2000)

Petiole-derived callus cultures

Cy3-[2-(xyl)-6-(6-(fer)glc)glc] (203)

Flowers

Cy3,5-di[6-(ace)glc] (181), Cy3-[6-(mal)glc], Pg3,5-di[6-(ace)glc] (47), Pg3,5-di-glc, Pg3-[6-(ace)glc], Pg3-[6-(ace)glc]-5-glc, Pg3-[6-(mal)glc], Pg3-[6-(mal)glc]-5-[6-(ace)glc] (48), Pg3-glc-5-[6-(ace)glc] (31)

34 (1998)

382 (1991) 383 (1995) 384 (1995)

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TABLE 10.2 Occurrence of Anthocyanins Reported after 1992 — continued Taxon Vitaceae Vitis vinifera g

Organ

Berries

Pigmenta

Referencesb

Dp-, Cy-, Pt3-[6-(ace)glc], Pn3-[6-(ace)glc] (278), Mv3[6-(ace)glc] (461), Dp3-[6-(cum)glc] (327), Cy-, Pt-, Pn-, Mv3-[6-(cum)glc], Dp-, Cy-, Pt-, Pn-, Mv3-glc, Dp-, Pt3,5-di-glc, Pn3-[6-(caf)glc] (281), Mv3-[6(caf)glc]

385 (1995) 386 (2004)

Notes: ace, acetic acid; oxa, oxalic acid; mal, malonic acid; suc, succinic acid; mly, malic acid; hba, p-OH-benzoic acid; gao, gallic (tri-OH-benzoyl) acid; cum, p-coumaric acid; caf, caffeic acid; fer, ferulic acid; sin, sinapic acid; hca, 3,5diOHcinnamic acid; tar, tartaric acid; ara, arabinose; xyl, xylose; rha, rhamnose; gal, galactose; glc, glucose; glu, glucuronic acid; 2-(xyl)glc, sambubiose; 2-(xyl)gal, lathyrose; 2-(rha)glc, neohesperidose; 6-(rha)gal, robinose; 6(rha)glc, rutinose; 2-(glc)glc, sophorose; 3-(glc)glc, laminariobiose; 6-(glc)glc, gentiobiose. a

See Table 10.1 for anthocyanidin abbreviations and linkage positions. Numbers in brackets refer to the year of the publication. c Numbers in bold represent the first report of the pigments not listed in previous editions of The Flavonoids.1–4 See Appendix A. d Possibly new anthocyanins. e Pigments assigned tentatively. f Each genus involved may include one or more samples (species or plant organs). Each sample contains one or more of the listed anthocyanins. g Structures are based on TLC and HPLC or MS data. h Produced by genetically modified violet carnations. i Produced during experimental workup. b

new anthocyanins based on rutinose have also been reported from Campanula (Campanulaceae),117 Lobelia (Lobeliaceae),118 Ceanothus (Rhamnaceae),32 Delphinium (Ranunculaceae),119 Lilium,120 Tulipa (Liliaceae),121,122 and Alstroemeria (Alstroemeriaceae).106 It is interesting to observe that a transgenic Eustoma (Gentianaceae) line produced by insertion of an Antirrhinum majus cDNA coding for UDP-glucosyl:flavonoid-3-O-glucosyltransferase contained in its petals significant levels of 3-rutinoside and 3-glucoside derivatives of delphinidin, in which glucose has replaced the 3-O-linked galactose present in the original anthocyanins of the nontransformed plants.123 After 1992, sambubiose units have mainly been found in new anthocyanins from Matthiola and Arabidopsis (Cruciferae) (Table 10.2), and in some new anthocyanins from Begonia (Begoniaceae),116 Vaccinium (Ericaceae),124 Sambucus (Caprifoliaceae),125 Ranunculus (Ranunculaceae),126 and Meconopsis (Papaveraceae).127,128 Among the disaccharides with more limited occurrence in anthocyanins, new reports on robinobiose include six 3-[6-(rhamnosyl)galactosides-5-glycosides of delphinidin and cyanidin isolated from purple Lisianthus (Gentianaceae) flowers,129 in addition to cyanidin 3-[2(galloyl)-6-(rhamnosyl)galactoside] from red flowers of the chenille plant Acalypha hispida (Euphorbiaceae).130 Two new anthocyanins containing lathyrose, delphinidin 3-[2-(xylosyl)galactoside]-5-[6-(acetyl)glucoside] and its deacetylated derivative, have been isolated from purple pods of pea (Pisum spp.).131 Both pigments showed moderate stability and antioxidative activity in a neutral aqueous solution. Three anthocyanins with a pelargonidin 3-lathyroside skeleton acylated with malonic acid have been isolated from scarlet flowers of Anemone coronaria.132 A minor anthocyanin accumulated in the cultured cells of Aralia cordata (Araliaceae) has been identified as peonidin 3-lathyroside.133 This disaccharide has

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previously been isolated mainly from species belonging to Umbelliferae4 and Araliaceae.134 Laminariobiose seems to have an even more restricted occurrence in anthocyanins, identified in anthocyanins isolated mainly from the genus Allium.18,135 Quite extraordinary, this disaccharide has been found linked to the 5-position of the major 3-deoxyanthocyanin isolated from the fern Blechnum novae-zelandiae.96 The structure of the major anthocyanin tradescantin in Tradescantia pallida has been determined to be cyanidin 3-[6-(2,5-di-(ferulyl)arabinosyl)glucoside]-7,3’-di-[6-(ferulyl)glucoside].136 The same disaccharide, 6-arabinofuranosyl-glucopyranose, has previously been found in zebrinin isolated from Zebrina pendula,137 which belongs to the same family (Commelinaceae) as Tradescantia. Tradescantin displays a very high stability,138 most probably because of its structural conformation, which allows sandwich-type complex formation. Two malonylated 3-gentiobiosyl derivatives of delphinidin, linked covalently to different flavones, have been isolated from the flowers of Eichhornia crassipes (Pontederiaceae).9,10 Anthocyanins that contain neohesperidose have been isolated from petals of the blue marguerite daisy Felicia amelloides (Asteraceae) as delphinidin 3-neohesperidoside-7-[6(malonyl)glucoside],139 as peonidin 3-neohesperidoside from petals of two cultivars of Cyclamen persicum (Primulaceae),140 and as the 3-[2-(rhamnosyl)-6-(malonyl)glucoside] and its deacylated form of delphinidin from petals of a mauve line of Clitoria ternatea (Leguminosae).141 Neohesperidose has previously only been identified in anthocyanins from species belonging to the gymnosperm family Podocarpaceae.142 10.2.4.3

Trisaccharides

Altogether 19 anthocyanins based on seven trisaccharides, 2-glucosyl-6-rhamnosylglucose, 2-xylosyl-6-rhamnosylglucose, 2-xylosyl-6-glucosylgalactose, 2-xylosyl-6-glucosylglucose (new), 6-(6-glucosylglucosyl)glucose, 3-(3-glucosylglucosyl)glucose, and 3-glucosyl-6glucosylglucose, have been identified. Among the novel anthocyanins containing a trisaccharide reported after 1992, the 3-[6-(rhamnosyl)-2-(xylosyl)glucoside] of delphinidin has been isolated as the major anthocyanin from scarlet flowers of Linum grandiflorum,106 while the same triglycoside of petunidin and peonidin has been isolated in minor amounts from fruits of Vaccinium padifolium.25 These latter fruits also contain three novel 3-sambubiosides of petunidin, peonidin, and malvidin,124 in contrast to previous reports on pigments of plants in Ericaceae, which show that a variety of 3-monoglycosides are regularly present. It is interesting to observe that cyanidin 3-[6-(6-((E)-sinapyl)glucosyl)-2-(xylosyl)glucoside] has been reported to be produced in Glehnia littoralis (Umbelliferae) callus cultures,34 and not the analogous 6-rhamnosyl-2-xylosylgalactose derivative identified in its relative Daucus carota.33 10.2.4.4

Glycosidic Linkages

Anthocyanins bear glycosidic moieties in the anthocyanidin 3-, 5-, 7-, 3’-, or 5’-position (Figure 10.6). Nearly all anthocyanins have a sugar located at the 3-position (Appendix A). The only exceptions are the 3’-[2-(galloyl)galactoside] and 3’-[2-(galloyl)-6-(acetyl)galactoside] of delphinidin isolated from blue flowers of the African water lily Nymphae´a caerulea26 and the 4’-glucoside and 7-[3-(glucosyl)-6-(malonyl)glucoside]-4’-glucoside of cyanidin from red onion (Allium cepa).18 The desoxyanthocyanins (Appendix A) including the new luteolinidin 5-[3-(glucosyl)-2-(acetyl)glucoside] recently isolated from the fern Blechnum novaezelandiae,96 of course, cannot have any sugar in their 3-positions. Several anthocyanidin 5-glycosides and anthocyanidin 7-glycosides without sugar in their 3-positions have previously been reported.8 However, all of these may be classified as tentative structures due to lack of data (e.g., long-range 1H–13C couplings in heteronuclear NMR spectra) for absolute identification of the linkage positions.

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600

500

400

300

200

100

0 3

5

7

3⬘

5⬘

4⬘

FIGURE 10.6 The number of anthocyanins with glycosyl moieties linked to the various anthocyanidin positions. The upper dark part of each bar represents the anthocyanins reported later than 1992. See Table 10.1 for structures.

About 146 and 65 novel anthocyanins reported after 1992 have a second sugar moiety located at their 5- and 7-positions, respectively (Appendix A). With the exception of two desoxyanthocyanins from the fern Blechnum procerum,143 no identified anthocyanin has sugars linked to both the 5- and 7-positions. In the same period, 51 new anthocyanins with a glucosyl moiety in the 3’-position have been reported. Most of these have been isolated from species belonging to Orchidaceae (16), Clitoria (Leguminosae) (12), Ranunculaceae (6), and Gentianaceae (5). However, a few were found in Compositae, Liliaceae, Rhamnaceae, Nymphaeaceae, Lobeliaceae, and Commelinaceae (Table 10.2). In contrast to most anthocyanidin 3’-glycosides reported, five delphinidin and cyanidin derivatives from flowers of Anemone coronaria (Table 10.2) have glucuronic acid instead of glucose linked to the B-ring.28,29 Similarly, glucose was replaced with galactose in delphinidin 3’-[2-(galloyl)-galactoside] and its acetylated derivative isolated from extracts of Nymphae´a caerulea flowers.26 In addition to the previously identified anthocyanins with a sugar in their 5’-positions from flowers of Clitoria ternatea (five anthocyanins) and Lobelia erinus (two anthocyanins), 12 further ternatins and preternatins have been isolated from Clitoria ternatea (Leguminosae),144,145 and three anthocyanins from the genus Dianella (Liliaceae). The three polyacetylated delphinidin 3,7,3’,5’-tetraglucosides from berries of two Dianella species146 showed exceptional blueness at in vivo pH values due to effective intramolecular copigmentation involving p-coumarylglucose units at the 7-, 3’-, and 5’-positions of the aglycone. It has also been reported that the five new polyacylated delphinidin 3,3’,5’-triglucosides from Clitoria ternatea flowers formed intramolecular stacking between the aglycone and the 3’,5’-coumarylglucosyl side chains in solution.144 Four cyanidin 4’-glucosides have recently been isolated from pigmented scales of red onion.147 These structures were established by extensive use of 2D NMR spectroscopy and electrospray LC–MS. The previous report on 4’-glucosyl linkages in two anthocyanins from

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Hibiscus esculentus148 was mainly based on lack of bathochromic shifts by the addition of AlCl3 to a solution containing these anthocyanins, which is inadequate as proof for absolute identification of the 4’-linkages. Among the desoxyanthocyanins, Nair and Mohandoss112 have previously indicated the occurrence of luteolinidin 4’-glucuronide from flowers Holmskioldia sanguinea (Verbenaceae). Compared with spectra of cyanidin 3-glycosides, the cyanidin 4’-glucosides from red onions showed hypsochromic shifts (10 nm) of visible lmax and hyperchromic effects on wavelengths around 440 nm, similar to pelargonidin 3-glycosides.147 Glycosidic substitution of the other B-ring hydroxyl groups (3’ and 5’) causes similar hypsochromic shifts of visible lmax.3

10.2.5 ANTHOCYANINS

WITH

ACYLATION

More than 65% of the reported anthocyanins with properly identified structures are acylated, and anthocyanin diversity is highly associated with the nature, number, and linkage positions of the acyl groups. The aromatic acyl groups of these anthocyanins include various hydroxycinnamic acids ( p-coumaric, caffeic, ferulic, sinapic, and 3,5-dihydroxycinnamic acids) and two hydroxybenzoic acids ( p-hydroxybenzoic and gallic acids). Malonic acid is the most frequent aliphatic acyl group, while acetic, malic, oxalic, succinic, and tartaric acids have a more restricted distribution. As much as four different acyl groups located at four different glycosyl moieties have been identified in Lobelinin B isolated from flowers of Lobelia erinus.149 The number of anthocyanins containing the different acyl moieties is presented in Figure 10.7. During the period of this review, Pale et al.27 have isolated a triacylated-tetraglucosylated cyanidin derivative (243) from flowers of Ipomoea asarifolia, which contained E-3,5dihydroxycinnamic acid linked to the 6-position of one of the glucosyl moieties. This acyl

140 120 100 80 60 40 20 0 cou

caf

fer

sin

cin

hba gao

mal ace

mli

suc

tar

oxa

sul

FIGURE 10.7 Numbers of anthocyanins containing the various acyl moieties identified in anthocyanins. The upper dark part of each bar represents the anthocyanins reported later than 1992. cou, p-coumaric acid; caf, caffeic acid; fer, ferulic acid; sin, sinapic acid; cin, 3,5-dihydroxycinnamic acid; hba, p-hydroxybenzoic acid; gao, gallic acid; mal, malonic acid; ace, acetic acid; mli, malic acid; suc, succinic acid; tar, tartaric acid; oxa, oxalic acid; sul, sulfate.

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499

group has previously not been identified in any anthocyanin. Several nonnaturally occurring acids have also been identified in acylated forms in anthocyanins isolated from wild carrot suspension cultures provided with these acids in the medium.150,151 Among the dicarboxylic acids, tartaryl has for the first time been identified in four anthocyanins (82, 246, 383, 401) isolated from flowers of Anemone coronaria.28,132 Interestingly, the first anthocyanins found conjugated with sulfate, malvidin 3-glucoside-5-[2-(sulfato)glucoside], and malvidin 3-glucoside-5-[2-(sulfato)-6-(malonyl)glucoside], have been isolated from violet flowers of Babiana stricta (Iridaceae).30 Several other flavonoid classes than anthocyanins have previously been reported to contain sulfate groups.152 10.2.5.1

Acylation with Phenolic Acids

Two hundred and seventy-nine anthocyanins with aromatic acylation have been identified (Appendix A), and 67% have been reported after 1992. Ninety-three anthocyanins are reported to be acylated with both aromatic and aliphatic acyl groups. 10.2.5.1.1 p-Coumaric Acid More than 150 anthocyanins acylated with p-coumaric acid have been reported. Among these, most of the 132 anthocyanins, which have been assigned with a complete structure (Appendix A), have the p-coumaryl unit(s) in glucose 6-position(s) within a glycosidic moiety linked to the 3-position of the aglycone. In anthocyanins from the genera Eustoma123,129 and Gentiana153,154 (Gentianaceae), the p-coumaryl was found to be linked to the 5-glucosyl and not the 3-glucosyl. However, in Albireodelphin D (373), isolated from Gentiana,154 this acyl moiety was connected to the 3’-glucosyl. This latter linkage position of the p-coumaryl has also been identified in delphinidin 3-[6-(rhamnosyl)glucoside]-7-[6-(p-coumaryl)glucoside]3’-[6-(p-coumaryl)glucoside] isolated from flowers of Ceanothus papillosus (Rhamnaceae),32 and in anthocyanins from orchids (Orchidaceae),155–157 Clitoria ternatea (Leguminosae) (called ternatins),4,144,145 and Dianella spp. (Liliaceae) fruits.146 Most of these anthocyanins from the two latter genera contained another p-coumaryl unit located within the 5’-glycosyl moieties. In delphinidin 3,7,3’,5’-tetra[6-(p-coumaryl)glucoside] from Dianella spp., as many as four 6-p-coumarylglucoside units were located at different aglycone positions.146 In anthocyanin 3-rutinosides acylated with p-coumaric acid isolated from species in Solanaceae, this acyl group was found to be linked to the rhamnose 4-position (Appendix A). A similar linkage has also been reported in anthocyanins from species belonging to Lobelia erinus (Lobeliaceae),118,149 and previously from Silene dioica (Caryophyllaceae), Viola spp. (Violaceae), and Iris spp. (Iridaceae). The identification by Terahara et al.158 of p-coumaryl linked to galactose in delphinidin 3-[6-(E-p-coumaryl)galactoside] isolated from leaves of red flower tea, Camellia sinensis, is really outstanding. In ten anthocyanins from various Petunia spp. (Solanaceae),159–165 the coumaryl unit had another glucosyl moiety connected to its 4-hydroxyl group, making diverse anthocyanins with 3-glucosyl-rhamnosyl-p-coumaryl-glucosyl-(acyl?) moieties. Similar esterification has also been found in 14 ternatins from Clitoria ternatea (Leguminosae),4,144,145 four anthocyanins from orchids (Orchidaceae),155–157 in delphinidin 3-[6-(4-(glucosyl)coumaryl)glucoside]5-[6-(malonyl)glucoside] from flowers of Triteleia bridgesii (Liliaceae),166 in cyanidin 3-[2-(glucosyl)-6-(4-(glucosyl)coumaryl)glucoside]-5-glucoside isolated from cabbage,137 and in cyanidin 3-[6-(4-(glucosyl)coumaryl)-2-(2-(sinapyl)xylosyl)glucoside]-5-[6-(malonyl) glucoside] from leaves and stems of Arabidopsis thaliana.167 In orchids, these alternating 3-glucosyl-p-coumaryl-glucosyl chains were characteristically located in the aglycone 3’-positions, while most of the ternatins contained this type of chain in both the aglycone 3’- and 5’-positions. The largest monomeric anthocyanin recorded to date, ternatin A1, has

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been found to be built by delphinidin, seven glucosyls, four p-coumaryls, and one malonyl units (molecular mass: 2108.87 g mol1).108 10.2.5.1.2 Caffeic Acid Most of the 100 anthocyanins that are acylated with caffeic acid have this cinnamyl moiety linked to a glucosyl 6-position (Appendix A). Some anthocyanins isolated from species belonging to Solanaceae (288, 365, 442, 478, 484)159–164,168,169 and Silene dioica (Caryophyllaceae) (166, 201)170 have a caffeyl located on the 4-position of the rhamnosyl unit of the disaccharide rutinose. This acyl group has also been shown to be attached to the 2- and 5-hydroxyl groups of arabinose in anthocyanidin 6-arabinofuranosylglucosides (166, 201) isolated from Zebrina pendula (Commelinaceae).137 Additionally, it has been linked to the 2-hydroxyl group of glucose in pelargonidin 3-[2-(2-(E-caffeyl)glucosyl)galactoside] from flowers of Pulsatilla cernua,22 and to the same position of the same disaccharide in several anthocyanins (234, 240, 246, 383, 393, 398, 401) isolated from flowers of Anemone coronaria,28,29 which also belong to Ranunculaceae. Rather exceptionally, caffeic acid is found to be esterified with a tartaryl hydroxyl in one end, and a glucosyl in the phenolic 4-hydroxyl in the other end in pelargonidin 3-[2-(xylosyl)6-(3-(3-(4-(glucosyl)caffeyl)-2-tartaryl)malonyl)galactoside] isolated from scarlet flowers of Anemone coronaria ‘‘St. Brigid.’’132 Several anthocyanins from species within each of the families Compositae, Orchidaceae, Solanaceae, and Convolvulaceae have a glucosyl in the phenolic 4-hydroxyl group of caffeic acid, making a chain of alternating glucosyl– caffeyl–glucosyl units (Table 10.2). In 15 anthocyanins from species in Convolvulaceae (Table 10.2), the last caffeyl unit with a glucosyl linked to the phenolic end has remarkably the sugar linked to the 3-hydroxyl of caffeic acid. 10.2.5.1.3 Ferulic Acid More than 59 different anthocyanins have been reported to be acylated with ferulic acid; however, only 39 have been assigned with a complete structure. These anthocyanins were isolated for the first time from species belonging to the following families: Cruciferae (18), Labiatae (5), Solanaceae (4), Umbelliferae (3), Convolvulaceae (2), Gentianaceae (2), Liliaceae (2), Commelinaceae (1), Lobeliaceae (1), and Orchidaceae4 (Table 10.2). Most of the anthocyanins have the ferulyl unit(s) in glucose 6-position(s) within a glycosidic moiety linked to the aglycone 3-position. However, this cinnamic acid has also been shown to be attached to the 4-hydroxyl group of rhamnose in three anthocyanidin 3-rutinosides (62, 443, 479) from red171 and purple172 potatoes (Solanaceae), and to the 2-hydroxyl group of xylose in pelargonidin 3-[6,2-di-(ferulyl)sambubioside]-5-[6-(malonyl)glucoside] isolated from flowers of Matthiola incana (Cruciferae).173 Remarkably, this acyl group has been shown to be attached to the 2and 5-hydroxyl groups of arabinose in cyanidin 3-[6-(2,5-di-(E-ferulyl)arabinosyl)-glucoside]7, 3’-di-[6-(E-ferulyl)-glucoside].136 This major anthocyanin from leaves of Tradescantia pallida (Commelinaceae) shows an extra absorption band at 583 nm at pH values above 4.0, which makes this pigment highly colored at these pH values.174 The high stability138 of this type of pigments with as much as four acyl units was assumed to be due to the difficulty of water molecule diffusion to the hydrophobic center formed by the acyl groups and the aglycone.175 Ferulyl has been found as part of the glycosidic moiety linked to the anthocyanidin 5-position only in delphinidin 3-[6-(rhamnosyl)galactoside]-5-[6-(ferulyl)glucoside] from flowers of Eustoma grandiflorum (Gentianaceae),129 to the 7-position in cyanidin 3-[6-(malonyl)glucoside]-7-[6-(E-ferulyl)glucoside]-3’-glucoside from Sophronitis coccinea (Orchidaceae)176 and cyanidin 3-[6-(2,5-di-(E-ferulyl)arabinosyl)-glucoside]-7,3’-di-[6-(Eferulyl) glucoside] from Tradescantia pallida,136 and to the 5’-position in Lobelinin B (413) from Lobelia erinus (Lobeliaceae).149

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In cyanidin 3-[6-(4-(glucosyl)ferulyl)sophoroside]-5-glucoside from red cabbage137 and malvidin 3-[6-(4-(4-(6-ferulyl)glucosyl)-E-p-coumaryl)rhamnosyl)glucoside]-5-glucoside from flowers Petunia hybrida,161 the ferulyl unit has a glucosyl moiety linked to its phenolic 4-hydroxyl group. 10.2.5.1.4 Sinapic Acid Most of the 26 anthocyanins that are acylated with sinapic acid have been isolated from cabbage (Brassica spp.), stock (Matthiola incana), mustard (Sinapis alba), and mustard weed (Arabidopsis thaliana) in Cruciferae, yam (Dioscorea alata) in Dioscoreaceae, and from the genera Phalaenopsis, Dendrobium, and Vanda in Orchidaceae4 (Table 10.2). In addition, the 3[6-(6-(sinapyl)glucosyl)-2-(xylosyl)galactoside] and 3-[6-(6-(sinapyl)glucosyl)galactoside] of cyanidin have been isolated from cell suspension cultures of an Afghan cultivar of Daucus carota (Umbelliferae).33 In anthocyanins, sinapyl is mainly connected to the 6-hydroxyl of glucose or 2-hydroxyl of xylose. This latter linkage was found in nine anthocyanins from stock, mustard, and mustard weed in Cruciferae.167,173,177 In some anthocyanins isolated from cabbage,178 sinapyl has also been found in the glucose 2-position (219, 220, 227, 229), while the 3-[4-(sinapyl)6-(glucosyl)glucosides] of cyanidin and peonidin isolated from jam179 have this acyl group located in the glucose 4-position. In anthocyanins isolated from orchids (222, 230, 376, 382), the sinapyl was part of the glycosidic moieties linked to the aglycone 7- and 3’-positions,180–182 while the other anthocyanins mentioned above had this acyl group linked to the glycoside in the aglycone 3-position. 10.2.5.1.5 p-Hydroxybenzoic Acid Most of the 16 anthocyanins that are acylated with p-hydroxybenzoic acid (Appendix A) have been isolated from flowers of Delphinium hybridum,109,119,183 Aconitum chinense,184 Consolida armeniaca (Ranunculaceae),115 Campanula species (Campanulaceae),117,185,186 or roots of Ipomoea batatas (Convolvulaceae).187,188 In the examined species from Ranunculacea and Campanula, one to as many as four p-hydroxybenzoyl moieties belong to the anthocyanidin 7-glycoside. In p-hydroxybenzoylated anthocyanins from sweet potatoes (Ipomoea batatas), this acyl group is located within the 3-glucoside. In addition, cyanidin 3-[6-(malonyl)glucoside]-7,3’-[6-(4-(glucosyl)-p-hydroxybenzoyl)glucoside] and cyanidin 3-[6-(6-(p-hydroxybenzoyl)glucosyl)-2-(xylosyl)galactoside] have been isolated from red-purple flowers of Dendrobium ‘‘Pramot’’ (Orchidaceae)189 and cell suspension cultures of Daucus carota (Umbelliferae),33 respectively. When determined, the p-hydroxybenzoyl of anthocyanins is in all cases linked to the 6-position of one glucosyl moiety. 10.2.5.1.6 Gallic Acid Eleven anthocyanins have been reported to be galloylated. Anthocyanins with gallic acid (3,4,5trihydroxybenzoic acid) as acyl substituent have been found in leaves of the giant water lily (Victoria amazonica) in Nymphae´aceae as the 3-[2-(galloyl)galactoside] of delphinidin and cyanidin.190 These anthocyanins together with their 6’’-acetylated analogs were also identified in Nymphae´a
marliacea191 and Nymphae´a alba.192 The 2’’-galloylgalactoside and 2-(galloyl)-6-(acetyl)galactoside of delphinidin have been identified in the blue flowers of Nymphae´a caerulea; however, these moieties were in this latter species located in the rare 3’-position.26 The distribution of galloylated anthocyanins outside Nymphae´aceae seems to be restricted. They occur in leaves in Aceraceae as the 3-[6-(galloyl)glucoside], 3-[6-(galloyl) rutinoside], and 3-[2,3-di-(galloyl)glucoside] of cyanidin,193–195 and as the 3-[2-(galloyl) galactoside] and 3-[2-(galloyl)-6-(rhamnosyl)galactoside] of cyanidin in flowers of Acalypha hispida (Euphorbiaceae).130 An anthocyanin from seeds of Abrus precatorius (Leguminosae) has tentatively been identified as delphinidin 3-p-coumaryl-galloylglucoside.196

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Acylation with Aliphatic Acids

Among the 178 anthocyanins with aliphatic acylation (Appendix A), more than 70% have been reported after 1992. 10.2.5.2.1 Malonic Acid One or two malonyl units have been found in 132 anthocyanins from a variety of families, and 100 have been reported during the period of this review. Most of these pigments have the malonyl unit(s) in glucose 6-position(s); however, the anthocyanins containing malonyl, which have been isolated from various flowers of Anemone coronaria (Ranunculaceae),28,29,132 has this dicarboxylic acyl group linked to the galactose 6-position. In another interesting report, Mazza and Gao197 have isolated the 3-malonylxyloside, 3-dimalonylxyloside, and 3-malonylarabinoside of cyanidin from seeds of Helianthus annuus; however, in these cases the linkage positions have not been determined. From species in Labiatae, the 3-[6-(p-coumaryl)glucoside]-5-[4,6-di-(malonyl)glucoside] of cyanidin, delphinidin, and pelargonidin, and the 3-[6-(caffeyl)glucoside]-5-[4,6-di(malonyl)glucoside] of the two latter anthocyanidins have been reported.203–205 The location of malonyl to the glucose 4-position has also been reported for cyanidin 3-[4-(malonyl)2-(glucuronosyl)glucoside] and pelargonidin 3-[6-(p-coumaryl)glucoside]-5-[4-(malonyl) glucoside] isolated from red flowers of Bellis perennis (Compositae)113 and Hyacinthus orientalis (Liliaceae),201 respectively. Malonyl substitution in the sugar 3-position of anthocyanins has been found in 3-[3-(malonyl)glucoside] and 3-[3,6-di-(malonyl)glucoside] of cyanidin isolated from various organs of some Allium species.202–205 This latter anthocyanin has also been identified in flowers of chrysanthemum (Dendranthema grandiflorum)206 and in many grasses.207 On mild hydrolysis, it was converted to the 3-[3-(malonyl)glucoside], indicating that the malonic acid linkage to the 3-position of glucose was more stable than the more common linkage at the 6-position of glucose.202 The occurrence of the diester structures of the malonic acid moiety in natural anthocyanin pigments has so far been reported in pigments from flowers of Eichhornia crassipes9,10 and chive, Allium schoenoprasum,11 where the anthocyanin–flavone and anthocyanin–flavonol disubstituted malonate structures were exhibited, respectively (Figure 10.8 and Figure 10.9). In some anthocyanins from flowers of Anemone coronaria, malonic acid is esterified with galactose in one end and tartaryl in the other end.29,132 Malonylation has been found in two 6-hydroxyanthocyanins from Alstroemeria, the 3-[6-(malonyl)glucosides] of 6-hydroxycyanidin and 6-hydroxydelphinidin,101,102 and in 5-carboxypyranocyanidin 3-[6-(malonyl)glucoside] from red onion.18 A pigment containing methyl-malonyl, pelargonidin 3-[2-(xylosyl)-6-(methyl-malonyl)galactoside], has been reported to have been isolated from scarlet flowers of Anemone coronaria.132 Methyl esterification of the terminal carboxyl group of malonyl units can easily occur in acidified methanolic solvents during extraction and in the isolation process.167,342 10.2.5.2.2 Acetic Acid Altogether 36 anthocyanins with one or two acetyl groups have been identified (Appendix A). The number given in parenthesis shows the number of anthocyanins reported as novel pigments in species in the various families: Verbenaceae (8), Liliaceae (5), Geraniaceae (6), Vitaceae (5), Nymphaeaceae (5), Alliaceae (1), Theaceae (1), Rutaceae (1), Melastomataceae (1), Labiatae (1), Leguminosae (1), and Blechnaceae (1). The acetyl groups are, in general, linked to glucosyl 6-positions; however, in anthocyanins from Nymphaea (129, 142, 322, 330, 331) and Tulipa (144, 332, 333), the galactosyl and rhamnosyl moieties, respectively, are acetylated. In the latter cases, the acetyl groups are located in the rhamnosyl 2- or 3-positions. Linkage to the rare 3-position has also been

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reported for the acetyl group of an anthocyanin–flavonol complex (537) from Allium schoenoprasum.11 Two other outstanding acetylated pigments, malvidin 3-[6-(p-coumaryl) glucoside]-5-[2-(acetyl)xyloside] and delphinidin 3-[6-(p-coumaryl)glucoside]-5-[4-(acetyl)6-(malonyl)glucoside], have been isolated from flowers of Tibouchina urvilleana208 and Salvia uliginosa,209 respectively. The acyl group of the two similar acetylated malvidin 3,5-diglucosides (465, 466), which have been isolated from Geranium flowers, is reported to be attached to either the 3-glucosyl210 or the 5-glucosyl,211 with the latter as the most probable linkage in both cases. The only report of acetylated anthocyanins outside angiosperm families is luteolinidin 5-[2-(acetyl)-3-(glucosyl)glucoside] from the fern Blechnum novae-zelandiae.96 10.2.5.2.3 Malic, Succinic, Oxalic, and Tartaric Acids Anthocyanins acylated with the dicarboxylic malic acid seem to be restricted to carnations (Dianthus). Wild-type carnation petals have been found to contain the 3-[6-(malyl)glucosides], 3-[6-(malyl)glucoside]-5-glucosides, and the 3-glucoside-5-glucoside (6’’,6’’’-malyl diesters) of pelargonidin and cyanidin.212–216 These two latter macrocyclic pigments219,221 are the only anthocyanins where the same acyl group is connected to two monosaccharides, which are attached at different locations at the anthocyanidin. The orientation of the malyl groups of these anthocyanins has been determined by long-range 2D heteronuclear NMR techniques (HMBC).216 Recently, Fukui et al.31 have shown that marketed genetically modified violet carnations produce analogous delphinidin-type anthocyanins by heterologous flavonoid 3’, 5’-hydroxylase gene expression. Anthocyanins acylated with succinic acid have previously been isolated from some species in the genus Centaurea (Compositae), and identified as the 3-[6-succinylglucoside]5-glucosides of cyanidin and pelargonidin.217–219 Later, the former pigment isolated from cornflower, Centaurea cyanus, was shown to be part of the self-assembled supramolecule protocyanin, composed of six molecules each of malonylflavone and succinylcyanin complexed with magnesium and ferric ions (Section 10.2.7).220 Succinyl has also been reported to occur in minor amounts in flowering tops of Phragmites australis (Gramineae) as cyanidin 3-[6-(succinyl)-glucoside],221 and the structures of the two major anthocyanins (Figure 10.9) in blue Agapanthus (Agapanthaceae) flowers have been found to be based on a p-coumarylated delphinidin diglycoside attached to a flavonol triglycoside via a succinic acid diester link.12 Oxalic acid is another dicarboxylic acid with restricted occurrence as an acyl moiety of anthocyanins. In addition to some European orchids flowers (Section 10.5.10),222 cyanidin 3-dioxalylglucoside has been isolated from fruits of Rubus laciniatus.57 Altogether six different anthocyanins acylated with oxalic acid have been reported. With the exception of cyanidin 3-[6-(oxalyl)glucoside], evidences for proper determination of the linkage position of this acyl moiety are absent. Tartaric acid has an even more limited distribution as acylation agent of anthocyanins, identified in only four anthocyanins (82, 246, 383, and 401) isolated from flowers of Anemone coronaria.28,132 In these pigments, one of the tartaryl hydroxyl groups is esterified with a carboxyl group of malonic acid. In pelargonidin 3-[2-(xylosyl)-6-(3-(3-(4-(glucosyl)caffeyl)2-tartaryl)malonyl)galactoside] (82), the other hydroxyl group of tartaryl is esterified with caffeyl.

10.2.6 DIMERIC FLAVONOIDS INCLUDING AN ANTHOCYANIN UNIT Most reported anthocyanins are monomeric in nature; however, new types of flavonoids consisting of an anthocyanin moiety covalently linked to another flavonoid unit have been reported in the period of this review. One class includes one anthocyanin unit and one flavone or flavonol unit attached covalently to each end of a common dicarboxylic acid. The other class involves one anthocyanin moiety covalently linked directly to a flavanol unit.

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Two dimeric pigments ((6’’’-(delphinidin 3-[6’’-(glucosyl)glucoside])) (6’’-(apigenin 7-glucosyl))malonate (534) and (6’’’-(delphinidin 3-[6’’-(glucosyl)glucoside])) (6’’-(luteolin 7-glucosyl))malonate (535) (Figure 10.8) have been isolated from the blue-violet flowers of Eichhornia crassipes (Pontederiaceae) by Toki et al.9,10 The major Eichhornia anthocyanin A has an apigenin 7-glucoside molecule (flavone) attached with an ester bond to one end of malonic acid, and delphinidin 3-gentiobioside linked with a similar bond to the other end. The minor Eichhornia anthocyanin B has a similar structure with apigenin 7-glucoside replaced by luteolin 7-glucoside. The three-dimensional structure of these pigments was suggested from the observation of negative Cotton effects at lmax (535 and 547 nm, R

HO

O 2

OH HO

4

3 OH

8

+ O

R H H OH OH

330: 331: 332: 333:

OH

3S 3R 3S 3R

OH

O

HO

OH

OH

O

OH OH

OH OH HO

O

OH

R O 534:

H

535:

OH

HO

OH

O

OH

O

OH HO

R OH

HO HO O

O

OH

OH O

O

O O

O

OH

O

O

OH

FIGURE 10.8 Afzelechin(4a ! 8)Pg3glc (530), epiafzelechin (4a ! 8)Pg3glc (531), catechin(4a ! 8)Pg3glc (532), epicatechin(4a ! 8)Pg3glc (533) isolated from extracts of strawberries, and (6’’’(delphinidin 3-[6’’-(glucosyl)glucoside])) (6’’-(apigenin 7-glucosyl))malonate (534) and (6’’’-(delphinidin 3-[6’’-(glucosyl)glucoside])) (6’’-(luteolin 7-glucosyl))malonate (535) from blue-violet flowers of Eichhornia crassipes. Pg3glc, pelargonidin 3-glucoside.

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OH OH HO

O O

HO

OH

OR

O

HO O HO OH OH

O

R O

O

O

OH

O

536:

H

537:

C(O)CH3

O

OH

O HO O OH

O

OH OH

O

O O

OH OH OH

R OH

538:

H

539:

CH2OH

OH O

O

OH

O O

OH O

OH

HO O

O

OH

OH

OH O

HO HO

O O

O

O

HO HO

OH

O

OH HO HO HO

HO O

O O OH

O

R

OH

O O

OH

FIGURE 10.9 (6’’-(cyanidin 3-glucosyl)) (2’’’’-(kaempferol 3-[2’’-(glucosyl)(glucoside)]-7-glucuronosyl))malonate (536) and (6’’-(cyanidin 3-[3’’-(acetyl)glucosyl])) (2’’’’-(kaempferol 3-[2’’-(glucosyl)(glucoside)]7-glucuronosyl))malonate (537) isolated from pale-purple flowers of chive (Allium schoenoprasum),11 and (6’’’-(delphinidin 3-[6’’-(p-coumaryl)glucoside]-7-glucosyl)) (6’’’’-(kaempferol 3-glucoside-7-xyloside4’-glucosyl))succinate (538) and (6’’’-(delphinidin 3-[6’’-(p-coumaryl)glucoside]-7-glucosyl)) (6’’’’-(kaempferol 3-glucoside-7-glucoside-4’-glucosyl))succinate (539) from blue Agapanthus flowers.12

respectively). The chromophore (delphinidin) and the copigment (flavone) occupy a folding conformation as a binary complex.9,10 Eichhornia anthocyanin A exhibited remarkable color stability in aqueous solution at mildly acidic pH values.223 The existence of intramolecular hydrophobic interactions between the chromophoric skeleton and the flavone group was

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indicated by reduction in the hydration constant when compared with the parent delphinidin 3-glycoside. The existence of other anthocyanin–flavone complexes has previously been shown or indicated in flowers of orchids,222,224 lupins,225 and Salvia patens.226 Two anthocyanin–flavonol complexes, ((6’’-(cyanidin 3-glucosyl)) (2’’’’-(kaempferol 3-[2’’-(glucosyl)(glucoside)]-7-glucuronosyl))malonate (536) and (6’’-(cyanidin 3-[3’’-(acetyl)glucosyl])) (2’’’’-(kaempferol 3-[2’’-(glucosyl)(glucoside)]-7-glucuronosyl))malonate (537) (Figure 10.9), have been isolated from the pale-purple flowers of chive (Allium schoenoprasum).11 These pigments, which were supplied with complete NMR assignments, were based on either cyanidin 3-glucoside or cyanidin 3-[3-(acetyl)glucoside] esterified to one end of malonic acid, and kaempferol 3-[2-(glucosyl)glucoside]-7-glucosiduronic acid connected to the other end. Compared to similar spectra of the same monomeric anthocyanins, the bathochromic shifts (9 nm) in the UV–vis spectra of the complexes revealed intramolecular association between the anthocyanin and flavonol units, which influenced the pigment color. The chemical shifts of the anthocyanidin H-4 in the two complexes were 0.3 ppm upfield for the same shifts of anthocyanins without connection to a flavonol moiety. Two similar complexes, (6’’’-(delphinidin 3-[6’’-(p-coumaryl)glucoside]-7-glucosyl)) (6’’’’-(kaempferol 3-glucoside7-xyloside-4’-glucosyl))succinate (538) and (6’’’-(delphinidin 3-[6’’-(p-coumaryl)glucoside]7-glucosyl)) (6’’’’-(kaempferol 3-glucoside-7-glucoside-4’-glucosyl))succinate (539) (Figure 10.9), have been isolated from the blue Agapanthus flowers (Agapanthaceae).12 In these structures, succinate was involved instead of malonate to connect delphinidin 3-[6-(p-coumaloyl)glucoside]-7-glucoside to either kaempferol 3,4’-di-glucoside-7-xyloside or kaempferol 3,7,4’-tri-glucoside. The other class involving one anthocyanin moiety covalently linked directly to a flavanol unit has been found as minor pigments in extracts of strawberries.13 These purple complexes were characterized by UV–vis spectroscopy, 2D NMR techniques, and electrospray MS to be afzelechin(4a ! 8)pelargonidin 3-O-b-glucopyranoside (530), epiafzelechin(4a ! 8)pelargonidin 3-O-b-glucopyranoside (531), catechin(4a ! 8)pelargonidin 3-O-b-glucopyranoside (532), and epicatechin(4a ! 8)pelargonidin 3-O-b-glucopyranoside (533) (Figure 10.8). The stereochemistry at the 3- and 4-positions of the flavan-3-ols was elucidated after assumption of the R-configuration at C-2. Each of the four pigments occurred in the NMR solvent as a pair of rotamers. Other complexes based on anthocyanins or anthocyanidins directly linked to flavanol(s) have been detected in wine mainly by LC–MS techniques59–62 (see Chapter 5).

10.2.7 METALLOANTHOCYANINS In the period of this review, Kondo et al. have presented several extraordinary papers in the field of metalloanthocyanins and their contribution to blue flower colors. Commelinin227 from blue flowers of Commelina communis has been found to consist of six molecules of delphinidin 3-[6-(p-coumaryl)glucoside]-5-[6-(malonyl)glucoside] (malonylawobanin) copigmented with six flavone (flavocommelin) molecules complexed with two magnesium atoms (Figure 10.10). Self-association was shown to exist between the anthocyanin moieties. Intact commelinin was also obtained by reconstruction of this supramolecule from its components. Cd-commelinin, in which Mg2þ was replaced with Cd2þ, has been studied with x-ray crystal structure. The blue flower color development and the stability of the color were explained by metal complexation of the anthocyanin and intermolecular hydrophobic association.227 The octaacetate derivative of the flavone part of this molecule has been determined by x-ray diffraction,228 and in the crystal the flavone molecules were arranged parallel to each other according to the periodicity of the crystal lattice. Intermolecular stacking of the flavone skeletons was, however, not observed, and the hydrophilicity of the glucose moieties was suggested as an important factor governing the self-association.

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OH O

MM OH

O

HO

OH O

F

O HO O

O

O

O

OH O

M

O

O HO OH

O

O

MeO O

HO HO

OH

M M

M M

O

HO

HO

F

OH

OH HO

F

F

OH

F F

OH

F OH

OH

O

FIGURE 10.10 The illustration figure (right) indicates the mechanism known to operate for commelinin found in Commelina communis by Kondo et al. Commelinin consists of six molecules of delphinidin 3-[6-(p-coumaryl)glucoside]-5-[6-(malonyl)glucoside] (malonylawobanin) (M, purple) copigmented with six flavone molecules (F, yellow) complexed with two magnesium atoms (red). (After Kondo, T. et al., Nature, 358, 515, 1992. With permission.)

Another metalloanthocyanin, protodelphin, similar to commelinin and protocyanin, has been isolated from flowers of Salvia patens.226 Protodelphin has been shown to be composed of six molecules of delphinidin 3-[6-(p-coumaryl)glucoside]-5-[6-(malonyl)glucoside], six molecules of apigenin 7,4’-diglucosides, and two magnesium ions.229 Compared to commelinin, protodelphin includes the same anthocyanin, malonylawobanin, which is, however, another flavone. Takeda et al.226 have been able to resynthesize the natural blue pigment in vitro by adding the three components together. Mg2þ could be substituted in vitro by other divalent metal cations (e.g., Co2þ, Ni2þ, Zn2þ, and Cd2þ ). Using synthetic apigenin 7,4’diglucosides derived from D- or L-glucose, Kondo et al.229 have shown that the sugars of the three flavone molecules in the self-association complex oriented the structure into an M helix (for D-glucose) or P helix (for L-glucose). The M helix was able to intercalate with the Mg2þ-malonylawobanin complex to form native pigment, whereas the P helix could not. They concluded that restricted chiral and structural recognition controlled the entire selfassembly of the metalloanthocyanin, and was responsible for the blue flower color. In 1998, Kondo et al.220 proposed a new molecular mechanism for blue color expression with protocyanin from cornflower, Centaurea cyanus. The protocyanin structure is similar to that of commelinin, composed of six molecules each of apigenin 7-glucuronide-4’-[6-(malonyl)glucoside] and succinylcyanin (153), complexed with magnesium and ferric ions.230 It was proposed that the molecular stacking of the aromatic units prevented hydration of the anthocyanidin nucleus. The blue color of protocyanin was found to be caused by ligand to metal charge transfer (LMCT) interaction between succinylcyanin and Fe3þ.220 This color mechanism (Figure 10.11) is different from that known to operate for commelinin. Metal complexes involving anthocyanins have previously been proposed also in blue flowers of Hydrangea macrophylla.80 Later, the color change and variation of hydrangea has been suggested to be caused by free Al3þ complexation of those components of the complex responding to slight vacuolar pH change.231,232

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O O

Mg

O

R1O

O

OH

2+ O

O

O

O O

Fe

OR2

O

O

OH

3+

R1O O

O

LMCT interaction R1 = 6-O -Succinyl-b-D-Glcp R2 = b-D-Glcp R3 = 6-O -Malonyl-b-D-Glcp R4 = b-D-Glc pA

FIGURE 10.11 Schematic representation of the LMCT interaction between the anthocyanin succinylcyanin and Fe3þ in protocyanin. (From Kondo, T. et al., Tetrahedron Lett., 39, 8307, 1998. With permission.)

It is well known that anthocyanins with hydroxyl groups in ortho-position to each other form complexes with aluminum ion leading to bathochromic and hyperchromic shifts in their absorption spectra. Complexation of Al3þ with synthetic and natural anthocyanins has been investigated in aqueous solutions within the pH range 2 to 5.233,234 As shown by UV–vis spectroscopic data, the complexes involved not only the colored forms but also the colorless forms of the pigment. 1H NMR analysis in CD3OD confirmed the conversion of the anthocyanin from the red flavylium form to the deep-purple quinonoidal forms upon coordination to Al3þ.233 From relaxation kinetics measurements (pH jump), complexation constants of Al3þ and several synthetic and natural anthocyanins have been calculated.233–235

10.2.8 ANTHOCYANIN COLORS

AND

STABILITY

One of the best-established functions of anthocyanins is in the production of flower color and the provision of colors attractive to plant pollinators. Considerable effort has been made to give explanations for the color variations expressed by anthocyanins in plants. Various factors including concentration and nature of the anthocyanidin, anthocyanidin equilibrium forms, the extent of anthocyanin glycosidation and acylation, the nature and concentration of copigmentation, metal complexes, intra- and intermolecular association mechanisms, and influence of external factors like pH, salts, etc. have been found to have impact on anthocyanin colors.80 The role of anthocyanins and flavones in providing stable blue flower colors in the angiosperms has more recently been outlined by Harborne and Williams.42 It was apparent

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from the data collected that delphinidin was the most common anthocyanidin in blue flowers, and that copigmentation with a specific flavone constituent was the most common mechanism for shifting the mauve colors of delphinidin glycosides toward blue. These anthocyanin– flavone complexes, where they exist, showed high flavone to anthocyanin ratios (e.g., 10:1), except when a metal cation was also present. The anthocyanin–flavone complexes in Eichhornia crassipes9,10 are unique in that the anthocyanin and the flavones were covalently linked through a central aliphatic acyl residue (Section 10.2.6). Similar bathochromic color effects have recently also been reported for dimeric anthocyanin–flavonol complexes in blue Agapanthus flowers (Agapanthaceae),12 and in purple flowers of chive (Allium schoenoprasum).11 In the latter case, the anthocyanidin is cyanidin. More about metalloanthocyanins and dimeric flavonoids containing anthocyanins is found in Sections 10.2.5 and 10.2.6, respectively. Some very interesting macrocyclic anthocyanins, the 3-glucoside-5-glucoside (6’’,6’’’-malyl diesters) of cyanidin and pelargonidin, have been isolated from carnations (Dianthus).214,215 Gonnet and Fenet215 have shown by CIELAB parameters that carnations with ‘‘cyclamen red’’ colors closely matched those of petals of some Rosa cultivars considered for comparison. However, these cyclamen colors in roses were based on the presence of cyanidin 3,5diglucoside in contrast to the carnations, which contained pelargonidin derivatives acylated with malic acid. These macrocyclic anthocyanins were, however, relatively labile and underwent readily ring opening to furnish the corresponding 3-(6’’-malylglucoside)-5-glucosides, and could only be extracted if neutral solvents were employed. In vivo these rare pigments appear to be stabilized by copigmentation with associated flavones. Wild-type carnations lack a flavonoid 3’,5’-hydroxylase gene, which implies that they cannot produce the corresponding delphinidin derivatives. Recently, Fukui et al.31 showed that marketed genetically modified violet carnations produced analogous delphinidin-type anthocyanins by heterologous flavonoid 3’,5’-hydroxylase gene expression. They concluded that the bluish hue of the transgenic carnation flowers was accounted for by three factors: accumulation of the delphinidin-type anthocyanins, the presence of strong copigmentation with flavone derivative, and a relatively high vacuolar pH of 5.5. The relationship between color and substitution patterns in anthocyanidins has been investigated with the aim of developing quantitative structure–color models.236 Experimental data for the lowest UV transition in 20 substituted anthocyanidins were reviewed. While a hypsochromic effect from hydroxyl and methoxyl moieties at positions 6 and 8 was reported here,236 it is interesting to note that a C-linked sugar in the 8-position has the opposite effect producing a more bluish color.20 Color and stability studies of the 3-glucosides of the six common anthocyanidins and petanin, petunidin 3-[6-(4-(p-coumaryl)rhamnosyl)glucoside]5-glucoside, in aqueous solutions during several months of storage revealed especially large variation at slightly acidic to slightly alkaline pH values.237,238 1H NMR spectroscopy has been used to characterize the aggregation processes leading to color stabilization of malvidin 3-glucoside.239 The concentrations of the different forms in aqueous solution were determined as a function of pH for several values of the total anthocyanin concentration. The pH-dependent color and structural transformations in aqueous solutions of some nonacylated anthocyanins and synthetic flavylium salts have been reexamined.240,241 It is known that polyacylated anthocyanins are very stable in neutral or weakly acidic aqueous solutions, whereas simple anthocyanins are quickly decolorized by hydration at the 2-position of the anthocyanidin nucleus. The shift to blue colors and increased anthocyanin stability are in many cases simply achieved by intramolecular copigmentation involving stacking between the anthocyanidin and the aromatic acyl groups.233,242–244 Both intraand intermolecular interactions have been found in aromatic monoacylated anthocyanins studied by 1D and 2D proton NMR spectroscopy.245 These compounds formed strong intramolecular p-complexes between the cinnamic acyl group and the anthocyanidin nucleus,

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the double bond of the acyl group involved as well as its aromatic ring. Upon increasing the concentration of the anthocyanins or lowering the temperature of the NMR sample, the p-complexes formed multinuclear complexes as shown by the resultant negative nuclear Overhauser effect (NOE) values. In a very detailed review, recent progress in the chemistry of polyacylated anthocyanins as flower color pigments has been outlined by Honda and Saito.246 It was recognized that both the bluing effect and stabilization of flower colors remarkably depended on the number of aromatic acids presented in the polyacylated anthocyanins. After classification of the polyacylated anthocyanins into seven types by the substitution pattern of the acyl functions, it was concluded that anthocyanins with the aromatic acyl groups in glycosyls in both the 7- and 3’-positions were considered to make the most stable colors in the flowers. Red-purple colors in the flowers of orchids have been shown to be derived from altogether 15 cyanidin and peonidin glycosides, with aromatic acylated sugars attached at both the 7- and 3’-positions (Table 10.2).155–157,176,180–182,189 Intramolecular associations between these planar molecules in orchids provided stable colors without the need for any copigment or metal cation.247 Figueiredo et al.247 proposed that the glycosyl-acyl ‘‘side chains’’ attached to both positions 3’ and 7 of the chromophore favored a better overlap and stronger interaction with the p-system of the central chromophore (Figure 10.12), than what was observed for other acylated anthocyanins. They supported the assessment by molecular calculations, which gave minimum energy conformation for a ‘‘sandwich’’ type with the 3’-chain folded ‘‘over’’ and the 7-chain folded ‘‘under’’ the chromophore (Figure 10.12). Similar acylation of glycosyls in anthocyanidin 7- and 3’-positions has also been reported for anthocyanins in Commelinaceae,136 Compositae,248 Liliaceae,148 and Rhamnaceae.32 The three acylated delphinidin 3,7,3’,5’-tetraglucosides from berries of two Dianella species (Liliaceae) showed exceptional blueness at in vivo pH values due to effective intramolecular copigmentation involving

FIGURE 10.12 Structure of cyanidin 3-[6-(malonyl)glucoside]-7-[6-(caffeyl)glucoside]-3’-[6-(4-(6-(4(glucosyl)caffeyl)glucosyl)caffeyl)glucoside] (258) optimized by molecular calculations. The anthocyanidin is represented in black, while substituents are drawn in gray. The acylated side chains attached to the 3’- and 7-positions of the chromophore interact favorably with the p-system of the central chromophore. (From Figueiredo, P. et al., Phytochemistry, 51, 125, 1999. With permission.)

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p-coumaryl-glucose units (GC) at the aglycone 7-, 3’-, and 5’-positions.148 Evidence was presented to show that the effectiveness of the copigmentation could be ranked: 3’,5’-GC > 7-GC > 3-GC. The blue flower color of Ceanothus papillosus (Rhamnaceae) was proposed to arise from a supramolecular complex of high stoichiometry including anthocyanins and kaempferol 3-[2-(xylosyl)rhamnoside].32 This copigmentation effect appeared to be quite specific, and did not occur to the same extent with other more common flavonols. An extraordinary, long wavelength visible absorption maximum at 680 nm was produced, which conferred additional blueness. Figueiredo et al.247 have also explored the role of malonic acid residues that are present in many anthocyanins. These dicarboxylic acyl groups appeared to provide color stabilization, due to an increase in acidity in the vacuolar solution of the petal. The pKa of malonic acid was 2.83 and deprotonation of the malonyl group provided protection against alkanization of the medium and hence loss of color. According to our data, only 17 anthocyanins acylated with hydroxycinnamic acids occur in both the cis (Z) and trans (E) configurations (Appendix A). George et al.249 have compared the pairs of 3-[6-(E/Z-p-coumaryl)glucoside]-5-[6-(malonyl)glucosides] of malvidin and delphinidin. They observed that the cis isomers exhibited « values about 1.5 times greater than the trans isomers, in both pairs. It was calculated (pK ’h values) that the cis forms were less prone to undergo hydration reactions forming the colorless anthocyanin forms. Based on computed structures, the more coplanar arrangement allowed by the cis isomers was postulated as the rationale supporting the enhanced color stability.249 When considering the color effect of this type of intramolecular copigmentation in vivo, one should bear in mind that the trans isomer seems to predominate, and that the conversion between the two isomers is rare. When Yoshida et al.250 studied the E,Z-isomerization reaction and stability of several types of acylated anthocyanins under the influence of UV irradiation, their interest was focused on the reason why isomerization reaction of some acyl residues was prevented in living plant cells. They concluded that the stability of anthocyanins under irradiation highly depends on molecular stacking. They proposed that light energy absorbed by cinnamoyl residues might be transferred to the anthocyanidin nucleus and released without any isomerization reaction or degradation of pigments. Thus, the flower color may be stable for a long time under strong solar radiation.

10.3 ANTHOCYANIN PRODUCTION 10.3.1 CELL CULTURES The interest in and demand for natural food colorants and pharmacologically interesting natural compounds have encouraged new research initiatives aimed at the development of more efficient means of harvesting anthocyanins. When growth procedures are optimized, cell culture systems have the potential of producing both higher anthocyanin concentrations within reduced time, and another selection of anthocyanins relative to production in whole plants. In a recent general review, Ramachandra Rao and Ravishankar251 have dealt with the production of high-value secondary metabolites including anthocyanins through plant cell cultures, shoot cultures, root cultures, and transgenic roots obtained through biotechnological means. In an overview of the status and prospects in the commercial development of plant cell cultures for production of anthocyanin, Zhang and Furusaki252 have focused on strategies for enhancement of anthocyanin biosynthesis to achieve economically viable technology. Production of anthocyanins in plant cell and tissue cultures has been reported for more than 30 species including Daucus carota, Fragaria
ananassa, Vaccinium spp., Vitis hybrida, Solanum tuberosum, Malus sylvestris, Aralia cordata, Perilla frutescens, Ipomoea batatas, Euphorbia millii, Strobilanthes dyeriana, Hibiscus sabariffa, Dioscorea cirrhosa, etc.35,252,253

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The production has shown to be influenced by a variety of environmental stimuli such as light irradiation, UV light, low temperature, oxygen level, hormones, fungal elicitors, low nutrient levels.251–253 Increased level of oxygen supply and light irradiation have, for instance, shown independently positive influence on the production of anthocyanins in suspended cultures of Perilla frutescens cells in a bioreactor.254 However, a combination of irradiation with a higher oxygen supply reduced the production. In Vaccinium pahalae cell cultures, anthocyanin yield was enhanced by increasing sucrose concentration in the liquid suspension medium and by manipulating the initial inoculum density.255 A cell culture system has the potential advantage of facilitating selective production of certain anthocyanins. The nine acylated anthocyanins produced by flowers of Hyacinthus orientalis regenerated in vitro were identical to those of field-grown flowers.256 However, the concentration of cyanidin 3-[6-(p-coumaryl)glucoside]-5-[6-(malonyl)glucoside] was considerably higher in the regenerated flowers. Lower concentration of 2,4-dichlorophenoxyacetic acid in the medium used for strawberry suspension cultures has, for instance, limited cell growth and enhanced both anthocyanin production and anthocyanin methylation.253 The ratio of peonidin-3-glucoside to the total anthocyanin content increased significantly under these conditions. A methylated anthocyanin like peonidin 3-glucoside is normally not found in intact strawberries, and although the activity of anthocyanin methyltransferase was not measured by Nakamura et al.,253 the results indicated that lower 2,4-dichlorophenoxyacetic acid concentrations enhanced the activity of anthocyanin methyltransferase. Do and Cormier257 have reported that increased osmotic potential in the medium resulted in a significant intracellular accumulation of peonidin-3-glucoside in Vitis vinifera cells. Similarly, jasmonic acid has been reported to increase the peonidin 3-glucoside content considerably, while the other major anthocyanins only experienced smaller increments.258 Another example of using cell cultures has been presented by Dougall et al.151 To improve understanding of the ways in which cinnamic acid groups alter the color retention of anthocyanins, a series of anthocyanins that differed systematically in their acyl group was needed. When cinnamic acids were fed to wild carrot suspension cultures, the proportion of acylated to nonacylated anthocyanins increased.151 With high relevance for future metabolic studies, Vitis vinifera cells grown in a bioreactor have been used for production of isotopically 13 C-labeled phenolic substances such as anthocyanins.259,260 The enrichment of labeling (between 40 and 65%) obtained for all compounds is sufficient to investigate their absorption and metabolism in humans. Similarly, 14C-L-phenylalanine has been incorporated into a range of polyphenolic compounds when fed to cell cultures.261,262 Experiments with Vaccinium pahalae berries and Vitis vinifera suspension cultures, using [14C]-sucrose as the carbon source, have demonstrated a 20 to 23% efficiency of 14C incorporation into the flavonoid-rich fractions.263 To improve production of anthocyanins, efforts have mainly been devoted to the optimization of biosynthetic pathways by both process and genetic engineering approaches. The productivity in the cultures is, however, determined by synthetic capacity, storage capacity, and the capacity to metabolize the compounds in the transport and detoxification processes.264 The potential of manipulation and optimization of postbiosynthetic events have recently been reviewed by Zhang et al.265 These events, including chemical and enzymatic modifications, transport, storage or secretion, and catabolism or degradation, were outlined with anthocyanin production in plant cell cultures as case studies. Bioreactor-based systems for mass production of anthocyanins from cultured plant cells have been described for several species.254,260,266–270 A highly productive cell line of Aralia cordata obtained by continuous cell aggregate cloning has, for instance, been reported to yield anthocyanins in concentrations as high as 17% on a dry weight basis.266 However, to date economic feasibility has not been established in part because of some unique engineering challenges inherent in mass cultivation of plant cultures.

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10.3.2 SYNTHESIS Since the early contributions of Willstatter and Robinson, several alternative approaches following mainly two routes have been considered for synthesis of anthocyanins.271 One of the routes includes condensation reactions of 2-hydroxybenzaldehydes with acetophenones, while the other uses transformations of anthocyanidin-related compounds like flavonols, flavanones, and dihydroflavonols to yield flavylium salts. The urge for plausible sequences of biosynthetic significance has sometimes motivated this latter approach. In the period of this review, new synthetically approaches in the field have also predominantly been following the same general routes; however, some new features have been shown in synthesis of pyranoanthocyanidins. In an interesting paper by Bernini et al.,272 compounds with a flavonoid structure have been selectively oxyfunctionalized at the C-2 carbon atom by dimethyldioxirane (DMD). Products obtained in this way appeared to be useful starting materials to access anthocyanidins. An example of this route is presented in Scheme 10.1. Here, 2,4-cis-flavane-4-acetate (A) was oxidized by DMD at room temperature, affording the corresponding C-2 hydroxy derivative (B) as the only product (63% yield). Further treatment of B with silica gel eliminated acetic acid to give C quantitatively. Then C was easily transformed into the flavylium salt (D) by simple addition of a 37% solution of HCl in water.

O

H

O

OH

DMD H

H

OAc A

O

OH

O

H+

Silica

+

OAc B

C

D

Following more traditionally routes, a recent one-step synthesis giving 3-deoxyanthocyanidins (apigeninidin and luteolinidin) in high yield involved the condensation reaction between 2,4,6-triacetoxybenzaldehyde and an acetophenone derivative in anhydrous methanolic hydrogen chloride.273 The reduction of quercetin 3-O-(6-O-rhamnosylglucoside), rutin, by zinc amalgam in 3% absolute methanolic hydrochloric acid has provided pure cyanidin 3-O-(6-O-rhamnosylglucoside) in good yield.274 New 3-desoxyanthocyanidins have been prepared according to a Grignard reaction of some flavones with appropriate alkyl- and aryl-magnesium bromides.275 The reaction of 5,7-dihydroxyflavone (chrysin) with an excess of phenylmagnesium bromide in THF under reflux conditions, followed by hydrochloric acid hydrolysis, afforded 1 in Scheme 10.2. Flavylium salts bearing a substituent at the 4-position are important compounds since they are known to be less sensitive to nucleophiles, especially water, and they give only minor amounts of the colorless pseudobases.276

O

HO

(1) RMgBr

O

HO

THF reflux

OH

O

(2) NH4Cl or dilute HCl

+ OH

R

Flavylium salts with 4-methyl substitution (e.g., 2 in Scheme 10.2) might be further gently reacted with aromatic aldehydes affording anthocyanidin pigments of the pyranoanthocyanidin type.275

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Compared to the more common flavylium salts, these latter pigments showed large bathochromic shifts (from about 100 to 200 nm), thus providing blue-violet and green colors, which are difficult to obtain with anthocyanidins in general. The pyranoanthocyanin in red wine called vitisin A has been found by synthetic experiments to be formed by the reaction of malvidin 3-glucoside with pyruvic acid.16 Its formation resulted from cyclization between C-4 and the hydroxyl group at C-5 of the original flavylium moiety with the double bond of the enolic form of pyruvic acid, followed by dehydration and rearomatization steps. Other pyranoanthocyanins in wine formed by the reaction of malvidin 3-glucoside with vinylphenols were first observed by Fulcrand et al.,277 and later synthesized by nucleophilic addition of vinylphenols to malvidin 3-glucoside.278 The former research group has also synthesized similar orange-colored anthocyanins from monoglucosylated anthocyanins and ethanol, alpha-ketoglutaric acid, acetone, or 3-hydroxybutan-2-one.279 See Chapter 5 for further information about anthocyanins in wine. Pyranoanthocyanins have also been formed by oxidative cycloaddition between anthocyanins from blackcurrant seeds and acetone,90 which should be kept in mind when acetone is used as solvent during extraction and isolation of natural anthocyanins. When the same research group isolated four new pyranoanthocyanins (pyranocyanin C and D and pyranodelphinin C and D) from an extract of blackcurrant seeds, these structures were confirmed by chemical synthesis involving blackcurrant anthocyanins and p-coumaric acid.91 Recently, pyranoanthocyanins have been obtained by a simple one-step reaction involving anthocyanins and cinnamic acids bearing at least one electron-donating substituent at the paraposition.280 Through this type of reaction with p-dimethylamino cinnamic acid, which is similar to the reaction of 4-substituted 3-desoxyanthocyanins with p-dimethylamino cinnamaldehyde,275 synthetic malvidin- and cyanidin-based anthocyanins with violet hues have been prepared.280

10.4 ANTHOCYANIN LOCALIZATION IN PLANT CELLS Anthocyanins are the most common water-soluble pigments in the plant kingdom, and are normally found dissolved uniformly in vacuolar solutions of epidermal cells. However, in cases like the Sphagnorubins,281 the pigments are so tenaciously bound to the cell wall that they are only extracted with difficulty. In species from more than 33 families, anthocyanins have been found located in pigmented bodies in vacuoles described as anthocyanoplasts (ACPs).282,283 While the cells matured, these structures often disappeared. The ACPs were thought to be membranous, enclosing the site of anthocyanin biosynthesis. When the nature of ACPs from colored skin tissues of ‘‘Kyoho’’ grapes was investigated under a microscope, it was indicated that each ACP was surrounded by a transparent membrane, which maintained the concentration of anthocyanin within an ACP higher than that in the vacuole.284 Later, it was, however, reported that the spherical pigmented bodies in cells of sweet potato (Ipomoea batatas) in suspension culture might be protein matrices,285,286 and that ACPs possess neither a membrane boundary nor an internal structure.286–288 A protein labeled VP24 was found to accumulate in the intravacuolar pigmented globules (cyanoplasts) and not in the tonoplast.286 The expression of VP24 was closely correlated with the accumulation of anthocyanin in the cell lines, and this protein was suggested to play an important role in trapping of large amounts of anthocyanins that have been transported into these vacuoles. More recently, sequence analysis has indicated that matureVP24 peptide is a member of the metalloprotease family, and might be a novel vacuolar localized aminopeptidase.289,290 Significant evidences have also been presented that enzymes involved in anthocyanin biosynthesis were associated with the cytoplasmic face of the endoplasmic reticulum.291 Although synthesized in the cytoplasm, the anthocya-

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nins, like many other flavonoids, may be rapidly transported across the tonoplast into the cell vacuole as indicated for anthocyanins of maize tissues.292 Anthocyanins thus assume their distinct color after transport to the vacuole; however, very little is still known about the trafficking mechanisms of anthocyanins and their precursor in plant cells. Not much was documented about the chemical nature and the functional significance of these inclusions in petal cells before Markham el al.293 reported intensively colored intravascular bodies in petals of carnations (Dianthus caryophyllus) and lisianthus (Eustoma grandiflorum), which they named anthocyanic vacuolar inclusions (AVIs). The AVIs occurred predominantly in the adaxial epidermal cells, and their presence was shown to have major influence on flower color by enhancing both intensity and blueness. Electron microscopy studies on lisianthus epidermal tissue failed to detect a membrane boundary in AVI bodies, and the isolated AVIs were shown to have a protein matrix. The presence of large AVIs produced marked color intensification in the inner zone of the petal by concentrating anthocyanins above levels that would be possible in vacuolar solution. A minor subset of the total anthocyanins (four cyanidin and delphinidin acylated 3,5-diglycosides) was bound to this matrix rather than the acylated delphinidin triglycosides, which were the major forms present in the petal extracts.293 ‘‘Trapped’’ anthocyanins differed from solution anthocyanins only in that they lacked a terminal rhamnose on the 3-linked galactose, revealing the specificity of the interactions. Recently, Conn et al.294 have reported that AVIs appeared as dark red-to-purple spheres of various sizes in vacuoles in two lines of grapevine (Vitis vinifera) cell suspension culture due to their interaction with anthocyanins. Compared with the total anthocyanin profile, the profile of the AVI-bound anthocyanins showed an increase of ~28 to 29% in acylated (p-coumarylated) anthocyanins in both lines. Figure 10.13 shows AVIs from Vitis vinifera,294 and AVIs from Eustoma grandiflorum and Dianthus caryophyllus.293

10.5 CHEMOTAXONOMIC PATTERNS The structures of nearly 540 different anthocyanins have been elucidated, and more than half of these have been reported after 1992. In the following sections, some chemotaxonomic considerations within 11 families have been included. These families have been chosen due to the fact that most of the new anthocyanins have been isolated from species belonging to these families. Each family has been represented with a general structure including all the anthocyanins we have registered in our files as identified in one or more species belonging to this family. The chemotaxonomic considerations are mainly limited to the pattern revealed by the new anthocyanins reported in these families in the period of this review. Some additional reports of chemotaxonomic relevance are mentioned below. The anthocyanin content of male and female cones of 27 species of Abies, Picea, Pinus, Pseudotsuga, and Tsuga (Pinaceae) has been determined, and only four anthocyanins were found.295 The anthocyanin content of 23 grass species (Poaceae) belonging to five subfamilies has been resolved, and altogether 11 anthocyanins were identified.296 A comprehensive survey of the flower pigment composition of 70 species and subspecies, 43 cultivars, and six artificial hybrids of Crocus (Iridaceae) used for chemotaxonomic investigations has been carried out.297 The anthocyanin content of petals of 28 Chilean species of Alstroemeria (Alstroemeriaceae) and 183 interspecific hybrids has been analyzed by HPLC.104 Flower color, hue, and intensity were measured by CIELAB parameters in fresh petals and compared with their anthocyanin content and the estimated flavonoid concentrations. The chemical basis of red flower pigmentation in species of Cotyledon, Crassula, and Tylecodon (Crassulaceae) has been outlined.298 Only six major anthocyanins were found in the 10 species and 22 samples investigated, and each of the genera showed a characteristic combination of compounds. The chemical basis of flower pigmentation based on six major anthocyanins in the genus

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FIGURE 10.13 Left: Microscopic images of dark-grown Vitis vinifera protoplast of FU-2 line under bright field microscopy (a, b) before and (c) after lysis, showing a single AVI in solution. Arrows indicate AVIs, and the black bar is scaled to 10 mm. V, vacuole; C, cytoplasm. (From Conn, S. et al., Biotechnol. Lett., 25, 835, 2003. With permission.) Right: (d) AVIs isolated from Eustoma grandiflorum, line 54, inner petal region, and (e) AVIs in an adaxial epidermal peel of Dianthus caryophyllus. (From Markham, K.R. et al., Phytochemistry, 55, 327, 2000. With permission.)

Lobostemon (Boraginaceae) has been presented.299 During a wide survey of flower flavonoids in a variety of sections in the genus Rosa, altogether 11 anthocyanins were identified.300,301 According to the anthocyanin distribution patterns in the genus, eight groups were classified chemotaxonomically.

10.5.1 ALLIACEAE The genus Allium (Alliaceae) comprises important vegetables like onions and chive. Among the 14 anthocyanins, which have been identified in various Allium species (Figure 10.14), ten novel anthocyanins with characteristic structures have been reported from this genus after 1993. Several of the anthocyanins from species in Allium have either a glucosyl (laminariobioside), malonyl, or acetyl moiety linked distinctively to the glucosyl 3-position,11,135,147, 202–205,302 which is very unusual. Most of the anthocyanins in this genus are based on cyanidin. Two covalent anthocyanin–flavonol complexes (Figure 10.9) have been isolated from the flowers of chive, Allium schoenoprasum.11 Red onion reveals one of the most characteristic anthocyanin patterns ever found. The main anthocyanins of some cultivars have been identified as the 3-[6-(malonyl)glucoside], 3-[3-(glucosyl)-6-(malonyl)glucoside], 3-[3-glucosyl)glucoside], and 3-glucoside of cyanidin.135,203,205 Without support from NMR or MS data, the 3-arabinoside and 3-malonylarabinoside of cyanidin have been reported to be among the main anthocyanins of Spanish red onion (cultivar ‘‘Morada de Amposta’’).303 Among the minor anthocyanins the 3-[3,6(dimalonyl)glucoside] and 3-[3-(malonyl)glucoside] of cyanidin as well as the 3,5-diglucosides of cyanidin and peonidin have been found.203 Additionally, peonidin 3-glucoside and peonidin

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FIGURE 10.14 The structures represent a general presentation of all the anthocyanins identified in each of the families Alliaceae, Convolvulaceae, Cruciferae, Gentianaceae, Geraniaceae, and Labiatae. See Table 10.2 for abbreviations.

3-malonylglucoside have been reported, however, without determination of the linkage between the acyl group and the sugar of the latter pigment.205 Recently, two pyranoanthocyanins, the 3-glucoside and 3-[6-(malonyl)glucoside] of 5-carboxypyranocyanidin,18 as well as four anthocyanins having a glucosyl in the cyanidin 4’-position,149 the 4’-glucoside, 3glucoside-4’-glucoside, 3-[3-(glucosyl)-6-(malonyl)glucoside]-4’-glucoside, and 7-[3-(glucosyl)6-(malonyl)glucoside]-4’-glucoside149 have been isolated in minor amounts.

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10.5.2 CONVOLVULACEAE Altogether 43 different anthocyanins have been reported to occur in Convolvulaceae (Figure 10.14). Most of these pigments have a glucose unit in the 5-position, and either a mono- or diacylated glucose or sophorose unit in the 3-position of peonidin, pelargonidin, cyanidin, and rarely delphinidin. The acyl groups are mainly caffeyl or coumaryl; however, ferulyl, p-hydroxybenzoyl, and malonyl have been reported. A triacylated-tetraglucosylated cyanidin derivative (243), which contained the novel E-3,5-dihydroxycinnamic acid linked to the 6-position of one of the glucosyl moieties, has recently been isolated from flowers of Ipomoea asarifolia.27 Even though some ternatins (414 – 416, 418) and cyanodelphin (417) actually have larger masses, the ‘‘Heavenly Blue Anthocyanin’’ (297), which is a peonidin 3-sophoroside-5-glucoside with three caffeylglucose residues,304 is among the largest monomeric anthocyanins that has been isolated ([M]þ ¼ 1759 amu). The Morning Glory flowers (Ipomoea/Pharbitis) exist in a wide range of color forms. There is a good correlation between scarlet flower color and the occurrence of pelargonidin derivatives.305,306 Lu et al.307 have showed that the flower color of Pharbitis nil gradually shifts to the blue region with increasing numbers of caffeic acid residues in polyacylated pelargonidin glycosides. Blue and mauve flower colors, attractive to bee pollinators, are generally based on delphinidin, petunidin, or malvidin. However, exceptional cases are found, for instance, in Ipomoea tricolor and Pharbitis nil where the blue flower colors are caused by the peonidin-based ‘‘Heavenly Blue Anthocyanin.’’308–310 Yoshida et al.311 have shown that the color change of Ipomoea tricolor while flowering was due to vacuolar pH changes from 6.6 to 7.7, at which range the anhydrobase anion of HBA was formed and stabilized by intramolecular stacking. A different acylated peonidin glycoside, isomeric with ‘‘Heavenly Blue Anthocyanin,’’312 and related cyanidin derivatives have been obtained from violet-blue flowers of Pharbitis nil308 and Ipomoea purpurea,305 while related pelargonidin derivatives have been isolated from red-purple flowers.306,308 One blue flowered species with more expectable delphinidin chromophore has been discovered in Evolvulus pilosus. The pigment in this plant, 397, which contains one malonyl unit linked to the 5-glucoside, provides a stable blue color at neutral pHs maintained by intermolecular stacking of the caffeyl moieties between the flavylium chromophores.313 None of the other anthocyanins reported from this family are malonylated.

10.5.3 CRUCIFERAE In total, around 45 different anthocyanins have been reported to occur in various species belonging to Cruciferae (Brassicaceae), and nearly all of them share the same type of structures (Figure 10.14). They have a glucosyl at the 5-position, which in some cases is malonylated, and a disaccharide at the 3-position, which is acylated with one or two cinnamic acids. In the genera Brassica178 and Raphanus,314,315 this disaccharide is a sophorose, while Arabidopsis,167 Sinapis,316 and Matthiola177,173 have a sambubioside in the same position. When one cinnamyl moiety occurs, it is attached to the 6-position of the inner hexose (glucose). The second cinnamic acid is linked to the 2-position of the outer hexose (xylose) when a sambubioside occurs, and at the 6-position of the outer hexose (glucose) when the corresponding sophoroside occurs. The cinnamic acids include coumaric acid, caffeic acid, ferulic acid, and sinapic acid. All anthocyanins are either based on cyanidin or pelargonidin, and 28 of these have been reported as novel in the period of this review.

10.5.4 GENTIANACEAE Altogether 22 anthocyanins, including three produced by genetic engineering, have been reported to occur in flowers from the family Gentianaceae (Figure 10.14). Nineteen among these have been identified as novel compounds in the period of this review. The examined

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species belonging to Gentiana contain one or more anthocyanins with a 3,5,3’-triglycosidic substitution pattern.153,154 The blue flowers are reported to contain delphinidin derivatives, while the pink flowers of this genus contain cyanidin derivatives.153,154 All the monosaccharides directly linked to the aglycone are glucosyl moieties. This is in contrast to anthocyanins isolated from Eustoma grandiflorum, which have a galactosyl or robinobiosyl attached to the 3-position, and no glycosyl moiety linked to the 3’-position.123,129 The new anthocyanins based on delphinidin isolated from flowers of Eustoma grandiflorum have been produced by genetic engineering after transformation with a UDP-glucose:flavonoid-3-O-glucosyltransferase cDNA from Antirrhinum majus. The galactose at the 3-position has been partly replaced in some anthocyanins by glucose during anthocyanin synthesis in the transformed plant.123

10.5.5 GERANIACEAE Thirteen different anthocyanins from species in Geraniaceae have been identified (Figure 10.14), and seven among these are novel pigments reported after 1994. The major anthocyanins of various Pelargonium species and cultivars were identified as the 3,5-diglucosides and 3-glucoside-5-[6-(acetyl)glucosides] of the six common anthocyanidins.317 The major factors responsible for color variation were shown to be the types and relative levels of pigments present. Variations in pH and copigment levels were not found to contribute significantly. Flowers with colors ranging from cream and pink through to deep purple, including salmon, orange, and red, were studied. While either flavonols or carotenoids were responsible for cream or yellow coloration, all other colors resulted from anthocyanin mixtures. Similar malvidin 3,5-diglucosides have also been reported in purplish-blue Geranium flowers.210,211 Even though the acetyl in these pigments has been reported attached both to the 3-glucose and to the 5-glucose, the latter is the most probable position.211 In addition, minor amounts of the 3,5-diglucosides of malvidin and cyanidin and the 3-glucosides of cyanidin and delphinidin have been identified in purplish-blue flowers of Geranium sylvaticum.210

10.5.6 LABIATAE Around 40 anthocyanins have been identified in one or more species belonging to Labiatae (Figure 10.14), and during the last decade seven have been identified for the first time in this family. The Labiatae is a large, highly evolved plant family with a wide geographical distribution, which constitutes an appropriate group of plants for investigation of the relationship between anthocyanin structure and flower color. Studies on the distribution pattern of anthocyanins in species of Salvia and other genera have shown that the red, scarlet, and pink-colored flower varieties contained pelargonidin, the blue ones delphinidin, and the amethyst- and grape-violet-colored ones were based on cyanidin derivatives.318,200 In a survey of 49 Labiatae species and cultivars, Saito and Harborne200 confirm the universal occurrence of anthocyanin 3,5-diglucosides, and the widespread occurrence of both aromatic and aliphatic acylation with p-coumaric and caffeic acids in the majority of the species. For the more conjugated anthocyanins, the disaccharide sophorose in the 3-position is a distinct feature. Lu and Foo319 have recently reviewed the polyphenolic content of Salvia including 20 anthocyanins. Phippen and Simon.320 have identified anthocyanins from the herb Ocimum basilicum with a slightly simpler structures than the more substituted anthocyanins found in Ajuga reptans,110,111 Ajuga pyramidalis,36 and Salvia uliginosa.209 The location of an aliphatic acyl group to the glucose 4-position as found in the 3-[6-(p-coumaryl)glucoside]-5-[4,6-di-(malonyl)glucosides] of cyanidin, delphinidin, and pelargonidin, the 3-[6-(caffeyl)glucoside]-5-[4,6-di-(malonyl)glucoside] of the two latter anthocyanidins,198–200 and delphinidin 3-[6-(p-coumaryl)glucoside]-5-[4-(acetyl)-6-(malonyl)glucoside] from flowers

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of Salvia uliginosa209 is very characteristic for Labiatae. Protodelphin (351), a metalloanthocyanin similar to commelinin and protocyanin (Section 10.2.7), has been detected in flowers of Salvia patens.226

10.5.7 LEGUMINOSAE More than 60 different anthocyanins have been identified in species belonging to the family Leguminosae (Figure 10.15). In the period of this review, 17 novel anthocyanins have been reported from this family, of which 13 are from Clitoria ternatea.141,144,145 Blue petals of Clitoria ternatea contain mainly ternatins (polyacylated delphinidin 3,3’,5’-triglucosides) and preternatins. The change in flower color from blue to mauve in this species is caused by lack of (polyacylated) glucosyl substitutions at both the 3’- and 5’-positions of the ternatins.141 The novel delphinidin 3-xylosylgalactoside 5-acetylglucoside and its deacetylated derivative have been isolated from purple pods of pea (Pisum spp.).129 Anthocyanins containing 3-galactoside (including 3-lathyroside) have previously been identified in the genus Lathyrus. The 3-rhamnoside-5-glucosides of petunidin (71%), delphinidin (12%), and malvidin (9%) have been isolated from the purple-blue flowers of Vicia villosa,321 while the 3-glucosides of delphinidin, petunin, and malvidin have been mainly identified in species belonging to Vigna, Phaseolus, and Glycine.322–324 Other anthocyanin patterns have been shown to be of chemotaxonomic value in the tribes Podalyrieae325 and Liparieae.326 The considerable variation in flower colors in the former tribe was not reflected in the chemical variation because the flower pigments were surprisingly conservative.

10.5.8 LILIACEAE Around 38 different anthocyanins have been reported to occur in various species belonging to Liliaceae (Figure 10.15). Seventeen have been reported after 1992, and many of these have extraordinary structures. Recently, Saito et al.20 have isolated 8-C-glucosylcyanidin 3-[6(malonyl)glucoside] from the purple flowers of Tricyrtis formosana cultivar Fujimusume, which is the first natural C-glycosylanthocyanin to be reported. Three acylated delphinidin 3,7,3’,5’-tetraglucosides have been isolated from the remarkably colored blue berries of two Dianella species.146 One of these pigments had as much as four 6-p-coumarylglucoside units located at different aglycone positions. Acetyl groups in anthocyanins are, in general, linked to glucosyl 6-positions; however, in four anthocyanins from tulips the acetyl group is located in the rhamnosyl 2- or 3-position.121,122 In delphinidin 3-[6-(4-(glucosyl)coumaryl)glucoside]5-[6-(malonyl)glucoside], which is one of the major anthocyanins isolated from blue-purple flowers of Triteleia bridgesii, the coumaryl unit had another glucosyl moiety connected to its 4-hydroxyl group.166 The other pigments in these flowers were delphinidin and cyanidin 3,5-diglucoside acylated with p-coumaryl and in some cases malonyl. Nearly 20 similar anthocyanidin 3,5-diglucosides with a cinnamic acid derivative located to the 6-position of the 3-sugar and possible malonyl or acetyl connected to the 5-sugar have been isolated from flowers of Hyacinthus orientalis.201,327,328 Red Hyacinthus petals contain pelargonidin derivatives, while the blue flowers have mainly delphinidin derivatives. Anthocyanins from flowers of Lilium have been reported to contain the 3-rutinoside-7-glucoside and 3-rutinoside of cyanidin.120

10.5.9 NYMPHAEACEAE Eleven different anthocyanins from water lilies have been identified (Figure 10.15), and six among these are novel compounds reported after 1992. One or more anthocyanins containing a galloylgalactosyl moiety have been isolated from all examined species belonging to the

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glc

glc

6

cum

4

glc

6

cum

6

cum

R1 O

4

glc

3'

OH

glc

R1 O 3'

6

cum

OH

glc

8

O

5' R2

O

O

7

HO

5' R2

O

glc

glc

rha

6 (ace,rha,cum) mal

(glc xyl)

O

5 6

glc

O

6

cum

(rha) (gal xyl) 2

3

O

3 4

glc

6

cum

4

O

glc

4

2

mal

6

cum

glc (rha)

6

rha (mal,cum,caf)

6

4 glc

2/3

(ace) mal

ace

ace

Leguminosae

Liliaceae

gao 2

O

glc 6

gal

3'

R1 3

O

gal

6

ace

4

hba) 6 cum glc

O

glc glc)

6

4

glc

(caf, fer)

R2

7 3

6

glc

O

(oxa)

mal (rha)

OH

gao

cum

OH

O

(caf, fer, sin)

2

OH

cum 4 (hba

3'

OH

O

(caf, sin)

6

R1 O

ace (glc

HO

glc

O

glc

glc

Orchidaceae

Nymphaeaceae R1 3'

HO

OH 5'

O

R2 3

O

5

glu

glc

O

6

glc

hba

6

glc

4

hba (caf)

62

glc

3

glc glc

O O

4

glc

hba glc

glc

6

caf (fer, cum)

(caf)

(gal) 6 (rha) 3

glc

mal

tar

3

caf

4

glc

2 (xyl) glc 2

caf

6

hba

4

R1 3

6

(caf, fer)

Solanaceae

7

3

cum

OH

O+

O

4

cum

glc

3'

rha

6

O hba

6

Ranunculaceae

FIGURE 10.15 The structures represent a general presentation of all the anthocyanins identified in each of the families Leguminosae, Liliaceae, Nymphaeaceae, Orchidaceae, Ranunculaceae, and Solanaceae. See Table 10.2 for abbreviations.

family Nymphaeaceae.26,190–192 This glycosidic moiety is located at the anthocyanidin 3-position in pink or reddish flowers and leaves; however, in the blue flowers of Nymphaea caerulea this moiety is located in the rare 3’-position. Some of these pigments are further

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acetylated on the galactosyl moiety. The pigments from Nymphaea caerulea are extraordinary due to their lack of glycosidic substitution at the 3-hydroxyl.192 The distribution of galloylated anthocyanins outside Nymphaeaceae is restricted to Acalypha hispida (Euphorbiaceae)130 and some species in Aceraceae.193–195

10.5.10 ORCHIDACEAE Around 30 anthocyanins have been identified in orchids (Figure 10.15), and 16 among these are novel compounds reported after 1993. In orchids, cyanidin 3-oxalylglycosides have previously been reckoned to be remarkable taxonomic markers of certain European genera (e.g., Dactylorhiza, Nigritella, Orchis, and Ophrys).222 Outside Orchidaceae, anthocyanins acylated with oxalic acid have only been reported to occur in Evergreen Blackberry (Rubus laciniatus Willd.).57 More recent reports on anthocyanins from flowers of the genera Dendrobium,181,189 Laelia,155,156 Cattleya,155,156 Bletilla,157 Phalaenopsis,180,329 Sophronitis,176 and Vanda179 in subfamily Epidendroideae show, however, a very different and characteristic pattern including substitution at the anthocyanidin 3,7,3’-positions. Flowers of two Dracula species (same subfamily) contain only various 3-glycosides of cyanidin and peonidin.330

10.5.11 RANUNCULACEAE Nearly 35 different anthocyanins have been reported to occur in one or more species in the family Ranunculaceae (Figure 10.15), and 24 of these have been reported after 1992 as novel compounds. Flowers of species in the genera Delphinium (blue),109 Consolida (blue-violet),115 and Aconitum (purplish-blue)184 contain similar anthocyanins with polyacyl substitution based on p-hydroxybenzoylglucose residues at the 7-hydroxyl of delphinidin, in addition to a more simple glycosyl moiety at the 3-position. Red flowers of Delphinium hybridum119,331 share a similar 3,7-disubstitution pattern based on pelargonidin instead of delphinidin. The reports on anthocyanins from Anemone coronaria,28,29,132 Pulsatilla cernua,22 and Ranunculus asiaticus126 reveal structures that are very different from the anthocyanins described above. Many of these latter pigments are based on lathyroside or sambubioside residues located at the 3-hydroxyl of delphinidin, pelargonidin, or cyanidin (Table 10.2). Among these, four unusual anthocyanins containing the acyl moiety tartaryl have been isolated from Anemone coronaria.28,29,132 Six of the anthocyanins in this plant have a glucuronoside in the 3’-position.

10.5.12 SOLANACEAE Altogether 50 different anthocyanins (Figure 10.15) have been reported to occur in the Solanaceae family.161,169 Reports on anthocyanins from the genus Solanum, including potatoes (Solanum tuberosum), reveal a dominance of one or more of the 3-[6-(4-p-coumaryl-rhamnosyl)-glucoside]-5-glucosides of malvidin, petunidin, delphinidin, peonidin, cyanidin, and pelargonidin. In some cases, the p-coumaryl moiety is replaced with sinapyl or caffeyl, and in other cases, the anthocyanins are reported without acylation. Similar anthocyanins, but pelargonidin derivatives, have also been found within the ornamental genus Petunia. In addition, diacylated 3-rutinoside-5-glucosides of malvidin, petunidin, delphinidin, and peonidin have also been isolated from flowers of various Petunia species and hybrids.159–165 Only some of the oldest reports on anthocyanins from species within Solanaceae present anthocyanins containing the disaccharides gentiobiose, sophorose, and a 3,7-diglucoside substitution pattern. The inheritance and biosynthesis of anthocyanin pigmentation in Petunia and Solanum have received immense interest throughout many decades,332–334 and the first experiments in genetically modifying anthocyanin flower color were carried out on Petunia hybrida.335

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This subject has been treated comprehensively in Chapter 3. Colorful potatoes have been suggested as potential sources for food colorants,336,337 and the major anthocyanin of the purple-fleshed potato ‘‘Congo,’’ petanin, shows higher color stability than simple anthocyanins at most pH values.236 The use of anthocyanins as taxonomic markers in the genus Petunia discussed in relation to the flower color and possible pollination vectors has been described by Ando et al.160 based on the presence of at least 24 anthocyanins in the flowers of 20 native taxa.

REFERENCES 1. Timberlake, C.F. and Bridle, P. Anthocyanins, The Flavonoids, Harborne, J.B., Mabry, T.J., and Mabry, H., Eds., Academic Press, New York, 1975, Chap. 5. 2. Hrazdina, G., Anthocyanins, The Flavonoids: Advances in Research, Harborne, J.B. and Mabry, T.J., Eds., Chapman & Hall, London, 1982, Chap. 3. 3. Harborne, J.B. and Grayer, R.J., The Anthocyanins, The Flavonoids: Advances in Research Since 1980, Harborne, J.B., Ed., Chapman & Hall, London, 1988, Chap. 1. 4. Strack, D. and Wray, V. The Anthocyanins, The Flavonoids: Advances in Research Since 1986, Harborne, J.B., Ed., Chapman & Hall, London 1994, Chap. 1. 5. Harborne, J.B. and Williams, C.A., Anthocyanins and other flavonoids, Nat. Prod. Rep., 12, 639, 1995. 6. Harborne, J.B. and Williams, C.A., Anthocyanins and other flavonoids, Nat. Prod. Rep., 15, 631, 1998. 7. Harborne, J.B. and Williams, C.A., Anthocyanins and other flavonoids, Nat. Prod. Rep., 18, 310, 2001. 8. Harborne, J.B. and Baxter, H., The Handbook of Natural Flavonoids, John Wiley, Chichester, 1999. 9. Toki, K. et al., Delphinidin 3-gentiobiosyl)(Apigenin 7-glucosyl)malonate from the flowers of Eichhornia crassipes, Phytochemistry, 36, 1181, 1994. 10. Toki, K. et al., Delphinidin 3-gentiobiosyl) (luteolin 7-glucosyl)malonate from the flowers of Eichhornia crassipes, Heterocycles, 63, 899, 2004. 11. Fossen, T. et al., Covalent anthocyanin–flavonol complexes from flowers of chive, Allium schoenoprasum, Phytochemistry, 54, 317, 2000. 12. Bloor, S.J. and Falshaw, R., Covalently linked anthocyanin–flavonol pigments from blue Agapanthus flowers, Phytochemistry, 53, 575, 2000. 13. Fossen, T., Rayyan, S., and Andersen, Ø.M., Dimeric anthocyanins from strawberry (Fragaria ananassa) consisting of pelargonidin 3-glucoside covalently linked to four flavan-3-ols, Phytochemistry, 65, 1421, 2004. 14. Bakker, J. et al., Identification of an anthocyanin occurring in some red wines, Phytochemistry, 44, 1375, 1997. 15. Bakker, J. and Timberlake, C.F., Isolation, identification, and characterization of new color-stable anthocyanins occurring in some red wines, J. Agric. Food. Chem., 45, 35, 1997. 16. Fulcrand, H. et al., A new class of wine pigments generated by reaction between pyruvic acid and grape anthocyanins, Phytochemistry, 47, 1401, 1998. 17. Fukui, Y. et al., Structure of rosacyanin B, a novel pigment from petals of Rosa hybrida, Tetrahedron Lett., 43, 2637, 2002. 18. Fossen, T. and Andersen, Ø.M., Anthocyanins from red onion, Allium cepa, with novel aglycone, Phytochemistry, 62, 1217, 2003. 19. Andersen, Ø.M. et al., Anthocyanin from strawberry (Fragaria ananassa) with the novel aglycon, 5-carboxypyranopelargonidin, Phytochemistry, 65, 405, 2004. 20. Saito, N. et al., The first isolation of C-glycosylanthocyanin from the flowers of Tricyrtis formosana, Tetrahedron Lett., 44, 6821, 2003. 21. Yoshida, K. et al., Structure of muscarinin A, and acylated anthocyanin, from purplish blue spicate flower petals of Muscari armeniacum, ITE Letters on Batteries, New Technologies & Medicine, 3, 35, 2002.

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22. Yoshitama, K. et al., An acylated pelargonidin diglycoside from Pulsatilla cernua, Phytochemistry, 47, 105, 1998. 23. Slimestad, R. and Andersen, Ø.M., Cyanidin 3-(2-glucosylgalactoside) and other anthocyanins from fruits of Cornus suecica, Phytochemistry, 49, 2163, 1998. 24. Toki, K. et al., Delphinidin 3-xylosylrutinoside in petals of Linum grandiflorum, Phytochemistry, 39, 243, 1995. ˚ ., and Andersen, Ø.M., Anthocyanin trisaccharides in blue berries of 25. Cabrita, L., Frøystein, N.A Vaccinium padifolium, Food Chem., 69, 33, 2000. 26. Fossen, T. and Andersen, Ø.M., Delphinidin 3’-galloylgalactosides from blue flowers of Nymphae´a caerulea, Phytochemistry, 50, 1185, 1999. 27. Pale, E. et al., Two triacylated and tetraglucosylated anthocyanins from Ipomoea asarifolia flowers, Phytochemistry, 64, 1395, 2003. 28. Saito, N. et al., Acylated anthocyanins from the blue-violet flowers of Anemone coronaria, Phytochemistry, 60, 365, 2002. 29. Toki, K. et al., Acylated cyanidin glycosides from the purple-red flowers of Anemone coronaria, Heterocycles, 60, 345, 2003. 30. Toki, K. et al., Malvidin 3-glucoside-5-glucoside sulphates from Babiana stricta, Phytochemistry, 37, 885, 1994. 31. Fukui, Y. et al., A rationale for the shift in colour towards blue in transgenic carnation flowers expressing the flavonoid 3’,5’-hydroxylase gene, Phytochemistry, 63, 15, 2003. 32. Bloor, S.J., Blue flower colour derived from flavonol–anthocyanin co-pigmentation in Ceanothus papillosus, Phytochemistry, 45, 1399, 1997. 33. Glaessgen, W.E. et al., Anthocyanins from cell suspension cultures of Daucus carota, Phytochemistry, 31, 1593, 1992. 34. Miura, H. et al., Anthocyanin production of Glehnia littoralis callus cultures, Phytochemistry, 48, 279, 1998. 35. Terahara, N. et al., Anthocyanins in callus induced from purple storage root of Ipomoea batatas L., Phytochemistry, 54, 919, 2000. 36. Madhavi, D.L. et al., Characterization of Anthocyanins from Ajuga pyramidalis Metallica Crispa cell cultures, J. Agric. Food Chem., 44, 1170, 1996. 37. Middleton, E. Jr., Kandaswami, C., and Theoharides, T.C., The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer, Pharmacol. Rev., 52, 673, 2000. 38. Bohm, H. et al., Flavonols, flavone and anthocyanins as natural antioxidants of food and their possible role in the prevention of chronic diseases, Z. Ernahrungsw., 37, 147, 1998. 39. Clifford, M.N.,Anthocyanins—nature,occurrence anddietaryburden,J.Sci.FoodAgric.,80,1063,2000. 40. Duthie, G.G., Duthie, S.J., and Kyle, J.A.M., Plant polyphenols in cancer and heart disease: implications as nutritional antioxidants, Nut. Res. Rev., 13, 79, 2000. 41. Duthie, G.G. et al., Antioxidant activity of anthocyanins in vitro and in vivo, ACS Symposium Series, 871 (Nutraceutical Beverages), American Chemical Society, Washington, DC, 90, 2004. 42. Harborne, J.B. and Williams, C.A., Advances in flavonoid research since 1992, Phytochemistry, 55, 481, 2000. 43. Scalbert, A. and Williamson, G., Dietary intake and bioavailability of polyphenol, J. Nutr., 130, 2073, 2000. 44. Murkovic, M., Physiological action of anthocyans, Ernaehrung Medizin, 17, 167, 2002. 45. Rice-Evans, C.A. and Packer, L., Flavonoids in Health and Disease, 2nd edn, Marcel Dekker, New York, 2003, 467. 46. Pietta, P., Minoggio, M., and Bramati, L., Plant polyphenols: structure, occurrence and bioactivity, Studies in Natural Products Chemistry, 28 (Bioactive Natural Products (Part I)), Elsevier Science Publishers, Amsterdam, 257, 2003. 47. Kong, J.M. et al., Analysis and biological activities of anthocyanins, Phytochemistry, 64, 923, 2003. 48. Prior, R.L., Absorption and metabolism of anthocyanins: potential health effects, Phytochemicals: Mechanisms of Action, 4th International Phytochemical Conference, ‘‘Phytochemicals: Mechanisms of Action’’, Pomona, CA (October 21–22, 2002), 2004.

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369. Kidøy, L. et al., Anthocyanins in Fruits of Passiflora edulis and P. suberosa, J. Food Compost. Anal., 10, 49, 1997. 370. Wang, H. et al., Quantification and characterization of anthocyanins in Balaton tart cherries, J. Agric. Food Chem., 45, 2556, 1997. 371. Lee, H.S., Characterization of major anthocyanins and color of red-fleshed Budd Blood Orange (Citrus sinensis), J. Agric. Food Chem., 50, 1243, 2002. 372. Underhill, S.J.R. and Critchley, C., Physiological, biochemical and anatomical changes in lychee (Litchi chinensis Sonn.) pericarp during storage, J. Hortic. Sci., 68, 327, 1993. 373. Sarni-Manchado, P. et al., Phenolic composition of Litchi fruit pericarp, J. Agric. Food Chem., 48, 5995, 2000. 374. Zhang, Z. et al., Purification and structural analysis of anthocyanins from litchi pericarp, Food Chem., 84, 601, 2004. 375. Wilbert, S.M., Schemske, D.W., and Bradshaw, H.D. Jr., Floral anthocyanins from two Monkeyflower species with different pollinators, Biochem. Syst. Ecol., 25, 437, 1997. 376. Bloor, S.J. et al., Identification of flavonol and anthocyanin metabolites in leaves of Petunia ‘‘Mitchell’’ and its LC transgenic, Phytochemistry, 49, 1427, 1998. 377. Griesbach, R.J., Stehmann, J.R., and Meyer, F., Anthocyanins in the ‘‘red’’ flowers of Petunia exserta, Phytochemistry, 51, 525, 1999. 378. Lin, H-.C., Liou, C-.C., and Tsai, T-.C., Taiwan Nongye Huaxue Yu Shipin Kexue, 39, 370, 2001 (Abstract). 379. Alcalde-Eon, C. et al., Identification of anthocyanins of pinta boca (Solanum stenotomum) tubers, Food Chem., 86, 441, 2004. 380. Herna´ndez-Pe´rez, M. et al., Phenolic composition of the ‘‘Moca´n’’ (Visnea mocanera L.f.), J. Agric. Food Chem., 44, 3512, 1996. 381. Narayan, M.S. and Venkataraman, L.V., Characterisation of anthocyanins derived from carrot (Daucus carota) cell culture, Food Chem., 70, 361, 2000. 382. Toki, K. et al., Pelargonidin 3-acetylglucoside in Verbena flowers, Phytochemistry, 30, 3828, 1991. 383. Toki, K. et al., Pelargonidin 3-glucoside-5-acetylglucoside in Verbena flowers, Phytochemistry, 40, 939, 1995. 384. Toki, K. et al., Acylated anthocyanins in Verbena flowers, Phytochemistry, 38, 515, 1995. 385. Baldi, A. et al., HPLC/MS application to anthocyanins of Vitis vinifera L., J. Agric. Food Chem., 43, 2104, 1995. 386. Nu´n˜ez, V. et al., Vitis vinifera L. cv. Graciano grapes characterized by its anthocyanin profile, Postharvest Biol. Technol., 31, 69, 2004.

APPENDIX A Checklist of all natural anthocyanidins (in bold) and anthocyanins. Anthocyanidins found in plants without sugar are labeled with numbers. For anthocyanins found after 1992 the numbers in italic correspond to the numbers in the reference list. A1 Pelargonidin (3,5,7,4’-tetrahydroxyflavylium) 1 3-Arabinoside 2 3-Xyloside 3 3-Rhamnoside 4 3-Galactoside 5 3-Glucoside 6 3-[2-(Xylosyl)galactoside] 7 3-[2-(Xylosyl)glucoside] 8 3-Rhamnoside-5-glucoside 9 3-[6-(Rhamnosyl)galactoside]

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3-[2-(Rhamnosyl)glucoside] 3-[6-(Rhamnosyl)glucoside] 3-Galactoside-5-glucoside 3-Glucoside-5-glucoside 3-Glucoside-7-glucoside 3-[2-(Glucosyl)glucoside] 3-[6-(Glucosyl)glucoside] 3-[6-(Rhamnosyl)-2-(xylosyl)glucoside] 3-[2-(Xylosyl)glucoside]-5-glucoside 3-[6-(Rhamnosyl)galactoside]-5-glucoside 3-[6-(Rhamnosyl)glucoside]-5-glucoside 3-[6-(Rhamnosyl)glucoside]-7-glucoside (331) 3-[6-(Rhamnosyl)-2-(glucosyl)glucoside] 3-[2-(Glucosyl)glucoside]-5-glucoside 3-[2-(Glucosyl)glucoside]-7-glucoside 3-[6-(Acetyl)glucoside] 3-[6-(Malonyl)glucoside] 3-[6-(Malyl)glucoside] 3-[6-(Caffeyl)glucoside] (360) 3-[6-(2-(Acetyl)rhamnosyl)glucoside] (122) 3-[6-(Acetyl)glucoside]-5-glucoside (384) 3-Glucoside-5-[6-(acetyl)glucoside] 3-[2-(Xylosyl)-6-(malonyl)galactoside] (29) 3-[2-(Xylosyl)-6-(methyl-malonyl)galactoside] (29) 3-[6-(Malonyl)glucoside]-5-glucoside 3-Glucoside-5-[6-(malonyl)glucoside] (327) 3-[6-(Malonyl)glucoside]-7-glucoside (331) 3-[6-(Malonyl)-2-(glucosyl)glucoside] 3-Glucoside-5-glucoside (6’’,6’’’-malyl diester) (215) 3-[6-(Succinyl)glucoside]-5-glucoside 3-[6-(4-(p-Coumaryl)rhamnosyl)glucoside] 3-[6-(p-Coumaryl)glucoside]-5-glucoside 3-[6-(p-Coumaryl)glucoside]-5-glucoside Z (327) 3-[6-(Caffeyl)glucoside]-5-glucoside 3-[2-(2-(Caffeyl)glucosyl)galactoside] (22) 3-[6-(3-(Glucosyl)caffeyl)glucoside] (360) 3-[6-(Ferulyl)glucoside]-5-glucoside (327) 3-[6-(Acetyl)glucoside]-5-[6-(acetyl)glucoside] (382) 3-[6-(Malonyl)glucoside]-5-[6-(acetyl)glucoside] (384) 3-[6-(p-Coumaryl)glucoside]-5-[6-(acetyl)glucoside] (327) 3-[6-(p-Coumaryl)glucoside]-5-[4-(malonyl)glucoside] (201) 3-[6-(p-Coumaryl)glucoside]-5-[6-(malonyl)glucoside] 3-[6-(Caffeyl)glucoside]-5-[6-(malonyl)glucoside] 3-[6-(Malonyl)glucoside]-7-[6-(caffeyl)glucoside] (354) 3-[6-(Ferulyl)glucoside]-5-[6-(malonyl)glucoside] (327) 3-[6-(p-Coumaryl)glucoside]-5-[4-(malonyl)-6-(malonyl)glucoside] 3-[6-(Caffeyl)glucoside]-5-[4-(malonyl)-6-(malonyl)glucoside] 3-[6-(Rhamnosyl)glucoside]-7-[6-(p-hydroxybenzoyl)glucoside] (331) 3-Glucoside-7-[6-(4-(glucosyl)p-hydroxybenzoyl)glucoside] (331) 3-[6-(4-(p-Coumaryl)rhamnosyl)glucoside]-5-glucoside

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60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94

A2 95 96 97 98 99 100 101 102 103

3-[2-(6-(p-Coumaryl)glucosyl)glucoside]-5-glucoside (310) 3-[2-(Glucosyl)-6-(p-coumaryl)glucoside]-5-glucoside (314) 3-[6-(4-(Ferulyl)rhamnosyl)glucoside]-5-glucoside (171) 3-[2-(6-(Caffeyl)glucosyl)glucoside]-5-glucoside 3-[2-(Glucosyl)-6-(caffeyl)glucoside]-5-glucoside (359) 3-[6-(3-(Glucosyl)caffeyl)glucoside]-5-glucoside (360) 3-[2-(Glucosyl)-6-(ferulyl)glucoside]-5-glucoside (314) 3-[2-(6-(Ferulyl)glucosyl)glucoside]-5-glucoside (314) 3-[2-(Xylosyl)-6-(p-coumaryl)glucoside]-5-[6-(malonyl)glucoside] (173) 3-[6-(Malonyl)glucoside]-7-[6-(4-(glucosyl)p-hydroxybenzoyl)glucoside] (331) 3-[2-(Xylosyl)-6-(ferulyl)glucoside]-5-[6-(malonyl)glucoside] (173) 3-[2-(Glucosyl)-6-(p-coumaryl)glucoside]-5-[6-(malonyl)glucoside] (314) 3-[2-(Glucosyl)-6-(ferulyl)glucoside]-5-[6-(malonyl)glucoside] (314) 3-[2-(6-(Caffeyl)glucosyl)-6-(p-coumaryl)glucoside]-5-glucoside (314) 3-[2-(6-(Ferulyl)glucosyl)-6-(p-coumaryl)glucoside]-5-glucoside (314) 3-[2-(2-(Sinapyl)xylosyl)-6-(p-coumaryl)glucoside]-5-glucoside (173) 3-[2-(6-(Caffeyl)glucosyl)-6-(caffeyl)glucoside]-5-glucoside (306) 3-[2-(6-(Caffeyl)glucosyl)-6-(ferulyl)glucoside]-5-glucoside (314) 3-[2-(6-(Ferulyl)glucosyl)-6-(caffeyl)glucoside]-5-glucoside (314) 3-[2-(6-(Ferulyl)glucosyl)-6-(ferulyl)glucoside]-5-glucoside (314) 3-[2-(2-(Ferulyl)glucosyl)-6-(ferulyl)glucoside]-5-glucoside (315) 3-[2-(2-(Sinapyl)xylosyl)-6-(ferulyl)glucoside]-5-glucoside (173) 3-[2-(Xylosyl)-6-(3-(3-(4-(glucosyl)caffeyl)-2-tartaryl)malonyl)galactoside] (29) 3-[2-(2-(Ferulyl)xylosyl)-6-(ferulyl)glucoside]-5-[6-(malonyl)glucoside] (173) 3-[2-(2-(Sinapyl)xylosyl)-6-(p-coumaryl)glucoside]-5-[6-(malonyl)glucoside] (173) 3-[6-(Malonyl)glucoside]-7-[6-(4-(6-(caffeyl)glucosyl)caffeyl)glucoside] (354) 3-[2-(2-(Sinapyl)xylosyl)-6-(ferulyl)glucoside]-5-[6-(malonyl)glucoside] (173) 3-[6-(Rhamnosyl)glucoside]-7-[6-(4-(glucosyl)p-hydroxybenzoyl)glucoside] (331) 3-[2-(6-(3-(Glucosyl)caffeyl)glucosyl)glucoside]-5-glucoside 3-[2-(Glucosyl)-6-(4-(glucosyl)caffeyl)glucoside]-5-glucoside (310) 3-[2-(6-(3-(Glucosyl)caffeyl)glucosyl)-6-(caffeyl)glucoside]-5-glucoside 3-[2-(6-(Caffeyl)glucosyl)-6-(4-(6-(caffeyl)glucosyl)caffeyl)glucoside]-5-glucoside (306) 3-[6-(Rhamnosyl)glucoside]-7-[6-(4-(6-(4-(6-(p-hydroxybenzoyl)glucosyl)phydroxybenzoyl)glucosyl)p-hydroxybenzoyl)glucoside] 3-[2-(6-(3-(Glucosyl)caffeyl)glucosyl)-6-(4-(6-(caffeyl)glucosyl)caffeyl)glucoside]5-glucoside (306) 3-[2-(6-(3-(Glucosyl)caffeyl)glucosyl)-6-(4-(6-(3-(glucosyl)caffeyl)glucosyl)caffeyl) glucoside]-5-glucoside Cyanidin (3,5,7,3’,4’-pentahydroxyflavylium) 3-Arabinoside 3-Xyloside 3-Rhamnoside 3-Galactoside 3-Glucoside 4’-Glucoside (147 ) 3-Arabinoside-5-glucoside 3-[2-(Xylosyl)galactoside] 3-[2-(Xylosyl)glucoside]

539

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104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153a

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3-Rhamnoside-5-glucoside 3-Glucoside-7-rhamnoside 3-[6-(Rhamnosyl)galactoside] 3-[2-(Rhamnosyl)glucoside] 3-[6-(Rhamnosyl)glucoside] 3-Galactoside-5-glucoside 3-Glucoside-5-glucoside 3-Glucoside-7-glucoside 3-Glucoside-3’-glucoside 3-Glucoside-4’-glucoside (135) 3-[2-(Glucosyl)galactoside] (23) 3-[2-(Glucosyl)glucoside] 3-[3-(Glucosyl)glucoside] 3-[6-(Glucosyl)glucoside] 3-[2-(Glucuronosyl)glucoside] 3-[2-(Xylosyl)-6-(rhamnosyl)glucoside] 3-[2-(Xylosyl)glucoside]-5-glucoside 3-[2-(Xylosyl)-6-(glucosyl)galactoside] 3-[6-(Rhamnosyl)glucoside]-5-glucoside 3-[6-(Rhamnosyl)glucoside]-3’-glucoside 3-[6-(Rhamnosyl)glucoside]-7-glucoside (120) 3-[2-(Glucosyl)-6-(rhamnosyl)glucoside] 3-Glucoside-5-glucoside-3’-glucoside 3-Glucoside-7-glucoside-3’-glucoside 3-[2-(Glucosyl)glucoside]-5-glucoside 3-[6-(Acetyl)galactoside] (192) 3-[4-(Acetyl)glucoside] 3-[6-(Acetyl)glucoside] 3-[6-(Oxalyl)glucoside] 3-[3-(Malonyl)glucoside] (202) 3-[6-(Malonyl)glucoside] 3-[6-(Succinyl)glucoside] (221) 3-[6-(Malyl)glucoside] 3-[6-(p-Coumaryl)glucoside] 3-[2-(Galloyl)galactoside] 3-[2-(Galloyl)glucoside] (193) 3-[6-(Caffeyl)glucoside] 3-[3-(Malonyl)-6-(malonyl)glucoside] (202) 3-[2-(Galloyl)-6-(acetyl)galactoside] (367) 3-[2-(Galloyl)3-(galloyl)glucoside] (193) 3-[6-(2-(Acetyl)rhamnosyl)glucoside] (122) 3-[6-(4-(Acetyl)rhamnosyl)glucoside] 3-[6-(Acetyl)glucoside]-5-glucoside 3-Glucoside-5-[6-(acetyl)glucoside] (317) 3-[2-(Xylosyl)-6-(malonyl)glucoside] (126) 3-[6-(Malonyl)glucoside]-5-glucoside 3-[3-(Glucosyl)-6-(malonyl)glucoside] (135) 3-[6-(Malonyl)glucoside]6-C-[glucoside] (20) 3-Glucoside-5-glucoside (6’’,6’’’-malyl diester) (214) 3-[6-(Succinyl)glucoside]-5-glucoside

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a

3-[6-(Succinyl)glucoside]-5-glucosidea 3-[4-(Malonyl)-2-(glucuronosyl)glucoside] 3-[6-(Malonyl)-2-(glucuronosyl)glucoside] 3-[2-(Xylosyl)-6-(p-coumaryl)glucoside] (116) 3-[2-(Xylosyl)-6-(p-coumaryl)glucoside] Z (116) 3-[2-(Xylosyl)-6-(caffeyl)glucoside] (116) 3-[2-(Xylosyl)-6-(caffeyl)glucoside] Z (116) 3-[2-(Galloyl)-6-(rhamnosyl)galactoside] (130) 3-[2-(Galloyl)-6-(rhamnosyl)glucoside] 3-Galactoside-5-[6-(p-coumaryl)glucoside] (129) 3-[6-(p-Coumaryl)glucoside]-5-glucoside 3-[6-(p-Coumaryl)glucoside]-5-glucoside Z 3-Glucoside-5-[6-(p-coumaryl)glucoside] (153) 3-[6-(4-(Caffeyl)rhamnosyl)glucoside] 3-[2-(Glucosyl)-6-(p-coumaryl)glucoside] (116) 3-[2-(Glucosyl)-6-(p-coumaryl)glucoside] Z (116) 3-[6-(Caffeyl)glucoside]-5-glucoside 3-[6-(Caffeyl)glucoside]-5-glucoside Z 3-Glucoside-5-[6-(caffeyl)glucoside] (153) 3-Glucoside-3’-[6-(caffeyl)glucoside] (353) 3-[2-(Glucosyl)-6-(caffeyl)glucoside] (358) 3-[2-(6-(Caffeyl)glucosyl)glucoside] (358) 3-[6-(Ferulyl)glucoside]-5-glucoside 3-[6-(6-(Ferulyl)glucosyl)galactoside] 3-[6-(6-(Sinapyl)glucosyl)galactoside] 3-[4-(Sinapyl)-6-(glucosyl)glucoside] 3-[6-(6-(Sinapyl)glucosyl)glucoside] 3-[6-(Rhamnosyl)galactoside]-5-[6-(p-coumaryl)glucoside] (129) 3-[6-(Acetyl)glucoside]-5-[6-(acetyl)glucoside] (382) 3-[6-(Malonyl)glucoside]-5-[6-(malonyl)glucoside] 3-[6-(p-Coumaryl)glucoside]-5-[6-(malonyl)glucoside] 3-[6-(p-Coumaryl)glucoside]-5-[6-(malonyl)glucoside] Z 3-[6-(Caffeyl)glucoside]-5-[6-(malonyl)glucoside] 3-[6-(Malonyl)glucoside]-3’-[6-(caffeyl)glucoside] (353) 3-[6-(Ferulyl)glucoside]-5-[6-(malonyl)glucoside] 3-[6-(p-Coumaryl)glucoside]-5-[4-(malonyl)-6-(malonyl)glucoside] 3-[6-(p-Coumaryl)glucoside]-5-[4-(malonyl)-6-(malonyl)glucoside] Z 3-[6-(Malonyl)-2-(xylosyl)glucoside]-7-glucoside (127, 128) 3-[6-(Malonyl)-2-(glucosyl)glucoside]-5-glucoside 3-[3-(Glucosyl)-6-(malonyl)glucoside]-4’-glucoside (147) -7-[3-(Glucosyl)-6-(malonyl)glucoside]-4’-glucoside (147) 3-[2-(Xylosyl)-6-(6-(p-hydroxybenzoyl)glucosyl)galactoside] 3-[6-(p-Coumaryl)-2-(xylosyl)glucoside]-5-glucoside 3-[6-(p-Coumaryl)-2-(xylosyl)glucoside]-5-glucoside Z (125) 3-[2-(Xylosyl)-6-(6-(p-coumaryl)glucosyl)galactoside] 3-[6-(4-(p-Coumaryl)rhamnosyl)glucoside]-5-glucoside 3-[2-(6-(p-Coumaryl)glucosyl)glucoside]-5-glucoside (357)

Component of the metalloanthocyanin protocyanin.

541

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3-[6-(p-Coumaryl)-2-(glucosyl)glucoside]-5-glucoside 3-[6-(4-(Caffeyl)rhamnosyl)glucoside]-5-glucoside 3-[2-(Xylosyl)-6-(6-(ferulyl)glucosyl)galactoside] 3-[2-(Xylosyl)-6-(6-(ferulyl)glucosyl)glucoside] (34) 3-Glucoside-3’-glucoside-7-[6-(caffeyl)glucoside] (176) 3-[6-(Caffeyl)-2-(glucosyl)glucoside]-5-glucoside (356) 3-[6-(3-(Glucosyl)caffeyl)glucoside]-5-glucoside (312) 3-[6-(Ferulyl)-2-(glucosyl)glucoside]-5-glucoside 3-[2-(Xylosyl)-6-(6-(sinapyl)glucosyl)galactoside] 3-[6-(Sinapyl)-2-(glucosyl)glucoside]-5-glucoside 3-[6-(Malonyl)glucoside]-3’-glucoside-7-[6-(caffeyl)glucoside] (176) 3-[6-(Malonyl)glucoside]-3’-glucoside-7-[6-(ferulyl)glucoside] (176) 3-[2-(6-(p-Hydroxybenzoyl)glucosyl)-6-(caffeyl)glucoside]-5-glucoside (188) 3-[2-(6-(p-Coumaryl)glucosyl)-6-(p-coumaryl)glucoside]-5-glucoside (114) 3-[2-(6-(p-Coumaryl)glucosyl)-6-(caffeyl)glucoside]-5-glucoside (27) 3-[2-(6-(Caffeyl)glucosyl)-6-(caffeyl)glucoside]-5-glucoside (305) 3-Glucoside-5-[6-(caffeyl)glucoside]-3’-[6-(caffeyl)glucoside] (153) 3-[2-(6-(Ferulyl)glucosyl)-6-(caffeyl)glucoside]-5-glucoside (35) 3-[6-(Ferulyl)-2-(2-(sinapyl)xylosyl)glucoside]-5-glucoside (173) 3-[2-(2-(Sinapyl)glucosyl)-6-(p-coumaryl)glucoside]-5-glucoside 3-[2-(2-(Sinapyl)glucosyl)-6-(ferulyl)glucoside]-5-glucoside 3-[2-(6-(Sinapyl)glucosyl)-6-(sinapyl)glucoside]-5-glucoside 3-Glucoside-7-[6-(sinapyl)glucoside]-3’-[6-(sinapyl)glucoside] (180) 3-[2-(6-(p-Coumaryl)glucosyl)-6-(p-coumaryl)glucoside]-5-[6-(malonyl)glucoside] (114) 3-[6-(p-Coumaryl)-2-(2-(sinapyl)xylosyl)glucoside]-5-[6-(malonyl)glucoside] (173) 3-[6-(Caffeyl)-2-(2-(sinapyl)xylosyl)glucoside]-5-[6-(malonyl)glucoside] (177) 3-[6-(Ferulyl)-2-(2-(sinapyl)xylosyl)glucoside]-5-[6-(malonyl)glucoside] (173) 3-[2-(2-(Sinapyl)glucosyl)-6-(p-coumaryl)glucoside]-5-[6-(malonyl)glucoside] (178) 3-[2-(6-(Ferulyl)glucosyl)-6-(ferulyl)glucoside]-5-[6-(malonyl)glucoside] (36) 3-[2-(2-(Sinapyl)glucosyl)-6-(ferulyl)glucoside]-5-[6-(malonyl)glucoside] (178) 3-[6-(Malonyl)glucoside]-7-[6-(sinapyl)glucoside]-3’-[6-(sinapyl)glucoside] (180) 3-[2-(Glucosyl)-6-(4-(glucosyl)coumaryl)glucoside]-5-glucoside 3-[2-(Glucosyl)-6-(4-(glucosyl)caffeyl)glucoside]-5-glucoside (312) 3-[2-(Glucosyl)-6-(4-(glucosyl)ferulyl)glucoside]-5-glucoside 3-[2-(2-(Caffeyl)glucosyl)galactoside]-7-[6-(caffeyl)glucoside]-3’-glucuronoside (29) 3-[2-(6-(3-(Glucosyl)caffeyl)glucosyl)-6-(caffeyl)glucoside]-5-glucoside (305) 3-[2-(6-(4-(6-(3-(Glucosyl)caffeyl)glucosyl)caffeyl)glucosyl)glucoside] (358) 3-[6-(6-(Sinapyl)glucosyl)glucoside]-7-[6-(sinapyl)glucoside]-3’-glucoside 3-[6-(4-(p-Coumaryl)rhamnosyl)glucoside]-5-[6-(malonyl)glucoside]-3’-[6(caffeyl)glucoside] Z, E (118, 365) 3-[6-(4-(Glucosyl)coumaryl)-2-(2-(sinapyl)xylosyl)glucoside]-5-[6-(malonyl)glucoside] (167) 3-[2-(2-(Caffeyl)glucosyl)-6-(malonyl)galactoside]-7-[6-(caffeyl)glucoside]-3’glucuronoside (28) 3-[2-(6-(p-Coumaryl)glucosyl)-6-(4-(6-(p-coumaryl)glucosyl)caffeyl)glucoside]5-glucoside (27) 3-[6-(2-(Caffeyl)arabinosyl)glucoside]-7-[6-(caffeyl)glucoside]-3’-[6-(caffeyl)glucoside] 3-[2-(6-(Caffeyl)glucosyl)-6-(4-(6-(3,5-dihydroxycinnamyl)glucosyl)caffeyl)glucoside]5-glucoside (355)

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244 245 246 247 248 249 250 251 252 253 254 255 256 257 258

A3 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277

543

3-[6-(Malonyl)glucosyl)-7-[6-(p-coumaryl)glucoside]-3’-[6-(4-(6-(pcoumaryl)glucosyl)coumaryl)glucoside] (156) 3-[6-(Malonyl)glucoside]-7-[6-(p-coumaryl)glucoside]-3’-[6-(4-(6(caffeyl)glucosyl)coumaryl)glucoside] (155) 3-[2-(2-(Caffeyl)glucosyl)-6-[3-(2-(tartaryl)malonyl)galactoside]-7-[6(caffeyl)glucoside]-3’-gulucuronoisde] (132) 3-[6-(Malonyl)glucoside]-7-[6-(p-coumaryl)glucoside]-3’-[6-(4-(6(caffeyl)glucosyl)caffeyl)glucoside] (156) 3-[6-(Malonyl)glucoside]-7-[6-(4-(6-(caffeyl)glucosyl)caffeyl)glucoside]-3’-[6(caffeyl)glucoside] (248) 3-[6-(Malonyl)glucoside]-7-[6-(caffeyl)glucoside]-3’-[6-(4-(6(caffeyl)glucosyl)caffeyl)glucoside] (156) 3-[6-(2-(Caffeyl)-5-(caffeyl)arabinosyl)glucoside]-7-[6-(caffeyl)glucoside]-3’-[6(caffeyl)glucoside] 3-[6-(2-(Ferulyl)-5-(ferulyl)arabinosyl)glucoside]-7-[6-(ferulyl)glucoside]-3’-[6(ferulyl)glucoside] (136) 3-[6-(3-(Glucosyl)-6-(sinapyl)glucosyl)glucoside]-7-[6-(sinapyl)glucoside]-3’-glucoside 3-[6-(Malonyl)glucoside]-7-[6-(4-(glucosyl)p-hydroxybenzoyl)glucoside]-3’-[6-(4(glucosyl)p-hydroxybenzoyl)glucoside] (189) 3-Glucoside-7-[6-(p-coumaryl)glucoside]-3’-[6-(4-(6-(4(glucosyl)coumaryl)glucosyl)coumaryl)glucoside] (157) 3-[2-(6-(3-(Glucosyl)caffeyl)glucosyl)-6-(4-(6-(caffeyl)glucosyl)caffeyl)glucoside]5-glucoside (305) 3-Glucoside-7-[6-(caffeyl)glucoside]-3’-[6-(4-(6-(4(glucosyl)caffeyl)glucosyl)caffeyl)glucoside] (157) 3-[6-(Malonyl)glucoside]-7-[6-(p-coumaryl)glucoside]-3’-[6-(4-(6-(4(glucosyl)coumaryl)glucosyl)coumaryl)glucoside] (157) 3-[6-(Malonyl)glucoside]-7-[6-(caffeyl)glucoside]-3’-[6-(4-(6-(4(glucosyl)caffeyl)glucosyl)caffeyl)glucoside] (157) Peonidin (3’-methoxy-3,5,7,4’-tetrahydroxyflavylium) 3-Arabinoside 3-Rhamnoside 3-Galactoside 3-Glucoside 3-Arabinoside-5-glucoside 3-[2-(Xylosyl)galactoside] (133) 3-[2-(Xylosyl)glucoside] 3-[4-(Arabinosyl)glucoside] 3-Rhamnoside-5-glucoside 3-[2-(Rhamnosyl)glucoside] (140) 3-[6-(Rhamnosyl)glucoside] 3-Galactoside-5-glucoside 3-Glucoside-5-glucoside 3-[2-(Glucosyl)glucoside] 3-[6-(Glucosyl)glucoside] (25) 3-[6-(Rhamnosyl)-2-(xylosyl)glucoside] 3-[6-(Rhamnosyl)glucoside]-5-glucoside 3-[2-(Glucosyl)glucoside]-5-glucoside 3-[6-(6-(Glucosyl)glucosyl)glucoside]

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278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297

3-[6-(Acetyl)glucoside] (385) 3-[6-(Malonyl)glucoside] 3-[6-(p-Coumaryl)glucoside] 3-[6-(Caffeyl)glucoside] (386) 3-Glucoside-5-[6-(acetyl)glucoside] (317) 3-[6-(Malonyl)glucoside]-5-glucoside (147) 3-[6-(p-Coumaryl)glucoside]-5-glucoside 3-[6-(3-(Glucosyl)caffeyl)glucoside] (360) 3-[4-(Sinapyl)-6-(glucosyl)glucoside] 3-[6-(4-(Coumaryl)rhamnosyl)glucoside]-5-glucoside 3-[6-(4-(Caffeyl)rhamnosyl)glucoside]-5-glucoside (169) 3-[6-(Caffeyl)-2-(glucosyl)glucoside]-5-glucoside 3-[6-(3-(Glucosyl)caffeyl)glucoside]-5-glucoside (360) 3-[2-(6-(p-Hydroxybenzoyl)glucosyl)-6-(caffeyl)glucoside]-5-glucoside (35) 3-[2-(6-(Caffeyl)glucosyl)-6-(caffeyl)glucoside]-5-glucoside 3-[2-(6-(Caffeyl)glucosyl)-6-(ferulyl)glucoside]-5-glucoside 3-[6-(4-(Glucosyl)caffeyl)-2-(glucosyl)glucoside]-5-glucoside 3-[6-(4-(4-(Glucosyl)coumaryl)rhamnosyl)glucoside]-5-glucoside (165) 3-[6-(4-(4-(6-(Caffeyl)glucosyl)coumaryl)rhamnosyl)glucoside]-5-glucoside (165) 3-[2-(6-(3-(Glucosyl)caffeyl)glucosyl)-6-(4-(6-(3(glucosyl)caffeyl)glucosyl)caffeyl)glucoside]-5-glucoside

A4 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324

Delphinidin (3,5,7,3’,4’,5’-hexahydroxyflavylium) 3-Arabinoside 3-Rhamnoside 3-Galactoside 3-Glucoside 3-[2-(Xylosyl)galactoside] 3-[2-(Xylosyl)glucoside] 3-Rhamnoside-5-glucoside 3-[2-(Rhamnosyl)glucoside] 3-[6-(Rhamnosyl)galactoside] 3-[6-(Rhamnosyl)glucoside] 3-Glucoside-5-glucoside 3-Glucoside-7-glucoside 3-[2-(Glucosyl)glucoside] 3-[6-(Glucosyl)glucoside] 3-[2-(Xylosyl)-6-(rhamnosyl)glucoside] (24) 3-[6-(Rhamnosyl)galactoside]-5-rhamnoside 3-[2-(Xylosyl)galactoside]-5-glucoside (131) 3-[2-(Xylosyl)glucoside]-5-glucoside 3-[6-(Rhamnosyl)galactoside]-5-glucoside (123) 3-[6-(Rhamnosyl)glucoside]-5-glucoside 3-[6-(Rhamnosyl)glucoside]-7-glucoside (117) 3-Glucoside-7-glucoside-3’-glucoside 3-Glucoside-3’-glucoside-5’-glucoside 3-[2-(Glucosyl)glucoside]-5-glucoside 3-[6-(Acetyl)galactoside] (367) 3-[6-(Acetyl)glucoside] 3-[6-(Malonyl)glucoside]

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b

3’-[2-(Galloyl)galactoside] (26) 3-[6-(p-Coumaryl)galactoside] (158) 3-[6-(p-Coumaryl)glucoside] (386) 3-[6-(p-Coumaryl)glucoside] Z 3-[2-(Galloyl)galactoside] 3-[2-(Galloyl)-6-(acetyl)galactoside] (191) 3’-[2-(Galloyl)-6-(acetyl)galactoside] (26) 3-[6-(2-(Acetyl)rhamnosyl)glucoside] (121) 3-[6-(3-(Acetyl)rhamnosyl)glucoside] (121) 3-Glucoside-5-[6-(acetyl)glucoside] (317) 3-[2-(Xylosyl)-6-(malonyl)glucoside] (126) 3-[2-(Rhamnosyl)-6-(malonyl)glucoside] 3-[6-(Malonyl)glucoside]-5-glucoside (144) 3-Glucoside-5-[6-(malonyl)glucoside] (345) 3-Glucoside-5-glucoside (6’’,6’’’-malyl diester) (215) 3-[6-(Malyl)glucoside]-5-glucoside (31) 3-[6-(p-Coumaryl)glucoside]-5-glucoside 3-Galactoside-5-[6-(p-coumaryl)glucoside] (123) 3-Galactoside-5-[6-(p-coumaryl)glucoside] Z (123) 3-Glucoside-5-[6-(p-coumaryl)glucoside] (154) 3-[6-(Acetyl)glucoside]-5-[6-(acetyl)glucoside] 3-[6-(Malonyl)glucoside]-5-[6-(malonyl)glucoside] (351) 3-[6-(Malyl)glucoside]-5-[6-(malyl)glucoside] (31) 3-[6-(p-Coumaryl)glucoside]-5-[6-(malonyl)glucoside] 3-[6-(p-Coumaryl)glucoside]-5-[6-(malonyl)glucoside] Z 3-[6-(p-Coumaryl)glucoside]-5-[6-(malonyl)glucoside]b 3-[6-(p-Coumaryl)glucoside]-5-[6-(malonyl)glucoside]c 3-[6-(Caffeyl)glucoside]-5-[6-(malonyl)glucoside] 3-[6-(p-Coumaryl)glucoside]-5-[4-(acetyl)-6-(malonyl)glucoside] (209) 3-[6-(p-Coumaryl)glucoside]-5-[4-(malonyl)-6-(malonyl)glucoside] (200) 3-[6-(Caffeyl)glucoside]-5-[4-(malonyl)-6-(malonyl)glucoside] 3-[2-(Xylosyl)galactoside]-5-[6-(acetyl)glucoside] (131) 3-[2-(Rhamnosyl)glucoside]-7-[6-(malonyl)glucoside] (139) 3-[6-(Malonyl)glucoside]-3’-glucoside-5’-glucoside (141) 3-[6-(4-(p-Coumaryl)rhamnosyl)glucoside]-5-glucoside 3-[6-(4-(p-Coumaryl)rhamnosyl)glucoside]-5-glucoside Z 3-[6-(Rhamnosyl)galactoside]-5-[6-(p-coumaryl)glucoside] (123) 3-[6-(Rhamnosyl)galactoside]-5-[6-(p-coumaryl)glucoside] Z (123) 3-[6-(Rhamnosyl)glucoside]-5-[6-(p-coumaryl)glucoside] (123) 3-[6-(Rhamnosyl)glucoside]-5-[6-(p-coumaryl)glucoside] Z (123) 3-[6-(4-(Caffeyl)rhamnosyl)glucoside]-5-glucoside (160) 3-Glucoside-5-[6-(p-coumaryl)glucoside]-3’-glucoside (154) 3-[6-(Rhamnosyl)galactoside]-5-[6-(ferulyl)glucoside] (123) 3-[6-(Rhamnosyl)galactoside]-5-[6-(ferulyl)glucoside] Z (123) 3-Glucoside-5-[6-(caffeyl)glucoside]-3’-glucoside (154) 3-[6-(p-Coumaryl)glucoside]-5-[4-(rhamnosyl)-6-(malonyl)glucoside]

Component of the metalloanthocyanin commelinin. Component of the metalloanthocyanin protodelphin.

c

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3-[6-(Malonyl)glucoside]-3’-[6-(p-coumaryl)glucoside]-5’-glucoside (141) 3-[6-(4-(Glucosyl)coumaryl)glucoside]-5-[6-(malonyl)glucoside] (166) 3-Glucoside-5-[6-(caffeyl)glucoside]-3’-[6-(p-coumaryl)glucoside] (154) 3-Glucoside-5-[6-(p-coumaryl)glucoside]-3’-[6-(caffeyl)glucoside] (154) 3-Glucoside-5-[6-(caffeyl)glucoside]-3’-[6-(caffeyl)glucoside] 3-Glucoside-7-[6-(sinapyl)glucoside]-3’-[6-(sinapyl)glucoside] (182) 3-[6-(Malonyl)glucoside]-7-[6-(4-(6-(p-hydroxybenzoyl)glucosyl)phydroxybenzoyl)glucoside] (115) 3-[6-(Malonyl)glucoside]-3’-[6-(p-coumaryl)glucoside]-5’-[6-(p-coumaryl)glucoside] (141) 3-[2-(6-(p-Coumaryl)glucosyl)-6-(p-coumaryl)glucoside]-5-[6-(malonyl)glucoside] (113) 3-[2-(6-(Ferulyl)glucosyl)-6-(p-coumaryl)glucoside]-5-[6-(malonyl)glucoside] (114) 3-[2-(6-(Ferulyl)glucosyl)-6-(ferulyl)glucoside]-5-[6-(malonyl)glucoside] (114) 3-[6-(Malonyl)glucoside]-7-[6-(sinapyl)glucoside]-3’-[6-(sinapyl)glucoside] (182) 3-[2-(2-(Caffeyl)glucosyl)-6-(3-(2-tartaryl)malonyl)galactoside]-7-[6-(caffeyl)glucoside] (29) 3-[6-(Rhamnosyl)glucoside]-7-[6-(p-coumaryl)glucoside]-3’-glucoside (32) 3-[6-(4-(4-(Glucosyl)coumaryl)rhamnosyl)glucoside]-5-glucoside (164) 3-Glucoside-3’-[6-(4-(glucosyl)coumaryl)glucoside]-5’-glucoside (141) 3-[6-(Rhamnosyl)glucoside]-7-[6-(4-(6-(p-hydroxybenzoyl)glucosyl)phydroxybenzoyl)glucoside] (117) 3-[6-(Malonyl)glucoside]-3’-[6-(4-(glucosyl)coumaryl)glucoside]-5’-glucoside (141) 3-[6-(Rhamnosyl)glucoside]-7-[6-(p-coumaryl)glucoside]-3’-[6-(p-coumaryl)glucoside] (32) 3-[6-(4-(4-(6-(Caffeyl)glucosyl)coumaryl)rhamnosyl)glucoside]-5-glucoside (164) 3-Glucoside-7-glucoside-3’-[6-(p-coumaryl)glucoside]-5’-[6-(p-coumaryl)glucoside] (146) 3-[6-(4-(6-(3-(Glucosyl)caffeyl)glucosyl)caffeyl)glucoside]-5-glucoside (223) 3-[2-(2-(Caffeyl)glucosyl)galactoside]-7-[6-(caffeyl)glucoside]-3’-glucuronoside (29) 3-[6-(Malonyl)glucoside]-7-[2-(glucosyl)-6-(4-(6-(p-hydroxybenzoyl)glucosyl)phydroxybenzoyl)glucoside] (115) 3-[6-(Malonyl)glucoside]-3’-[6-(4-(6-(p-coumaryl)glucosyl)coumaryl)glucoside]5’-glucoside (141) 3-[6-(Malonyl)glucoside]-3’-[6-(4-(glucosyl)coumaryl)glucoside]-5’-[6-(pcoumaryl)glucoside] (141) 3-[6-(4-(6-(3-(Glucosyl)caffeyl)glucosyl)caffeyl)glucoside]-5-[6-(malonyl)glucoside] (313) 3-[2-(2-(Caffeyl)glucosyl)-6-(malonyl)galactoside]-7-[6-(caffeyl)glucoside]3’-glucuronoside (29) 3-Glucoside-7-[6-(p-coumaryl)glucoside]-3’-[6-(p-coumaryl)glucoside]-5’-[6-(pcoumaryl)glucoside] (146) 3-[6-(Malonyl)glucoside]-7-[2-(6-(p-hydroxybenzoyl)glucosyl)-6-(4-(6-(phydroxybenzoyl)glucosyl)p-hydroxybenzoyl)glucoside] (115) 3-[2-(2-(Caffeyl)glucosyl)-6-(3-(2-tartaryl)malonyl)galactoside]-7-[6-(caffeyl)glucoside]3’-glucuronoside (29) 3-[6-(Malonyl)glucoside]-7-[6-(4-(6-(caffeyl)glucosyl)caffeyl)glucoside]-3’-[6(caffeyl)glucoside] 3-[6-(p-Coumaryl)glucoside]-7-[6-(p-coumaryl)glucoside]-3’-[6-(p-coumaryl)glucoside]5’-[6-(p-coumaryl)glucoside] (146)

378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403

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418

A5 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434

547

3-[6-(Rhamnosyl)glucoside]-7-[6-(4-(6-(4-(glucosyl)p-hydroxybenzoyl)glucosyl)phydroxybenzoyl)glucoside] (117) 3-Glucoside-3’-[6-(4-(glucosyl)coumaryl)glucoside]-5’-[6-(4(glucosyl)coumaryl)glucoside] (141) 3-[6-(Rhamnosyl)glucoside]-7-[6-(4-(6-(4-(6-(p-hydroxybenzoyl)glucosyl)phydroxybenzoyl)glucosyl)p-hydroxybenzoyl)glucoside] 3-[6-(Malonyl)glucoside]-3’-[6-(4-(6-(4-(glucosyl)coumaryl)glucosyl)coumaryl) glucoside]-5’-glucoside (141) 3-[6-(Malonyl)glucoside]-3’-[6-(4-(glucosyl)coumaryl)glucoside]-5’-[6-(4(glucosyl)coumaryl)glucoside] 3-[6-(Malonyl)glucoside]-3’-[6-(4-(6-(p-coumaryl)glucosyl)coumaryl)glucoside]-5’-[6-(pcoumaryl)glucoside] (145) 3-[6-(Malonyl)glucoside]-3’-[6-(4-(6-(4-(glucosyl)coumaryl)glucosyl)coumaryl) glucoside]-5’-[6-(p-coumaryl)glucoside] (141) 3-[6-(Malonyl)glucoside]-3’-[6-(4-(6-(p-coumaryl)glucosyl)coumaryl)glucoside]-5’-[6-(4(glucosyl)coumaryl)glucoside] (141) 3-[6-(4-(p-Coumaryl)rhamnosyl)glucoside]-5-[6-(malonyl)glucoside]-3’-[6(caffeyl)glucoside]-5’-[6-(caffeyl)glucoside] 3-[6-(4-(p-Coumaryl)rhamnosyl)glucoside]-5-[6-(malonyl)glucoside]-3’-[6(caffeyl)glucoside]-5’-[6-(ferulyl)glucoside] 3-[6-(Malonyl)glucoside]-3’-[6-(4-(6-(p-coumaryl)glucosyl)coumaryl)glucoside]-5’-[6-(4(6-(p-coumaryl)glucosyl)coumaryl)glucoside] 3-[6-(Malonyl)glucoside]-3’-[6-(4-(6-(4-(glucosyl)coumaryl)glucosyl)coumaryl) glucoside]-5’-[6-(4-(glucosyl)coumaryl)glucoside] (141) 3-[6-(Malonyl)glucoside]-3’-[6-(4-(6-(4-(glucosyl)coumaryl)glucosyl)coumaryl) glucoside]-5’-[6-(4-(6-(p-coumaryl)glucosyl)coumaryl)glucoside] 3-[6-(Rhamnosyl)glucoside]-7-[3-(3-(6-(4-(6-(p-hydroxybenzoyl)glucosyl)phydroxybenzoyl)glucosyl)glucosyl)-6-(4-(6-(p-hydroxybenzoyl)glucosyl)phydroxybenzoyl)glucoside] 3-[6-(Malonyl)glucoside]-3’-[6-(4-(6-(4(glucosyl)coumaryl)glucosyl)coumaryl)glucoside]-5’-[6-(4-(6-(4(glucosyl)coumaryl)glucosyl)coumaryl)glucoside] Petunidin (3’-methoxy-3,5,7,4’,5’-pentahydroxyflavylium) 3-Arabinoside 3-Rhamnoside 3-Galactoside 3-Glucoside 3-[2-(Xylosyl)glucoside] (25) 3-Rhamnoside-5-glucoside 3-[6-(Rhamnosyl)glucoside] 3-Glucoside-5-glucoside 3-Glucoside-7-glucoside (345) 3-[2-(Glucosyl)glucoside] 3-[6-(Glucosyl)glucoside] 3-[6-(Rhamnosyl)-2-(xylosyl)glucoside] (25) 3-[6-(Rhamnosyl)glucoside]-5-glucoside 3-[6-(6-(Glucosyl)glucosyl)glucoside] 3-[2-(Glucosyl)-6-(rhamnosyl)glucoside]-3’-glucoside 3-[6-(Acetyl)glucoside]

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435 436 437 438 439 440 441 442 443 444 445

3-[6-(Malonyl)glucoside] 3-[6-(p-Coumaryl)glucoside] 3-Glucoside-5-[6-(acetyl)glucoside] (317) 3-[6-(p-Coumaryl)glucoside]-5-glucoside 3-[6-(Malonyl)glucoside]-7-[6-(malonyl)glucoside] (346) 3-[6-(p-Coumaryl)glucoside]-5-[6-(malonyl)glucoside] 3-[6-(4-(p-Coumaryl)rhamnosyl)glucoside]-5-glucoside (169) 3-[6-(4-(Caffeyl)rhamnosyl)glucoside]-5-glucoside (169) 3-[6-(4-(Ferulyl)rhamnosyl)glucoside]-5-glucoside (172, 328) 3-[6-(4-(4-(Glucosyl)coumaryl)rhamnosyl)glucoside]-5-glucoside (160) 3-[6-(4-(4-(6-(Caffeyl)glucosyl)coumaryl)rhamnosyl)glucoside]-5-glucoside (161)

A6 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481

Malvidin (3’,5’-dimethoxy-3,5,7,4’-tetrahydroxyflavylium) 3-Arabinoside 3-Rhamnoside 3-Galactoside 3-Glucoside 3-Xyloside-5-glucoside 3-[2-(Xylosyl)glucoside] 3-Rhamnoside-5-glucoside 3-[6-(Rhamnosyl)glucoside] 3-Glucoside-5-glucoside 3-Glucoside-7-glucoside 3-[3-(Glucosyl)glucoside] 3-[6-(Glucosyl)glucoside] 3-[6-(Rhamnosyl)glucoside]-5-glucoside 3-[2-(Glucosyl)glucoside]-5-glucoside 3-[6-(6-(Glucosyl)glucosyl)glucoside] 3-[6-(Acetyl)glucoside] (385) 3-[6-(Malonyl)glucoside] (339) 3-[6-(p-Coumaryl)glucoside] (97) 3-[6-(Caffeyl)glucoside] 3-[6-(Acetyl)glucoside]-5-glucoside (210) 3-Glucoside-5-[6-(acetyl)glucoside] (211) 3-Glucoside-5-[2-(sulfato)glucoside] (30) 3-[6-(Malonyl)glucoside]-5-glucoside (339) 3-Glucoside-5-[6-(malonyl)glucoside] (30) 3-[6-(p-Coumaryl)glucoside]-5-glucoside 3-[6-(p-Coumaryl)glucoside]-5-[2-(acetyl)xyloside] (208) 3-Glucoside-5-[2-(sulfato)-6-(malonyl)glucoside] (30) 3-[6-(Malonyl)glucoside]-7-[6-(malonyl)glucoside] (346) 3-[6-(p-Coumaryl)glucoside]-5-[6-(malonyl)glucoside] 3-[6-(p-Coumaryl)glucoside]-5-[6-(malonyl)glucoside] Z 3-[6-(4-(p-Coumaryl)rhamnosyl)glucoside]-5-glucoside 3-[6-(4-(p-Coumaryl)rhamnosyl)glucoside]-5-glucoside Z (161) 3-[6-(4-(Caffeyl)rhamnosyl)glucoside]-5-glucoside (161) 3-[6-(4-(Ferulyl)rhamnosyl)glucoside]-5-glucoside (172) 3-[6-(4-(4-(6-(Caffeyl)glucosyl)coumaryl)rhamnosyl)glucoside] (163) 3-[6-(4-(4-(6-(p-Coumaryl)glucosyl)coumaryl)rhamnosyl)glucoside]-5-glucoside (168)

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3-[6-(4-(4-(6-(Caffeyl)glucosyl)coumaryl)rhamnosyl)glucoside]-5-glucoside (162) 3-[6-(4-(4-(6-(Ferulyl)glucosyl)coumaryl)rhamnosyl)glucoside]-5-glucoside (161) 3-[6-(4-(4-(6-(Caffeyl)glucosyl)caffeyl)rhamnosyl)glucoside]-5-glucoside (162)

A7 485

5-Methylcyanidin (5-methoxy-3,7,3’,4’-tetrahydroxyflavylium) 3-Glucoside

A8 486

7-Methylpeonidin 5 Rosinidin (7,3’-dimethoxy-3,5,4’-trihydroxyflavylium) 3-Glucoside-5-glucoside

A9 487 488

5-Methyldelphinidin 5 Pulchellidin (5-methoxy-3,7,3’,4’,5’-pentahydroxyflavylium) 3-Rhamnoside 3-Glucoside

A10 5-Methylpetunidin 5 Europinidin (5,3’-dimethoxy-3,7,4’,5’-tetrahydroxyflavylium) 489 3-Galactoside 490 3-Glucoside A11 5-Methylmalvidin 5 Capensinidin (3,7,4’-trihydroxy-5,3’,5’-trimethoxyflavylium) 491 3-Rhamnoside A12 492 493 494

7-Methylmalvidin 5 Hirsutidin (3,5,4’-trihydroxy-7,3’,5’-trimethoxyflavylium) 3-Glucoside (97) 3-[6-(p-Coumaryl)glucoside] (97) 3-Glucoside-5-glucoside

A13 495 496 497 498

6-Hydroxypelargonidin (3,5,6,7,4’-pentahydroxyflavylium) 3-Glucoside (102) 3-[6-(Rhamnosyl)glucoside] (101) 3-Glucoside-5-glucoside 3-[2-(Glucosyl)glucoside]

A14 499 500 501

6-Hydroxycyanidin (3,5,6,7,3’,4’-hexahydroxyflavylium) 3-Glucoside 3-[6-(Malonyl)glucoside] (100) 3-[6-(Rhamnosyl)glucoside]

A15 502 503 504

6-Hydroxydelphinidin (3,5,6,7,3’,4’,5’-heptahydroxyflavylium) 3-Glucoside (101) 3-[6-(Rhamnosyl)glucoside] 3-[6-(Malonyl)glucoside] (101)

A16 505 506 507 508 509

Apigeninidin (5,7,4’-trihydroxyflavylium) Apigeninidin 5-Glucoside 7-Glucoside 5-Glucoside-7-glucoside 5-[5-(Caffeyl)glucoside]

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A17 510 511 512 513 514

Flavonoids: Chemistry, Biochemistry, and Applications

Luteolinidin (5,7,3’,4’-tetrahydroxyflavylium) Luteolinidin 5-Glucoside 7-Glucoside 5-Glucoside-7-glucoside 5-[3-(Glucosyl)-2-(acetyl)glucoside] (96)

A18 Tricetinidin (5,7,3’,4’,5’-pentahydroxyflavylium) 515 Tricetinidin A19 7-Methylapigeninidin (5,4’-dihydroxy-7-methoxyflavylium) 516 7-Methylapigeninidin (83) A20 6-Hydroxy-5-methylapigeninidin 5 Carajuron (5-methoxy-6,7,4’-trihydroxyflavylium) 517 6-Hydroxy-5-methylapigeninidin (86) A21 5,4’-Dimethyl-6-hydroxyapigeninidin 5 Carajurin (6,7-dihydroxy-5,4’dimethoxyflavylium) 518 5,4’-Dimethyl-6-hydroxyapigeninidin A22 5-Methylluteolinidin (5-methoxy-7,3’,4’-trihydroxyflavylium) 519 5-Methylluteolinidin (84) A23 6-Hydroxy-5-methylluteolinidin (5-methoxy-6,7,3’,4’-tetrahydroxyflavylium) 520 6-Hydroxy-5-methylluteolinidin (86) A24 5,4’-Dimethyl-6-hydroxyluteolinidin (5,4’-dimethoxy-6,7,3’,4’-tetrahydroxyflavylium) 521 5,4’-Dimethyl-6-hydroxyluteolinidin (86) A25 Riccionidin A (Figure 10.3) 522 Riccionidin A (96) A26 5-Carboxypyranopelargonidin (Table 10.1) 523 5-Carboxypyranopelargonidin 3-glucoside (13) A27 5-Carboxypyranocyanidin 3-glucoside (Table 10.1) 524 5-Carboxypyranocyanidin 3-glucoside (Table 10.1) (18) 525 5-Carboxypyranocyanidin 3-[6-(malonyl)glucoside] (Table 10.1) (18) A28 Rosacyanin B (Figure 10.3) 526 Rosacyanin B (17) A29 Sphagnorubin A (Figure 10.3) 527 Sphagnorubin A A30 Sphagnorubin B (Figure 10.3) 528 Sphagnorubin B A31 Sphagnorubin C (Figure 10.3) 529 Sphagnorubin C

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Dimeric flavonoids including anthocyanidin 530 Afzelechin(4a ! 8)pelargonidin 3-glucoside (Figure 10.8) (13) 531 Epiafzelechin(4a ! 8)pelargonidin 3-glucoside (Figure 10.8) (13) 532 Catechin(4a ! 8)pelargonidin 3-glucoside (Figure 10.8) (13) 533 Epicatechin(4a ! 8)pelargonidin 3-glucoside (Figure 10.8) (13) 534 (6’’’-(Delphinidin 3-[6’’-(glucosyl)glucoside])) (6’’-(apigenin 7-glucosyl))malonate (Figure 10.8) (9) 535 (6’’’-(Delphinidin 3-[6’’-(glucosyl)glucoside])) (6’’-(luteolin 7-glucosyl))malonate (Figure 10.8) (10) 536 (6’’-(Cyanidin 3-glucosyl)) (2’’’’-(kaempferol 3-[2’’-(glucosyl)(glucoside)]-7glucuronosyl))malonate (Figure 10.9) (11) 537 (6’’-(Cyanidin 3-[3’’-(acetyl)glucosyl])) (2’’’’-(kaempferol 3-[2’’-(glucosyl) (glucoside)]7-glucuronosyl))malonate (Figure 10.9) (11) 538 (6’’’-(Delphinidin 3-[6’’-(p-coumaryl)glucoside]-7-glucosyl)) (6’’’-(kaempferol 3glucoside-7-xyloside-4’-glucosyl))succinate (Figure 10.9) (12) 539 (6’’’-(Delphinidin 3-[6’’-(p-coumaryl)glucoside]-7-glucosyl)) (6’’’-(kaempferol 3glucoside-7-glucoside-4’-glucosyl))succinate (Figure 10.9) (12)

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11

Flavans and Proanthocyanidins Daneel Ferreira, Desmond Slade, and Jannie P.J. Marais

CONTENTS 11.1 11.2 11.3

Introduction ............................................................................................................. 553 Nomenclature........................................................................................................... 554 Structures and Distribution...................................................................................... 555 11.3.1 Flavans, Flavan-3-ols, Flavan-4-ols, and Flavan-3,4-diols ......................... 555 11.3.1.1 Flavans ........................................................................................ 558 11.3.1.2 Flavan-3-ols ................................................................................. 559 11.3.1.3 Flavan-4-ols ................................................................................. 568 11.3.1.4 Flavan-3,4-diols ........................................................................... 568 11.3.2 Proanthocyanidins....................................................................................... 568 11.3.2.1 B-Type Proanthocyanidins .......................................................... 568 11.3.2.2 A-Type Proanthocyanidins.......................................................... 586 11.3.3 Nonproanthocyanidins with Flavan or Flavan-3-ol Constituent Units ........................................................................................ 587 11.3.4 Complex Tannins ........................................................................................ 593 11.3.5 Miscellaneous .............................................................................................. 600 11.3.6 NMR and Conformational Analysis of Proanthocyanidins........................ 600 11.3.7 HPLC–MS Analysis of Proanthocyanidins................................................. 605 References .......................................................................................................................... 606

11.1 INTRODUCTION In order to ensure continuity of the excellent coverage of this topic, first by Haslam1,2 and later by Porter,3,4 this chapter will follow broadly the format of the 19883 and 19944 contributions. Complementary to these are reviews by Hemingway,5 Porter,6 and Ferreira et al.7–12 Owing to the comprehensiveness of the Porter reviews3,4 and in view of the large number of compounds covered therein, the current contribution is focused on developments in the post-1992 period. The proanthocyanidins represent a major group of phenolic compounds that occur ubiquitously in woody and some herbaceous plants.3–5,8,11,12 Leucocyanidins are defined as monomeric flavonoids (flavan-3,4-diols and flavan-4-ols), which produce anthocyanidins (1) by cleavage of a C

O bond on heating with mineral acid.2,3 The proanthocyanidins are flavan-3-ol oligomers that produce anthocyanidins by cleavage of a C

C interflavanyl bond under strongly acidic conditions. This classification is somewhat arbitrary since several biflavonoids with C

O

C interflavanyl bonds and a few trimeric analogs containing both C

C and C

O

C interflavanyl bonds have recently been identified (see Table 11.10 and Table 11.11). 553

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Together with the bi- and triflavonoids, the proanthocyanidins constitute the two major classes of complex C6

C3

C6 secondary metabolites. The bi- and triflavonoids5,13 represent products of oxidative coupling of flavones, flavonols, dihydroflavonols, flavanones, isoflavones, aurones, auronols, and chalcones and thus consistently possess a carbonyl group at C-4 or its equivalent in every constituent flavonoid unit (see Chapter 17). The proanthocyanidins, on the contrary, are usually thought to originate by ionic coupling at C-4 (C-ring) of an electrophilic flavanyl unit, generated from a flavan-4-ol4 or a flavan-3,4-diol,5 to a nucleophilic flavanyl moiety, often a flavan-3-ol. However, the limits between the bi- or triflavonoids and proanthocyanidins are of random nature in view of the growing number of ‘‘mixed’’ dimers, e.g., flavan-3-ol ! dihydroflavonol, and ‘‘nonproanthocyanidins’’ comprising oxidatively coupled flavan-3-ols. The past 20 to 25 years have witnessed remarkable growth in our understanding of the basic structures and physicochemical properties of the proanthocyanidins. When taken in conjunction with a growing realization of their biological significance (described in, e.g., Chapters 4 to 6), such a comprehension of their chemical characteristics has highlighted the importance of this area of natural products chemistry.

11.2 NOMENCLATURE The system of nomenclature proposed by Hemingway et al.14 and extended by Porter3,4 is applied consistently and is briefly summarized as follows: 1. The names of the basic flavan units are given in Table 11.1. All flavans and flavan-3-ols in this list possess 2S and 2R,3S absolute configuration, respectively, for example, catechin (2). Those with a 2R,3R configuration are prefixed with ‘‘epi,’’ e.g., epicatechin (3). Units possessing a 2S configuration are differentiated by the enantio (ent) prefix, e.g., ent-epicatechin (4) exhibiting 2S,3S absolute configuration (Figure 11.1). 2. The flavanoid skeleton is drawn and numbered in the way as illustrated for catechin (2). 3. The location of the interflavanyl bond in dimers and oligomers is denoted within parentheses as in carbohydrates. The orientation of the interflavanyl bond at C-4 is denoted as a or b as in the IUPAC rules. Thus, the familiar procyanidin B-1 (5) is named epicatechin(4b ! 8)-catechin, the analogous prodelphinidin (6) is named epigallocatechin-(4b ! 8)catechin, and the 2S analog (7) is named ent-catechin-(4b ! 6)-ent-epiafzelechin. 4. A-type proanthocyanidins are often incorrectly named due to the fact that the DEF moiety in, e.g., trimeric analogs, is rotated through 1808. The proposed system3,4,15 cognizant of this aspect will thus be used. Proanthocyanidin A-2 (8) is thus named epicatechin-(2b ! 7, 4b ! 8)-epicatechin. The proper name for the trimeric analog 9 is epicatechin-(2b ! 7, 4b ! 8)-epicatechin-(4b ! 8)-epicatechin. 5. The rules apply equally well to the nomenclature of ether-linked proanthocyanidins, e.g., compound 10 is epioritin-(4b ! 3)-epioritin-4b-ol.16 6. The constituent units of proanthocyanidin oligomers may be differentiated by using ABC, DEF, etc., designations as indicated in structure 9, or alternatively using T, M, or B designations for top, middle, or bottom units, respectively, as was proposed by Porter.4 These systems have the advantage that the same numbering system may be used for each monomeric unit. With reference to Table 11.1, butiniflavan (11) is named from three proanthocyanidin dimers based on 4-subtituted 2S-7,3’,4’-trihydroxyflavan (2S-flavans unsubstituted at C-3 possess the same orientation of substituents at C-2 as 2R-flavan-3-ols) isolated from Cassia petersiana.17 The name is derived from the close structural relationship between flavan (11)

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TABLE 11.1 Proanthocyanidin Nomenclature: Proanthocyanidin Type and Names of (2R,3S) Monomer Units (2S-Flavans) Hydroxylation Pattern Proanthocyanidin

Monomer

3

5

7

8

3’

4’

5’

Procassinidin Probutinidin Proapigeninidin Proluteolinidin Protricetinidin Prodistenidin Propelargonidin Procyanidin Prodelphinidin Proguibourtinidin Profisetinidin Prorobinetinidin Proteracacinidin Promelacacinidin Propeltogynidin Promopanidin

Cassiaflavan Butiniflavan Apigeniflavan Luteoliflavan Tricetiflavan Distenin Afzelechin Catechin Gallocatechin Guibourtinidol Fisetinidol Robinetinidol Oritin Mesquitol Peltogynane Mopanane

H H H H H OH OH OH OH OH OH OH OH OH OCH2OCH2-

H H OH OH OH OH OH OH OH H H H H H H H

OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH

H H H H H H H H H H H H OH OH H H

H OH H OH OH H H OH OH H OH OH H OH H OH

OH OH OH OH OH H OH OH OH OH OH OH OH OH OH OH

H H H H OH H H H OH H H OH H H OH H

and the 2S-7,3’,4’-trihydroxyflavanone, butin. Proanthocyanidins with a butiniflavan moiety substituted at C-4 are then classified as probutinidins (see Table 11.14, Figure 11.2).

11.3 STRUCTURES AND DISTRIBUTION The naturally occurring compounds in the flavan, flavan-3-ol, flavan-4-ol, flavan-3,4-diol, and proanthocyanidin classes, together with their plant sources, are listed in Table 11.2–Table 11.17. The lists are confined to new compounds reported in the post-1992 period or those that have been overlooked in the 1994 review, and therefore must be considered in conjunction with the corresponding tables of the Porter reviews to be comprehensive. Since many of the monomeric analogs have been published under trivial names these will be retained to facilitate electronic literature searches. Unfortunately, a considerable number of these potentially chiral compounds have been reported without assignment of absolute configuration, and are hence presented as such.

11.3.1 FLAVANS, FLAVAN-3-OLS, FLAVAN-4-OLS, AND FLAVAN-3,4-DIOLS Owing to the purported role of the flavans and flavan-3-ols as nucleophilic chain-terminating units, and of the flavan-4-ols and flavan-3,4-diols (leucoanthocyanidins) as electrophilic chain-extension units in the biosynthesis of the proanthocyanidins,4 the chemistry of these four classes of compounds is intimately linked to that of the proanthocyanidins. The most important features of the flavans and flavan-3-ols pertaining to the chemistry of the proanthocyanidins are the nucleophilicity of their A-rings, the aptitude of the heterocyclic ring of flavan-3-ols to cleavage and subsequent rearrangements, the susceptibility of analogs with pyrocatechol- or pyrogallol-type B-rings to phenol oxidative

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+ O

8

HO

(HO)n

O

A

OH

OH

C OH

(1)

(2)

OH

(3)

OH HO

OH

B

O

R1

OH

OH OH

O

HO

OH

(4)

B

A

OH

C OH

OH HO

OH HO

8 D

O

O

OH

F OH

OH OH

OH OH HO

OH E

6

(5) R1 = H (6) R1 = OH

OH OH HO

O

HO

A

(7)

B

O

OH

C 4

O OH 7 8 D

OH O

OH HO

OH

F

E OH HO

(8)

B

O A

OH

HO

OH

C

O OH

OH

OH

OH

OH

HO

HO

B

O

H

A

C

D O

HO

OH O

F

E

(9)

O 3

E

I

HO

OH

HO

G

OH

HO

OH

O OH

OH

F D

(10) HO

OH

FIGURE 11.1 Structures of compounds 1–10.

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Flavans and Proanthocyanidins OH HO

O

OH HO

OH

O

(12)

(11)

OR1

OH MeO

O

HO

OMe

O

(13) R1 = Me (14) R1 = H

OR1

(15) R1 = H (16) R1 = Me

OH

OMe OR2 MeO

HO

O

O

OR1

OMe

(18) R1 = H, R2 = Me (19) R1 = Me, R2 = H

(17)

OH

OMe OH HO

O

OMe

O

(21)

(20)

OH

O

OH

OH OH O

HO

O

OH

O

(22)

(23) OH O O

HO

5

O

OH

7

O 9

OH HO

(24) FIGURE 11.2 Structures of compounds 11–25.

2 3 4

(25)

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TABLE 11.2 The Natural Flavans Class 1. Simple flavans

Compound

Structure

Source

Ref.

Tupichinol C 5,7,3’-Tri-OMe-4-OH 5,4’-Di-OH-7,3’-di-OH 5,7,4’-Tri-OH 5,7-Di-OH-4’-OMe 5-OH-7,3’,5’-tri-OMe 7,3’-Di-OH-4’-OMe 7,4’-Di-OH-3’-OMe

(12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) (28)/(29) (30)

Tupistra chinensis Mariscus psilostachys

18 19

Faramea guianensis

20

Cyperus conglomerates Terminalea argentea

19 22

Cyperus conglomerates Brosimum acutifolium

19 23

Broussonetia kazinoki

24

Brosimum acutifolium

25

2. Prenylated

Kazinol Q Kazinol R Acutifolin A Acutifolin B Acutifolin C Acutifolin D/E Acutifolin F

coupling, and the conformational mobility of their benzopyran rings. The predominant feature of the flavan-4-ols and flavan-3,4-ols in the same context is their role as precursors of flavan-4-yl carbocations or A-ring quinone methide electrophiles. The stability of the carbocations and hence the ease and rate of their formation from the benzylic alcohol precursors is dependent on the degree of delocalization of the positive charge over the A-ring, and on the potential of the B-ring to contribute toward stabilization via an A-conformation.10 11.3.1.1

Flavans

In contrast to the ubiquitous distribution of flavonoids hydroxylated at C-3 or C-4 of their heterocyclic rings, the unsubstituted flavans (2-phenylchromans) are more rarely found. The flavans co-occur with chalcones, flavanones, flavan-3,4-diols, flavonols, and 1,3-diphenylpropanes.10 Several new simple flavans, including tupichinol C (12)18 with its rare (2R) absolute configuration, were identified. Among the remaining analogs the absolute configuration at C-2 has been established for flavans 13 and 14 only.19 Flavan 13 had 2S absolute configuration while 14 was obtained as a racemate.19 For the remaining simple flavans, 15, 16,20 17,21 and 18 and 19,22 as well as the prenylated analogs 20,21 21, 22,23 kazinols Q (23) and R (24),24 and acutifolins A–F (25–30),25 (Figure 11.2 and Figure 11.3) the configurational issue has simply been ignored. This is an unfortunate situation since simple techniques like measurement of optical rotation and circular dichroic (CD) data readily facilitate unequivocal assignment of absolute configuration. For example, simple flavans with 2S absolute configuration usually exhibit negative optical rotations,26 and vice versa for 2R configuration.27 The more sensitive CD technique exhibits a negative Cotton effect for the 1Lb electronic transition of the aromatic chromophore in the 270 to 290 nm region of the CD spectra of 2S-flavans and

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559

a positive one for 2R-flavans.28,29 Since derivatization of phenolic functionalities may sometimes influence the sign of the optical rotation, the CD method should be routinely employed to unequivocally establish the absolute configuration of nonracemic flavans. Biogenetically, acutifolin A (25) may be derived from the co-occurring brosimine B (31) via base-catalyzed pyran-ring cleavage and oxygenation of the A-ring (Scheme 11.1). Subsequent recyclization of the B-ring quinone methide intermediate (32) would then lead to the formation of the unique bicyclo[3.3.1]non-3-ene-2,9-dione ring system of acutifolin A (25).25 The flavans exhibit a wide range of biological activities. Details of these may be found in the appropriate references. 11.3.1.2

Flavan-3-ols

Two flavan-3-ols with new hydroxylation patterns were reported (Table 11.3). (2R,3R)5,7,2’,5’-Tetrahydroxyflavan-3-ol (33) was obtained from Prunus prostrata30 and (þ)-5,6,7,8,3’,4’-hexahydroxyflavan-3-ol (elephantorrhizol) (34) from Elephantorrhiza goetzei.31 The absolute configuration of 33 was established by comparison of CD data with those of epicatechin, and that of 34 based on the positive optical rotation. The new epirobinetinidol (35) was isolated from commercial wattle (Acacia mearnsii) bark exstract,32 ent-mesquitol (36) from Dichrostachys cinerea,33 and the first guibourtinidol, (2R,3S)guibourtinol (37), from Cassia abbreviata.34 The absolute configuration of these compounds was again properly assessed via the CD for 35 and 37, and sign of the optical rotation for 36 (Figure 11.4). A large number and variety of new derivatives of known flavan-3-ols have be reported (Table 11.3). It should again be emphasized that in many instances the issue of absolute configuration assessment has simply been ignored. As for the flavans, this may be conveniently done by CD. The CD curves of flavan-3-ols exhibit two Cotton effects for the 1La and 1Lb electronic transitions of the A-ring aromatic chromophore in the 240 and 280 nm regions, respectively.35–37 Analogs with 2R and 2S absolute configurations gave negative and positive Cotton effects, respectively, in the 280 nm (1Lb transition) region. The sign of the Cotton effect of the 1La transition at ~240 nm is consistently opposite to that at longer wavelength. In addition to identification of flavan-3-ols and derivatives from natural sources (Table 11.3, Figure 11.3–Figure 11.5, Figure 11.7, and Figure 11.8), several synthetic studies and efforts at establishing absolute configuration have been reported. The modified Mosher method has been successfully applied to configurational definition of the flavan-3-ols and 4-arylflavan-3-ols,69 and the A-type proanthocyanidins.70 The first stereoselective synthesis of a series of flavan-3-ol permethylaryl ethers as well as the free phenolic forms was recently developed.34,37,71 Substantial efforts were also devoted toward the synthesis of 13C- and other labeled flavan-3-ols.72–74 The 4b-carboxymethylepicatechin, dryopteric acid (46), was recently synthesized via nucleophilic substitution at C-4 of 4b-acetoxyepicatechin.47 The synthetic protocol (Scheme 11.2) toward the flavan-3-ol permethylaryl ethers is based upon the transformation of retro-chalcones into 1,3-diarylpropenes. These compounds are then subjected to asymmetric dihydroxylation to give diarylpropan-1,2-diols that are used as chirons for essentially enantiopure flavan-3-ols. The protocol is demonstrated in Scheme 11.2 for the synthesis of the tetra-O-methyl-3-O-acetyl derivatives 61a, 61b, 62a, and 62b of (þ)-catechin (2), (
)-ent-catechin, (
)-epicatechin (3), and (þ)-ent-epicatechin (4).71 The (E)-retro-2-methoxymethylchalcone methyl ether (57) was transformed by consecutive reduction (H2–Pd and NaBH4) and elimination [SOCl2 and 1,8-diazabicyclo[5.4.0]undec7-ene(1,8-DBU)] of the ensuing alcohol (58), exclusively affording the (E)-1,3-diarylpropene

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OMe

OMe MeO

O

O

O

(27)

(26) OH OH

OH

OH

HO HO

HO

O

O

(30)

(28)/(29)

OH OH

OH HO

O

HO OH OH

OH

O

OH

HO

OH

(34)

OH

(33) OH OH

HO

HO

O

OH

OH O

OH

OH OH

OH

(35)

(36)

O H HO

O

[O]

O H O

(31)

(25)

O

OH

(32)

FIGURE 11.3 Structures of compounds 26–36 including Scheme 11.1: Proposed biogenetic conversion of brosimine B (31) into acutifolin A (25).

(deoxodihydrochalcone) (59). Treatment of this (E)-propene at 08C with AD-mix-a (see Ref. 71 for the relevant K.B. Sharpless references) in the two-phase system ButOH–H2O (1:1) afforded the (þ)-(1S,2S)-syn-diol (60a) in 80% yield and high optical purity (99% ee). The (
)-(1R,2R)-syn-diol (60b) was similarly formed by using AD-mix-b in the same two-phase

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TABLE 11.3 Naturally Occurring Flavan-3-ols and Related Compounds Class 1. Free phenolic

2. O-Glycosides

3. C-Glycoside 4. Simple esters

5. Simple ethers

6. C-4 Alkylated

Compound

Structure

Source

Ref.

(2R,3R)-5,7,2’,5’-Tetra-OH Elephantorrhizol Epirobinetinidol Ent-mesquitol Guibourtinidol Catechin-3-O-b-D-Glp Catechin-7-O-b-D-Glp-3’-Me Afzelechin-3-O-a-L-Rhp Afzelechin-4’-O-b-D-Glp Epiafzelechin-3-O-b-D-Alp Epicatechin-5-O-b-D-Glp Davalliosides A and B Epicatechin-5-O-b-D-Xylp Anadanthoside Epicatechin-5-O-b-D-Glp-3-benzoate Barbatoflavan Ent-afzelechin-7-O-b-D-Glp Catechin-5-O-b-D-Glp-4’-Me Catechin-7-O-b-D-Glp Catechin-3-O-b-D-Glp (2-cinnamoyl) Catechin-3-O-b-D-Glp (6-cinnamoyl) Catechin-3-O-b-D-Glp (2,6-bis-cinnamoyl) Epicatechin-8-C-b-D-Galp Epigallocatechin-3-O-Ga Epigallocatechin-3-O-Ga-5,3’,5-tri-OMe Epigallocatechin-3-O-(4-OH-Bz) Gallocatechin-3’-O-Ga Gallocatechin-4’-O-Ga Gallocatechin-7,3’-di-O-Ga Gallocatechin-7,4’-di-O-Ga Epigallocatechin-3-O-(3,5-di-Me)-Ga Epigallocatechin-3-O-(4-OH-3-OMe)benzoate Amurensisin (see Section 11.3.2.1.1) Ent-gallocatechin-4’-Me Gallocatechin-4’-Me Epicatechin-5,7,3’-tri-Me Epicatechin-5,7-di-Me-3’, 4’-methylenedioxy Peltogynoid analog Catechin-7-Me Catechin-3’-Me Guibourtinidol-7-Me Tupichinol A Tupichinol B Dryopteric acid

(33) (34) (35) (36) (37) (38) (39) (44) (45) (47) (48) (50), (51) (66) (69) (71) (72) (73) (76) (78) (79) (80) (81) (77) (40) (41) (42) (53) (54) (55) (56) (67) (68)

Prunus prostrata Elephantorrhiza goetzei Commercial wattle bark extract Dichrostachys cinerea Cassia abbreviata Quercus marilandica Muenchh. Picea abies Cassipourea gerrardii Selliguea feei Drynaria propinqua Davallia mariesii Moore Brosimopsis acutifolium Anadenanthera macrocarpa Celastrus orbiculatus Campanula barbata Daphniphyllum oldhamii Celastrus angulatus Hordeum vulgare L. Inga umbellifera

30 31 32 33 34 38 39 45 46 48 49 51 58 60 62 63 64 65 67 68

Theobroma cacao L. Cistus incanus Sedum sediforum Cistus salvifolius Pithecellobium lobatum

66 40 41 42 52

Stryphnodendron adstringens

59

(120) (43) (49) (52) (63) (64) (65) (70) (74) (75) (46)

Vitus amurensis Cassia trachypus Panda oleosa Cinnamomum camphora

Cassine papillosa Prunus prostrata Pinus sylvestrus Crinum bulbispermum Tupistra chinensis Selliguea feei

104 43 44 50

33 30 57 61 18 46, 47 continued

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TABLE 11.3 Naturally Occurring Flavan-3-ols and Related Compounds — continued Class 7. A-ring substituted

Compound

Structure

Source

Ref.

Pyranochromene Pyranochromene Cinchonain Cinchonain Apocynin A Apocynin B Cinchonain Cinchonain Apocynin C Apocynin D Shanciol Shanciol A Shanciol B Shanciol C

(83) (84) (85) (86) (87) (88) (89) (90) (91) (92) (93)/(94) (95) (96) (97)

Lupinus angostifolius

75

Castanopsis hystrix

76

Apocynum venetum

77

C. hystrix

26

A. venetum

77

Pleione bulbocodioides

78 80, 81

system (87% yield, 99% ee). These conversions proceeded slowly with reaction times in the range 12 to 48 h. The enantiomeric purity of the diols was determined by observing the H-1 and H-2 spin systems of the corresponding mono- or bis-MTPA esters, which show different chemical shifts in the 1H nuclear magnetic resonance (NMR) spectra of the two diastereoisomers. The absolute configuration was tentatively assigned according to the Sharpless model (see Ref. 71 for appropriate references) for AD-mix (Figure 11.6, Scheme 11.3). Simultaneous deprotection and cyclization of diols 60a and 60b with 3 M HCl in MeOH followed by acetylation yielded the 2,3-trans- (~50%) (61a and 61b) and for the first time 2,3cis-flavan-3-ol methylether acetate derivatives (~20%) (62a and 62b) in excellent enantiomeric excesses (>99%). The optical purity was assessed by 1H NMR using [Eu(hfc)3] as chiral shift reagent. The absolute configuration of the derivatives of the trans- and cis-flavan-3-ol derivatives was assigned by comparison of CD data with those of authentic samples in the catechin or epicatechin series flavan-3-ols.35,36 Thus, the absolute configuration of the flavan-3-ol methyl ether acetates confirms the assigned configuration of the diols as derived from the Sharpless model. The protocol was subsequently adapted to also provide synthetic access to a variety of flavan-3-ol diastereoisomers in their free phenolic forms.34,37 The co-occurrence of 4’-O-methylepigallocatechin and peltogynoid-type analog (63) in Cassine papillosa was demonstrated53 and their biogenetic relationship established by transformation of the flavan-3-ol into 63 using acetone and toluene-p-sulfonic acid. This reaction occurs readily at room temperature, proceeds with retention of the C-2 and C-3 configurations, and is general for a variety of flavan-3-ols.54 Twelve years after the latter paper was published, Fukuhara et al.55,56 confirmed these novel observations using a similar process to form the ‘‘planar’’ catechin analog (82) (Figure 11.7). The rare series of naturally occurring flavan-3-ols with an additional pyran ring4 was extended by identification of the two epicatechin analogs 83 and 84,75 as well as four phenylpropanoid-substituted catechins, 85, 86, 89, and 90,76 of the cinchonain type (Figure 11.8). The structure of the latter four compounds, including their absolute configurations, were elucidated on the basis of spectroscopic evidence and also by the synthesis of analogs 89

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OH

OH HO

R2O

O OH

O

OR3

(37)

OR1 OH

(38) R1 = β-D-glucopyranosyl-O-α-L-

OR3 OH HO

O

(39)

R1

rhamnopyranosyl, R2 = R3 = H = H, R2 = β-D-glucopyranosyl, R3 = Me

OR3

(40) R1 = 3,4,5-tri-OH-benzoyl(galloyl), R2 = R3 = H (41) R1 = galloyl, R2 = R3 = Me (42) R1 = 4-OH-benzoyl, R2 = R3 = H

OR1 OR2

OH OR2

OMe HO

O

HO

OH

O OR1

OH OH

OH

(44) R1 = α-L-rhamnopyranosyl, R2 = H (45) R1 = H, R2 = β-D-glucopyranosyl

(43)

OH

OH HO

O

R2O

R3

O

OR3

OR1

OH OR1

R2

OH

(46) R1 = H, R2 = CH2CO2H, R3 = OH (47) R1 = β-D-allopyranosyl, R2 = H, R3 = H

(48) R1 = β-D-glucopyranosyl, R2 = R3 = H (49) R1 = R2 = R3 = Me

O NH H

HO

OH

OH O

OH O OH

O

OH

O MeO

O

O

OH OH

OH

(50)/(51) FIGURE 11.4 Structures of compounds 37–52.

OMe

(52)

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OH

OH OR3

R1O

O

OMe HO

OR2

O

OH OH (53) (54) (55) (56)

OH O

R1 R1 R1 R1

= = = =

R3 R2 R2 R3

OH

= H, R2 = galloyl = H, R3 = galloyl = galloyl, R3 = H = galloyl, R2 = H

(63)

OH OH R1O

O

HO

OH

OR2

OH O

OH OH

O

HO HO

O

OH

(66)

(64) R1 = Me, R2 = H (65) R1 = H, R2 = Me

OH OH HO

O O

HO

OH

O

OMe

O

OH

OH OH O

HO O

OH (69)

OH (67) R1 = OMe (68) R1 = H

R1

OH MeO

O

OH HO

O O

OH OR1 (70)

OH

OH

O

(71) R1 = β-D-glucopyranosyl

FIGURE 11.5 Structures of compounds 53–56 and 63–71.

and 90 via acid-catalyzed condensation of catechin and caffeic acid (see also Ref. 77). Comparison of the CD data of compounds 85, 86, 89, and 90 with those of cinchonains 1a–1d has led to extensive revision of previous structures (see Ref. 76). The gallocatechin- and epigallocatechin-type analogs, apocynins A–D (87, 88, 91, and 92) were identified in Apocynum venetum.78

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Flavans and Proanthocyanidins

MeO

OMOM

OMe

MeO

OMOM

OMe

i OMe OMe

O

OMe OMe

(57)

OH

(58)

ii MeO

OMOM OH

OMe

MeO

OMOM

OMe

iii OMe

OMe

OH

iv MeO

OMe OMe

(60a)/(60b)

(59)

OMe

O

OMe MeO

+

OMe

O

OMe

OAc

OAc

OMe

OMe (61a)/(61b)

(62a)/(62b) (60a)–(62a) = Configuration shown (60b)–(62b) = Enantiomer

Scheme 11.2 OMe OMe OH H MeO

β

x− mi

H

-

β-attack OMe H MeO

H α-attack OMOM

AD OMe

OH

OMOM

OMe

(1R,2R) : (60b)

OMe AD

-m

ix−

α

OMOM

(59)

MeO

H H OH OMe

Scheme 11.3

OMe

OH

(1S,2S) : (60a)

OMe

FIGURE 11.6 Structures of compounds 57–62 including Scheme 11.2: Reagents and conditions: i, Pd–H2, EtOH, then NaBH4, EtOH; ii, SOCl2, CH2Cl2, then 1,8-DBU, CH2Cl2, reflux; iii, AD-mix-a or AD-mix-b, ButOH–H2O (1:1, v/v), MeSO2NH2, 08C; iv, 3 M HCl, MeOH–H2O (3:1, v/v), then Ac2O, pyridine, and Scheme 11.3: Sharpless model for assigning absolute configuration of syn-diols.

An interesting new group of flavan-3-ol analogs containing an additional C6–C2 unit at C-5 (A-ring) has been isolated from the tubes of Pleione bulbocodioides.79–81 Shanciol, called a dihydrophenanthropyran, was obtained in partially racemized form (93)/(94), and is accompanied by shanciol A (95), shanciol B (96), and shanciol E (97). These compounds are

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OH

OR1 HO

O

OH GlcO

OH

O OH

OAc OMe

OH (73)

(72) R1 = β-D-glucopyranosyl

OH

Me MeO

OMe

O

HO

O

OH

OH

OH

R1

OGlc (74) R1 = H (75) R1 = OMe

(76)

OH

OH HO HO HO

GlcO

OH O H

O

OH

OH OH

O

OH

OH

(78)

OH OH (77)

OH OH HO

OH HO

O

O O

OH R1O O

OH O

OH

(82)

OH OR2

(79) R1 = cinnamoyl, R2 = H (80) R1 = H, R2 = cinnamoyl (81) R1 = R2 = cinnamoyl

FIGURE 11.7 Structures of compounds 72–81.

conspicuously accompanied by their isoflavan-4-ol isomers, e.g., shanciol C (98).80 Flavan-3ols with an A-ring phenethyl group, e.g., 95, were implied as possible biogenetic precursors to these dihydrophenanthropyrans (Figure 11.8 and Figure 11.9).80 Nonproanthocyanidins with flavan or flavan-3-ol constituent units as well as ‘‘complex tannins,’’ i.e., polyphenols in which a flavan-3-ol unit is connected to a hydrolyzable tannin through a C

C linkage are discussed in Sections 11.3.3 and 11.3.4, respectively.

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Flavans and Proanthocyanidins Me

HO O

OH O

OH OH

OH (83)

HO

Me

OH

O

O

O

R1

OH

OH

OH

OH O

O

OH

OH OH

OH

(84)

R1

OH OH

OH HO

HO

O

OH OH

(85)

, R1 = H

(86)

, R1 = H

(87)

, R1 = OH

(88)

, R1 = OH

O (89)

, R1 = H

(90)

, R1 = H

(91)

, R1 = OH

O OH OH OH

O

OH O

O

OH

OH MeO

OH

O

OMe

OH (92)

OH (93) (94) Enantiomer of (93)

HO

R1 OH MeO

O

OMe

OMe OH MeO

O

OH

OMe

(95) R1 = OMe (96) R1 = H

OH HO

(97)

FIGURE 11.8 Structures of compounds 82–97.

OH

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11.3.1.3

Flavonoids: Chemistry, Biochemistry, and Applications

Flavan-4-ols

A limited number of new flavan-4-ols has been reported since 1992 (Figure 11.9). Additions to this class of compounds comprise the 2,4-cis-flavan-4-ols (99 and 100),82 pneumatopterins A–D (101–104),83 and xuulanins (105 and 106).84 (2S)-5,7,4’-Trihydroxyflavan-4-ol (107) was claimed to have been identified from natural sources also.85 This may be unlikely in view of the high reactivity of 5-oxyflavan-3,4-diols as electrophiles in weakly acidic conditions.7,10 The absolute configuration of compound 100 was established as 2S,4S by reference to the ORD data of its likely flavanone precursor and using the relative configuration as established by 1H NMR coupling constants of the heterocyclic protons.82 A series of flavan-4-ols, e.g., 108, was conveniently prepared by metal hydride reduction of the corresponding flavanone.86 The flavan-4-ols were converted into the 4-methoxyflavans, e.g., 109, by acid-catalyzed solvolysis in methanol. Both these classes of compounds are currently evaluated as anticancer drugs. Enantiomerically enriched cis-flavan-4-ols have been prepared by lipase-catalyzed kinetic resolution of racemic counterparts.87 11.3.1.4

Flavan-3,4-diols

The four flavan-3,4-diols (110–113) (Figure 11.9) were isolated from the seeds of Musa sapientum.88 These were claimed to be the leucoguibourtinidins ent-epiguibourtinidol-4a-ol (110), ent-guibourtinidol-4a-ol (111), (
)-(2S,3R,4R)-2,3-trans-flavan-3,4-diol (112), the first flavan3,4-diol devoid of A-ring hydroxylation, and the leucopelargonidin, ent-epiafzelechin-4a-ol (113). The relative 2,3-trans-3,4-cis configuration of compounds 111 and 112 (3J2,3 ¼ 10.5, 3 J3,4 ¼ 3.1 Hz and 3J2,3 ¼ 10.5, 3J3,4 ¼ 2.5 Hz, respectively) was convincingly deduced from 1H NMR data of the per-O-acetyl derivatives. However, the proposed 2,3-cis-3,4-trans configuration of the O-acetyl derivatives of 110 and 113 did not appear to be supported by coupling constants (3J2,3 ¼ 2.5, 3J3,4 ¼ 10.5 Hz and 3J2,3 ¼ 3.5, 3J3,4 ¼ 9.5 Hz, respectively) and suggests that a reinterpretation of data is now required. A further feature that casts doubt on the validity of the structural claims is the apparent stability of leucopelargonidin (113) in contrast to the well-established reactivity of flavan-3,4-diols with 5,7-dihydroxy A-rings.10 The 8-O-methylepioritin-4a-ol (114)89 complements the rare series of flavan-3,4-diols where O-methylation had occurred at one of the phenolic hydroxyl functions (Figure 11.10). Compounds 115–122 were obtained from various Lonchocarpus species.82,84,90 The enzymatic conversion of a variety of dihydroflavonols via stereospecific reduction to cis-flavan-3,4-diols using flower extracts of Dianthus caryoplyllus L. was also demonstrated.91 In addition, the chiroptical data of the eight diastereomeric flavan-3,4-diols have recently been reported.92 These data permit unambiguous assignment of the absolute configuration at C-2 via the sign of the 1Lb transition of the aromatic A-ring chromophore near 280 nm. A negative Cotton effect in this region invariably reflects 2R configuration and a positive one 2S configuration. The configuration at the C-3 and C-4 stereocenters then follows from the relative configurational assignment via 1H NMR coupling constants. For additional information regarding the chemistry of the flavans, flavan-3-ols, flavan4-ols, and flavan-3,4-diols the reader is referred to Refs. 7–12.

11.3.2 PROANTHOCYANIDINS 11.3.2.1

B-Type Proanthocyanidins

Proanthocyanidins of the B-type are characterized by singly linked flavanyl units, usually between C-4 of the chain-extension unit and C-6 or C-8 of the chain-terminating moiety. They are classified according to the hydroxylation pattern of the chain-extension units (see Table 11.1).

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O

MeO

OMe OH

HO

O

OMe O

O

O

OH OMe OMe

OMe

(99)

(98)

Me O

GlcO

O

O

R1

MeO

OGlc OH

(100)

OMe OMe

(101) R1 = CH2OH (102) R1 = Me

Me HO

O

O

O R1

R1 O

R2

O

O

(105) R1 = H, R2 = OMe (106) R1 = H, R2 = OEt (119) R1 = R2 = OMe

OH OH

(103) R1 = Me (104) R1 = CH2OH

OH

OH HO

HO

O

OH

O

OH

(107)

(108) R1 = H (109) R1 = Me

OR1

OH R1

O OH

OH HO

O OH OH

OH

(113)

FIGURE 11.9 Structures of compounds 98–113 and 119.

OH (110)

, R1 = OH

(111)

, R1 = OH

(112)

, R1 = H

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Flavonoids: Chemistry, Biochemistry, and Applications OH

OMe

OMe

HO

O

O

O OH

OH

OMe OMe OMe

(114)

(115)

O

OMe O

O

O

O

MeO

O

OMe OMe OMe

OMe OMe OMe

(116)

(117)

O

R3 O

O

O

O

O

MeO

R1

OMe OMe OMe

OMe R 2 (120) R1 = R2 = OMe, R3 = OH (121) R1 = OH, R2 = OMe, R3 = H (122) R1 = R2 = OH, R3 = H

(118)

OH OH

HO

HO

O

OH OH OH OH HO

O OH HO

OH

OH

OGa 8

OH

O

6

O

HO OH

O

OH

OH

(124)

OH

OH OH

OH

OH

OH 8

OH HO

OH

OGa

HO

O

OH

O

OH HO

8

OH

(123)

FIGURE 11.10 Structures of compounds 114–118 and 120–124.

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Flavans and Proanthocyanidins

571

A considerable number of new compounds have been added since 1992, such a sustained research effort motivated by the growing realization of the importance of these secondary metabolites in health, food, agriculture, and various other industrial applications. Information in this regard may be found in the cited references. A significant number of the new entries are derivatized via, e.g., galloylation and glycosylation, hence stressing the relevance of the flavan-3-ols exhibiting similar derivatization (Table 11.3). 11.3.2.1.1 Procyanidins (3,5,7,3’,4’-Pentahydroxylation) The procyanidins maintained their position as a dominant and ubiquitous group of naturally occurring proanthocyanidins. A limited number of structures will be shown, especially with a view to demonstrate perusal of the nomenclature system at the tri- and tetrameric levels, e.g., trimer (123) and tetramer (124) (Figure 11.10). New structures for di-, tri-, and tetrameric procyanidins are listed in Table 11.4. The roots of Polygonum coriarium afforded a ‘‘mixed’’ procyanidin–prodelphinidin glucosylated tetra- and hexamer, both carrying various galloyl groups.102 Possible structures were also proposed for the ‘‘mixed’’ procyanidin and prodelphinidin tri- and tetramers from Geranium sanguineum,103 and for oligomeric proanthocyanidins D14–D19 from Quercus robur.100 A number of ‘‘mixed’’ procyanidins or prodelphinidin analogs with exceptionally complex structures have been identified from the roots of Clementsia semenovii105 and Rhodiala pamiroalaica.106,107 Owing to the space requirements for the naming of these macromolecules, these are listed in the text only. In addition, the authors stated that indicated configurations are relative; hence, it is unclear whether the proanthocyanidin community should indeed consider the structures of these compounds as well as those cited in Refs. 100–103, 105–107 as sufficiently defined. The analogs from C. semenovii are: CS-3, 7-O-(6-O-galloyl-b-D-Glcp ! 6-O-b-D-Glcp ! 6-O-b-D-Glcp ! 6-O-b-D-Glcp ! 6-O-b-D-Glcp)-(þ)-catechin-(4a ! 8)(
)-epigallocatechin-(4b ! 8)-(þ)-catechin-(4a ! 8)-(
)-epigallocatechin-(4b ! 8)-(
)-epigallocatechin-(4b ! 8)-(
)-epigallocatechin, and CS-4, 3-O-galloyl-7-O-[6-O-galloyl-b-DGlcp ! 6-O-b-D-Glcp ! 6-O-b-D-Glcp]-(þ)-gallocatechin-(4a ! 8)-[(þ)-catechin-(4a ! 8)-3-O-galloyl-(
)-epigallocatechin]2-(4b ! 8)-(
)-epigallocatechin. The compounds from R. pamiroalaica are: RP-1, 7-O-[6-O-galloyl-b-D-Glcp ! O-b-D-Glcp ! O-b-D-Glcp]-(þ)-gallocatechin-(4a ! 8)-(
)-epicatechin-(4b ! 8)-(
)epicatechin-(4b ! 8)-(þ)-catechin-(4a ! 8)-5-O-[6-O-galloyl-b-D-Glcp ! O-b-D-Glcp ! O-b-D-Glcp]-(þ)-catechin, RP-2, 7-O-[O-b-D-Glcp ! O-b-D-Glcp]-(
)-epicatechin-(4b ! 6)-7-O-b-D-Glcp-(
)-epicatechin-(4b ! 6)-3-O-galloyl-(
)-epigallocatechin-(4b ! 6)-3-Ogalloyl-(
)-epigallocatechin-(4b ! 6)-3-O-galloyl-5-O-b-D-Glcp-(
)-epicatechin, RP-3, 7-O-(6-O-galloyl-b-D-Glcp)-3-O-galloyl-(
)-epigallocatechin-(4b ! 8)-[(
)-epicatechin-(4b ! 8)-(3-O-galloyl-(
)-epigallocatechin)]2-(4b ! 8)-5-O-(b-D-Glcp-6-O-b-D-Glcp)-(þ)catechin, and RP-4, 7-O-(6-O-galloyl-b-D-Glcp)-3-O-galloyl-(
)-epigallocatechin-(4b ! 8) -[3-O-galloyl-(
)-epicatechin]-(4b ! 8)-[3-O-galloyl-(
)-epigallocatechin]-(4b ! 8)-[3-Ogalloyl-(
)-epicatechin]-(4b ! 8)-[3-O-galloyl-5-(b-D-Glcp ! 6-O-galloyl-b-D-Glcp)]-(
) -epigallocatechin. We also need to point out the often improper use of proanthocyanidin nomenclature. In Ref. 104, both vitisinol (125) and amurensisin (126) were classified as procyanidins; per definition they do not belong to this class of compounds (Figure 11.11). Vitisinol (125) is rather a member of the nonproanthocyanidin class with flavan or flavan-3-ol constituent units (see Section 11.3.3), while amurensisin (126) is simply a gallic acid derivative of epicatechin (see Section 11.3.1.2). In addition to the contributions dealing with the isolation and structural elucidation of procyanidins, several excellent papers describing the synthesis and chemical manipulation of the proanthocyanidins in general have been published. These may be listed as follows:

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TABLE 11.4 Naturally Occurring Flavan-4-ols and Flavan-3,4-diols Class 1. Flavan-4-ol

2. Flavan-3,4-diol

Compound

Structure

Source

Ref.

Furanoflavan Furanoflavan Pneumatopterin A Pneumatopterin B Pneumatopterin C Pneumatopterin D Xuulanin 4b-Demethylxuulanin-4b-ethyl ether (2S)-5,7,4’-Tri-OH-flavan-4-ol Ent-epiguibourtinidol-4a-ol Ent-guibourtinidol-4a-ol 2,3-trans-3,4-cis-Flavan-3,4-diol Ent-epiafzelechin-4a-ol 8-O-methylepioritin-4a-ol Compound Compound Compound Compound Compound Compound Compound Compound

(99) (100) (101) (102) (103) (104) (105) (106) (107) (110) (111) (112) (113) (114) (115) (116) (117) (118) (119) (120) (121) (122)

Lonchocarpus subglaucescens

82

Pneumatopteris pennigera

83

Lonchocarpus xuul

84

Streptococcus sobrinus Musa sapientum

85 88

Acacia caffra Lonchocarpus subglaucescens

89 82

L. xuul L. xuul/L. yucatanensis

84 90

1. Continuation of the crucial role of acid-catalyzed depolymerization of proanthocyanidin polymers and subsequent capture of incipient flavanyl-4-carbocations by sulfur and oxygen nucleophiles, toward structural elucidation.108–113 This approach was successfully applied to demonstrate the presence of covalently bonded glycoside moieties in the chain-extension units of mangrove (Bruguiera gymnorrhiza) bark proanthocyanidins,108 and the presence of 3-O-galloyl groups in the extension units of polymeric proanthocyanidins of Hamamelis virginiana.111 It also highlighted the risk of using extended thiolysis to provide meaningful estimates of the molecular weight of polymeric proanthocyanidins, as well as the use of thiolysis as a means of obtaining ‘‘quantitative’’ information on the composition of ‘‘mixed’’ polymers.109 The latter work was also extended to the acid-catalyzed phloroglucinolysis of Pecan (Caraya illinoensis) nut pith proanthocyanidins.113 A conspicuous feature of the degradation studies on the mangrove and pecan proanthocyanidins is the demonstration of the susceptibility of the C4–C10 bond of both the C-4 thio- and phloroglucinol adducts to cleavage under acidic conditions. This is demonstrated in Figure 11.11, Scheme 11.4 for an intermediate thioether (127). Protonation of the electron-rich A-ring leads to the weakening and subsequent cleavage of the C4–C10 bond in 128 under influence of the electron-donating benzyl sulfanyl (or phloroglucinol113) moiety. The sulfonium species (129) or its phloroglucinol equivalent113 is then susceptible to various rearrangements. Note that this process represents the equivalent of the cleaving of the interflavanyl

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OH

HO HO

OH OH

O

HO O

O

HO OH

O

O

O HO

OH

O

OH

OH

(125)

OH

OH

(126)

OH OH

OH

OH B HO

HO

O A

C OH

OH 8

ORha

OH

OR HO

O

OH

E O

O

HO

O

R1

OH

OH

F

D

O OH

O

OH

O

(132) (133) (134) (135)

(130) R = H (131) R = galloyl

OH R1 R1 R1 R1

= = = =

R2 = H OH, R2 = H H, R2 = OMe OH, R2 = OMe

OH

OH

H+

HO

O

SCH2Ph

OH

H

OH OH

OH R2

OH OH

O

OMe

O

OH

HO

OH

OH

OH OH

(127)

SCH2Ph

(128)

OH OH HO

O

OH

etc. OH OH

SCH2Ph

(129)

FIGURE 11.11 Structures of compounds 125–135 including Scheme 11.4: Proposed route to the acidcatalyzed cleavage of the C4–C10 bond in C-4 thiobenzylflavan-3-ols.

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bond under acidic conditions but under the influence of an external electron-donating sulfur or phloroglucinol nucleophile. 2. Synthesis as a means of unequivocal structure elucidation. Synthetic studies continued to make important contributions toward the unambiguous structure elucidation of the naturally occurring proanthocyandins. Prevalent amongst these is the synthesis of a series of di- and trimeric profisetinidins exhibiting both 2,3-trans- and cis-relative configuration of the constituent fisetinidol units,114 the development of a protocol to generate the interflavanyl bond of procyanidins under neutral conditions,115 the synthesis of 2H-,116 13C-, and 14C-labeled catechins and procyanidins,117–121 the synthesis of a high molecular mass condensed tannin,122 synthesis of ether-linked proteracacinidins or promelacacinidins,123 and a highlight of the review period, a series of papers dealing with synthesis of the proanthocyanidins found in cacao,124 unequivocal proof of the 4b-configuration in procyanidins B-2,125 stereoselective synthesis of an unnatural procyanidin diastereoisomer, epicatechin-(4a ! 8)-epicatechin,126 and a process to synthesize (6 ! 6)-, (6 ! 8)-, and (8 ! 8)-linked catechin and epicatechin dimers as well as their 3,3-di-O-gallate esters.127 In addition, a stereoselective route to octa-Obenzylprocyanidin B-3 was also described.128 3. X-ray and CD analysis. The structure of procyanidin B-1 was unequivocally confirmed by x-ray analysis of its deca-O-acetyl derivative by Weinges,129 one of the pioneers in the field of proanthocyanidin chemistry. One of the most powerful methods to establish the absolute configuration at C-4 of the T-unit in dimeric A- and B-type proanthocyanidins remains the chiroptical method via application of the aromatic quadrant rule.130 This has been repeatedly demonstrated by the author’s own work and several other contributions listed in Refs. 7–12. 11.3.2.1.2 Prodelphinidins (3,5,7,3’,4’,5’-Hexahydroxylation) In addition to the ‘‘mixed’’ procyanidin–prodelphinidin tri- and tetramers listed in Table 11.5 and Section 11.3.2.1.1,105–107 a large number of new prodelphinidins have been reported. These are collated in Table 11.6. The roots of C. semenovii afforded a complex series of prodelphinidin oligomers.138,139 The structures were deduced by chemical and enzymatic degradation, as well as spectroscopic data. These are compounds CS-1, 7-O-[6-O-galloyl-bD-Glcp-6 ! O-b-D-Glcp-6 ! O-b-D-Glcp-6 ! O-b-D-Glcp]-(þ)-gallocatechin-(4a ! 8)-(þ)gallocatechin-(
)-epigallocatechin-(4b ! 8)-(
)-epigallocatechin-(4b ! 8)-(
)-epigallocatechin-(4b ! 8)-(þ)-catechin, CS-2, 3-O-galloyl-7-O-(b-D-Glcp-6 ! O-b-D-Glcp-(
)-epigallocatechin-(4a ! 8)-[3-O-galloyl-(
)-epicatechin]-(4b ! 8)-[3-O-galloyl-(
)-epigallocatechin](4b ! 8)-[3-O-galloyl-5-O-(6-O-galloyl-O-b-D-Glcp)]-(
)-epicatechin, rhodichimoside, 7-O[b-D-Glcp-O-b-D-Glcp]2-3-O-galloyl-(
)-epigallocatechin]-(4b ! 8)-[3-O-galloyl-(
)-epigallocatechin]-(4b ! 8)-3-O-galloyl-(
)-epigallocatechin, rhodichin, 7-O-b-D-Glcp-3-O-galloyl(
)-epigallocatechin-(4b ! 8)-[(
)-epigallocatechin]2-(4b ! 8)-epigallocatechin-(4b ! 6)-3O-galloyl-(
)-epigallocatechin. A ‘‘mixed’’ propelargonidin–prodelphinidin–procyanidin pentamer, PZ-5, was identified in Ziziphus jujuba.140 Prodelphinidin polymers of undefined structure were also obtained from white clover (Trifolium repens L.) flowers141 and Onobrychis viciifolia (sainfoin).142 The two unique dimeric compounds, samarangenins A (130) and B (131),133 comprise two epigallocatechin moieties possessing the characteristic C ! D-ring linkage of B-type proanthocyanidins as well as a C–O bond between a B-ring carbon and an oxygen function of the pyrogallyl-type ring of the 3-O-galloyl moiety at the DEF unit (Figure 11.11). Accordingly, they represent the first doubly linked proanthocyanidins that possess interflavanyl bonds originating from both two-electron (the 4 ! 8 bond) and one-electron (the carbon ! oxygen) bond processes.

4. ‘‘Mixed’’ tetramers

3. ‘‘Mixed’’ trimers

2. Trimers

1. Dimers

Class

Compound

Catechin-(4a ! 8)-gallocatechin (tentative) Catechin-(4a ! 8)-epigallocatechin Catechin-(4a ! 8)-catechin-3-O-b-D-Glp 3-O-Ga-ent-epicatechin-(4a ! 8)-ent-epicatechin Ent-epicatechin-(4a ! 8)-ent-epicatechin-3-O-Ga 3-O-Ga-ent-epicatechin-(4a ! 8)-ent-epicatechin-3-O-Ga Ent-epicatechin-(4a ! 6)-ent-epicatechin Epicatechin-(4b ! 8)-catechin-3-O-(4-OH)benzoate Epicatechin-(4b ! 8)-epigallocatechin Epicatechin-(4b ! 8)-gallocatechin 3-O-Ga-catechin-(4b ! 8)-catechin-3-O-Ga Epicatechin-(4b ! 6)-epicatechin-3-O-Ga Catechin-3-O-b-D-Glp-(4a ! 8)-catechin-3-O-b-D-Gl(2-cinnamoyl)pyranoside Catechin-3-O-b-D-Glp-(4a ! 8)-epicatechin-3-O-b-D-Gl(6-cinnamoyl)pyranoside Epicatechin-(4b ! 8)-epicatechin-(4b ! 6)-epicatechin 3-O-Ga-ent-epicatechin-(4a ! 8)-3-O-Ga-ent-epicatechin-(4a ! 8)-ent-epicatechin 3-O-Ga-epicatechin-(4b ! 8)-3-O-Ga-ent-epicatechin-(4a ! 8)-ent-epicatechin Catechin-(4a ! 8)-gallocatechin-(4a ! 8)-gallocatechin Epiafzelechin-(4b ! 8)-epicatechin-(4b ! 8)-catechin Epicatechin-(4b ! 6)-epiafzelechin-(4b ! 8)-epicatechin-(4b ! 6)-epicatechin (davallin) 3-O-Ga-7-O-[O-(6-O-Ga)-b-D-Glp]-epigallocatechin-(4b ! 8)epicatechin-(4b ! 8)-epicatechin-(4b ! 8)-epigallocatechin Epicatechin-(4b ! 8)-3-O-Ga-epigallocatechin-(4b !8)-epicatechin-(4b ! 8)-epicatechin

TABLE 11.5 The Natural Procyanidins

(124)

(123)

Structure

Lonchocarpus spp. Ziziphus jujuba Davalia mariesii Polygonum coriarium

Craetagus laevigata/Malus pumila Byrsonima crassifolia

Hamamelis virginiana Ziziphus jujuba Alhagi sparsifolia Quercus robur Vitus amurensis Inga umbellifera

Cistus incanus Croton lechleri Quercus marilandica Muenchh. Byrsonima crassifolia

Source

90 98 94, 95 101

164, 165 96

97 98 99 100 104 68

40 93 38 96

Ref.

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TABLE 11.6 The Natural Prodelphinidins Class 1. Dimers

Compound

Structure

Gallocatechin-(4a ! 6)-gallocatechin Gallocatechin-(4a ! 6)-epigallocatechin Gallocatechin-(4a ! 8)-epicatechin Epigallocatechin-(4b ! 8)-epigallocatechin Epigallocatechin-(4b ! 8)-gallocatechin (prodelphinidin B1)

Cistus incanus Croton lechleri

Samarangenin A

(130)

Samarangenin B Epigallocatechin-(4b ! 6)-epigallocatechin

(131)

4-O-Methylgallocatechin-(4a ! 8)-4’-O-methylgallocatechin 3-O-Ga-Epigallocatechin-(4b ! 6)-gallocatechin 3-O-Ga-Epigallocatechin-(4b ! 8)-gallocatechin 3-O-Ga-Epigallocatechin-(4b ! 8)-epigallocatechin Epigallocatechin-(4b ! 6)-epigallocatechin-3-O-Ga Epigallocatechin-(4b ! 8)-epigallocatechin-3-O-(4-OH)-benzoate Gallocatechin-(4a ! 8)-epigallocatechin-3-O-Ga Gallocatechin-(4a ! 8)-epigallocatechin-3-O-(4-OH)-benzoate 2. Trimers Gallocatechin-(4a ! 8)-gallocatechin-(4a ! 8)-epigallocatechin Gallocatechin-(4a ! 8)-gallocatechin-(4a ! 8)-gallocatechin Epigallocatechin-(4b ! 8)-gallocatechin-(4a ! 8)-catechin Epigallocatechin-(4b ! 8)-gallocatechin-(4a ! 8)-gallocatechin

Source

Ref. 40 93

Cistus salvifolius 42 Psidium guajava/ 131, Pithecellobium 132 lobatum Syzygium 133 samarangens/ S. aqueum Stryphnodendron adstringens

59

Cistus incanus

134 135

C. salvifolius

42

S. adstringens

59

Croton lechleri Ribes nigrum Cistus albidus

93 136 137

11.3.2.1.3 Propelargonidins (3,5,7,4’-Tetrahydroxylation) The limited numbers of new propelargonidins are listed in Table 11.7. This is in addition to the ‘‘mixed’’ procyanidin–propelargonidin tetramer, davallin (Table 11.5),94,95 the ‘‘mixed’’ propelargonidin–procyanidin trimer, epiafzelechin-(4b ! 8)-epicatechin-(4b ! 8)-catechin (Table 11.5),98 and the ‘‘mixed’’ propelargonidin–prodelphinidin–procyanidin pentamer PZ-2.140 11.3.2.1.4 Profisetinidins (3,7,3’,4’-Tetrahydroxylation) The profisetinidins are the most important proanthocyanidins of commerce, making up the major constituents of wattle and quebracho tannins. New entries are collated in Table 11.8. The structures of the di- and trimeric profisetinidins from Pithecellobium dulce (Guamu´chil) were rigorously corroborated via synthesis.114 The synthetic approach was additionally motivated by the precariousness of unequivocally differentiating between 2,3-cis-3,4-transand 2,3-cis-3,4-cis-confugurations of the chain-extension units on the basis of 1H NMR coupling constants.150,151 Furthermore, the powerful nuclear Overhauser effect (NOE) method for differentiating between 2,4-cis- and 2,4-trans-substitution152 is less useful at the di- and trimeric levels due to the adverse effects of dynamic rotational isomerism about the interflavanyl bond(s) on 1H NMR spectra at ambient temperatures.

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TABLE 11.7 The Natural Propelargonidins Class 1. Dimers

2. Trimers

a

Compound

Structure

Source

Ref.

3-O-(a-L-Rhamnopyranosyl)afzelechin-(4a ! 8)epiafzelechin-3-O-vanillate 3-O-(a-L-Rhamnopyranosyl)afzelechin-(4a ! 8)epicatechin-3-O-vanillate 3-O-(a-L-Rhamnopyranosyl)afzelechin-(4a ! 8)epiafzelechin-3-O-syringate 3-O-(a-L-Rhamnopyranosyl)afzelechin-(4a ! 8)epicatechin-3-O-syringate 3-O-Ga-epiafzelechin-(4b ! 8)-epicatechin-3-O-Gaa 3-O-Ga-epiafzelechin-(4b ! 8)-epicatechin-3-O-Ga 3-O-Ga-epiafzelechin-(4b!6)-epicatechin-3-O-Ga Epiafzelechin-(4b ! 8)-4b-carboxymethylepiafzelechin Me ester Epiafzelechin-(4b ! 8)-epiafzelechin-(4b ! 8)-4Me-epigallocatechin Afzelechin-(4a ! 8)-afzelechin-(4a ! 8)-afzelechin (C-glucosylated?)

(132)

Joannesia princeps

143

Green tea Green tea

144 145

Drynaria fortunei

146

Heisteria pallida

147

Aegle marmelos

148

(133) (134) (135)

(4b ! 8) bond tentatively assigned.

The principles that govern the base-catalyzed C-ring isomerization of dimeric profisetinidins152–154 also control a series of similar rearrangements in the trimeric bis-fisetinidolcatechins (136–139)155–158 and related bis-fisetinidol-epicatechins (Figure 11.12).159 Analogs possessing constituent chain-extension units with 3,4-cis-configuration (ABC unit in, e.g., 137) are subject to extensive 1,3-migrations in intermediate B-ring quinone methides and hence to the formation of exceptionally complex reaction mixtures.156–159 Compound 139 afforded no less than 16 conversion products, the structures of which were unequivocally established.157 This has subsequently led to the development of a more controlled synthesis that is based upon the repetitive formation of the interflavanyl bond and pyran ring rearrangement of the chain-extension unit under mild basic conditions.160 Thus, in contrast to the unrestrained course of the base-catalyzed C-ring rearrangement reactions of profisetinidin triflavonoids possessing 2,3-trans–3,4-cis-flavanyl constituent units, the stepwise construction of the dipyranochromene framework via sequential interflavanyl bond formation and pyran ring rearrangement permitted concise synthetic access to phlobatannins at the trimeric level, e.g., the hexahydrodipyrano[2,3-f:2’,3’-h]chromene (140).160 The readily occurring cleavage of the interflavanyl bond in proanthocyanidins that exhibit C-5 oxygenation of the A-ring of their chain-extension units, with sulfur or oxygen nucleophiles under acid catalysis, plays a crucial role in the structural elucidation of this complex group of natural products. In the 5-deoxy series of compounds, e.g., the fisetinidol-(4a ! 8)catechin (141), this C(sp3)–C(sp2) bond is remarkably stable under a variety of conditions and has resisted efforts at cleavage in a controlled fashion. Such a stable interflavanyl bond has adversely affected both the structural investigation of the polymeric proanthocyanidins in black wattle bark and of those from other commercial sources, as well as the establishment of the absolute configuration of the chain-terminating flavan-3-ol moieties in the 5-deoxyoligoflavanoids. It has recently been demonstrated that the interflavanyl bond

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TABLE 11.8 The Natural Profisetinidins Class 1. Dimers

Compound

Structure

Fisetinidol-(4a ! 8)-6-Me-catechin

Epifisetinidol-(4b ! 8)-catechin Epifisetinidol-(4b ! 8)-epicatechin 2. Trimers Bis-epifisetinidol-(4b ! 6:4b ! 8)-catechin Bis-epifisetinidol-(4b ! 6:4b ! 8)-epicatechin Fisetinidol-(4a ! 8)-catechin-(6 ! 4b)-epifisetinidol Fisetinidol-(4a ! 8)-epicatechin-(6 ! 4b)epifisetinidol Bis-fisetinidol-(4a ! 6:4a ! 8)-catechin-3-O-Ga 3. Phlobatannin Compound related Compound Compound Compound Compound Compound Compound Compound

(145) (146) (147) (148) (149) (150) (151) (152)

Source

Ref.

Commercial wattle bark extract Pithecellobium dulce

32 114

P. dulce

114

Burkea africana Guibourtia coleosperma Colophospermum mopane Baikiaea plurijuga

149 155 155 156

C. mopane B. plurijuga C. mopane/B. plurijuga B. plurijuga

156 156 159

in the proanthocyanidins, including the 5-deoxy analogs and their permethylaryl ethers, is readily subject to reductive cleavage with sodium cyanoborohydride [Na(CN)BH3] in trifluoroacetic acid (TFA) at 08C.161–163 Thus, under acidic conditions profisetinidin (141) is protonated at C-8 (D-ring) and the interflavanyl bond in intermediate 142 cleaved by delivery of the equivalent of hydride ion either at C-4(C) to give the constituent flavan-3-ol moieties 2 and 143, or at C-2(C) to give the 1,3-diarylpropan-2-ol (144) and catechin (2) (see Ref. 163) (Figure 11.13, Scheme 11.5). The protocol is as effective for the permethylaryl ether of 141, for procyanidin B-3 and B-4, and also for A-type proanthocyanidins163 (vide infra). 11.3.2.1.5 Prorobinetinidins (3,7,3’,4’,5’-Pentahydroxylation) The prorobinetinidins also feature prominently in wattle bark extract.3 In the period under review, new entries, listed in Table 11.9, have been identified from wattle bark,32 Robinia pseudacacia,166 and Stryphnodendron adstringens.167 The recent investigation of commercial wattle bark extract32 has led to the identification of robinetinidol-(4b ! 8)-catechin (153) and robinetinidol-(4b ! 8)-gallocatechin (154), the first prorobinetinidins with a 3,4-cis C-ring configuration, as well as a prorobinetinidin-type tetrahydropyrano[2,3-h]chromene isomerization intermediate (155) (Figure 11.14). Compounds of the class 155 as well as dimeric analogs possessing the DEF-GHI core of 155 readily form from the ‘‘conventional’’ tri- and biflavanoids, respectively, by rearrangement of the pyran heterocycle(s) under mild basic conditions. The mechanisms explaining their intricate genesis were extensively reviewed.7,9,10 Such a susceptibility of the constituent flavanyl units of proanthocyanidins to intramolecular rearrangement via B-ring quinone methide intermediates under basic conditions was also demonstrated in an unusual dimerization–rearrangement reaction of catechin at pH 12 and 408C.168

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OH HO

B

O A

OH

C OH

OH

a

OH

E

HO

HO OH

H

O

O OH

b

I

, b

(137) a

, b

(138) a

, b

(139) a

, b

OH

F

D

(136) a

OH G OH OH

HO

O A

OH HO

HO OH

B

HO

O

OH

OH

OH HO

A

O D

H

OH

C 10

HO

OMe

G

OH

OH HO

E

O

OH

F

D

E

C

G

OH OH

B

F

I

OH O

OH O

H OH

(145)

OH

I HO

(140) OH OH HO

OH HO

O A

HO OH

C

HO

OH HO

D I

HO

OH

F

OH

C

O D OH G

O

(147) OH

(148) (146)

OH

FIGURE 11.12 Structures of compounds 136–140 and 145–148.

OH

F OH

HO

H

E

O

HO

OH

OH

OH I

E

O

G

H OH

OH HO

O A

B

B

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OH HO

O A

OH

OH

O

HO

OH

F OH

OH

H+

E

O D

HO

OH

C

HO

OH

B

H

OH

OH 8

O

OH OH

(141)

OH

(142)

OH Na(CN)BH3 OH

OH E HO

O D

HO

F

A

OH

C OH

OH OH

(2)

B

O

OH

HO

OH OH

OH

(143)

OH

(144)

FIGURE 11.13 Structures of compounds 141–144 including Scheme 11.5: Proposed route to the reductive cleavage of the interflavanyl bond in proanthocyanidins.

In the heartwood of R. pseudacacia, the flavan-3,4-diol, leucorobinetinidin (robinetinidol4a-ol), as the incipient electrophile for prorobinetinidin biosynthesis, coexists with a variety of monomeric flavonoids invariably possessing C-4 oxygenation,166 hence reducing the nucleophilicity of their A-rings compared to that of the corresponding functionality in the C-4 deoxy compounds, e.g., catechin. R. pseudacacia therefore represents a rare metabolic pool where oligomer formation has to occur via the action of a very potent electrophile on chain-terminating units apparently lacking the nucleophilicity that is associated with natural sources in which proanthocyanidin formation is paramount. The diversity of the oxidation level of the chain-terminating moieties suggests that the biflavanoids in R. pseudacacia may be interrelated via oxidation–reduction of these units. 11.3.2.1.6 Proteracacinidins (3,7,8,4’-Tetrahydroxylation) In contrast to the large number of oligomeric proanthocyanidins with resorcinol- or phloroglucinol-type A-rings of the chain-extension units,3,4 those possessing pyrogallol-type A-rings (7,8-dihydroxylation) are rare. The first proteracacinidin analogs were identified as recently as 1994. Since then a considerable number (Table 11.10) of these compounds have been isolated from two members of the Leguminosae, Acacia caffra and A. galpinii.16,169–177 A conspicuous feature of the compounds listed in Table 11.10 is the heterogeneity of the interflavanyl bond in this class of naturally occurring proanthocyanidins. Both carbon and oxygen centers participate in interflavanyl bond formation and it would appear as if both one- and two-electron processes play a prominent role in establishing the interflavanyl linkage(s). This presumably reflects the poor nucleophilicity of the pyrogallol-type A-ring of the monomeric flavan-3,4-diol precursors, hence permitting alternative centers to participate in the interflavanyl bond forming process.

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TABLE 11.9 The Natural Prorobinetinidins Class 1. Dimers

2. Phlobatannin related

Compound

Structure

Source

Ref.

Robinetinidol-(4b ! 8)-catechin Robinetinidol-(4b ! 8)-gallocatechin Robinetinidol-(4b ! 6)-robinetinidol-4b-ol Robinetinidol-(4b ! 6)-robinetinidol-4a-ol Robinetinidol-(4a ! 2’)-robinetinidol-4b-ol Robinetinidol-(4a ! 2’)-robinetinidol-4a-ol Robinetinidol-(4a ! 2’)-dihydrorobinetin Robinetinidol-(4b ! 6)-dihydrorobinetina Robinetinidol-(4a ! 8)-dihydrorobinetin Robinetinidol-(4a ! 2’)-robinetina Robinetinidol-(4b ! 2’)-7,3’,4’,5’-tetra-OH-flavone Robinetinidol-(4b ! 8)-epigallocatechin Robinetinidol-(4a ! 8)-epigallocatechin Robinetinidol-(4b ! 8)-epigallocatechin-3-O-Ga Robinetinidol-(4a ! 8)-epigallocatechin-3-O-Ga Robinetinidol-(4a ! 6)-gallocatechin Robinetinidol-(4a ! 6)-epigallocatechin Compound

(153) (154)

Commercial black wattle bark Robinia pseudacacia

32

Stryphnodendron adstringens

(155)

Commercial black wattle bark

166

167

32

a

Dihydrorobinetin is (2R,3R)-2,3-trans-7,3’,4’,5’-tetrahydroxydihydroflavonol and robinetin the corresponding flavonol.

Considerable effort has been devoted to confirm the constitution and absolute configuration of both the carbon–carbon and carbon–oxygen analogs via biomimetic syntheses.16,170–172,176 In addition, the compounds possessing carbon–oxygen linkages are susceptible to ready reductive cleavage under acidic conditions, hence permitting unequivocal structural elucidation of the constituent flavanyl moieties.174 Definition of the axial chirality of analogs possessing biphenyl linkages, e.g., the four compounds from A. galpinii173 and compound 156, was unambiguously done by circular dichroism (Figure 11.15). 11.3.2.1.7 Promelacacinidins (3,7,8,3’,4’-Pentahydroxylation) The natural occurrence of promelacacinidins was until recently restricted to the heartwoods of Prosopis glandulosa3 and Acacia melanoxylon.4 The investigations of the heartwood constituents of A. caffra and A. galpinii also revealed the presence of a limited number of promelacacinidins (Table 11.11) as well as ‘‘mixed’’ di- and trimeric proteracacinidin or promelacacinidins (see Table 11.10). Notable from Table 11.10 and Table 11.11 is the considerable number of proteracacinidins and promelacacinidins at both the di- and trimeric levels possessing 2,3-cis-3,4-cisflavan-3,4-diol ‘‘terminating’’ moieties. It has been demonstrated that melacacidin (158) is basically inert toward solvolysis or epimerization at C-4.179,180 This was recently confirmed during the thiolysis of 4b-chloroepioritin derivatives.181 Such stability may be ascribed to hydrogen bonding between the axial C-3(OH) and the heterocyclic oxygen, which locks the C-ring in a half-chair conformation with C2eq, C3ax, and C4eq substituents.179,180 In this conformation, the appropriate C4 s* orbital is at an angle of ~458 above the plane of the

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OH HO

O A

HO

OH HO

OH OH

I

OH

C

OH

OH

E

F

D

B

O A

OH

O

G

HO

OH

C OH

HO

OH

B

HO

HO G

OH

I

O

OH

F

D

HO

E

O

O

HO

OH H

H

(149)

OH

(150)

OH

OH OH

HO

B

O A

OH

C

OH

OH HO

HO

E

O

G

HO HO

O

HO

O OH

H HO

H (151)

HO OH

B

OH

I

OH HO

OH

F

D

O

OH

OH A

OH E

C

O D

OH

F OH

I

OH G

OH

(152)

OH

OH OH

HO A

OH

B

O

OH

OH HO

HO

OH HO

E

O

G

HO

O

OH

F

D I

OH

OH

C

OH OH

R OH

OH HO

O

(155)

H HO

OH OH

FIGURE 11.14 Structures of compounds 149–155.

(153) R = H (154) R = OH

O

OH OH

OH

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TABLE 11.10 The Natural Proteracacinidins Class 1. Dimers

2. ‘‘Mixed’’ dimers

3. Trimers

4. ‘‘Mixed’’ trimers

Compound

Structure

Source

Ref.

Ent-oritin-(4b ! 7:5 ! 6)-epioritin-4a-ol Ent-oritin-(4b ! 5)-epioritin-4b-ol Epioritin-(4b ! 3)-epioritin-4b-ol Oritin-(4a ! 7:5 ! 6)-epioritin-4a-ol Oritin-(4b ! 7:5 ! 6)-epioritin-4a-ol Epioritin-(4b ! 7:5 ! 6)-epioritin-4a-ol Epioritin-(4b ! 7:5 ! 6)-oritin-4a-ol Epioritin-(4b ! 5:3 ! 4)-oritin-4a-ol Oritin-(4a ! 5)-epioritin-4b-ol Ent-epioritin-(4a ! 5)-epioritin-4b-ol Epioritin-(4b ! 5)-epioritin-4a-ol Ent-oritin-(4b ! 5)-epioritin-4a-ol Epioritin-(4b ! 6)-oritin-4a-ol Epioritin-(4b ! 6)-ent-oritin-4a-ol Ent-oritin-(4b ! 6)-epioritin-4a-ol Ent-oritin-(4b ! 5)-oritin-4a-ol Ent-oritin-(4a ! 6)-epioritin-4a-ol Ent-oritin-(4a ! 6)-oritin-4a-ol Ent-oritin-(4a ! 6)-epioritin-4b-ol Epioritin-4a-ol-(6 ! 6)-epioritin-4b-ol (2S)-7,8,4’-Trihydroxyflavan-(4b ! 6)-epioritin-4a-ol Epimesquitol-(4b ! 4)-epioritin-4b-ol Epioritin-(4b ! 6)-epimesquitol-4a-ol Epioritin-(4b ! 6)-epimesquitol-4b-ol Epimesquitol-(4b ! 6)-epioritin-4a-ol Epioritin-(4b ! 6)-epioritin-(4a ! 4)-epioritin-4a-ol Epioritin-(4b ! 3)-epioritin-(4b ! 6)-epioritin-4b-ol Epioritin-(4b ! 6)-oritin-(4a ! 6)-epioritin-4a-ol Oritin-(4b ! 6)-oritin-(4a ! 6)-epioritin-4a-ol Epioritin-(4b ! 6)-epioritin-(4b ! 6)-epioritin-4a-ol Epioritin-(4b ! 3)-epioritin-(4b ! 6)-epimesquitol-4a-ol

(156)

Acacia caffra

169 89 16 173

(10) A. galpinii

(157)

A. caffra A. galpinii A. caffra A. galpinii

173 175

A. caffra A. galpinii

176

A. caffra A. galpinii A. caffra A. galpinii A. caffra A. caffra A. caffra

177 182 16 176

A. caffra

174

A. caffra A. galpinii A. caffra A. caffra

177 177 174

A-ring and ‘‘buried’’ in the heterocyclic ring that screens its overlap by an external nucleophile. Since a C-4 antibonding orbital orthogonal to the A-ring would permit the most effective delocalization of A-ring electron density or stabilization of electron deficiency at C-4, it is clear why an all-cis C-ring configuration is more common for flavan-3,4-diols with 7,8-dihydroxylated A-rings. These compounds, no doubt, will have a reduced need for delocalization of the aromatic A-ring electron density than their counterparts with more electron-rich resorcinol- and phloroglucinol-type A-rings. It may then also explain the stability and abundance of the flavan-3,4-diol, teracacidin, as well as the growing number of diand trimers with 2,3-cis-3,4-cis-flavanyl constituent units all possessing 7,8-dihydroxy A-rings and axial C-3 hydroxyl groups.4,89,171,172,174,177

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Flavonoids: Chemistry, Biochemistry, and Applications OH

OH HO

HO

O 3

OH

5 6

O 4

4 5

O

(156) HO

OH

HO

O

HO

OH

OH

O

OH O

(157)

O

OH

HO

OH

OH

OH

OH OH OH

OH

(158)

HO

OH

B

O A

C

OH

OH HO

OH

HO

O

G HO

E OH

F

D

O OH HO

I

OH O

(160) HO

OH

(159)

H (CH2)10CH3

OH OH

OH

O HO

OH

O

HO

(161) Two atropisomers

OH

(CH2)10CH3 OH HO

OH

O

O

HO

OH HO

OH

O

HO

OH

(CH2)8 OH

O

(163) Two atropisomers

(CH2)8 OH

O

(162)

FIGURE 11.15 Structures of compounds 156–163.

11.3.2.1.8 Proguibourtinidins (3,7,4’-Trihydroxylation) The pro- and leucoguibourtinidins with their 7,4’-dihyroxy phenolic functionality represent a rare group of proanthocyanidins. New analogs are listed in Table 11.12. The structures of the dimers from C. abbreviata were rigorously established using 1H NMR and CD techniques, as

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TABLE 11.11 The Natural Promelacacinidins Class 1. Dimers

2. ‘‘Mixed’’ dimers 3. ‘‘Mixed’’ trimers

Compound

Source

Ref.

Epimesquitol-(4b ! 6)-epimesquitol-4b-ol Mesquitol-(4b ! 6)-3,7,8,3’,4’-pentahydroxyflavone Epimesquitol-(4b ! 5)-3,7,8,3’,4’-pentahydroxyflavone See Table 11.10 See Table 11.10

Acacia caffra A. nigrescens

170 178

well as semisynthesis from starting materials with known absolute configuration.183 The structure of guibourtinidol-(4a ! 8)-afzelechin from Ochna calodendron was claimed on the basis of 1H NMR evidence only,184 while the known guibourtinidol-(4a ! 8)-epiafzelechin was also identified in the stems of Cassia biflora.185 11.3.2.1.9 Procassinidins (7,4’-Dihydroxylation) The procassinidins with their 7,4’-dihydroxyflavan chain-extension units represent a rare group of naturally occurring proanthocyanidins and only four compounds were reported in the previous review.4 Seven new analogs were identified in the bark of C. petersiana186 and are listed in Table 11.13. Synthesis as the permethylaryl acetate derivatives was done by reduction of the flavanone, including the optically pure (2S)-di-O-methylliquirtigenin, to the flavan-4-ol, which then served as electrophile in the Lewis acid (TiCl4) catalyzed coupling with the appropriate flavan-3-ol permethylaryl ether, e.g., penta-O-methylepi- or -gallocatechin.186 The cassiflavan-type myristinins A–F (160–163) (Figure 11.15) were identified in Myristica cinnamomea.214 11.3.2.1.10 Probutinidins (7,3’,4’-Trihydroxylation) The probutinidins (see Section 11.2) represent a second class of proanthocyanidins with flavan chain-extension units. Only five members of this class of compounds have been identified (Table 11.14). Their structures and absolute configurations were also confirmed by synthesis via reduction of the flavanone, butin, followed by acid-catalyzed condensation with the appropriate flavan-3-ol.17,187 A notable feature of the synthetic studies was the apparent preference for (4 ! 8) bond formation reported by both groups of authors.

TABLE 11.12 The Natural Proguibourtinidins Class 1. Dimers

2. Phlobatannin related

Compound Guibourtinidol-(4b ! 8)-epiafzelechin Guibourtinidol-(4b ! 8)-epicatechin Guibourtinidol-(4b ! 8)-afzelechin Guibourtinidol-(4a ! 6)-afzelechin Ent-guibourtinidol-(4b ! 8)-epicatechin Guibourtinidol-(4a ! 8)-afzelechin Compound

Structure

(159)

Source

Ref.

Cassia abbreviata

183

Ochna calodendron Colophospermum mopane

184 155

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TABLE 11.13 The Natural Procassinidins Class Dimers

11.3.2.2

Compound Cassiaflavan-(4a ! 8)-epicatechin Cassiaflavan-(4a ! 8)-epigallocatechin Cassiaflavan-(4b ! 8)-epicatechin Cassiaflavan-(4b ! 8)-epigallocatechin Cassiaflavan-(4b ! 8)-gallocatechin Ent-cassiaflavan-(4b ! 8)-epicatechin Cassiaflavan-(4a ! 6)-epicatechin Cassiaflavan (myristinin A) Cassiaflavan (myristinin D) Ent-cassiaflavan atropisomers (myristinin B and C) Ent-cassiaflavan atropisomers (myristinin E and F)

Structure

(160) (162) (161) (163)

Source

Ref.

Cassia petersiana

186

Myristica cinnamomea

214

A-Type Proanthocyanidins

In contrast to proanthocyanidins of the B-type, where the constituent flavanyl units are linked via only one bond, analogs of the A-class possess an unusual second ether linkage to C-2 of the T-unit. This feature introduces a high degree of conformational stability at the interflavanyl bonding axes of dimeric analogs that culminates in high quality and unequivocal NMR spectra, conspicuously free of the effects of dynamic rotational isomerism. Compounds of this class are readily recognizable from the characteristic AB-doublet (3J3,4 ¼ 3.4 Hz) for both 3,4-trans- and 3,4-cis-C-ring protons32 in the heterocyclic region of their 1H NMR spectra, and may possess either (2a,4a)- or (2b,4b)-double interflavanyl linkages. These alternatives are readily differentiated via CD data, which show negative and positive Cotton effects in the 220 to 240 nm region for (2a,4a)- and (2b,4b)-configurations, respectively.32,188 As a consequence of these favorable structural features and because of their considerable biological activity,189,190 a substantial effort has been devoted to a continued search for new analogs. The proposed and by now well-established system of nomenclature (see Section 11.2) will be used, leading in some instances to a change of published names as far as the a,bdesignations are concerned. New entries are listed in Table 11.15. The report on aesculitannins A–G from the seed shells of Aesculus hippocastanum191 demonstrates three important chemical methods to facilitate the unequivocal structural elucidation of the A-type proanthocyanidins. These protocols include thiolytic degradation using phenylmethanethiol in acidic medium, oxidative formation of the ether linkage when

TABLE 11.14 The Natural Probutinidins Class Dimers

Compound

Source

Ref.

Butiniflavan-(4b ! 8)-catechin Butiniflavan-(4a ! 8)-catechin Butiniflavan-(4b ! 8)-epicatechin Butiniflavan-(4a ! 8)-epicatechin Butiniflavan-(4b ! 8)-epigallocatechin

Cassia nomame

187

C. petersiana

17

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the carbon–hydrogen bond at C-2 and the 4-flavanyl constituent are cofacial using hydrogen peroxide in sodium hydrogen carbonate solution, and transformation of the thermodynamically less stable 2,3-cis-flavan-3-ol moieties into 2,3-trans units via base-catalyzed epimerization at C-2. An interesting paper reported the conversion of B- into A-type proanthocyanidins via oxidation using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals under neutral conditions.212 The feasibility of the method was demonstrated by transformation of procyanidins B-1 and B-2 into proanthocyanidins A-1 and A-2, respectively. Indirect evidence for the intermediacy of p-quinone methides of types 164 and 165 in the oxidative conversion of B- into A-type proanthocyanidins came from the oxidation of epigallocatechin with the homogenate of banana flesh polyphenol oxidase (Figure 11.16).213 When the anthocyanin malvidin-3-Oglucoside was treated with epicatechin in ethanol at 358C in a sealed tube, the major product was identified as the promalvidin A-type compound, malvidin-3-glucoside-(2 ! 7, 4 ! 8)epicatechin (166).215 The problem of assigning the absolute configuration at the stereocenters of the F-ring of the A-type proanthocyanidins was also addressed.163 This straightforward general chemical method is based upon the consecutive reductive cleavage of the acetal functionality (cleavage a) and interflavanyl C

C bond (cleavage b). Thus, separate treatment of the hepta-O-methyl ethers 167 and 168 of procyanidins A-1 and A-2 with Na(CN)BH3 in TFA at 08C (Figure 11.17, Scheme 11.6) gave conversion into the respective monomeric units, i.e., the ent-catechin and catechin derivatives (171 and 173) from the A-1 derivative (167), and the ent-catechin and epicatechin derivatives (171 and 172) from the A-2 derivative (168). Cleavage ‘‘a’’ of the carbon–oxygen bond is presumably triggered by protonation of the C-7 (D-ring) acetal oxygen and concomitant delivery of the equivalent of a hydride ion at the antibonding (s*) orbital of the carbon–oxygen bond in a predominant SN2 manner. Such a transfer of hydride ion apparently occurs from a complex between the reducing agent and the axial C-3 (C-ring) oxygen lone pair, the proximity of the boron–hydrogen bonds to the backside of the acetal carbon atom being a prerequisite for reduction of the acetal bond. Reduction thus leads to ‘‘inversion’’ of configuration at C-2 (C-ring) of both B-type procyanidin intermediates (169 and 170). These intermediates are prone to facile reductive cleavage of their interflavanyl bonds (cleavage b)162 to give the ent-catechin derivative (171) from the ABC unit and, respectively, the epicatechin and catechin derivatives (172 and 173) from the DEF moieties. The location of the free hydroxyl group at the A-ring unambiguously defines the D-ring oxygen that is involved in the acetal functionality of the parent compounds (167 and 168). A similar reductive cleavage using Zn–HCl was also used to facilitate structural elucidation of the dracoflavans (Table 11.15).203 Despite the apparent clarity of the nomenclature rules, several papers in the area of the A-type proanthocyanidins still lack proper implementation of these rules. The reader must therefore ascertain the correctness of published names. In addition, the reader is also referred to the growing body of evidence of the physiological importance of these compounds, data of which can be found in several of the papers listed in the references.

11.3.3 NONPROANTHOCYANIDINS

WITH

FLAVAN

OR

FLAVAN-3-OL CONSTITUENT UNITS

In addition to the extensive range of di- and trimeric oligoflavanoids with rearranged C-rings, dubbed phlobatannins (see Section 11.3.2.1.4, Table 11.8, Table 11.9, and Table 11.12), daphnodorins A–D and larixinol were earlier reported as rearranged biflavonoid metabolites comprising either flavan or flavan-3-ol and 4,2’,4’,6’-tetrahydroxychalcone (chalconaringenin) constituent units.3,4 Since then a considerable number of new analogs, collated in Table 11.16, have been reported.

1. Dimers

Class

Compound

Procyanidins Epicatechin-(2b ! 7:4b ! 6)-epicatechin (procyanidin A-6) Epicatechin-(2b ! 5:4b ! 6)-epicatechin (procyanidin A-7) Epicatechin-(2b ! 7:4b ! 6)-catechin Epicatechin-(2b ! 7:4b ! 6)-ent-catechin Epicatechin-(2b ! 7:4b ! 6)-ent-epicatechin Epicatechin-(2b ! 7:4b ! 8)-afzelechin (geranin B) Ent-epicatechin-(2a ! 7:4a ! 8)-catechin (pavetannin A-2) 3-O-a-L-Arabinopyranosyl-ent-epicatechin-(2b ! 7:4a ! 8)-catechin Propelargonidins Epiafzelechin-(2b ! 7:4b ! 8)-ent-afzelechin 7-O-Me-Epiafzelechin-(2b ! 7:4b ! 8)-epiafzelechin 7-O-Me-Epiafzelechin-(2b ! 7:4b ! 8)-ent-afzelechin Ent-epiafzelechin-(2a ! 7:4a ! 8)-quercetin Ent-epiafzelechin-3-O-p-OH-benzoate-(2a ! 7:4a ! 8)-epiafzelechin Ent-epiafzelechin-(2a ! 7:4a ! 8)-ent-afzelechin Epiafzelechin-(2b ! 7:4b ! 8)-afzelechin (geranin A) Epiafzelechin-(2b ! 7:4b ! 8)-gallocatechin (geranin C) Prodelphinidins Epigallocatechin-(2b ! 7:4b ! 8)-epicatechin Prorobinetinidins Robinetinidol-(2b ! 7:4b ! 8)-catechin Proluteolinidins 7-O-b-D-Glp-luteoliflavan-(2b ! 7:4b ! 8)-(2R)-5,7,3’,4’-tetrahydroxyflavanone (diinsininol) 7-O-b-D-Glp-luteoliflavan-(2b ! 7:4b ! 8)-ent-naringenin (diinsinin) Prodistenidins 6-Methyl-5-O-methyl-epidistenin-(2b ! 7:4b ! 8)-(2S)-7-OH-5-OMe-flavan (dracoflavan B1) 6-Methyl-5-O-methyl-ent-epidistenin-(2a ! 7:4a ! 8)-(2S)-7-OH-5-OMe-flavan (dracoflavan B2) Miscellaneous 7-Hydroxy-5-methoxy-6-methylflavan-(2b ! 7:4b ! 8)-(2S)-7-OH-5-OMe-flavan (dracoflavan C1) 7-Hydroxy-5-methoxy-6-methylflavan-(2a ! 7:4a ! 8)-(2S)-7-OH-5-OMe-flavan (dracoflavan C2)

TABLE 11.15 The Natural A-Type Proanthocyanidins

203

203

Dragon’s blood (Daemonorops)

Dioclea lasiophylla

Dragon’s blood (Daemonorops)

200

Geranium niveum

202

30 196 197 198, 199 Prunus prostrata P. armeniaca

Sarcophyte piriei

70 195

Cassipourea gerrardii C. gummiflua

32

199 194 66

Geranium niveum Pavetta owariensis Theobroma cacao L.

588

Acacia mearnsii

191 191, 192 193

Ref.

Aesculus hippocastanum A. hippocastanum/Theobroma cacao Arachis hypogea L.

Source

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Flavonoids: Chemistry, Biochemistry, and Applications

3. Tetramers

2. Trimers

5,7-Di-OH-6-Me-flavan-(2b ! 7:4b ! 8)-7-OH-5-OMe-flavan (dracoflavan D1) 5,7-Di-OH-6-Me-flavan-(2a ! 7:4b ! 8)-7-OH-5-OMe-flavan (dracoflavan D2) Procyanidins Epicatechin-(4b ! 8)-epicatechin-(2b ! 7:4b ! 8)-epicatechin (aesculitannin A) Epicatechin-(2b ! 7,4b ! 8)-ent-catechin-(4b ! 8)-epicatechin (aesculitannin B)a Epicatechin-(2b ! 7,4b ! 8)-epicatechin-(2b ! 7,4b ! 8)-epicatechin (aesculitannin C) Epicatechin-(2b ! 7,4b ! 8)-epicatechin-(2b ! 7,4b ! 8)-catechin (aesculitannin D) Epicatechin-(2b ! 7,4b ! 8)-epicatechin-(4b ! 8)-ent-epicatechin (pavetannin B-1) Epicatechin-(2b ! 7,4b ! 8)-epicatechin-(4b ! 8)-epicatechin (pavetannin B-2) Epicatechin-(2b ! 7,4b ! 6)-epicatechin-(4b ! 8)-epicatechin (pavetannin B-3) Epicatechin-(2b ! 7,4b ! 6)-ent-epicatechin-(4a ! 8)-epicatechin (pavetannin B-4) Epicatechin-(2b ! 7,4b ! 6)-catechin-(4a ! 8)-epicatechin (pavetannin B-5) Epicatechin-(2b ! 7,4b ! 8)-epicatechin-(4b ! 8)-catechin (pavetannin B-6) Epicatechin-(2b ! 7,4b ! 8)-ent-epicatechin-(2a ! 7,4a ! 8)-ent-catechin (pavetannin B-7) Epicatechin-(2b ! 7,4b ! 8)-epicatechin-(2b ! 7,4b ! 8)-ent-catechin (pavetannin B-8) Epicatechin-(2b ! 7,4b ! 8)-catechin-(4b ! 8)-catechin Epicatechin-(4a ! 8)-epicatechin-(2b ! 7,4b ! 8)-epicatechin Epicatechin-(2b ! 7,4b ! 6)-epicatechin-(2b ! 7,4b ! 8)-epicatechin Epicatechin-(4b ! 6)-epicatechin-(2b ! 7,4b ! 8)-epicatechin 3-O-Arabinopyranosylepicatechin-(2b ! 7,4b ! 8)-epicatechin-(4b ! 8)-epicatechin (3-T-O-a-L-arabinopyranosylcinnamtannin B1) 3-O-Galactopyranosylepicatechin-(2b ! 7,4b ! 8)-epicatechin-(4b ! 8)-epicatechin (3-T-O-b-D-galactopyranosylcinnamtannin B1) Propelargonidins Epiafzelechin-(2b ! 7,4b ! 8)-epiafzelechin-(4b ! 8)-afzelechin (selligueain A) Epiafzelechin-(2b ! 7,4b ! 8)-epiafzelechin-(4b ! 8)-afzelechin-4b-acetic acid methyl ester [epiafzelechin-(2b ! 7,4b ! 8)-epiafzelechin-(4b ! 8)-3’-deoxydryopteric acid methyl ester] (selligueain B) Epiafzelechin-(2b ! 7,4b ! 8)-afzelechin-(2b ! 7,4b ! 8)-afzelechin (geranin D) Procyanidins Epicatechin-(4b ! 6)-epicatechin-(2b ! 7,4b ! 8)-epicatechin-(4b ! 8)-epicatechin (pavetannin C-1) Epicatechin-(2b ! 7,4b ! 8)-ent-epicatechin-(4a ! 8)-ent-epicatechin-(4a ! 8)-epicatechin (pavetannin C-2) 205 206 207 189 66

P. owariensis Aesculus hippocastanum Parameria laevigata Moldenke Vaccinium macrocarpon Ait. (Cranberry) Theobroma cacao L.

Pavetta owariensis

Geranium niveum

Flavans and Proanthocyanidins continued

205, 209

199

46, 208

194 194, 209 194 204 194, 204

Pavetta owariensis P. owariensis/Ecdysanthera utilis P. owariensis P. owariensis P. owariensis

Selliguea fecei

191

Aesculus hippocastanum

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589

b

In the original paper aesculitannin B was named epicatechin-(2b ! 7,4b ! 8)-ent-catechin-(4a ! 8)-epicatechin. Indicated as (4a ! 8) in the original manuscript.

Epicatechin-(2b ! 7,4b ! 8)-epicatechin-(4b ! 8)-epicatechin-(4b ! 8)-epicatechin (aesculitannin E) Epicatechin-(2b ! 7,4b ! 8)-ent-catechin-(4b ! 8)-b-epicatechin-(4b ! 8)-epicatechin (aesculitannin F) Epicatechin-(2b ! 7,4b ! 8)-epicatechin-(4b ! 8)-b-epicatechin-(2b ! 7,4b ! 8)-epicatechin (aesculitannin G) Epicatechin-(2b ! 7,4b ! 8)-epicatechin-(4b ! 6)-epicatechin-(4b ! 8)-epicatechin (parameritannin A-1) Epicatechin-(2b ! 5,4b ! 6)-epicatechin-(2b ! 7,4b ! 8)-epicatechin-(4b ! 8)-epicatechin (parameritannin A-2) Epicatechin-(2b ! 7,4b ! 6)-epicatechin-(2b ! 7,4b ! 8)-epicatechin-(4b ! 8)-epicatechin (parameritannin A-3) ‘‘Mixed’’ propelargonidins/procyanidins Epiafzelechin-(2b ! 7,4b ! 8)-epicatechin-(4b ! 8)-epicatechin-(4b ! 8)-epicatechin (pavetannin C-3) Epiafzelechin-(2b ! 7,4b ! 8)-ent-afzelechin-(4a ! 8)-ent-epicatechin-(2a ! 7,4a ! 8)-ent-catechin (pavetannin C-4) Epiafzelechin-(2b ! 7,4b ! 8)-ent-catechin-(4a ! 8)-ent-epicatechin-(2a ! 7,4a ! 8)-ent-catechin (pavetannin C-5)

Compound

192

207, 211

210

Parameria laevigata Moldenke

Pavetta owariensis

Ref.

Aesculus hippocastanum

Source

590

a

Class

TABLE 11.15 The Natural A-Type Proanthocyanidins — continued

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Flavans and Proanthocyanidins

OMe OH

O HO

O

HO

OH

OH

O

OMe OGlc O

OH

HO

OH

OH O

OH O

OH

(164)

HO (165)

OH

OH

HO OH

(166)

OH

HO

HO HO O

OH

O HO

OH

O O

O

OH O

O

OH

O

OH OH

OH

(174) (Genkwanol A)

O

(175) (Genkwanol B)

OH HO HO O HO

HO OH O

O

OH

O

O

OH OH

O

O

HO

8

OH

O

(176) (Genkwanol C)

OH OH (177) (Wikstrol A and B)

HO

HO

OH O HO

O OH

O

OH O

OH

OH O

O

OH (178) (Daphnodorin E)

O

HO

O

OH (179) (Daphnodorin F)

FIGURE 11.16 Structures of compounds 164–166 and 174–179.

OH

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OMe MeO

O A

OMe

B OMe

a O OH

C

MeO

B

O A

OMe

C

Cleavage a

OMe

D O

OH

OMe

F

HO

OH

MeO

OMe

F OH

(167)

OMe

E

O D

E

OMe

b

OMe

(169)

OMe

(168)

(170)

Cleavage b

OMe OMe MeO

B

O A

HO

O D

OMe

C OH

E OMv

F OH

(172)

OMe (173)

OMe (171)

FIGURE 11.17 Scheme 11.6: Proposed route to the reductive cleavage of both interflavanyl bonds in A-type proanthocyanidins including the structures of compounds 167–173.

The basic carbon framework of an afzelechin moiety coupled at C-8 to the a-carbon of a chalconaringenin unit is evident in the structures of the three genkwanols (174–176) (Figure 11.16). Their structures were meticulously corroborated by the collective utilization of 1H and 13 C NMR data, x-ray analysis, and the modified Mosher method.216–218 Two related but nonrearranged compounds comprising 5,7,4’-trihydroxflavone and afzelechin constituent units, the (3 ! 8)-coupled atropisomeric wikstrols A and B (177), were shown to arise by acid-catalyzed rearrangement of daphnodorin B.219 Additional entries are shown in Figure 11.18. New structures or chemistry emerging from the remarkable ‘‘black tea pool’’ are also listed in Table 11.16. Theaflavonin (190) and desgalloyl theaflavonin (191) are B,B’-linked bisflavonoids formed presumably via oxidative coupling of the flavonol glucoside, isomyricitrin, and 3-O-galloylepigallocatechin and epigallocatechin, respectively (Figure 11.19).225 The R absolute configuration of the atropisomeric biphenyl linkages of compounds 189–191 was established by comparison of CD data with those of theasinensis C and E possessing R and S axial chirality, respectively. Theadibenzotropolone A (192), the first theaflavin-type trimer in black tea, and theaflavin-3-gallate were formed by the reaction of (
)-epicatechin and (
)-epigallocatechin gallate with horseradish peroxidase in the presence of H2O2.226 Its presence in black tea was confirmed by liquid chromatography–electrospray ionization tandem mass spectrometry (MS). An informative schematic representation of the enzymatic

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TABLE 11.16 The Natural Nonproanthocyanidins with Flavan or Flavan-3-ol Constituent Units Compound Genkwanol A Genkwanol B Genkwanol C Wikstrol A atropisomer Wikstrol B atropisomer Daphnodorin E Daphnodorin F Daphnodorin G Daphnodorin H Daphnodorin I Daphnodorin J Daphnodorin K Daphnodorin L Daphnodorin M Daphnodorin N Damalachawin Theogallinin Theoflavonin Desgalloyl theaflavonin Theadibenzotropolone A Theaflavate A Theacitrin A Theaflavate B Isotheaflavin-3’-O-gallate Neotheaflavin-3-O-gallate

Structure

Source

Ref.

(174) (175) (176) (177) (177) (178) (179) (180) (181) (182) (183) (184) (185) (186) (187) (188) (189) (190) (191) (192) (193) (194) (195) (196) (197)

Daphne genkwa Sieb. et Zucc.

Wikstroemia sikokiana

216 217 218 219

D. odora Thumb.

220

D. odora

221

D. odora

222

D. acutiloba

223

Dracaena cinnabari Camellia sinensis (black tea)

224 225

C. sinensis (black tea)

226 227 228 229

conversion of the polyphenols in the tea leaves was also reported.225 Theaflavate A (193) formed when epicatechin-3-O-gallate was oxidized with K3Fe(CN)6.227 Compounds 195–197 were also produced via chemical oxidation of the appropriate flavan-3-ol or flavan-3-Ogallate precursors (Figure 11.20).229

11.3.4 COMPLEX TANNINS The term, complex tannin, appears to be established as descriptor for the class of polyphenols in which a flavan-3-ol unit, representing a constituent unit of the ‘‘condensed tannins’’ (proanthocyanidins), is connected to a ‘‘hydrolyzable (gallo-or ellagi-) tannin’’ through a carbon–carbon linkage. Since the first demonstration of their natural occurrence,230 a considerable number of these unique secondary metabolites have been reported.3,4 New additions (Table 11.17) to this series of compounds come exclusively from the groups of Nonaka and Nishioka, and Okuda and Yoshida in Japan. Malabathrins A (198), E (199), and F (200) (Figure 11.20 and Figure 11.21), which are composed of a C-glucosidic ellagitannin and a C

C coupled epicatechin moiety, were isolated from the leaves of Melastoma malabatricum.231 The S chirality for both the hexahydroxydiphenoyl (HHDP) groups in malabathrin A (198) was deduced from its CD curve, which exhibited positive and negative Cotton effects at 233 and 262 nm, respectively. Its

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Flavonoids: Chemistry, Biochemistry, and Applications HO

HO

OH

OH O

O

O

OH

HO

OH

HO O

O

OH

OH O

O

O OH

OH OH

OH

(180) (Daphnodorin G)

(181) (Daphnodorin H) OH

HO

HO

OH HO

O

OH

OH

O

b

a

OH OH

O O

O

O

OH OH

(182) (Daphnodorin I)

OH

or

a=b

(183)

OH

a=b

OH

HO

(Daphnodorin J)

O O

O

HO

OH

OH

HO

O

OH

O

OH

O

(185) (Daphnodorin L)

HO HO

OH O HO

(184) or Atropisomer (Daphnodorin K)

O

O

(186)

(Daphnodorin M)

(187)

(Daphnodorin N)

FIGURE 11.18 Structures of compounds 180–187.

OH

O

O

OH

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Flavans and Proanthocyanidins

OH HO

MeO

OH HO

RO

O

H

HO

O

H

OH

HO MeO

OH

HO

OH

OH CO2H O

OH

OH HO

(188) (Damalachawin)

OH

O OH

(189) R = galloyl (Theogallinin)

OH

OH

OH R1O HO

OH

O

HO

O

OH O

HO

OH

OH

O

O

OH

HO

O OHOH

OH

HO

O

O

HO

OH

OH

(192)

OH HO

O

HO O

HO

OH

O O

O

(190) R1 = galloyl, R2 = β-D-glucopyranosyl (Theaflavonin) (191) R1 = H, R2 = β-D-glucopyranosyl (Desgalloyl theaflavonin)

OH

OH HO

OH OR2

OH

O

OH

OH

OH

OH (193) (Theaflavate A)

HO

O

OH

OH

O

HO

O HO

O

HO

HO

OH

OH O HO

O

(194) (Theacitrin A)

O

HO

HO O

OH OH

FIGURE 11.19 Structures of compounds 188–194.

O

O

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Flavonoids: Chemistry, Biochemistry, and Applications

OH OH HO

O

OH

OH O

O

OH

OH O

OH

OH

O O

HO

OH

O

OH

HO

HO

O

O

OH OH

OH OH

OH

O

OH

OH (196) (Isotheoflavin-39-O-gallate)

(195) (Theaflavate B)

HO

OH HO

OH

OH

OH OH HO HO

OH HO

HO OH

O

CO O

OH

O

OH

H

O

O HO

OH

O OC

CO

CO

OH O

OH

O

OH

O O

O O

CO

HO

HO OH

OH

OH

HO

O

OH HO

(197) (Neotheoflavin-3-O-gallate)

(199) (Malabathrin E)

HO

OH HO

OH

HO

OH

OH OH

CO

CO HO

O

O

O O

O HO

CO

CO

O OC

H

HO

HO OH

O OH

CO

OH HO HO

OH HO

OH

(198) (Malabathrin A)

FIGURE 11.20 Structures of compounds 195–199.

OH OH

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Flavans and Proanthocyanidins

TABLE 11.17 The Natural Complex Tannins Compound Malabathrin A Malabathrin E Malabathrin F Guajavin A Guajavin B Psidinin A Psidinin B Psidinin C Psiguavin Strobilanin Camelliatannin C Camelliatannin D Camelliatannin E Camelliatannin F Camelliatannin G Stachyuranin A Stachyuranin B Stachyuranin C

Structure (198) (199) (200) (201) (203) (205) (207) (209) (211) (213) (214) (216) (215) (217) (218) (219) (220) (221)

Source

Ref.

Melastoma malabatricum

231

Psidium guajava

232

Platycarya strobilacea Sieb. et Zucc. Camellia japonica

233 234–236

Stachyurus praecox Sieb. et Zucc.

237

structure was unequivocally confirmed by acid-catalyzed condensation of the ellagitannin, casuarinin, and epicatechin-3-O-gallate. The cyclopentenone moiety in malabathrins E (199) and F (200) is regarded as the product of oxidative conversion of the HHDP group at O(2)– O(3) of glucose in, e.g., malabathrin A (198).231 The 1H NMR spectrum of guajavin A (201) at room temperature was complicated due to the effects of conformational isomerism, a feature that was commonly observed in complex tannins where the C-8 position of the flavan-3-ol unit is substituted.232 Structural elucidation of guajavins A (201) and B (203) was done by comparison of their 13C NMR data with those of the related catechin analogs, stenophyllanin A (202) and acutissimin B (204), respectively, and by synthesis via acid-catalyzed condensation of gallocatechin with the ellagitannins, stachyurin, and vescalagin, respectively. The 1H and 13C NMR spectra of psidinins A (205), B (207), and C (209) similarly resembled those of their catechin analogs, mongolicains A (206) and B (208), and stenophyllinin A (210), respectively, thus readily facilitating the structural elucidation of the former three compounds (Figure 11.22). Psiguavin (211), in which the B-ring of the flavan-3-ol unit is extensively rearranged, is considered to be derived biosynthetically from eugenigrandin A (partial structure [212]) by successive oxidation of the pyrogallol B-ring, benzylic acid-type rearrangement, and decarboxylation, followed by oxidative coupling as is indicated in Figure 11.23 (Scheme 11.7).232 Camelliatannins C (214) and E (215) with their C-6 and C-8 substituted epicatechin moieties, respectively, represent the first examples of complex tannins lacking a C

C bond between C-1 of glucose and the HHDP group at O-2 of the glucose unit (Figure 11.24). These bonds could, however, be readily formed by treatment of analogs 214 and 215 with polyphosphoric acid, hence transforming them into camelliatannins B and A, respectively.235 Camelliatannins C (214) and E (215) may thus be considered as precursors to the ‘‘normal’’ type of

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HO

OH HO

OH

HO

OH (200) (Malabathrin F)

CO

CO

O

OH H

O O

O HO

CO

CO

O OC

O

O

OH

HO

HO

OH

OH

HO

HO

OH HO

OH HO

OH

HO

(201) R = OH (Guajavin A) (202) R = H (Stenophyllanin A)

OH CO

OH

O

CO

HO

OH

O O O

O HO

CO

HO

HO

CO

O OC

H

O

OH

OH R

OH

HO

HO

OH HO

OH HO

OH

OH OH

OH

HO

OH

OH OH

CO

CO HO

O

O

R

O O HO

CO

HO

HO OH

O CO

O OC

H

OH OH OH

HO

OH HO

FIGURE 11.21 Structures of compounds 200–204.

OH

(203) R = OH (Guajavin B) (204) R = H (Acutissimin B)

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HO

OH HO

OH

HO

OH R

OH CO

OH (205) R = OH (PsidininA) (206) R = H (Mongolicain A)

CO

O

OH

O H

O O

O HO

CO

HO

HO

CO

O OC

HO O

OH

OH HO

OH HO

OH OH R

CO HO

OH

OH HO

O

CO

O H

O HO

OH HO

OH

HO

OH

O O

O

OH

O OC

CO

CO

OH O

HO

OH

HO

HO OH

CO O

OH HO

OH H

O O

O HO

HO

CO

CO

CO

(209) R = OH (Psidinin C) (210) R = H (Stenophyllinin A)

OH

O OC

O

R

O O

HO

HO OH

OH OH HO

OH HO

O HO

(207) R = OH (Psidinin B) (208) R = H (Mongolicain B)

OH HO

OH

HO

OH CO

CO

O H

O O HO

CO

HO

HO

O

O OC

CO

OH OH

H

OH

O HO

HO

OH O

O

HO (211) (Psiguavin)

FIGURE 11.22 Structures of compounds 205–211.

OH O

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OH OH

HO

O

OH

OH

O

OH OH OH

O HO

Oxidation HO

OH

O

O

O

H OH O

O

H OH

H O

OH

CO

H O

CO

O

(212) OH

OH CO2H

Rearrangement

HO

O

OH CO2H

O

OH

H O

−CO2

(211)

CO

FIGURE 11.23 Scheme 11.7: Proposed route to the transformation of eugenigrandin A (212) into psiguavin (211).

complex tannins and may be anticipated to co-occur in plant sources containing the latter class of metabolites. Camelliatannin D (216) represents the first example composed of dimeric hydrolyzable tannin and flavan-3-ol constituent units.234 Camelliatannin A presumably serves as the biogenetic precursor to both camelliatannins F (217) and G (218). Stachyuranins A (219) and B (220) also lack the C

C linkage between C-1 of the glucose moiety and the aroyl group at O-2 of glucose (Figure 11.25). When dissolved in aqueous methanol at room temperature, stachyuranin A (219) is gradually converted into stenophyllanin A,230 which presumably suggests that the latter compound is produced nonenzymatically from 219 in plants.

11.3.5 MISCELLANEOUS A new series of polyphenols, named castavinols, has been isolated from Bordeaux red wines.238 The three analogs (222–224) (Figure 11.25) (or their C-ring enantiomers) were speculated to form via [1,2]-addition of diacetyl, a C-4 yeast metabolite, to, e.g., malvidin3-O-glucoside (225) (Figure 11.26, Scheme 11.8). The resultant intermediate (226) would then cyclize by addition of the vinylic double bond to the electrophilic carbonyl carbon to give a C-3 carbocation (227), which is reduced, presumably under enzymatic control from the yeast, to compound 222. The remaining analogs (223 and 224) may similarly be derived from peonidin- and petunidin-3-glucoside, respectively.

11.3.6 NMR

AND

CONFORMATIONAL ANALYSIS

OF

PROANTHOCYANIDINS

Conformational analysis of proanthocyanidins is, in principle, concerned with the conformation of the pyran heterocycle and with the phenomenon of conformational isomerism due to

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Flavans and Proanthocyanidins

HO

OH HO

OH

HO

OH HO

OH CO

CO O

HO

CO

HO

OH

HO

O O O

HO

CO

CO

HO

O OC

H

HO

O

OH HO

OH

OH HO

OH HO

OH HO

HO OH

OH OH R O OC H

CO O O

OH HO

OH

OH

(214) R= 6-epicatechin (Camelliatannin C) (215) R= 8-epicatechin (Camelliatannin E)

OH

(213) Strobilanin OH HO OH CO O

HO HO

CO O O

OC

OH H

OH

OH HO OH HO

OH

O

CO

HO

(217) (Camelliatannin F)

O

OH HO HO

HO

HO OH

O CO O

HO HO

OH HO

OH

O

HO

CO

HO

HO

CO O O CO

HO

O OH O

OH

CO

OH

OH HO HO

OH

H OH

O OC H

O

O

OH HO

OH

HO

OH OH

OH

CO O O

CO O

HO

OH

OH

OH

OH HO

(216) (Camelliatannin D)

OH CO O

HO

O

HO

OH

CO O O

OC O O

OH HO

(218) (Camelliatannin G)

FIGURE 11.24 Structures of compounds 213–218.

OH

O

CO

HO

H

HO

HO

O

OH

COOH

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OH

(219) R1 = 8-catechin, R2 = galloyl (Stachyuranin A) (220) R1 = 6-catechin, R2 = H (Stachyuranin B)

HO CO O

HO HO

CO O O CO

HO

OR2 OH R1 O OC H

OH HO

OH

OH HO

OH HO

(221) (Stachyuranin C)

HO HO

COOH HO

O

OH

HO CO O

HO HO

HO

CO OH HO HO

O

CO O

O H OH

O OC H

OH HO

O

O

R

O OH

OH

CO O O

HO

OH

OH

HO

HO

OMe

HO OH

OH HO O

O

OH OH

O

(222) R = OMe or C-ring enantiomer (223) R = H or C-ring enantiomer (224) R = OH or C-ring enantiomer

FIGURE 11.25 Structures of compounds 219–224.

restricted rotation about the interflavanyl bond axis or axes. Realization of the fact that the conformational itinerary of the heterocyclic rings involves a dynamic equilibrium between E- and A-conformers239 had a profound impact in this field. Useful discussions dealing with various aspects of the conformational behavior of the proanthocyanidins may be extracted from Refs. 4, 7–12. The utilization of the full array of modern 1H and 13C NMR methodology has led to various contributions regarding the proton and carbon assignments as well as the conformations of di- and trimeric proanthocyanidins.240–249 Vercauteren and coworkers241 differentiated C-4 ! C-8- and C-4 ! C-6-linked peracetylated procyanidins [catechin-(4a ! 8)-catechin-(4a ! 6)catechin] by initial complete assignment of proton and carbon resonances of the appropriate dimers, followed by observation of differences in correlation of H-4 (C) with the quaternary carbons of the A–C- and D–F-ring junctions. The same group242 also confirmed the C-8 substitution of the DEF and GHI units in the peracetate of procyanidin C-1 [catechin-(4a ! 8)-catechin-(4a ! 8)-catechin] in an HMBC experiment. De Bruyne et al.243 subsequently provided a full analysis of the 1H and 13C NMR data of procyanidin B-3 [catechin-(4a ! 8)-

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OMe OH

HO

O OMe OH

O HO O

O

OH

OH OH

(225)

O

OMe OH

HO

O OMe O OGlc OH O

(226)

OMe OH

HO

O OMe O

(222) or C-ring enantiomer

OGlc OH

O

(227) FIGURE 11.26 Scheme 11.8: Proposed route to the formation of castavinols including the structures of compounds 225–227.

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catechin]. Two-dimensional NMR sequences were also used to assign the proton and carbon resonances of procyanidin A-2 [epicatechin-(2b ! 7, 4b ! 8)-catechin].244 Rimpler and coworkers240 used the peracetates of tri- and tetrameric procyanidins with epicatechin constituent units to define a further diagnostic shift parameter facilitating establishment of the interflavanyl bonding position. Williamson and coworkers245 similarly reported fully assigned 1H and 13 C NMR data of procyanidin B-2 [epicatechin-(4b ! 8)-epicatechin] and its per-O-acetyl derivative. Hemingway et al.246 produced evidence that both H-6 and C-6 resonances of free phenolic flavan-3-ols are downfield from H-8 and C-6, hence indicating that the chemical shifts of A-ring protons are indeed reversed compared to those commonly reported. Tobiason et al.247 demonstrated the temperature dependence of the pyran ring proton coupling constants of catechin. Such a temperature dependence of the coupling constants was also reproduced from the Boltzmann distribution of the conformational ensemble generated by the GMMX searching program.247 Additional useful information may be extracted from Ref. 248 as well as the preceding two papers in the series by the same authors. Reference 248 deals with the complete and unequivocal 1H and 13C NMR assignments of a range of green tea polyphenols. Investigations of the conformational properties of the flavan-3-ols and oligomeric proanthocyanidins have hitherto involved a variety of molecular mechanics and molecular orbital computations in combination with crystal structures, time-resolved fluorescence, as well as 1H and 13C NMR methods. Representative references to all these techniques may be found in the papers listed in Refs. 241–247, 250. These ‘‘NMR papers’’ incidentally also represent the major contributions regarding the conformation of proanthocyanidins, and may be summarized in a conformational context by reference to the significant contributions of Hatano and Hemingway.251,252 NMR analysis of procyanidin B-1 [epicatechin-(4b ! 8)-catechin] and B-3 [catechin(4a ! 8)-catechin] permitted full assignment of the H- and C-resonances for both the compact (228) and the more extended (229) conformer in the free phenolic form (Figure 11.27). In organic solvents, the more extended rotamer of procyanidin B-1 is preferred over the more compact rotamer (10:7) but in D2O the more compact rotamer dominates (10:2). When procyanidin B-3 is dissolved in organic solvents, the more compact rotamer (228) is slightly preferred (8:10). With D2O as solvent only trace proportions of the more extended rotamer (229) are detected. In this solvent, rotational conformation exchange is detected despite the observation of two distinct and sharp sets of signals for each rotamer. The heterocyclic ring of the ABC unit exists in an approximate half-chair conformation in each rotamer for both procyanidins B-1 and B-3. The heterocyclic ring of the ABC unit exists in an approximate half-chair conformation in each rotamer for both procyanidin B-1 and B-3. Coupling constants of the protons of the pyran rings of the DEF moieties indicate substantial axial orientation of the E-ring (see compounds 230 and 231 for E- and A-conformers of the DEF unit of procyanidin B-3). Line shape analysis of H-3 (F) indicated that the ‘‘abnormal’’ coupling constants of the F-ring protons were reminiscent of a comparatively high-energy skewed-boat conformation for procyanidin B-1 and between a half-chair and a skewed-boat for procyanidin B-3 rather than to E  A-conformational exchange, which has hitherto been used to explain the smaller than anticipated coupling constants. Hatano and Hemingway251,252 used NOE studies to assess the association of catechin and procyanidin B-3 with oligopeptides (see also relevant results in Refs. 253–256). The observed intermolecular NOEs indicating the preferred sites in the association of catechin and procyanidin B-3 with the tetrapeptide Gly–Pro–Gly–Gly are shown in 232 and 233, respectively. The molecular shapes of both the polyphenol and polypeptide are important features as far as selectivity is concerned.

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OH HO

O A

OH

B HO

OH

C

B

O A

OH

C

OH

HO

OH

OH

E

O

HO

OH

OH OH

F

E

HO

O

D

OH

F

D

HO

OH OH

OH

(228) (Compact rotamer of procyanidin B-3) C3−C4−C8−C9 torsion angle, (−)

(229) (Extended rotamer of procyanidin B-3) C3−C4−C8−C9 torsion angle, (+)

OH OH D

HO

Flavan-3-ol

H

D

HO

OH FO

H

HF

H

H

H HO

E

Flavan-3-ol O E

H

OH

OH

(231) A-conformer

OH

(230) E-conformer

OH

+

H OC H G

O 2C H

NH

N

+

H

H

NH2 HO

H

H

CO

O

OHOC B

C OH

H CO2G H H

N

OH H H

OH E

HO

O D

OH

H

NH

OH OH

C

CO

O A

B

N

H

OH

H A

CO

H

HN CO

HO

H2N H

OH

F OH

OH (232)

OH

(233)

FIGURE 11.27 Structures of compounds 228–233.

11.3.7 HPLC–MS ANALYSIS

OF

PROANTHOCYANIDINS

The various MS methods to determine the molecular composition of the constituent monomeric units in proanthocyanidins oligomers are summarized in Ref. 257. Contributions focusing on proanthocyanidin analysis via the HPLC–MS protocol included a wide range of plant-derived foods and beverages, and are summarized in Refs. 12, 258–261. In addition, references to additional significant contributions in this area are readily available via several of the excellent electronic search engines that are at our disposal.

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REFERENCES 1. Haslam, E., Natural proanthocyanidins, in The Flavonoids, Harborne, J.B., Mabry, T.J., and Mabry, H., Eds., Chapman & Hall, London, 1975, chap. 10. 2. Haslam, E., Proanthocyanidins, in The Flavonoids — Advances in Research, Harborne, J.B. and Mabry, T.J., Eds., Chapman & Hall, London, 1982, chap. 7. 3. Porter, L.J., Flavans and proanthocyanidins, in The Flavonoids — Advances in Research Since 1980, Harborne, J.B., Ed., Chapman & Hall, London, 1988, chap. 2. 4. Porter, L.J., Flavans and proanthocyanidins, in The Flavonoids — Advances in Research Since 1986, Harborne, J.B., Ed., Chapman & Hall, London, 1994, chap. 2. 5. Hemingway, R.W., Biflavonoids and proanthocyanidins, in Natural Products of Woody Plants 1: Chemicals Extraneous to the Lignocellulosic Cell Wall, Rowe, J.W., Ed., Springer Verlag, New York, 1989, chap. 7.6. 6. Porter, L.J., Condensed tannins, in Natural Products of Woody Plants 1: Chemicals Extraneous to the Lignocellulosic Cell Wall, Rowe, J.W., Ed., Springer Verlag, New York, 1989, chap. 7.7. 7. Ferreira, D. et al., Diversity of structure and function in oligomeric flavanoids, Tetrahedron, 48, 1743, 1992. 8. Ferreira, D. and Bekker, R., Oligomeric proanthocyanidins: naturally occurring O-heterocycles, Nat. Prod. Rep., 13, 411, 1996. 9. Ferreira, D. et al., Condensed tannins, Fortschr. Chem. Org. Naturst., 77, 21, 1999. 10. Ferreira, D., Nel, R.J.J., and Bekker, R., Condensed tannins, in Comprehensive Natural Products Chemistry, Barton, D.H.R. and Nakanishi, K., Eds., Pergamon Press (Elsevier), New York, 1999, 3, chap. 3.19. 11. Ferreira, D. and Li., X-C., Oligomeric proanthocyanidins: naturally occurring O-heterocycles, Nat. Prod. Rep., 17, 193, 2000. 12. Ferreira, D. and Slade, D., Oligomeric proanthocyanidins: naturally occurring O-heterocycles, Nat. Prod. Rep., 19, 517, 2002. 13. Geiger, H., Biflavonoids and triflavonoids, in The Flavonoids — Advances in Research Since 1986, Harborne, J.B., Ed., Chapman & Hall, London, 1994, chap. 4. 14. Hemingway, R.W., Foo, L.Y., and Porter, L.J., Linkage isomerism in trimeric and polymeric 2,3-cis-procyanidins, J. Chem. Soc., Perkin Trans. 1, 1209, 1982. 15. Kolodziej, H. et al., On the nomenclature of oligoflavanoids with an A-type unit, J. Nat. Prod., 56, 1199, 1993. 16. Bennie, L. et al., Oligomeric flavanoids. Part 32. Structure and synthesis of ether-linked proteracacinidin and promelacacinidin proanthocyanidins from Acacia caffra, Phytochemistry, 53, 785, 2000. 17. Coetzee, J. et al., Oligomeric flavanoids. Part 30. Structure and synthesis of butiniflavan-epicatechin and -epigallocatechin probutinidins, Phytochemistry, 52, 737, 1999. 18. Pan, W-B. et al., New flavans, spirostanol sapogenins and a pregnane genin from Tupistra chinensis and their cytotoxicity, J. Nat. Prod., 66, 161, 2003. 19. Garo, E. et al., Five flavans from Mariscus psilostachys, Phytochemistry, 43, 1265, 1996. 20. Sauvain, M. et al., Isolation of flavans from the Amazonian shrub Faramea guianensis, J. Nat. Prod., 57, 406, 1994. 21. Abdel-Mogib, M., Baisaf, S.A., and Ezmirly, S.T., Two novel flavans from Cyperus conglomeratus, Pharmazie, 55, 693, 2000. 22. Garcez, F. et al., Triterpenoids, lignans and flavans from Terminalea argentea, Biochem. Syst. Ecol., 31, 229, 2003. 23. Torres, S.L. et al., Two flavans from Brosimum acutifolium, Phytochemistry, 44, 347, 1997. 24. Ko, H-H. et al., Cytotoxic isoprenylated flavans of Broussonetia kazinoki, J. Nat. Prod., 62, 164, 1999. 25. Takashima, J. and Ohsaki, A., Acutifolins A-F, a new flavan-derived constituent and five new flavans from Brosimum acutifolium, J. Nat. Prod., 64, 1493, 2001. 26. Achenbach, H., Stoecker, M., and Constenia, M.A., Constituents of tropical medicinal plants. Part 31. Flavonoid and other constituents of Bauhinia manca, Phytochemistry, 27, 1835, 1988.

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180. Clark-Lewis, J.W. and Williams, L.R., Flavan derivatives. XVII. Epimerization of the benzylic 4-hydroxyl group in flavan-3,4-diols and the formation of 4-alkyl ethers by solvolysis, Aust. J. Chem., 20, 2152, 1967. 181. Coetzee, J., Malan, E., and Ferreira, D., The formation and stability of flavans with 2,3-cis-3,4-cis configuration, Tetrahedron, 55, 9999, 1999. 182. Malan, E. et al., The structure and synthesis of a 7,8,4’-trihydroxyflavan-epioritin dimer from Acacia caffra, Phytochemistry, 44, 529, 1997. 183. Malan, E. et al., The structure and synthesis of proguibourtinidins from Cassia abbreviata, Phytochemistry, 41, 1209, 1996. 184. Messanga, B. et al., Calodenin C. A new guibourtinidol-(4a ! 8)-afzelechin from Ochna calodendron, Plant Med., 64, 760, 1998. 185. Rani, M. and Kalidhar, S.B., Chemical investigation of Cassia biflora stems, J. Indian Chem. Soc., 75, 386, 1998. 186. Coetzee, J. et al., Oligomeric flavanoids. Part 31. Structure and synthesis of the first procassinidin dimers based on epicatechin, and gallo- and epigallocatechin, Phytochemistry, 53, 795, 2000. 187. Hatano, T. et al., Flavan dimers with lipase inhibitory activity from Cassia nomame, Phytochemistry, 46, 893, 1997. 188. Barrett, M.W. et al., Plant proanthocyanidins. Part 6. Chiroptical studies. Part 95. Circular dichroism of procyanidins, J. Chem. Soc., Perkin Trans. 1, 2375, 1979. 189. Foo, L.Y. et al., A-type proanthocyanidin trimers from cranberry that inhibit adherence of uropathogenic P-fimbriated Escherichia coli, J. Nat. Prod., 63, 1225, 2000. 190. Foo, L.Y. et al., The structure of cranberry proanthocyanidins which inhibit adherence of uropathogenic P-fimbriated Escherichia coli, Phytochemistry, 54, 173, 2000. 191. Morimoto, S., Nonaka, G., and Nishioka, I., Tannins and related compounds. LIX. Aesculitannins, novel proanthocyanidins with doubly-bonded structures from Aesculus hippocastanum L., Chem. Pharm. Bull., 35, 4717, 1987. 192. Porter, L.J., Ma, Z., and Chan, B.G., Cacao procyanidins: major flavanoids and identification of some minor metabolites, Phytochemistry, 30, 1657, 1991. 193. Lou, H. et al., A-type proanthocyanidins from peanut skins, Phytochemistry, 51, 297, 1999. 194. Balde, A.M. et al., Proanthocyanidins from stem bark of Pavetta owariensis. Part 2. Dimeric and trimeric proanthocyanidins possessing a doubly linked structure from Pavetta owariensis, Phytochemistry, 30, 4129, 1991. 195. Drewes, S.E. and Taylor, C.W., Methylated A-type proanthocyanidins and related metabolites from Cassipourea gummiflua, Phytochemistry, 37, 551, 1994. 196. Prasad, D. et al., An A-type proanthocyanidin from Prunus armeniaca, J. Nat. Prod., 61, 1123, 1998. 197. Rawat, M.S.M. et al., Proanthocyanidins from Prunus armeniaca roots, Phytochemistry, 50, 321, 1999. 198. Calzada, F. et al., Geranins A and B, new antiprotozoal proanthocyanidins from Geranium niveum, J. Nat. Prod., 62, 705, 1999. 199. Calzada, F. et al., Geranins C and D, additional new antiprotozoal A-type proanthocyanidins from Geranium niveum, Planta Med., 67, 677, 2001. 200. Barreiros, A.L.B.S. et al., A-type proanthocyanidin antioxidant form Dioclea lasiophylla, Phytochemistry, 55, 805, 2000. 201. Ma, C-M. et al., Inhibitory effects on HIV-1 protease of constituents from the wood of Xanthoceras sorbifolia, J. Nat. Prod., 63, 238, 2000. 202. Ogundaini, A. et al., Isolation of two new antiinflammatory biflavanoids from Sarcophyte piriei, J. Nat. Prod., 59, 587, 1996. 203. Arnone, A. et al., Constituents of Dragon’s blood. 5. Dracoflavans B1, B2, C1, C2, D1, and D2, new A-type deoxyproanthocyanidins, J. Nat. Prod., 60, 97, 199. 204. Balde, A.M. et al., Proanthocyanidins from stem bark of Pavetta owariensis, 3. NMR study of acetylated trimeric proanthocyanidins possessing a doubly-linked structure, J. Nat. Prod., 56, 1078, 1993.

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205. Balde, A.M. et al., Oligomeric proanthocyanidins possessing a doubly linked structure from Pavetta owariensis, Phytochemistry, 38, 719, 1995. 206. Santos-Buelga, C., Kolodziej, H., and Treutter, D., Procyanidin trimers possessing a doubly linked structure from Aesculus hippocastanum, Phytochemistry, 38, 499, 1995. 207. Kamiya, K. et al., Studies on Jamu and the medicinal resources of Indonesia. Part 4. Studies on the constituents of bark of Parameria laevigata Moldenke, Chem. Pharm. Bull., 49, 551, 2001. 208. Baek, N.I. et al., Potential sweetening agents of plant origin. 29. Studies on Indonesian medicinal plants. 6. Selligueain A, a novel highly sweet proanthocyanidin from the rhizomes of Selliguea feei, J. Nat. Prod., 56, 1532, 1993. 209. Lin, L.C., Kuo, Y.C., and Chou, C.J., Immunomodulatory proanthocyanidins from Ecdysanthera utilis, J. Nat. Prod., 65, 505, 2002. 210. Balde, A. et al., Tetrameric proanthocyanidins containing a double interflavanoid (A-type) linkage from Pavetta owariensis, Phytochemistry, 40, 933, 1995. 211. Kamiya, K. et al., A-type proanthocyanidins from the bark of Parameria laevigata, Heterocycles, 60, 1697, 2003. 212. Kondo, K. et al., Conversion of procyanidin B-type (catechin dimer) to A-type: evidence for abstraction of C-2 hydrogen in catechin during radical oxidation, Tetrahedron Lett., 41, 485, 2000. 213. Tanaka, T., Kondou, K., and Kouno, I., Oxidation and epimerization of epigallocatechin in banana fruits, Phytochemistry, 53, 311, 2000. 214. Sawadjoon, S. et al., Atropisomeric myristinins: selective COX-2 inhibitors and antifungal agents from Myristica cinnamomea, J. Org. Chem., 67, 5470, 2002. 215. Remy-Tanneau, S. et al., Characterization of a colorless anthocyanin-flavan-3-ol dimer containing both carbon-carbon and ether interflavanoid linkages by NMR and mass spectrometry, J. Agric. Food Chem., 51, 3592, 2003. 216. Baba, K. et al., Structure of a new spirobiflavonoid, genkwanol A, from the root of Daphne genkwa Sieb. et Zucc., Yakugaku Zasshi, 107, 525, 1987. 217. Baba, K. et al., A spirobiflavonoid genkwanol B from Daphne genkwa, Phytochemistry, 31, 975, 1992. 218. Baba, K., Taniguchi, M., and Kozawa, M., A third spirobiflavonoid genkwanol C from Daphne genkwa, Phytochemistry, 33, 914, 1993. 219. Baba, K., Taniguchi, M., and Kozawa, M., Three biflavonoids from Wikstroemia sikokiana, Phytochemistry, 37, 879, 1994. 220. Baba, K. et al., Biflavonoids from Daphne odora, Phytochemistry, 38, 1021, 1995. 221. Taniguchi, M. and Baba, K., Three biflavonoids from Daphne odora, Phytochemistry, 42, 1447, 1996. 222. Taniguchi, M., Fujiwara, A., and Baba, K., Three flavonoids from Daphne odora, Phytochemistry, 45, 183, 1997. 223. Taniguchi, M. et al., Two biflavonoids from Daphne acutiloba, Phytochemistry, 49, 863, 1998. 224. Himmelreich, U. et al., Damalachawin, a triflavonoid of a new structural type from Dragon’s blood of Dracaena cinnabari, Phytochemistry, 39, 949, 1995. 225. Hashimoto, F., Nonaka, G., and Nishioka, I., Tannins and related compounds. CXIV. Structure of novel fermentation products, theogallinin, theaflavonin and desgalloyl theaflavonin from black tea, and changes of tea leaf polyphenols during fermentation, Chem. Pharm. Bull., 46, 1383, 1992. 226. Sang, S. et al., Theadibenzotropolone A, a new type pigment from enzymatic oxidation of (
)epicatechin and (
)-epigallocatechin gallate and characterized from black tea using LC/MS/MS, Tetrahedron Lett., 43, 7129, 2002. 227. Wan, X. et al., A new type of tea pigment — from the chemical oxidation of epicatechin gallate and isolated from tea, J. Sci. Food Agric., 74, 401, 1997. 228. Davies, A.L. et al., A polyphenolic pigment from black tea, Phytochemistry, 46, 1397, 1997. 229. Lewis, J.R. et al., Theaflavate B, isotheaflavin-3’-O-gallate and neotheaflavin-3-O-gallate: three polyphenolic pigments from black tea, Phytochemistry, 49, 2511, 1998. 230. Nonaka, G., Nishimura, H., and Nishioka, I., Tannins and related compounds. Part 26. Isolation and structures of stenophyllanins A, B and C, novel tannins from Quercus stenophylla, J. Chem. Soc., Perkin Trans. 1, 163, 1985.

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231. Yoshida, T. et al., Tannins and related polyphenols of melastomataceous plants. V. Three new complex tannins from Melastoma malabathricum L., Chem. Pharm. Bull., 40, 1727, 1992. 232. Tanaka, T. et al., Tannins and related compounds. CXVI. Six new complex tannins from the bark of Psidium guajava L., Chem. Pharm. Bull., 40, 2092, 1992. 233. Tanaka, T. et al., Tannins and related compounds. CXXIV. Five new ellagitannins, platycaryanins A, B, C, and D, and platycariin, and a new complex tannin, strobilanin, from the fruits and bark of Platycarya strobilacea Sieb. et Zucc., and biomimetic synthesis of C-glycosidic ellagitannins from glucopyranose-based ellagitannins, Chem. Pharm. Bull., 41, 1708, 1993. 234. Han, L. et al., Tannins of theaceous plants. V. Camelliatannins F, G and H, three new tannins from Camellia japonica, Chem. Pharm. Bull., 42, 1399, 1994. 235. Hatano, T. et al., Tannins and related polyphenols of theaceous plants. VIII. Camelliatannins C and E, new complex tannins from Camellia japonica leaves, Chem. Pharm. Bull., 43, 1629, 1995. 236. Hatano, T. et al., Camelliatannin D, a new inhibitor of bone resorption from Camellia japonica leaves, Chem. Pharm. Bull., 43, 2033, 1995. 237. Han, L. et al., Tannins of Stachyurus species. III. Stachyuranins A, B and C, three new complex tannins from Stachyurus praecox leaves, Chem. Pharm. Bull., 43, 2109, 1995. 238. Castagnino, C. and Vercauteren, J., Castavinol, a new series of polyphenols from Bordeaux red wine, Tetrahedron Lett., 37, 7739, 1996. 239. Porter, L.J. et al., Conformational analysis of flavans: proton NMR and molecular mechanical (MM2) studies of the benzopyran ring of 3’,4’,5,7-tetrahydroxyflavan-3-ols: the crystal and the molecular structure of the procyanidin (2R,2S,4R)-3’,4’,5,7-tetramethoxy-4-(2,4,6-trimethoxyphenyl)flavan-3-ol, J. Chem. Res. (S), 86 (M, 830), 1986. 240. Ho¨r, M., Heinrich, M., and Rimpler, H., Proanthocyanidin polymers with antisecretory activity and proanthocyanidin oligomers from Guazuma ulmifolia, Phytochemistry, 42, 109, 1996. 241. Balas, L. and Vercauteren, J., Extensive high-resolution reverse 2D NMR analysis for the structural elucidation of procyanidin oligomers, Magn. Reson. Chem., 32, 386, 1994. 242. Balas, L., Vercauteren, J., and Laguerre, M., 2D NMR structure elucidation of proanthocyanidins: the special case of the catechin-(4a ! 8)-catechin-(4a ! 8)-catechin trimer, Magn. Reson. Chem., 33, 85, 1995. 243. De Bruyne, T. et al., Unambiguous assignments for free dimeric proanthocyanidin phenols from 2D NMR, Phytochemistry, 43, 265, 1996. 244. Vivas, N. et al., A complete structural and conformational investigation of procyanidin A2 dimer, Tetrahedron Lett., 37, 2015, 1996. 245. Khan, M.L., Haslam, E., and Williamson, M.P., Structure and conformation of the procyanidin B2 dimer, Magn. Reson. Chem., 35, 854, 1997. 246. Hemingway, R.W. et al., Conformation and complexation of tannins: NMR spectra and molecular search modeling of flavan-3-ols, Magn. Reson. Chem., 34, 424, 1996. 247. Tobiason, F.L. et al., Temperature dependence of (þ)-catechin pyran ring proton coupling constants as measured by NMR and modeled using GMMX search methodology, Tetrahedron Lett., 38, 985, 1997. 248. Vdovin, A.D., Kuliev, Z.A., and Abdullaev, N.D., 1H and 13C NMR spectrometry in the study of flavan-3-ols, proanthocyanidins, and their derivatives. III. 13C NMR spectroscopy of flavan-3-ols an proanthocyanidins, Chem. Nat. Compd., 33, 417, 1997. 249. Davies, A.L. et al., 1H and 13C assignments of some green tea polyphenols, Magn. Reson. Chem., 34, 887, 1996. 250. Laouenan, P. et al., NMR structural investigations and conformational analysis of condensed tannins. A continuing challenge due to restricted rotation about the interflavanyl linkage, Analusis, 25, M29, 1997. 251. Hatano, T. and Hemingway, R.W., Association of (þ)-catechin and catechin-(4a ! 8)-catechin with oligopeptides, J. Chem.. Soc., Chem. Commun., 2537, 1996. 252. Hatano, T. and Hemingway, R.W., Conformational isomerism of phenolic procyanidins: preferred conformations in organic solvents and water, J. Chem. Soc., Perkin Trans. 2, 1035, 1997. 253. Charlton, A.J. et al., Tannin interactions with a full-length human salivary proline-rich protein display a stronger affinity than with single proline-rich repeats, FEBS Lett., 382, 289, 1996.

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254. Baxter, N.J. et al., Multiple interactions between polyphenols and a salivary proline-rich protein repeat results in complexation and precipitation, Biochemistry, 36, 5566, 1997. 255. Charlton, A.J., Haslam, E., and Williamson, M.P., Multiple conformations of the proline-rich protein/epigallocatechin gallate complex determined by time-averaged nuclear Overhauser effects, J. Am. Chem. Soc., 124, 9899, 2002. 256. Charlton, A.J. et al., Polyphenol/peptide binding and precipitation, J. Agric. Food Chem., 50, 1593, 2002. 257. Lazarus, S.A. et al., High-performance liquid chromatography/mass spectrometry analysis of proanthocyanidins in foods and beverages, J. Agric. Food Chem., 47, 3693, 1999. 258. Lazarus, S.A. et al., High-performance liquid chromatography/mass spectrometric analysis of proanthocyanidins in foods and beverages, Methods Enzymol., 335, 46, 2001. 259. Lazarus, S.A. et al., Analysis and purification of proanthocyanidin oligomers, Methods Polyphenol Anal., 267, 2003. 260. Gu, L. et al., Liquid chromatography/electron spray ionization mass spectrometric studies of proanthocyanidins in foods, J. Mass Spectrom., 38, 1272, 2003. 261. Gu, L. et al., Screening of foods containing proanthocyanidins and their structural characterization using LC–MS/MS and thiolytic degradation, J. Agric. Food Chem., 51, 7513, 2003.

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Flavones and Flavonols K.M. Valant-Vetschera and E. Wollenweber

CONTENTS 12.1 12.2 12.3 12.4 12.5

Introduction ........................................................................................................... 618 Organization of the Tables..................................................................................... 618 Flavones ................................................................................................................. 619 Flavonols................................................................................................................ 645 Flavones with Other Substituents .......................................................................... 679 12.5.1 C-Methylflavones and C2/C3-Substituted Flavones ............................... 679 12.5.2 Methylenedioxyflavones .......................................................................... 692 12.5.3 C-Prenylflavones ..................................................................................... 692 12.5.4 O-Prenylflavones ..................................................................................... 693 12.5.5 Pyranoflavones ........................................................................................ 693 12.5.6 Furanoflavones........................................................................................ 693 12.5.7 Furano- and Pyrano-Substitution ........................................................... 695 12.5.8 C-Prenyl- and Pyrano-Substitution ......................................................... 695 12.5.9 C-Linked Aromatic- and Ketopyrano-Substitution ................................ 696 12.5.10 Tephrosia Flavones.................................................................................. 696 12.5.11 Artocarpus Flavones ................................................................................ 698 12.5.12 Flavone–Coumarin Hybrids.................................................................... 698 12.6 Flavonols with Other Substituents ......................................................................... 698 12.6.1 C-Methylflavonols................................................................................... 698 12.6.2 Methylenedioxyflavonols......................................................................... 699 12.6.3 C-Prenylflavonols .................................................................................... 700 12.6.4 O-Prenylflavonols.................................................................................... 709 12.6.5 Pyranoflavonols....................................................................................... 709 12.6.6 Furanoflavonols ...................................................................................... 709 12.6.7 C-Prenyl- and Pyrano-Substitution ......................................................... 711 12.6.8 Flavonols with Aromatic Substituents .................................................... 711 12.6.9 Various Cycloflavonols ........................................................................... 711 12.6.10 Hybrid Structures.................................................................................... 711 12.6.11 Furanoflavonols of Vellozia .................................................................... 711 12.7 Flavone and Flavonol Esters ................................................................................. 712 12.8 Chlorinated Flavonoids.......................................................................................... 712 12.9 Flavonoids of Helminthostachys............................................................................. 714 12.10 Comments on Distribution and Accumulation ...................................................... 714 References .......................................................................................................................... 716 Appendix ............................................................................................................................ 737

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12.1 INTRODUCTION Flavonoid analyses are mostly concentrating on plants which are of either pharmaceutical interest or of commercial value. In addition, flavonoids are important factors in biological interactions between living organisms. This is best illustrated by the last review ‘‘Advances in flavonoid research since 1992’’ focusing on these topics.1 In contrast, mere distribution studies or chemosystematically oriented compilations are rare (e.g., on Asteraceae).2 Naturally, the presently known distribution of flavones and flavonols in plants reflects the current scientific interests, and hence the interpretation of their chemodiversity must be made with caution. The main part of this compilation consists of extensive tables listing the flavonoids and their plant sources, which are commented accordingly. The data originate primarily from excerpts of current literature, the use of Chemical Abstracts and of Current Contents (Life Sciences and Agriculture) databases, supported by a review on prenylated flavonoids3 and data taken from the Handbook of Natural Flavonoids.4 Whenever possible, original literature was consulted to verify structures and their sources. The use of electronically available information lead to inclusion of most recent publications, but the present compilation cannot be claimed to be complete. Apologies go to colleagues whose publications may have been overlooked, and notification on reports that escaped our attention is strongly encouraged. For compilation and arrangement of compounds, earlier reviews and surveys were taken as the basis.5,6 In comparison to the previously published reviews, the increasing number and complexity of structures observed is striking. Thus it became quite difficult to list all of these structures in a logical sequence, particularly prenylated derivatives with additional cyclized substituents. Substitution patterns used for grouping of the flavone and flavonol derivatives are as follows. OH-, OMe-groups; C-methyl; methylenedioxy groups; C-prenylation; O-prenylation; (dihydro)furanosubstitution; pyranosubstitution; complex cyclosubstitution; aromatic substitution; esterification; chlorination. These residues may also occur combined in one flavonoid structure. In many cases, abbreviation of substitutents could no longer be made without ending up with hardly understandable chemical nomenclature (e.g., complex-O-cyclosubstitution). This problem was already obvious in the publication of Barron and Ibrahim3 who shifted to illustrations of such complex compounds. Consequently, figures of structures showing characteristic substitution patterns will complete the tabulated information provided here.

12.2 ORGANIZATION OF THE TABLES All tables are organized along the same lines. For the numbering of the basic flavonoid molecule, we refrained to use the system being recommended by the Royal Society of Chemistry, in which primed numbers are mixed in with unprimed numbers. Instead, we still use the more commonly practiced system of most flavonoid scientists: the structures are arranged by number and position, in ascending order, of substituent at ring C being cited first, followed by the substituents in ring A, and then by those in ring B in primed numbers. We also prefer this convention for our tables, for reasons of increased structural information. Thus, for instance, cirsilineol is 5,4’-dihydroxy-6,7,3’-trimethoxyflavone, morin is 3,5,7,2’,4’-pentahydroxyflavone, to give two examples. To further increase the value of information, compounds are listed according to increasing numbers of hydroxyl- and methoxyl-groups, and by increasing complexity of other substituents. Further columns inform about trivial names of the compounds, plant sources (species) and families (abbreviated), accumulation sites, and references. Plant sources are not listed for widespread compounds such as apigenin or kaempferol and some further compounds as had been done previously.6 Instead, they are either marked

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as ‘‘many records,’’ or, where applicable, as ‘‘widespread in Asteraceae’’ or other larger families. Acknowledged trivial names are cited in column 3, unreasonable names such as ‘‘dechloro-chlorapigenin’’ are omitted. We strictly follow the priority rule when a new trivial name had first been given to a different structure. In some cases, widely accepted synonyms are included (e.g., cyclomulberrin/cyclomulberrochromene3). The listing of accumulation sites forms an essential part of the tables (under the column head ‘‘Plant organs’’). In particular, attention focuses on the presence of flavonoids in exudates if indicated by the authors (marked with the abbreviation ‘‘ext.,’’ if not clear from a term like ‘‘bud exudate’’). Critical sources are listings such as ‘‘whole plant’’ which could mean anything from aerial parts to inclusion of roots and flowers. Despite our efforts, we received a single reply only from the authors addressed. Hence the correctness of ‘‘whole plant’’ was confirmed only for two flavonols isolated from Andrographis viscosula.7 Details on specific accumulation sites and specific accumulation trends will be discussed in the text relating to the respective tables. For easier navigation through the tabulated data, some further specifics should be pointed out to the reader. In this context, citing ‘‘last edition’’ refers to Wollenweber.3 – Abbreviations such as -OH ¼ hydroxyl, -OMe ¼ methoxy, -Me ¼ methyl are used throughout text and tables. Further abbreviations used to describe the flavonoid structure are explained in a footnote to Table 12.3. – Basic OH-substituted compounds not (yet) found in nature are noted in brackets, prior to their corresponding methyl derivates. – Compounds already listed in previous editions, but without being reported from any new source, are only cited by name. – Products that have been reported for the first time since compilation of the previous tables are marked with an asterisk. The same applies for new trivial names. – Names missing in previous editions have been added now (also marked by an asterisk), explaining for literature citations older than the beginning of the reporting period (e.g., Ref. 8). – In column ‘‘Plant species,’’ these are grouped by families and are listed alphabetically for each flavonoid. For individual compounds of single publications, a maximum of two species per genus is noted; more than two species are abbreviated by ‘‘spp.’’ – In the same column, flavonoids known so far only in glycosidic combination or in acylated form are marked ‘‘Glycoside only’’ and ‘‘Ester only,’’ respectively. No citations or sources are specified in these cases. – Abbreviations of family names given in the following column should be generally understandable. Rare family names are written in full. – Synthesis is noted under the head ‘‘Plant organs.’’ Some recently synthesized compounds that are likely to be found in nature, sooner or later, are cited in brackets, for example, the 7-methyl ether of 6-hydroxygalangin, or 8-C-methylapigenin. These are marked ‘‘synthesis only.’’ – Some previously compiled flavonoids,6 which are still only known as synthetic products, have been omitted from the current tables. – Revised structures are indicated referring to respective publications.

12.3 FLAVONES A total of 309 entries on the distribution of flavones and their methyl ethers are summarized in Table 12.1. The substitution patterns range from unsubstituted flavone to octa-O-substituted flavones. As expected, the number of plant species accumulating these structures is

10 11 12

9

8

OMe-Substitution

5,7-diOH

Di-O-substituted flavones (5,6-diOH) 6-OMe 5,6-diOMe

Mono-O-substituted flavones 5-OH 5-OMe (6-OH) 6-OMe (7-OH) 7-OMe 2’-OH 2’-OMe (3’-OH) 3’-OMe (4’-OH) 4’-OMe

Unsubstituted flavone

OH-Substitution

Chrysin

Primuletin

Flavone

Trivial Name

Anomianthus dulcis Artemisia campestris spp. glutinosa Baccharis viminea Baccharis viminea Mikania hirsutissima Heliotropium pycnophyllum Eriodictyon sessilifolium Mimulus moschata Propolis from Egypt European Propolis Bees Wax

Plant Species

Annonac. Asterac. Asterac. Asterac. Asterac. Boragin. Hydrophyll. Scrophul.

Family

Leaf Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial parts Aerial p., ext. Leaf resin Aerial p., ext.

Plant Organ

131 132 129 133 134 36 135 108 136 137 138

Ref.

620

5 6 7

4

2 3

1

No.

TABLE 12.1 Flavones and Their Methyl Ethers

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7,4’-diOH

4’-OH 8,2’-diOH 8-OH 2’,5’-diOH 3’,4’-diOH

23 24 25 26 27

(6,4’-diOH) 6-OH (7,8-diOH)

5,8-diOH 5,2’-diOH 5-OH (6,7-diOH) 7-OH (6,3’-diOH)

5-OH

21 22

20

19

18

14 15 16 17

13

2’-OMe

7-OMe

7,8-diOMe*

4’-OMe

6,3’-diOMe

6-OMe*

2’-OMe

5,7-diOMe

7-OMe

Isopratol

Primetin — — —

Tectochrysin

Godmania aesculifolia Dracaena cinnabari Glycyrrhiza eurycarpa Glycyrrhiza pallidiflora Trigonella spp.

Glycoside only

Dalbergia cochinchinensis

Uvaria rufas Baccharis viminea Baccharis viminea Lychnophora markgravii Godmania aesculifolia Heliotropium pycnophyllum Pelargonium crispum Collinsonia canadensis Hoslundia opposita Bees wax Leptospermum scoparium

Bignon. Agavac. Fabac. Fabac. Fabac.

Fabac.

Myrtac.

Annonac. Asterac. Asterac. Asterac. Bignon. Boragin. Geraniac. Lamiac. Lamiac.

Leaf Resin Root Root Aerial parts

Stem

Leaf

Root Aerial p., ext. Aerial p., ext. Aerial parts Aerial p., ext. Aerial p., ext. Leaf exudate Aerial p., ext. Twigs

continued

146 147 17 148 149

145

139 129 133 140 141 36 142 143 144 138 21

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Flavones and Flavonols 621

5,7,8-triOH 5,8-diOH 5,7-diOH

7-OH 5-OH

5-OH

33 34 35 36

37 38

39 40

43

(5,6,2’-triOH) 5-OH — (5,6,3’-triOH) —

5-OH

32

5,6,3’-triOMe

6,2’-diOMe 5,6,2’-triOMe

7,8-diOMe 5,7,8-triOMe

5,8-diOMe 7,8-diOMe

7-OMe* 8-OMe

5,6,7-triOMe

6,7-diOMe

Moslosooflavone*

7-Methyl-wogonin

Norwogonin Pediflavone* Wogonin

Mosloflavone*

Negletein

Baicalein Oroxylin A

Trivial Name

Scutellaria planifolia Didymocarpus pedicellatus Tetracera indica Scutellaria planifolia Adenostoma sparsifolium Bupleurum scorzonerifolium Polygonum senegalense Andrographis affinis Uvaria rufas Nothofagus solandri Collinsonia canadensis Mosla soochouensis

Gomphrena boliviana Scutellaria seleriana Adenostoma sparsifolium Bupleurum scorzonerifolium Desmos chinensis Gomphrena boliviana Collinsonia canadensis Uvaria rufas Mosla soochouensis

Plant Species

Lamiac. Gesneriac. Dilleniac. Lamiac. Rosac. Umbellif. Polygon. Acanthac. Annonac. Fagac. Lamiac. Lamiac.

Amaranth. Lamiac. Rosac. Umbellif. Anonaceae Amaranth. Lamiac. Annonac. Lamiac.

Family

Root Immat. leaf Aerial parts Root Aerial p., ext. Root Leaf surface Whole plant Root Aerial p., ext. Aerial p., ext. Whole herb

Whole plant Aerial parts Aerial p., ext. Root Root Whole plant Aerial p., ext. Root Whole herb

Plant Organ

55 154 155 55 19 152 156 157 139 158 143 153

150 151 19 152 62 150 143 139 153

Ref.

622

41 42

5,6-diOH 7-OH

30 31

7-OMe 5,6-diOMe

Tri-O-substituted flavones 5,6,7-triOH 5,7-diOH 6-OMe

28 29

OMe-Substitution

OH-Substitution

No.

TABLE 12.1 Flavones and Their Methyl Ethers — continued

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5-OH

47 48 49 50 51 52 53 54

5,7,4’-triOH 7,4’-diOH 5,4’-diOH 5,7-diOH 7-OH 5-OH

5,7,2’-triOH 7,2’-diOH 5,2’-diOH

44 45 46

5-OMe 7-OMe 4’-OMe 5,4’-diOMe 7,4’-diOMe

7,2’-diOMe* 5,7,2’-triOMe*

5-OMe* 7-OMe

Apigenin Thevetiaflavon Genkwanin Acacetin

Echioidinin

Artemisia afra Artemisia diffusa Baccharis trinervis Calea tenuifolia Hieracium amplexicaule Ophrysosporus charrua Eucryphia, 6 spp. Marchesinia brachiata Monoclea gottschei Cunila angustifolia Dorystoechas hastata Lycopus virginicus Perovskia spp. Salvia sclarea Salvia syriaca Salvia, 3 spp. Sideritis spp. Teucrium marum, T. polium Mirabilis viscosa Currania robertiana Escallonia pulverulenta

Many records Many records

Scutellaria planifolia Andrographis alata Andrographis lineata Andrographis rothii Andrographis viscosula Andrographis rothii Andrographis viscosula Many records

Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Cunoniac. Hepaticae Hepaticae Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Nyctagin. Pteridaceae Saxifrag.

Lamiac. Acanthac. Acanthac. Acanthac. Acanthac. Acanthac. Acanthac. plant plant plant plant plant plant

Aerial parts Aerial p., ext. Leaf Aerial parts Aerial p., ext. Aerial parts Leaf, bud, ext. Thallus Thallus Aerial parts Aerial p., ext. Aerial parts Aerial p., ext. Aerial p., ext. Aerial parts Aerial p., ext. Aerial parts Aerial p., ext. Aerial p., ext. Frond exud. Aer. p., res. ex.

Root Whole Whole Whole Whole Whole Whole

Flavones and Flavonols continued

160 161 162 163 32 164 165 166 22 167 168 169 170 168 171 41 172 168 43 173 42

55 159 14 13 10 13 10

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623

8-OH 5-OH

70 71

5,6,7-triOMe* 6,7,8-triOMe

6,8-diOMe*

5,7-diOH

69

3’,4’,5’-triOMe*

68

(3’,4’,5’-triOH)

3’-OMe 4’-OMe* 7,4’-diOMe 7,4’-diOMe 3’,4’-diOMe* 7,3’,4’-triOMe

7,2’,4’-triOMe*

6,2’,3’-triOMe

5,7,4’-triOMe

OMe-Substitution

Tetra-O-substituted flavones (5,6,7,8-tetraOH) 5,8-diOH 6,7-diOMe

67

7,3’,4’-triOH 7,4’-diOH 7,3’-diOH 3’-OH 3’-OH 7-OH

(7,2’,4’triOH)

5,8,2’-triOH 7,8,4’triOH 5,2’,5’-triOH (6,2’,3’-triOH)

OH-Substitution

Alnetin

Geraldone Farnisin* Tithonine Tithonine

Trivial Name

Godmania aesculifolia Nothofagus cunninghamii Lindera lucida

Scutellaria repens

Fissistigma lanuginosum Betula davurica

Primula veris

Acacia farnesiana Albizia odoratissima Virola michelli Launaea asplenifolia

Albizia odoratissima

Glycoside only

Anarrhinum forskalii Antirrhinum, 4 spp.

Plant Species

Bignon. Fagac. Laurac.

Lamiac.

Annonac. Betulaceae

Primul.

Mimosac. Mimosac. Myristic. Asterac.

Leaf Leaf Synthesis Root Synthesis Synthesis Aerial p., ext. Aerial p., ext. Twigs

Flower

Seed Root bark Leaf Whole plant? Synthesis

Root bark

Aerial p., ext. Aerial p., ext.

Scrophul. Scrophul.

Mimosac.

Plant Organ

Family

178 179 24 180 24 24 141 158 181

177

175 174 176 8 176

174

108 108

Ref.

624

65 66

60 61 62 63 64

59

55 56 57 58

No.

TABLE 12.1 Flavones and Their Methyl Ethers — continued

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5,6,7-triOH 5,4’-diOH 5,7-diOH 5,6-diOH

7-OH 6-OH 5-OH

77 78 79 80

81 82 83 84

(5,7,8,2’-tetraOH) 5,8,2’-triOH 5,7,2’-triOH

5,7,4’-triOH 5,6,4’-triOH

75 76

85 86

(5,6,7,2’-tetraOH) 5,7,2’-triOH 5,6,7,4’-OH

73 74

72

7-OMe 8-OMe

5,6,4’-triOMe 5,7,4’-triOMe 6,7,4’-triOMe 5,6,7,4’-tetraOMe 5,6,7,4’-tetraOMe 5,6,7,4’-tetraOMe 5,6,7,4’-tetraOMe

4’-OMe 6,7-diOMe 6,4’-diOMe 7,4’-diOMe

6-OMe 7-OMe

6-OMe

5,6,7,8-tetraOMe 5,6,7,8-tetraOMe

Scutevulin

Salvigenin

Cirsimaritin Pectolinarigenin Ladanein

Hispidulin Sorbifolin

Scutellarein

Many records, mostly from Asteraceae Many records, mostly from Asteraceae Artemisia argyri Marrubium trachyticum Mentha
piperita Micromeria albanica Nepeta pungens, N. saturejoides Ocimum, 5 spp. Orthosiphon stamineus Salvia cyanescens Salvia hypoleuca, S. stenophylla Salvia syriaca Glycoside only Orthosiphon stamineus Many records, mostly Asteraceae and Lamiaceae Chromolaena odorata Citrus sinensis Orthosiphon stamineus Ficus altissima

Centaurea jacea Duranta plumieri Many records, mostly from Asteraceae Ambrosia ambrosioides Onopordon sibthorpianum Mentha
piperita Thymus herba barona

Godmania aesculifolia Nothofagus cunninghamii

Asterac. Rutac. Lamiac. Morac.

Lamiac.

Asterac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac.

Asterac. Asterac. Lamiac. Lamiac.

Asterac. Verben.

Bignon. Fagac.

Aerial p., ext. Oil Aerial parts Aerial parts

Aerial parts

Aerial parts Aerial parts Aerial parts Aerial parts Leaf surface Leaf surface Aerial parts Aerial parts Aerial p., ext. Aerial p., ext.

Aerial p., ext. Aerial parts Aerial parts Aerial parts

Aerial p., ext. Stem

Leaf Aerial p., ext.

continued

193 16 191 30

191

187 187 185 188 189 190 191 192 41 171

133 184 185 186

182 183

146 158

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Flavones and Flavonols 625

5,2’-diOH

5,7-diOH 7-OH 5-OH

5,7,8,4’-tetraOH

5,8,4’-triOH 5,7,4’-triOH

5,7,8-triOH 5,7,8-triOH 5,4’-diOH 5,8-diOH 5,7-diOH

87

88 89 90

91

92 93

94

4’-OMe 4’-OMe 7,8-diOMe 7,4’-diOMe* 8,4’-diOMe

7-OMe 8-OMe

8,2’-diOMe 5,8,2’-triOMe 7,8,2’-triOMe

7,8-diOMe

OMe-Substitution

Bucegin

Takakin Takakin

4’-Hydroxy-wogonin

Isoscutellarein

Skullcapflavone I

Trivial Name

Helicteres isora Chrysothamnus nauseosus Madia sativa Madia, 4 spp. Zinnia acerosa

Centaurea chilensis Chrysothamnus nauseosus Madia, 3 spp. Zinnia acerosa Licania densiflora Scutellaria repens Bupleurum scorzonerifolium Verbena littoralis Odixia achlaena, O.angusta Ozothamnus scutellifolius

Adrographis affinis Andrographis echioides Andrographis paniculata Baccharis pilularis Odixia achlaena, O.angusta Ozothamnus scutellifolius

Andrographis affinis Andrographis elongata Andrographis lineata Andrographis rothii Scutellaria planifolia

Plant Species

Sterculiac. Asterac. Asterac. Asterac. Asterac.

Asterac. Asterac. Asterac. Asterac. Chrysobal. Lamiac. Umbellif. Verben. Asterac. Asterac.

Acanthac. Acanthac. Acanthac. Asterac. Asterac. Asterac.

Acanthac. Acanthac. Acanthac. Acanthac. Lamiac.

Family

Leaf Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext.

Leaf þ stem Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial parts Root Root Aerial parts Aerial p., ext. Aerial p., ext.

Whole plant Whole plant Whole plant Aerial p., ext. Aerial p., ext. Aerial p., ext.

Whole plant Whole plant Whole plant Whole plant Root

Plant Organ

204 199 133 201 133

198 199 200 133 202 180 152 203 197 197

157 195 11 196 197 197

157 194 14 13 55

Ref.

626

95 96 97

OH-Substitution

No.

TABLE 12.1 Flavones and Their Methyl Ethers — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

5,7,2’,6’-tetraOH 5,2’,6’-triOH

5,7,2’-triOH 5-OH 5,7,3’,4’-tetraOH 7,3’,4’-triOH 5,3’,4’-triOH

113 114 115 116 117

5,7,2’,3’-tetraOH 5,7,2’,4’-tetraOH 5,2’,4’-triOH 5-OH

105 106 107 108 109 110 111 112

(5,6,3’,5’-tetraOH)

(5,6,2’,6’-tetraOH) 5-OH

5,7,2’,5’-tetraOH* 5-OH

99 100 101 102

103 104

5-OH

98

5-OMe 7-OMe

6’-OMe 7,2’6’triOMe*

7-OMe*

7-OMe 7,2’,4’-triOMe 5,7,2’,4’-tetraOMe

5,6,3’,5’-tetraOMe

6,2’,6’-triOMe 5,6,2’,6’-tetraOMe

7,2’,5’-triOMe* 5,7,2’5’-tetraOMe*

5,7,8,4’-tetraOMe

7,8,4’-triOMe

Luteolin

Norartocarpetin Artocarpetin

Cerosillin

Zapotinin Zapotin

Arnica longifolia Artemisia barrelieri Dubautia arborea Wunderlichia crulsiana Heliotropium stenophyllum Nonea lutea, N. pulla

Andrographis paniculata Many records

Scutellaria planifolia Andrographis viscosula Andrographis elongata

Casimiroa tetrameria

Casimiroa tetrameria

Eucryphia jinksi Calceolaria irazuensis Asterella blumeana Citrus reticulata Calceolaria, 3 spp. Calceolaria irazuensis Citrus sinensis Scutellaria baicalensis Androgoraphis neesiana Andrographis rothii

Asterac. Asterac. Asterac. Asterac. Boragin. Boragin.

Acanthac.

Lamiac. Acanthac. Acanthac.

Rutac.

Rutac.

Cunoniac. Scrophul. Hepaticae Rutac. Scrophul. Scrophul. Rutac. Lamiac. Acanthac. Acanthac.

Flower Aerial p., ext. Leaf exudate Aerial parts Leaf exudate Aerial p., ext.

Whole plant

Root Whole plant Whole plant

Leaf

Leaf

Leaf, bud, ext. Aerial p., ext. Thallus Fruit peel Aerial p., ext. Aerial p., ext. Oil Root Whole plant Whole plant

Flavones and Flavonols continued

210 132 211 212 213 36

11

55 10 194

209

209

165 108 205 206 207 108 16 208 12 13

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627

OH-Substitution

5,7,4’-triOH 5,7,3’-triOH

7,4’-diOH 7,3’-diOH 5,4’-diOH

No.

118 119

120 121 122 Velutin

Chrysoeriol Diosmetin

Trivial Name Eucryphia lucida, E. jinksii Salvia hypoleuca Salvia sclarea Sideritis spp. Teucrium marum Antirrhinum, 3 spp. Petunia parviflora Many records Artemisia iwayomogi, A. molinieri Artemisia caerulescens Dubautia arborea Eupatorium altissimum Ozothamnus scutellifolius Tithonia calva Nonea rosea Aeonium glutinosum Cyperus alopecuroides Acacia farnesiana Hypericum perforatum Phyllospadix japonica Artemisia caerulescen Artemisia iwayomog Artemisia oliveriana Bahia glandulos Bracteantha viscosa Haplopappus baylahuen Helichrysum bracteatum Heterotheca pilosa Madia sativa Senecio viscosa

Plant Species

Aerial p., ext. Aerial p., ext. Leaf exudate Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Inflor. Seed Callus Whole plant Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial parts Aerial p., ext. Stem and leaf resin Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext.

Leaf, bud, ext. Aerial p., ext. Aerial p., ext. Aerial parts Aerial p., ext. Aerial p., ext. Aerial p., ext.

Cunoniac. Lamiac. Lamiac. Lamiac. Lamiac. Scrophul. Solanac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Boragin. Crassul. Cyperac. Mimosac. Guttiferae Zosterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac.

Plant Organ

Family

161 132 211 215 197 182 36 216 217 175 218 219 132 161 220 221 222 223 32 182 133 32

165 41 168 172 168 108 214

Ref.

628

5,3’-diOMe 5,4’-diOMe* 7,3’-diOMe

3’-OMe 4’-OMe

OMe-Substitution

TABLE 12.1 Flavones and Their Methyl Ethers — continued

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5,3’-diOH

5,7-diOH

5-OH

123

124

125

7,3’,4’-triOMe

3’,4’-diOMe

7,4’-diOMe

Pilloin

Nonea lutea, N. pulla Eucryphia, 4 spp. Monoclea gottschei Eriodictyon sessilifolium Salvia candidissima Salvia chinopeplica Salvia sclarea Teucrium marum Kitaibelia vitifolia Mirabilis viscosa Antirrhinum, 3 spp. Petunia parviflora Salpiglossis sinuata Lethedon tannaensis Lantana montevidensis Artemisia iwayomogi Baccharis trinervis Onoprodon laconicum Godmania aesculifolia Eucryphia milleganii Lycopus virginicus Notholaena nivea Antirrhinum braun-blanquetii, A. graniticum Calea tenuifolia Chrysothamnus viscidiflorus Monoclea gottschei, M. forsteri Asarina barkleyana Baccharis trinervis Calea tenuifolia Nonea pulla Eucryphia lucida, E.milleganii Orthosiphon stamineus Sideritis spp. Teucrium botrys

Boragin. Cunoniac. Hepaticae Hydrophyll. Lamiac. Lamiac. Lamiac. Lamiac. Malvac. Nyctagin. Scrophul. Solanac. Solanac. Thymelaeac. Verben. Asterac. Asterac. Asterac. Bignon. Cunoniac. Lamiac. Pteridaceae Scrophul. Asterac. Asterac. Hepaticae Scrophul. Asterac. Asterac. Boragin. Cunoniac. Lamiac. Lamiac. Lamiac.

Aerial p., ext. Leaf, bud, ext. Thallus Leaf resin Aerial parts Leaf Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Leaf Aerial p., ext. Aerial p., ext. Leaf Aerial parts Aerial p., ext. Leaf, bud, ext. Aerial parts Frond exud. Aerial p., ext. Aerial parts Aerial p., ext. Thallus Aerial p., ext. Leaf Aerial parts Aerial p., ext. Leaf, bud, ext. Aerial parts Aerial parts Aerial p., ext.

Flavones and Flavonols continued

36 165 22 135 224 225 168 168 226 43 108 214 214 227 228 161 162 184 141 165 169 45 108 163 199 22 108 162 163 36 165 191 172 168

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629

5,7,4’-triOH

135

134

5,2’-diOH (5,6,7,8,4’-pentaOH) 5,8,4’-triOH

133

131 132

7,3’,4’,5’-tetraOH Penta-O-substituted flavones (5,6,7,8,2’-pentaOH) (5,8,2’-triOH 5,7,2’-triOH

(6,7,3’,4’-tetraOH) 7,3’-diOH (6,7,3’,5’-tetraOH) 7-OH (7,2’,4’,5’-tetra-OH)

OH-Substitution

6,8-diOMe

6,7-diOMe

6,7,8-triOMe

6,7-diOMe) 6,8-diOMe*

7,2’,4’,5’-tetraOMe*

6,3’,5’-triOMe*

6,4’-diOMe

5,7,3’,4’-tetraOMe

OMe-Substitution

Desmethyl-sudachitin

Isothymusin

Tenaxin 1

Grantionin*

Abrectorin

Trivial Name

Ambrosia trifida Madia capitata Biebersteinia orphanidis Scutellaria repens

Agastache barberi Becium grandiflorum Nepeta spp. Ocimum gratissimum Prunus cerasus

Scutellaria baicalensis Scutellaria repens

Calliandra californica

Inula grantioides

Kitaibelia vitifolia Anarrhinum forskalii Antirrhinum, 5 spp. Lethedon tannaensis Lantana montevidensis

Plant Species

Lamiac. Lamiac. Lamiac. Lamiac. Rosac. — Asterac. Asterac. Bieberstein. Lamiac.

Lamiac. Lamiac.

Fabac.

Asterac.

Malvac. Scrophul. Scrophul. Thymelaeac. Verben.

Family

p., ext.

p., ext. p., ext. p., ext.

Leaf surface Leaf, ext. Leaf surface Aerial parts Fruit Synthesis Aerial p., ext. Aerial p., Ext. Leaf surface Root

Root Root Synthesis

Root

Aerial parts

Aerial Aerial Aerial Leaf Aerial

Plant Organ

189 230 189 231 232 24 233 200 234 180

180 24

a

229

34

226 108 108 227 228

Ref.

630

129 130

128

127

126

No.

TABLE 12.1 Flavones and Their Methyl Ethers — continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 630 8.9.2005 10:37am

Flavonoids: Chemistry, Biochemistry, and Applications

5,6,4’-triOH

5,7,8-triOH 5,6,8-triOH 5,6,7-triOH 5,4’-diOH

(5,8-diOH

5,7-diOH

5,6-diOH

136

137 138 139 140

141

142

143

7,8,4’-triOMe

6,8,4’-triOMe

6,7,4’-triOMe)

6,4’-diOMe* 7,4’-diOMe 8,4’-diOMe* 6,7,8-triOMe

7,8-diOMe

Pebrellin*

Nevadensin

‘‘Pedunculin’’

Xanthomicrol

Pilosin *

Thymusin

Lamiac.

Leaf exudate Aerial p., ext. Whole plant Aerial parts Whole plant Aerial parts Aerial pars Leaf surface Leaf surface Aerial parts Aerial p., ext. Aerial parts Vegetative p. Leaf surface Aerial p., ext. Res. exud. Aerial p., ext. Aerial p., ext. Aerial parts Aerial p., ext. Leaf surface Leaf surface Aerial p., ext. Aerial parts Synthesis Aerial parts Synthesis

Asterac. Asterac. Asterac. Asterac. Asterac. Fabac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Asterac. Lamiac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Bieberstein. Lamiac. Rosac. Tamaric. Calycadenia truncata Bracteantha viscosa Helichrysum, 8 spp. Hymenoxis scaposa Varthemia iphionoides Ononis natrix Cunila angustif., C. incana Dracunculus kotschyi Nepeta, 5 spp. Ocimum gratissimum Satureja montana Thymus herba barona Tithonia, 5 spp. Ocimum, 4 spp. Ambrosia trifida Baccharis griesebachii Madia capitata Tithonia calva Simsia cronquistii Viguiera rosei Biebersteinia orphanidis Ocimum, 5 spp. Rosa centifolia cv. muscosa Tamarix dioica Mentha
piperita

Aerial parts Leaf surface Glandul. hairs Aerial parts Leaf surface

Lamiac. Lamiac. Lamiac. Lamiac. Lamiac.

Mentha
piperita Nepeta assurgens Origanum
intercedens Thymus herba baron Ocimum americanum var. pilosum

Flavones and Flavonols continued

190 233 242 200 182 243 244 234 190 18 245 24 185 24

b

236 222 237 238 239 240 167 189 189 231 241 186

185 189 235 186 190

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 631 8.9.2005 10:37am

631

7-OH 6-OH 5-OH

145

(5,6,7,2’,4’-pentaOH) 5,7,2’-triOH 5,6,7,3’,4’-pentaOH 6,7,3’,4’-tetraOH 5,7,3’,4’-tetraOH 5,6,3’,4’-tetraOH

5,6,7,4’-tetraOH 5,6,7,3’-tetraOH 7,3’,4’-triOH 5,3’,4’-triOH 5,7,4’-triOH

148 149 150 151 152

153 154 155 156 157

3’-OMe 4’-OMe 5,6-diOMe 6,7-diOMe 6,3’-diOMe

5-OMe* 6-OMe 7-OMe

6,4’-diOMe*

5,6,7,8,4’-pentaOMe 5,6,7,8,4’-pentaOMe

5,6,8,4’-tetraOMe 5,7,8,4’-tetraOMe* 6,7,8,4’-tetraOMe

5,6,7,8-tetraOMe*

OMe-Substitution

Many records, mostly Asterac. and Lamiac. Many records, mostly Asterac. and Lamiac.

Cirsiliol Jaceosidin

Nodifloretin

Tamarix dioica Tabebuia caraiba Arrabidaea chica f. cuprea Many records, mostly from Asteraceae Leiothrix flavescens Monoclea gottschei Mentha pulegium Salvia blepharophylla Mentha suaveolens

Baccharis griesebachii Biebersteinia orphanidis Godmania aesculifolia Ononis natrix Cunila angustifolia, C. fasciculata Nepeta transcaucasica Ocimum, 7 spp. Satureja montana Rosa centifolia cv. muscosa Tamarix dioica Citrus sinensis Citrus ‘‘Dancy tangerine’’

Nothofagus menziesii Citrus reticulata

Plant Species

Tamaridone* 6-Hydroxy-luteolin Carajuflavone* Nepetin Pedalitin

Tangeretin Tangeretin

Gardenin B

Trivial Name

Aerial parts Leaf Leaf Capitula Thallus Leaf surface Leaf Leaf surface

Eriocaul. Hepaticae Lamiac. Lamiac. Lamiac.

Only synth. Res. exud. Leaf surface Aerial p., ext. Aerial parts Aerial parts Aerial p., ext. Leaf surface Aerial p., ext. Aerial p., ext. Aerial parts Fruit peel oil Leaf

Aerial p., ext. Peel

Plant Organ

Tamaric. Bignon. Bignon.

Asterac. Bieberstein. Bignon. Fabac. Lamiac. Lamiac. Lamiac. Lamiac. Rosac. Tamaric. Rutac. Rutac.

Fagac. Rutac.

Family

15 22 249 250 249

245 247 248

24 242 234 141 240 167 246 190 241 18 245 16 114

158 206

Ref.

632

147

146

4’-OH

OH-Substitution

144

No.

TABLE 12.1 Flavones and Their Methyl Ethers — continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 632 8.9.2005 10:37am

Flavonoids: Chemistry, Biochemistry, and Applications

5,6,4’-triOH

5,6,3’-triOH 5,6,3’-triOH 3’,4’-diOH 5,4’-diOH

5,3’-diOH

159

160

163

161 162

5,7,3’-triOH

158

6,7,4’-triOMe

7,4’-diOMe 7,4’-diOMe 5,6,7-triOMe* 6,7,3’-triOMe

7,3’-diOMe

6,4’-diOMe

Eupatorin

Cirsilineol

Desmethyl-centaureidin

Dorema aucheri

Arnica longifolia Baccharis gaudichaudiana Sideritis spp. Duranta plumieri Arctotis venusta Artemisia argyri Monoclea gottschei Acinos alpinus, Ac. suaveolens Calamintha nepeta Mentha, 3 spp. Micromeria, 3 spp. Ocimum lamiifolium Origanum, 7 spp. Origanum
intercedens Thymbra capitata Thymbra capitata, T. spicata Ocimum lamiifolium Salvia blepharophylla Arrabidaea brachypoda Artemisia oliveriana Centaurea macrocephala Oncosiphon grandiflorum Palafoxia spacelata Tecomella undulata Hyssopus officinalis Lycopus europaeus Ocimum, spp. Teucrium alyssifolium Teucrium marum Thymus herba barona Ziziphoras hispanica Lippia citriodora Umbellif.

Asterac. Asterac. Lamiac. Verben. Asterac. Asterac. Hepaticae Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Bignon. Asterac. Asterac. Asterac. Asterac. Bignon. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Verben.

210 251 172 183 32 186 22 252 252 252 252 190 252 235 253 252 190 250 254 220 255 32 182 256 170 170 190 257 168 186 170 258 259 260

Flavones and Flavonols continued

Flower Aerial parts Aerial parts Stem Aerial p., ext. Aerial parts Thallus Aerial parts Aerial parts Aerial parts Aerial parts Leaf surface Aerial parts Glandul. hairs Aerial parts Aerial parts Leaf surface Leaf Epicut. wax Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Leaf Aerial p., ext. Aerial p., ext. Leaf surface Aerial parts Aerial p., ext. Aerial parts Aerial p., ext. Aerial parts Synthesis Aerial p., ext.

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 633 8.9.2005 10:37am

633

OH-Substitution

5,7-diOH

5,6-diOH

No.

164

165

7,3’,4’-triOMe

Eupatilin

Trivial Name

Plant Organ Veget. parts Flower Aerial parts Aerial p., ext. Aerial parts Aerial parts Aerial parts Leaf surface Aerial parts Aerial p., ext. Aerial parts Aerial parts Aerial p., ext. Aerial parts Aerial parts Aerial p., ext. Aerial parts Gland. trich. Aerial p., ext. Aerial parts Aerial p., ext. Aerial p., ext. Thallus Aerial p., ext. Aerial parts Aerial parts Aerial parts Aerial parts Aerial parts Leaf surfce

Family Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Hepaticae Lamiac. Lamiac. Asterac. Lamiac. Lamiac. Lamiac. Lamiac.

Plant Species Achillea santolina Arnica longifolia Chromolaena arnottiana Eupatorium altissimum Mikania minima Vernonia saligna Mentha
piperita Ocimum, spp. Orthosiphon stamineus Salvia macrosiphon, S. mirzayani Salvia syriaca Sideritis spp. Trichostema lanata Artemisia giraldii Artemisia ludoviciana var. mexicana Artemisia oliveriana Artemisia mongolica Artemisia umbelliformis Artemisia nitida, A.verlotiorum Baccharis gaudichaudiana Inula brittanica Tanacetum polycephalum Monoclea gottschei Salvia sclarea Sideritis spp. Artemisia argyri Calamintha nepeta Mentha
piperita Micromeria, 3 spp. Ocimum lamiifolium

261 210 262 215 263 264 185 190 191 41 171 172 41 265 266 220 265 267 132 251 196 220 22 168 172 186 252 185 252 190

Ref.

634

6,3’,4’-triOMe

OMe-Substitution

TABLE 12.1 Flavones and Their Methyl Ethers — continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 634 8.9.2005 10:37am

Flavonoids: Chemistry, Biochemistry, and Applications

166 167 168 169 170

4’-OH 3’-OH 7-OH 6-OH 5-OH

5,6,7,3’-tetraOMe* 5,6,7,4’-tetraOMe 5,6,3’,4’-tetraOMe 5,7,3’,4’-tetraOMe 6,7,3’,4’-tetraOMe

Ageconyflavon B*

Aerial parts Aerial p., ext. Aerial parts Aerial parts Aerial parts Whole plant

Aerial parts Aerial parts Aerial parts Aerial parts Aerial parts Aerial parts Aerial p., ext. Aerial p., ext. Aerial parts Aerial p., ext. Leaf exudate Aerial p., ext. Aerial parts Aerial parts Leaf surface Aerial parts Leaf surface Aerial parts Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial parts Aerial parts Aerial p., ext. Aerial parts

Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Asterac.

Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac.

Origanum onites Salvia sclarea Salvia syriaca Satureja thymbra Thymbra capitata, T. spicata Ageratum conyzoides

Achillea conferta Achillea santolina Artemisia argyri Artemisia austriaca Artemisia giraldii Artemisia sieversiana Artemisia mongolica, A. verlotiorum Centaurea macrocephala Chromolaena arnottiana Eupatorium altissimum Lagophylla glandulosa Parthenium incanum Cunila angustifolia, C. incana Mentha longifolium Mentha pulegium Micromeria albanica Ocimum americanum var. americanum Orthosiphon stamineus Salvia dominica Salvia macrosiphon, S.mirzayani Salvia syriaca Sideritis spp. Teucrium alyssifolium Teucrium botrys Teucrium pseudochamaepitys

Flavones and Flavonols continued

269 53 186 270 265 271 132 255 262 215 236 182 167 272 249 188 190 191 168 41 168 172 257 168 273

252 168 171 252 252 268

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 635 8.9.2005 10:37am

635

5,7,8,4’-tetraOH 5,7,8,3’-tetraOH

185 186

176 177

3’-OMe 4’-OMe

8-OMe

7,8-diOMe 8,6’-diOMe 7,8,6’-triOMe 8,2’,6’-triOMe 7,8,2’,6’-tetraOMe

7,8-diOMe 7,8,2’5’tetraOMe*

7,8,2’,4’-tetraOMe

7,8-diOMe 7,8,2’-triOMe 7,8,2’,3’-tetraOMe

5,6,7,3’,4’-pentaOMe

OMe-Substitution

Altisin Hypolaetin Onopordin

Rivularin

Rehderianin I

Wightin

(Norwightin)

Sinensetin

Trivial Name

Licania pyrifolia Centaurea chilensis Madia, 4 spp. Onopordum laconicum Viguiera decurrens Glycoside only Glycoside only

Scutellaria baicalensis

Andrographis affinis

Mentha longifolia

Chrysobal. Asterac. Asterac. Asterac. Asterac.

Lamiac.

Acanthac.

Lamiaceae

Aerial parts Leaf þ stem Aerial p., ext. Aerial parts Aerial p., ext.

Root

Whole plant

Aerial parts

Aerial p., ext. Leaf Aerial p., ext. Aerial p., ext. Aerial parts Aerial parts Fruit peel oil Leaf

Lamiac. Rutac. Asterac. Asterac. Asterac. Lamiac. Rutac. Rutac.

Ziziphoras hispanica Citrus ‘‘Dancy tangerine’’ Chromolaena odorata Conoclinium coelestinum Eupatorium coelestinum Orthosiphon stamineus Citrus sinensis Citrus ‘‘Dancy tangerine’’ Glycoside only

Plant Organ

Family

Plant Species

202 198 200 184 244

208

157

272

170 114 193 215 274 191 16 114

Ref.

636

175

172 173 174

178 179 180 181 182 183 184

OH-Substitution

(5,7,8,2’,3’-pentaOH) 5,2’,3’-triOH 5,3’-diOH 5-OH (5,7,8,2’,4’-pentaOH) 5-OH (5,7,8,2’,5’-pentaOH) 5,2’,5’-triOH 5-OH (5,7,8,2’,6’-pentaOH) 5,2’,6’-triOH 5,7,2’-triOH 5,2’-diOH 5,7-diOH 5-OH 5,7,8,3’,4’-pentaOH 5,7,3’,4’-tetraOH

171

No.

TABLE 12.1 Flavones and Their Methyl Ethers — continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 636 8.9.2005 10:37am

Flavonoids: Chemistry, Biochemistry, and Applications

5,7,3’,4’,5’-pentaOH

5,7,4’,5’-tetraOH 5,7,3’,5’-tetraOH

5,7,5’-triOH

202 203

204

(5,7,2’,4’,6’-pentaOH)

5,7,2’,4’,5’-pentaOH 5-OH

(5,7,2’,3’,4’-penta-OH)*

(5,6,2’,4’,5’-penta-OH) 5,4’,5’-triOH (5,6,3’,4’,5’-pentaOH)

(5,6,2’,3’,6’-penta-OH)

200 201

197 198 199

196

195

194

193

(5,7,8,3’,5’penta-OH) 5,7-diOH (5,6,2’,3’,4’-penta-OH)

8,3’-diOH 5,7-diOH 5-OH

188 189 190 191

192

5,7,4’-triOH

187

3’,4’-diOMe

3’-OMe 4’-OMe

5,7,2’,4’,6’-pentaOMe*

7,2’,4’,5’-tetraOMe

5,7,2’,3’,4’-penta-OMe*

5,6,3’,4’.5’-pentaOMe

6,2’-diOMe*

5,6,2’,3’,6’-pe-OMe

5,6,2’,3’,4’-pe-OMe*

8,3’,5’triOMe*

5,7,4’-triOMe* 8,3’,4’-triOMe 7,8,3’,4’-tetraOMe 5,7,8,3’,4’-pentaOMe

8,3’-diOMe

Apometzgerin

Selgin

Tricetin

Isoetin (Hieracin)

Cerosillin B

Isosinensetin

Andrographis viscosula Eucalyptus globulus Kunzea ericoides Leptospermum scoparium Metrosideros excelsa Metrosideros umbellata Artemisia caerulescens Nonea lutea, N. pulla Asarina procumbens Nonea pulla Asarina procumbens

Andrographis lineata Glycoside only Artemisia campestris ssp. glutinosa Calliandra californica

Teucrium quadrifarium

Casimiroa tetrameria

Casimiroa tetrameria

Limnophila rugosa

Conyza spp. Hemizonia lutescens Verbena littoralis Cowania mexicana var. Stansburiana Cowania mexicana var. Stansburiana Citrus sinensis Ficus altissima

Acanthac. Myrtac. Myrtac. Myrtac. Myrtac. Myrtac. Asterac. Boragin. Scrophul. Boragin. Scrophul.

Asterac. Fabac.

Acanthac.

Lamiac.

Scrophul. — Rutac. — Rutac.

Asterac. Asterac. Verben. Rosac. Rosac. Rutac. Morac.

Whole plant Pollen Pollen Pollen Pollen Pollen Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext.

Aerial parts Root

Whole plant

?

Aerial parts — Leaf — Leaf

Resin. exud. Aerial p., ext. Aerial parts Aerial p., ext. Aerial p., ext. Fruit peel oil Aerial parts

Flavones and Flavonols continued

10 20 20 20 20 20 132 36 278 36 278

277 229

14

276

275 — 209 — 209

42 133 203 19 19 16 30

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 637 8.9.2005 10:37am

637

5,7-diOH

5-OH

208

209

218

217

216

212 213 214 215

211

(5,8,3’,4’,5’-pentaOH)* 5,5’-diOH (6,7,3’,4’,5’-pentaOH) 6,7,4’-triOH 6,7-diOH 7-OH — Hexa-O-substituted flavones (5,6,7,8,2’,4’-hexaOH) 5,2’,4’-triOH (5,6,7,8,2’,5’-hexaOH) 5,2’,5’-triOH (5,6,7,8,2’,6’-hexaOH) 5,6,2’,6’-tetraOH

5,5’-diOH 5,4’-diOH

206 207

7,8-diOMe

6,7,8-triOMe

6,7,8-triOMe*

Tamadone*

Tamarix dioica

Artemisia giraldii

3’,5’-diOMe* 3’,4’,5’-triOMe 6,3’,4’,5’-tetraOMe 6,7,3’,4’,5’-pentaOMe

Epimedium brevicornum Agelaea pentagyna Castilleja fissifolia Xerophyta retinervis Lethedon tannaensis Centaurea incana Betonica officinalis (¼Stachys) Lethedon tannaensis Nonea pulla Asarina procumbens Centaurea incana Walsura piscidia Ficus maxima Murraya paniculata Neoraputia paraensis Neoraputia paraensis

Plant Species

Artemisia giraldii

Prosogerin E Prosogerin D Prosogerin C

Corymbosin

Lethedocin* 7-Methyl-tricin*

Tricin

Trivial Name

8,3’,4’-triOMe*

5,7,3’,4’,5’-pentaOMe

7,3’,4’,5’-tetraOMe

3’,4’,5’-triOMe

7,3’,4’-triOMe* 7,3’,5’-triOMe*

3’,5’-diOMe

OMe-Substitution

Tamaric.

Asterac.

Asterac.

Berberid. Connarac. Scrophul. Velloziac. Thymelaeac. Asterac. Lamiac. Thymelaeac. Boragin. Scrophul. Asterac. Meliac. Morac. Rutac. Rutac. Rutac.

Family

Aerial parts

Aerial parts

Aerial parts

Aerial parts Leaf Aerial p., ext. Leaf Leaf Aerial parts Aerial parts Leaf Aerial p., ext. Aerial p., ext. Aerial parts Aerial parts Leaf Leaf Aerial parts Fruit

Plant Organ

245

287

287

279 280 278 105 227 281 282 227 36 108 281 283 77 284 285 286

Ref.

638

210

5,7,4’-triOH

OH-Substitution

205

No.

TABLE 12.1 Flavones and Their Methyl Ethers — continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 638 8.9.2005 10:37am

Flavonoids: Chemistry, Biochemistry, and Applications

5,2’,6’-triOH 5,6,2’-triOH 5,2’-diOH 5,6,7,8,3’,4’-hexaOH* 5,7,8,3’,4’-pentaOH 5,6,7,3’,4’-pentaOH 5,8,3’,4’-tetraOH 5,7,3’,4’-tetraOH 5,6,7,8-tetraOH 5,3’,4’-triOH

5,8,4’triOH 5,7,4’-triOH

5,7,3’-triOH

5,6,4’-triOH

8,3’-diOH 5,4’-diOH

219 220 221 222 223 224 225 226 227 228

229 230

231

232

233 234

5,6,7,4’-tetraOMe* 6,7,8,3’-tetraOMe

7,8,3’-triOMe

6,8,4’-triOMe Thymonin

Acerosin

Sudachitin

Sideritiflavon

6-OMe 8-OMe 6,7-diOMe* 6,8-diOMe 3’,4’-diOMe 6,7,8-triOMe

6,7,3’triOMe 6,8,3’-triOMe

Skullcapflavon II

6,7,8-triOMe 7,8,6’-triOMe 6,7,8,6’-tetraOMe

Helichrysum, 8 spp. Madia, 3 spp. Mentha spicata Thymus herba barona Mentha longifolia Tithonia calva Viguiera rosei Biebersteinia orphanidis Calycadenia, 3 spp. Biebersteinia orphanidis Madia capitata Acinos alpinus, Ac. suaveolens Calamintha nepeta, C. sylvatica Mentha, 3 spp. Mentha
piperita Mentha spicata Micromeria, 3 spp. Origanum, 9 spp. Origanum
intercedens Satureja salzmannii Thymus spp. Vernonia saligna Calycadenia multiglandulosa Madia dissitiflora Cleome droserifolia

Glycoside only Nepeta, 6 spp. Helichrysum, 8 spp.

Leiothrix flavescens

Asterac. Asterac. Lamiac. Lamiac. Lamiac. Asterac. Asterac. Bieberstein. Asterac. Bieberstein. Asterac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Asterac. Asterac. Asterac. Capparid.

Lamiac. Asterac.

Eriocaul.

Whole plant Aerial p., ext. Leaf Aerial parts Aerial parts Aerial p., ext. Aerial p., ext. Leaf surface Leaf exudate Leaf surface Aerial p., ext. Aerial parts Aerial parts Aerial parts Aerial parts Leaf Aerial parts Aerial parts Glandul. hairs Aerial parts Aerial parts Aerial parts Leaf exudate Aerial p., ext. Aerial parts

Leaf surface Whole plant

Capitula

Flavones and Flavonols continued

237 200 288 186 272 182 244 234 236 234 200 252 252 252 185 288 252 252 235 252 252 264 236 200 289

189 237

15

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 639 8.9.2005 10:37am

639

5,6-diOH

4’-OH 3’-OH 5-OH

237

238 239 240

5,6,7,8,3’,4’-hexaOMe

5,6,7,8,3’-pentaOMe 5,6,7,8,4’-pentaOMe 6,7,8,3’,4’-pentaOMe

7,8,3’,4’-tetraOMe

6,7,8,4’-tetraOMe 6,8,3’,4’-tetraOMe

OMe-Substitution

Nobiletin

5-Desmethyl-nobiletin

Gardenin D Hymenoxin

Trivial Name

Cunila incana Mentha spicata Micromeria albanica Ocimum americanum var. americanum Satureja montana Citrus sinensis Citrus ‘‘Dancy tangerine’’ Murraya paniclulata Antirrhinum graniticum Conoclinium greggii Ozothamnus lycopodioides Viguiera rosei Citrus sinensis Citrus ‘‘Dancy tangerine’’

Cunila angustifolia Micromeria albanica Thymus herba barona Calycadenia truncata, C. villosa Tithonia calva Viguiera rosei Biebersteinia orphanidis Ononis natrix Ocimum
citriodorum Citrus ‘‘Dancy tangerine’’ Mentha spica Micromeria albanica Origanum onites Satureja salzmannii Thymus membranaceus

Plant Species

Aerial parts Leaf Aerial parts Leaf surface Aerial p., ext. Fruit peel oil Leaf Leaf Aerial p., ext. Aerial parts Aerial p., ext. Aerial p., ext. Fruit peel oil Leaf

Aerial parts Aerial parts Aerial parts Leaf exudate Aerial p., ext. Aerial p., ext. Leaf surface Aerial parts Leaf surface Leaf Leaf Aerial parts Aerial parts Aerial parts Aerial parts

Lamiac. Lamiac. Lamiac. Asterac. Asterac. Asterac. Bieberstein. Fabac. Lamiac. Rutac. Lamiac. Lamiac. Lamiac. Lamiac. Lamiac.

Lamiac. Lamiac. Lamiac. Lamiac. Lamiac. Rutac. Rutac. Rutac. Scrophul. Asterac. Asterac. Asterac. Rutac. Rutac.

Plant Organ

Family

167 288 188 190 241 16 114 291 108 292 69 244 16 114

167 188 186 236 182 244 234 240 190 114 288 188 290 290 290

Ref.

640

241

5,3’-diOH 5,7-diOH

OH-Substitution

235 236

No.

TABLE 12.1 Flavones and Their Methyl Ethers — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

267

262 263 264 265 266

261

5,7,8,2’,3’,4’-hexaOH 5,4’-diOH 5-OH (5,7,8,2’,3’,6’-hexaOH) 5,7,3’,6’-tetraOH

(5,6,8,3’,4’,5’-hexaOH) 5,6,8,3’-tetraOH

5,7,3’-triOH 5,4’-diOH 5,3’-diOH 6,7-diOH 5,7-diOH 5,6-diOH 4’-OH 6-OH 5-OH

252 253 254 255 256 257 258 259 260

247 248 249 250 251

5,6,7,2’,4’,5’-hexaOH 5,7,2’,4’-tetraOH 5,2’,5’-triOH 5,7-diOH 5-OH (5,6,7,3’,4’,5’-hexaOH) 5,3’,4’,5’-tetraOH 5,7,3’,4’-tetraOH 5,3’,5’-triOH 5,3’,4’-triOH 5,7,4’-triOH

242 243 244 245 246

8,2’-diOMe

7,8,2’,3’-tetraOMe 7,8,2’,3’,4’-pentaOMe

4’,5’-diOMe (5,6,8,3’,4’,5’-hexaOMe)

5,6,7,3’,4’,5’-hexaOMe

6,4’,5’-triOMe 6,7,3’,5’-tetraOMe 6,7,4’,5’-tetraOMe 5,3’,4’,5’-tetraOMe 6,3’,4’,5’-tetraOMe 7,3’,4’,5’-tetraOMe 5,6,7,3’,5’-pentaOMe* 5,7,3’,4’,5’-pentaOMe* 6,7,3’,4’,5’-pentaOMe

6,7-diOMe 6,5’-diOMe 6,7,4’-triOMe* 6,7,5’-triOMe 6,3’,5’-triOMe

6,5’-diOMe 6,7,5’-triOMe 6,2’,4’,5’-tetraOMe 6,7,2’,4’,5’-pentaOMe

Ganhuangenin

Serpyllin

Zhizinin Ageratum conyzoides Glycoside only Glycoside only Andrographis lineata

Chromolaena arnottiana Murraya paniculata Murraya paniculata Neoraputia paraensis

Umuhengerin

Acanthac.

Asterac.

Asterac. Rutac. Rutac. Rutac.

Asterac.

Whole plant

Aerial parts

14

c

26 215 292 186 285 291 294 259 259 268 259 262 291 291 285 28

291

293

continued

Aerial parts Aerial p., ext. Aerial parts Aerial parts Aerial parts Leaf Synthesis Synthesis Synthesis Whole plant Synthesis Aerial parts Leaf Leaf Aerial parts Synthesis

Asterac. Asterac. Asterac. Asterac. Rutac. Rutac.

Artemisia assoana Conoclinium coelestinum Conoclinium greggii Artemisia argyri Neoraputia paraensis Murraya paniculata

Ageratum conyzoides

Leaf

Rutac.

Synthesis

Murraya paniculata

Ageconyflavon C*

Arteanoflavon

Arcapillin Tabularin Agehoustin G

Glycoside only

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Flavones and Flavonols 641

285 286 287 288

284

278 279 280 281 282 283

277

(5,7,2’,3’,4’,5’-hexaOH) 5,7,4’-triOH 5,7,3’-triOH 5,4’-diOH 5,7-diOH 5,3’-diOH 5-OH Hepta-O-substituted flavones (5,6,7,8,2’,3’,6’-heptaOH) 5,7,3’,6’-tetraOH (5,6,7,8,2’,4’,5’-heptaOH) 5,7,2’,4’-tetraOH 5,2’,5’-triOH 5,2’,4’-triOH 2’,4’-diOH

(5,6,2’,3’,5’,6’-hexOH)

(5,6,2’,3’,4’,6’-hexaOH)

(5,7,8,2’,4’,5’-hexaOH) 5,7,2’,4’-tetraOH (5,7,8,2’,5’,6’-hexaOH) 5,7,2’,5’-tetraOH (5,7,8,3’,4’,5’-hexaOH) 5,7,3’,4’,5’-pentaOH 5,7,3’,5’-tetraOH 5,7,5’-triOH 5,3’-diOH 5,7-diOH

OH-Substitution

6,8,5’-triOMe 6,7,8,4’-tetraOMe 6,7,8,5’-tetraOMe 5,6,7,8,5’-pentaOMe

Ononis natrix

Fabac.

Aerial p., ext.

Root Scutellaria planipes

6,8,2’-triOMe*

Scrophul.

Leaf

Asterac. Psiadia punctulata

Leaf

Leaf

Aerial p., ext.

Plant Organ

Leaf Aerial parts Leaf Leaf

Rutac.

Rutac.

Asterac.

Family

Asterac. Asterac. Asterac. Asterac.

Casimiroa tetrameria

Casimiroa tetrameria

Bracteantha viscosa

Plant Species

Psiadia punctulata Psiadia arabica Psiadia punctulata Psiadia punctulata

Agecorynin-D

Trivial Name

2’,3’,5’-triOMe* 2’,4’,5’-triOMe* 7,2’,3’,5’-tetraOMe* 2’,3’,4’,5’-tetraOMe* 7,2’,4’,5’-tetraOMe 7,2’,3’,4’,5’-pentaOMe

5,6,2’,3’,5’,6’-hexaOMe

5,6,2’,3’,4’,6’-hexaOMe

8-OMe 8,4’-diOMe 8,3’,4’-triOMe 7,8,4’,5’-tetraOMe 8,3’,4’,5’-tetraOMe 5,7,8,3’,4’,5’-hexaOMe

8,6’-diOMe

8,5’-diOMe

OMe-Substitution

278

55

295

295 9 295 295

209

209

222

Ref.

642

276

270 271 272 273 274 275

269

268

No.

TABLE 12.1 Flavones and Their Methyl Ethers — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

*For explanation, please see text. a Revised to 6,8-diMe, see text. b Revised to 6,8,4’-triOMe, see text. c Revised to 5,6,7,3’,4’,5’-Me, see text.

307 308 309

Octa-O-substituted flavones (5,6,7,8,2’,3’,4’,5’-octaOH) 5,3’-diOH 3’-OH 6,7,8,2’,4’,5’-hexaOMe 5,6,7,8,2’,4’,5’-heptaOMe 5,6,7,8,2’,3’,4’,5’-octaOMe

6,7,2’,4’,5’-pentaOMe 5,6,7,2’,4’,5’-hexaOMe 6,7,2’,3’,4’,5’-hexaOMe 5,6,7,2’,3’,4’,5’-heptaOMe

(5,6,7,2’,3’,4’,5’-heptaOH) 5,3’-diOH 3’-OH 5-OH

5,6,7,8,3’,5’-hexaOMe 5,6,7,8,4’,5’-hexaOMe 5,6,7,3’,4’,5’-hexaOMe 6,7,8,3’,4’,5’-hexaOMe

302 303 304 305 306

4’-OH 3’-OH 8-OH 5-OH

297 298 299 300

6,8,3’,4’-tetraOMe 8,3’,4’,5’-tetraOMe 6,7,8,3’,5’-pentaOMe* 6,7,8,4’,5’-pentaOMe

5,6,7,8,3’,4’,5’-heptaOMe

5,7,5’-triOH 5,6,7-triOH 5,4’-diOH 5,3’-diOH

293 294 295 296

6,7,8,4’-tetraOMe

6,7,8,4’,5’-pentaOMe 6,7,8,2’,4’,5’-hexaOMe 5,6,7,8,2’,4’,5’-heptaOMe

301

(5,6,7,8,3’,4’,5’-OH) 5,3’,5’-triOH

5,2’-diOH 5-OH

292

289 290 291

Agehoustin D Agehoustin C Agehoustin A

Psiadiarabicin Agecorynin G Agecorynin F Agehoustin B

5’-Methoxy-nobiletin

Gardenin A

Gardenin C

Scaposin ‘‘Trimethyl-wogonin’’

Gardenin E

Agehoustin F Agehoustin E Agecorynin-C

Ageratum corymbosum Ageratum corymbosum

Murraya paniculata Tamarix dioica Conoclinium greggii Ozothamnus lycopodioides

Cleome droserifolia Tamarix dioica Murraya paniculata

Murraya paniculata Tamarix dioica

Asterac. Asterac.

Rutac. Tamaric. Asterac. Asterac.

Capparid. Tamaric. Rutac.

Rutac. Tamaric.

Aerial parts Aerial parts

Synthesis Leaf Aerial parts Aerial parts Aerial p., ext.

Aerial parts Aerial parts Leaf

Leaf Aerial parts

296 296

24 291 245 292 69

289 245 291

291 245

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644

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growing. Since the last complilation,6 some eight compounds (scut-6-Me, scut-6,7-diMe, scut6,4’-diMe, scut-6,7,4’-triMe; lut-3’-Me, 6-OH-lut-6-Me, 6-OH-lut-6,7-diMe, and 6-OH-lut6,3’-diMe) fall in the category of ‘‘widespread’’ in addition to apigenin, genkwanin (apigenin7-Me), acacetin (ap-4’-Me), and luteolin. Thus, no specific sources have been listed for these compounds. The number of newly described structures increased by about 50 entries during the reporting period. These include a series of 2’- and 5’-substituted flavones, which have been reported from several Asteraceae such as from leaves of Psiadia punctulata.9 The genus Andrographis (Acanthaceae) yielded several of these more complex substituted flavones, isolated from whole plants.10–14 In contrast to other reports on Andrographis,7 the meaning of ‘‘whole plant’’ could not be clarified, with root tissue probably included in the analysis as well. Since all Andrographis species are annuals, inclusion of root tissue probably has little influence on the flavonoid composition. Capitula of Leiothrix flavescens (Eriocaulaceae) yielded a new flavone with a rare 5,6,7,8,3’,4’-hexahydroxy substitution (compound 264 in Table 12.1).15 This is remarkable insofar as many of the listed flavones are (poly)methoxy derivatives and other hexahydroxyflavones are known as glycosides only. Most of the source reports concern equally the families of the Asteraceae and Lamiaceae, followed by Rutaceae. However, it must be taken into consideration that the long list may rather be due to the number of species and not to the number of genera. The large number of results in both families may also be due to the research focus on these groups by the authors. In these families, flavone accumulation is mostly reported in leaves, aerial parts and in exudates. Species of the genus Scutellaria (Lamiaceae) form an exception, with analyses concentrating on roots since those are used pharmaceutically. According to the distribution of flavones in aerial parts and leaves in other Lamiaceae, similar results should also be expected from Scutellaria. Genera of the Rutaceae accumulate flavones primarily in aerial parts and leaves. Many of these compounds, however, were found in fruit peels of Citrus, particularly those with higher methylation patterns (e.g., compound 194, Table 12.116). None of the reports, however, indicate possible external accumulation on vegetative tissue of Rutaceae. Reports on other families are much lower in number. In Fabaceae and Mimosaceae, flavones and their methyl ethers are described from all parts of the plants, including roots of, for example, Glycyrrhiza eurycarpa, which primarily accumulates a series of prenylated derivatives.17 None of the reports cited here indicate external occurrence. In Rosaceae, only few reports exist on the external accumulation of higher methylated flavone aglycones.18,19 The occurrence of tricetin was proved for the pollen of several genera from the Myrtaceae,20 with only one report concerning accumulation in leaves.21 Very few reports exist on families such as Solanaceae and Moraceae. This is quite in contrast to the large number of reports on prenylated flavones accumulated particularly in the Moraceae. Of the nonflowering plants, only few reports relate to the fronds of ferns. Within the mosses, apparently only the thalli of Hepaticae yielded flavones and their methyl ethers.22 Some flavone structures have been revised during the reporting period. The structure of 5,8,2’-triOH-6,7-diOMe flavone (compound 131 in Table 12.1) had been ascribed to a product isolated from Scutellaria baicalensis.23 After synthesis, it needs to be revised to 5,7,2’-triOH-6,8-diOMe flavone (compound 132, Table 12.1).24 Pedunculin, earlier isolated from Tithonia species and claimed as 5,8-diOH-6,7,4’-triOMe-flavone (compound 141, Table 12.1),25 needs to be revised, after synthesis, to 5,7-diOH-6,8,4’-triOMe flavone ¼ nevadensin (compound 142 in Table 12.1).24 In the previous review, the compound 5,6,7,4’-tetraOH-3’,5’diOMe had erroneously been cited as a component of Artemisia assoana.6 Data have now been included for the correct structure, 5,7,4’-triOH-6,3’,5’-triOMe flavone (compound 251 in Table 12.1).26 A further flavone reported from Ageratum conyzoides (compound 263 in

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Flavones and Flavonols

645

Table 12.1) as 5,6,8,3’,4’,5’-hexamethoxyflavone,27 was revised to 5,6,7,3’,4’,5’-hexaOMe flavone (compound 261 in Table 12.1) after synthesis.28

12.4 FLAVONOLS Some 393 reports on flavonols and their distribution are listed in Table 12.2. During the reporting period, the number of new sources also increased, leading to reduction of listings in the very widespread compounds kaempferol, kaempferol-3-methyl ether, quercetin, and quercetin-3-methyl ether. About 54 compounds are reported as new structures, a number equaling that of the flavones. These include a series of polymethoxylated derivatives from species of the Asteraceae, where they are reported to occur in aerial parts as well as in leaf exudates. Species from the Rutaceae accumulate highly methoxylated flavonols in leaves as well as in fruit peels, whereas species of Fabaceae were found to accumulate such compounds mainly in the heartwood. A hexamethoxylated flavonol (compound 369 in Table 12.2) was isolated from Distemonanthus benthamianus (Fabaceae),29 a species also known for accumulation of complex cycloflavonols (Table 12.4). Of the Moraceae, only one report concerns the genus Ficus, which produces another hexamethoxylated flavonol (compound 279 in Table 12.2) in the aerial parts.30 The same applies to accumulation of flavonol aglycones in roots of Duroia hirsuta (Rubiaceae).31 The number of 2’- and 5’-substituted derivatives appears to be lower than that of the corresponding flavones. Most of the new source reports concern species from the Asteraceae, with many of the flavonols being isolated from aerial parts, where they are accumulated externally. They range from simple to more complex structures. There appears to be a tendency towards 6-methoxylation rather than towards 8-methoxylation, in addition to possible OMe-substitution of other positions of the flavonol molecule. Flavonols with 6,8-di-O-methylation and additional OMe-groups are also found in several genera such as Senecio,32 Psiadia,33 or Inula,34 to cite but a few examples. Aerial parts, fruits, flowers, and bark tissue of a series of Rutaceae species yielded a number of hexamethoxylated flavonols. Once more, the complexity of metabolic pathways in this family is demonstrated by the formation of such compounds. The number of entries for this family is the second largest following the Asteraceae, but it must be taken into account that only a few genera of this large family are concerned. The third largest group concerns Heliotropium species of the family Boraginaceae, where particularly leaf exudates yielded flavonols.35,36 For species of Alkanna, flavonols were reported for aerial parts without indicating possible external occurrence.37 Interestingly, almost no flavones were reported from Heliotropium (see Table 12.1), and species of the genus Nonea were so far found to accumulate flavones only in their exudates.36 Further distribution studies will have to confirm the possible chemosystematic value of these accumulation trends. A number of new listings concern the families of Scrophulariaceae and Solanaceae. In both cases the number of reports concerning external accumulation is also increased. Thus, further research will probably reveal that this phenomenon is more widespread in these families as is obvious from the present data. In Fabaceae, most reports concern accumulation in heartwood, with a few exceptions such as leaves of Millettia racemosa.38 However, no indication to possible external accumulation is made. Similar to flavone accumulation data, pollen of Myrtaceae were also found to accumulate flavonols.20 Very few reports exist on Gymnosperms such as Cryptomeria (Taxodiaceae)39 or Ephedra,40 without indication of external accumulation. So far, no new reports on flavones are known for these taxa. In contrast to the numerous reports on flavones in Lamiaceae, only very few genera were found to accumulate flavonols in their exudates. The accumulation of 5,6-di-O-methylated derivatives in species of Salvia41 may be of chemosystematic significance, in relation to other

OMe-Substitution

5,7-diOH

5

Galangin

Trivial Name

Baccharis viminea Cassinia quinquefaria Flourensia cernua Gnaphalium microcephalum Helichrysum, 8 spec. Helichrysum aureum Helichrysum aureonitens Heterothalamus psiadioides Odixia, 6 spp. Heliotropium filifolium Millettia racemosa Nothofagus alessandri Nothofagus antarctica Nothofagus, 6 spp. Ribes viscosissimum Woodsia scopulina Bees wax Propolis from Arizona European Propolis Propolis from Chile Propolis from Egypt Helichrysum aureum Helichrysum picardii Lychnophora markgravii

Pongamia pinnata

Plant Species

Asterac. Asterac. Asterac.

Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Boragin. Fabac. Fagac. Fagac. Fagac. Grossular. Pteridac.

Fabac.

Family

Aerial p., ext. Aerial p. (ext.) Aerial parts

Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial parts Leaf Aerial p., ext. Leaf exudate Leaf Leaf Aerial p., ext. Aerial p., ext. Leaf exudate Fronds, ext.?

Root bark

Plant Organ

129 222 182 298 237 32 299 300 197 35 38 301 302 158 303 304 138 305 137 306 136 32 307 140

297

Ref.

646

3-OMe

Tri-O-substituted flavonols 3,5,7-triOH

Di-O-substituted flavonols 3,7-diOH 3,7-diOMe* (3,4’-diOH) 3-OH 4’-OMe

OH-Substitution

4

3

1 2

No.

TABLE 12.2 Flavonols and Their Methyl Ethers

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Flavonoids: Chemistry, Biochemistry, and Applications

3,5-diOH

5-OH

3-OH — (3,7,8-triOH) 3,7-diOH (3,5,2’-triOH) 3,7,4’-triOH

7

8

9 10

12

11

3,7-diOH

6

8-OMe

5,7-diOMe 3,5,7-triOMe

3,7-diOMe

7-OMe

5-OMe Izalpinin

Ozothamnus, 5 spp. Pseudognaphalium cheiranthifolium Heliotropium filifolium Heliotropium huascuense Heliotropium megalanthum Heliotropium pycnophyllum Heliotropium sinuatum Heliotropium stenophyllum Nothofagus, 5 spp. Woodsia scopulina Propolis from Arizona Propolis from Chile Baccharis viminea Helichrysum aureum Ozothamnus ledifolius Heliotropium pycnophyllum Capparis tweediana Nothofagus antarctica Nothofagus, 6 spp. Propolis from Arizona Pseudognaphalium cheiranthifolium Heliotropium huascuense Heliotropium megalanthum Heliotropium pycnophyllum Escallonia leucantha Notholaena ekmannii Asterac. Boragin. Boragin. Boragin. Saxifrag. Pteridac.

Asterac. Asterac. Asterac. Boragin. Capparid. Fagac. Fagac.

Asterac. Asterac. Boragin. Boragin. Boragin. Boragin. Boragin. Boragin. Fagac. Pteridac.

p., ext. p., ext.

p., ext. p., ext. p., ext. p., ext.

Res. exudate Leaf exudate Leaf exudate Aerial p., ext. Resin. exud. Frond exud.

Aerial Aerial Aerial Aerial Leaf Aerial Aerial

Aerial p., ext. Res. exudate Leaf exudate Leaf exudate Leaf exudate Aerial p., ext. Leaf exudate Aerial p., ext. Aerial p., ext. Fronds, ext.?

continued

197 308 35 309 213 36 310 36 158 304 305 306 129 32 197 36 311 302 158 305 308 309 213 36 42 312

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Flavones and Flavonols 647

3,5,7-triOH

(3,5,6-triOH 5,7-diOH

5,6-diOH 3,7-diOH 3,7-diOH 3,6-diOH 3,5-diOH 5-OH

14

15 16

17 18

25 26

3,5,7,8-tetraOH 5,7,8-triOH 5,7,8-triOH 3,5,8-triOH 3,5,7-triOH

Tetra-O-substituted flavonols 3,5,6,7-tetraOH

13

3-OMe 3-OMe 7-OMe 8-OMe

3,7-diOMe 5,6-diOMe 5,6-diOMe 5,7-diOMe 6,7-diOMe 3,6,7-triOMe 3,5,6,7-tetraOMe

7-OMe) 3,6-diOMe

6-OMe

OMe-Substitution

8-Hydroxy-galangin

Alnustin

Alnusin

6-Hydroxy-galangin

Trivial Name

Nothofagus, 3 spp. Ozothamnus, 3 spp. Ozothamnus ledifolius Helichrysum aureum Ozothamnus expansifolius Nothofagus antarctica Nothofagus alessandri Nothofagus, 7 spp.

Gomphrena boliviana, G. martiana Anaphalis margaritacea Gnaphalium microcephalum Helichrysum, 8 spp. Pseudognaphalium cheiranthifolium Gnaphalium affine Salvia columbariae Trichostema lanatum

Adenostoma sparsifolium Cassinia quincefaria Platanus acerifolia Anaphalis margaritacea Cassinia quinquefaria Gnaphalium microcephalum Adenostoma sparsifolium

Plant Species

Fagac. Asterac. Asterac. Asterac. Asterac. Fagac. Fagac. Fagac.

Amaranth. Asterac. Asterac. Asterac. Asterac. Asterac. Lamiac. Lamiac.

Rosac. Asterac. Platanac. Asterac. Asterac. Asterac. Rosac.

Family

Synthesis Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Leaf Aerial p., ext.

Aerial p., ext. Aerial p., ext. Bud Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Synth. only Whole plant Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial parts Aerial parts Aerial p., ext. Aerial p., ext. Synthesis

Plant Organ

47 158 197 197 32 197 302 301 158

298 222 298 19 313 150 298 298 237 308 314 41 41 47

a

19 222

Ref.

648

19 20 21 22 23 24

OH-Substitution

No.

TABLE 12.2 Flavonols and Their Methyl Ethers — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

3,5-diOH

7-OH 5-OH 5-OH 3-OH

29

30 31 32 33 34 35 36 37 38 39 40 41

3,5,7,2’-tetraOH 3,5,2’-triOH 3,5,7-triOH 3,5,7,4’-tetraOH 5,7,4’-triOH 3,7,4’-triOH 3,5,4’-triOH

5,8-diOH 5,7-diOH

27 28

3-OMe 5-OMe 7-OMe

7-OMe 2’-OMe

3,5,8-triOMe 3,7,8-triOMe 3,7,8-triOMe 5,7,8-triOMe 3,5,7,8-tetraOMe

7,8-diOMe

3,7-diOMe 3,8-diOMe

Rhamnocitrin

Datiscetin Datin Ptaeroxylol Kaempferol Isokaempferide

Methylgnaphalin Methylgnaphalin

Isognaphalin Gnaphalin

Many records Many records Propolis from Arizona Ambrosia trifida Artemisia campestris Baccharis pilularis Madia elegans Madia sativa Ozothamnus expansifolius, O. scutellifolius Stevia subpubescens Heliotropium stenophyllum

Ozothamnus expansifolius, O. hookeri Nothofagus solandri, N. truncata

Woodsia scopulina Nothofagus solandri Anaphalis margaritacea Gnaphalium luteo-album Gnaphalium microcephalum Gymnosperma glutinosum Helichrysum aureum Helichrysum bracteiferum Helichrysum picardii Ozothamnus ericifolius., O. purpurescens Nothofagus alessandri Nothofagus, 5 spp. Ozothamnus ledifolius Nothofagus solandri Woodsia scopulina

Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Boragin.

Asterac. Fagac.

Pteridac. Fagac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Fagac. Fagac. Asterac. Fagac. Pteridac.

Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Leaf exudate Aerial p., ext. Aerial p., ext. Aerial p., ext.

Aerial p., ext. Aerial p., ext.

305 233 132 133 201 236 197 182 36

197 158

304 158 298 315 298 196 32 237 307 197 301 158 197 158 304

Flavones and Flavonols continued

Fronds, ext.? Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p. (ext.) Aerial p., ext. Leaf Aerial p., ext. Aerial p., ext. Aerial p., ext. Fronds, ext.?

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 649 8.9.2005 10:37am

649

OH-Substitution

3,5,7-triOH

7,4’-diOH 5,4’-diOH

No.

42

43 44 Kumatakenin

Kaempferide

Trivial Name Boragin. Crassul. Fagac. Laurac. Nyctagin. Pteridac. Scrophul. Scrophul. Solanac. Viscac. Asterac. Asterac. Asterac. Asterac. Cunoniac. Fagac. Hydrophyll. Nyctagin. Pteridac. Scrophul.

Heliotropium chenopodiaceum var. ericoideum Aeonium leucoblepharum, Ae.nobile Nothofagus cunninghamii Aniba sp. Mirabilis viscosa Notholaena nivea Calceolaria irazuensis Mimulus cardinalis Solanum paludosum Viscum cruciatum Baccharis pilularis Baccharis viminea Chrysothamnus nauseosus Ozothamnus scutellifolius Eucryphia jinksii Nothofagus menziesii, N. nervosa Eriodictyon sessilifolium Mirabilis viscosa Currania robertiana Calceolaria irazuensis Brazilian propolis Propolis from Chile Chrysothamnus nauseosus Achillea ageratum Alkanna orientalis Heliotropium chenopodiaceum var. ericoideum Heliotropium pycnophyllum Cleome spinosa Aeonium spp. Eucryphia lucida Asterac. Asterac. Boragin. Boragin. Boragin. Capparid. Crassul. Cunoniac.

Family

Plant Species

Aerial p., ext. Aerial parts Aerial parts Resin. exud. Aerial p., ext. Aerial p., ext. Aerial p., ext. Leaf, bud, ext.

Leaf exudate Aerial p., ext. Aerial p., ext. Wood, bark Aerial p., ext. Frond exud. Aerial p., ext. Aerial p., ext. Aerial parts Cuticular wax Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Leaf, bud, ext. Aerial p., Ext. Leaf resin Aerial p., ext. Frond exud. Aerial p., ext.

Plant Organ

35 216 158 316 43 45 108 108 317 318 133 129 133 197 165 158 135 43 173 108 319 306 199 320 37 35 36 321 216 165

Ref.

650

3,5-diOMe 3,7-diOMe

4’-OMe

OMe-Substitution

TABLE 12.2 Flavonols and Their Methyl Ethers — continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 650 8.9.2005 10:37am

Flavonoids: Chemistry, Biochemistry, and Applications

5,7-diOH

3,7-diOH 3,5-diOH

45

46 47

5,4’-diOMe* 7,4’-diOMe

3,4’-diOMe

Ermanin Aeonium spp. Eucryphia lucida Nothofagus menziesii, N. nervosa Fouquieria splendens Mirabilis viscosa Currania robertiana Notholaena nivea Barosma crenulata Petunia surfina Viscum album Brazilian Propolis Amomum koenigii Flourensia cernua Haplopappus hirtellus Madia elegans Ozothamnus scutellifolius Serratula strangulata Stevia subpubescens Heliotropium stenophyllum Cleome spinosa Aeonium sedifolium

Nothofagus cunninghamii Pelargonium fulgidum Salvia cyanescens Mirabilis viscosa Bosistoa brassii Evodia merrillii Calceolaria arachnoidea Chamaesaracha sordida Solanum paludosum Viscum album Viscum cruciatum Amomum koenigii

Zingib. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Boragin. Capparid. Crassul.

Fagac. Geraniac. Lamiac. Nyctagin. Rutac. Rutac. Scrophul. Solanac. Solanac. Viscac. Viscac. Zingib. Boragin. Crassul. Cunoniac. Fagac. Fouquierac. Nyctagin. Pteridac. Pteridac. Rutac. Solanac. Viscac. Fruit Aerial p., ext. Aerial parts Aerial p., ext. Aerial p., ext. Whole plant Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext.

Aerial p., ext. Leaf exudate Aerial parts Aerial p., ext. Leaf Fruit Aerial p., ext. Aerial p., ext. Aerial parts Aerial p., ext. Cut. wax Fruit Aerial parts Aerial p., ext. Leaf, bud, ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Frond exud. Frond exud. Aerial p., ext. Aerial p., ext. Cut. wax

Flavones and Flavonols continued

158 142 192 43 322 323 108 214 317 44 318 324 37 216 165 158 325 43 173 45 326 214 318 319 324 182 327 201 197 328 182 36 321 216

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 651 8.9.2005 10:37am

651

3,5,8,4’-tetraOH (3,6,7,4’-tetraOH)

4’-OH 5-OH

OH-Substitution

3,5,7,4’-tetraOMe*

3,5,7-triOMe 3,7,4’-triOMe

OMe-Substitution

Pratoletin

Trivial Name

Artemisia rupestris Baccharis pilularis Grindelia nana Grindelia tenella Haplopappus hirtellus Haplopappus sonorensis Ozothamnus scutellifolius Senecio viscosa Stevia subpubescens Xanthocephalum gymnosp. Heliotropium pycnophyllum Cleome spinosa Aeonium goochia, Ae. Lindleyi Eucryphia lucida, E. milliganii Nothofagus cunninghamii Dorystoechas hastata Aniba spp. Mirabilis viscosa Currania robertiana Calceolaria chelidonioides Cryptomeria japonica Amomum koenigii Amomum koenigii

Salvia chinopeplica Aniba spp. Mirabilis viscosa Notholaena nivea Calceolaria mexicana

Plant Species

Aerial parts Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial parts Aerial parts Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Leaf, bud, ext. Aerial p., ext. Aerial parts Wood and bark Aerial p., ext. Frond exud. Aerial p., ext. Leaf Fruit Fruit

Leaf Wood, bark Aerial p., ext. Frond exud. Aerial p., ext.

Lamiac. Laurac. Nyctagin. Pteridac. Scrophul. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Boragin. Capparid. Crassul. Cunoniac. Fagac. Lamiac. Laurac. Nyctagin. Pteridac. Scrophul. Taxodiac. Zingib. Zingib.

Plant Organ

Family

132 129 133 182 327 329 197 32 182 182 36 321 216 165 158 168 316 43 173 108 39 324 324

225 316 43 45 108

Ref.

652

50 51

48 49

No.

TABLE 12.2 Flavonols and Their Methyl Ethers — continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 652 8.9.2005 10:37am

Flavonoids: Chemistry, Biochemistry, and Applications

5,8-diOH

5,7-diOH

3,5-diOH 5-OH

3,5,6,7,4’-pentaOH*

5,6,7,4’-tetraOH 3,6,7,4’-tetraOH

61 62

63

64

65 66

67 68

69 70

7,3’,4’-triOH 3,7,4’-triOH 3-OH

57 58 59 60

Penta-O-substituted flavonols (3,5,6,7,8-pentaOH) 5,7,8-triOH 3,5,7-triOH

6,7,4’-triOH 7,4’-diOH 3,7,8,4’-tetraOH 7,4’-diOH 3,7,3’,4’-tetraOH

52 53 54 55 56

3-OMe 5-OMe

3,5,6,7,8-pentaOMe

6,7,8-triOMe 3,6,7,8-tetraOMe

3,6,8-triOMe

3,6,7-triOMe

3,6-diOMe* 6,8-diOMe

3-OMe 3’-OMe 7,3’,4’-triOMe 3,7,3’,4’-tetraOMe

Vogeletin

6-Hydroxy-kaempferol

Araneol

Geraldol

Glycoside only

Helminthia echioides

Gnaphalium chilense, G. microcephalum Gnaphalium affine Pseudognaphalium cheiranthifolium, P. vira vira

Anaphalis margaritacea Gymnosperma glutinosum Gymnosperma glutinosum Helichrysum, 8 spp.

Pseudognaphalium cheiranthifolium

Cassinia arcuata Anaphalis margaritacea Helichrysum, 8 spp.

Parkia clappertoniana Acacia montana Dalbergia odorifera Glycyrrhiza spec. Millettia racemosa

3,8-triOMe* Fisetin

Graziela mollissima

3-OMe 3,6-diOMe

Asterac.

Asterac. Asterac. Asterac.

Asterac. Asterac. Asterac. Asterac.

Asterac.

Asterac. Asterac. Asterac.

Fabac. Mimosac. Fabac. Fabac. Fabac.

Asterac.

Aerial parts Synthesis Synthesis

338 47 28

278 298 237 335 308 336 298 196 133 237 335 298 314 337

331 332 333 334 38

330

continued

Aerial p., ext. Aerial p., ext. Aerial p., ext. Synthesis Aerial parts Synthesis Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Synthesis Aerial p., ext. Aerial parts Leaf trichome

Leaf Heartwood Heartwood Liquorice Leaf

Aerial parts

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 653 8.9.2005 10:37am

Flavones and Flavonols 653

OH-Substitution

3,5,7,4’-tetraOH

3,5,6,4’-tetraOH 3,5,6,7-tetraOH 5,7,4’-triOH

No.

71

72 73 74

Trivial Name

Glycoside only Achillea micrantha Ageratina espinosa Ambrosia chamissonis Brickellia eupatorioides Calycadenia multiglandulosa, C. villosa Centaurea, 4 spp. Eupatorium altissimum Flourensia cernua Grindelia robusta Grindelia squarrosa Heteranthemis viscidihirta Heterotheca villosa Oncosiphon grandiflorum Perityle lemmonii Psiadia dentata Stevia berlandieri

Ambrosia artemisifolia Ageratina espinosa Carthamus tinctorius Centaurea incana Chrysactinia mexicana Eupatorium altissimum, E. serotinum Heteranthemis viscidihirta Xanthium strumarium Aeonium, 3 spp. Adenostoma sparsifolium Brazilian propolis

Plant Species

Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac.

Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Crassul. Rosac.

Family

Synthesis Synthesis Synthesis Aerial parts Aerial p., ext. Aerial p., ext. Aerial p., ext. Leaf exudate Aerial p., ext. Aerial p., ext. Aerial p., ext. Leaf exudate Aerial p., ext. Leaf exudate Aerial p., ext. Aerial p., ext. Aerial p., ext. Leaf Aerial p., ext.

Aerial p., ext. Aerial p., ext. Petal (nat.?) Aerial parts Aerial p., ext. Aerial p., ext. Leaf exudate Aerial p., ext. Aerial p., ext. Aerial p., ext.

Plant Organ

182 133 339 281 182 215 340 32 216 19 341 342 313 47 343 133 233 215 236 182 215 182 344 182 340 182 32 133 345 182

Ref.

654

7-OMe 4’-OMe 3,6-diOMe

6-OMe

OMe-Substitution

TABLE 12.2 Flavonols and Their Methyl Ethers — continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 654 8.9.2005 10:37am

Flavonoids: Chemistry, Biochemistry, and Applications

5,6,4’-triOH

5,6,7-triOH

3,7,4’-triOH

3,5,4’-triOH

3,5,7-triOH

3,5,6-triOH 3,5,6-triOH 5,4’-diOH

75

76

77

78

79

80 81 82

7,4’-diOMe* 7,4’-diOMe 3,6,7-triOMe

6,4’-diOMe

6,7-diOMe

5,6-diOMe

3,4’-diOMea

3,7-diOMe

Penduletin

Betuletol

Eupalitin

Achillea ageratum Achillea nana Ageratina espinosa Baccharis pedunculata Baccharis trinervis Brickellia eupatorioides Flourensia cernua Grindelia tarapacana

Zanthoxylum bungeanum

Salvia columbariae Trichostema lanatum Artemisia austriaca Baccharis pilularis Brickellia longifolia Heterotheca villosa Aeonium glutinosum Gnaphalium microcephalum Mirabilis viscosa Rosa centifolia cv. muscosa Brazilian Propolis

Tanacetum parthenium Alkanna orientalis Aeonium, 5 spp. Salvia cyanescens Gardenia, 5 spp. Barbacenia rubro-virens Parthenium incanum Pulicaria dysenterica Pulicaria dysenterica Tanacetum parthenium Pulicaria dysenterica

Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac.

Rutac.

Lamiac. Lamiac. Asterac. Asterac. Asterac. Asterac. Crassul. Asterac. Nyctagin. Rosac.

Asterac. Boragin. Crassul. Lamiac. Rubiac. Velloziac. Asterac. Asterac. Asterac. Asterac. Asterac.

Synthesis Pericarp Synthesis Aerial parts Aerial p., ext. Aerial p., ext. Aerial parts Aerial parts Aerial p., ext. Aerial p., ext. Aerial p., ext.

Leaf, flower Aerial parts Aerial p., ext. Aerial parts Bud exudate Leaf surface Aerial p., ext. Aerial p., ext. External Aerial parts External Synthesis Aerial p., ext. Aerial p., ext. Aerial parts Aerial p., ext. Aerial parts Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext.

Flavones and Flavonols continued

49 37 216 192 346 105 182 182 347 48 347 28 41 41 270 129 348 182 216 298 43 18 319 342 349 313 320 196 133 350 351 215 182 352

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 655 8.9.2005 10:37am

655

5,7-diOH

5,6-diOH

3,4’-diOH 3,5-diOH 5-OH

84

85 86 87

OH-Substitution

83

No.

5,6,7-triOMe 6,7,4’-triOMe 3,6,7,4’-tetraOMe

‘‘Tanetin’’ Candidol Mikanin

Santin

Trivial Name

Baccharis pilularis Achillea sibirica subsp. mongolica Ageratina espinosa Brickellia eupatorioides

Grindelia robusta Lagophylla glandulosa Oncosiphon grandiflorum Tanacetum polycephalum Alkanna orientalis Aeonium, 3 spp. Trixis vauthieri Achillea latiloba Achillea atrata ssp. multifida Achillea multifida Ageratina espinosa Anthemis tinctoria Artemisia barrelieri Brickellia eupatorioides Eupatorium cannabinum Grindelia tarapacana Grindelia glutinosa Grindelia squarrosa Perityle lemmonii Stevia berlandieri Tanacetum microphyllum Aeonium, 3 spp. Drummondita hassellii Pulicaria dysenterica Tanacetum parthenium

Plant Species

Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext.

Leaf exudate Leaf exudate Aerial p., ext. Aerial p., ext. Aerial parts Aerial p., ext. Leaf Aerial p., ext. Aerial parts Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial parts Aerial p., ext. Aerial p., ext. Aerial p., ext. Leaf exudate Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial parts Aerial p., ext. Aerial parts External Aerial parts

Asterac. Asterac. Asterac. Asterac. Boragin. Crassul. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Crassul. Rutac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac.

Plant Organ

Family

196 354 133 215

b

344 236 32 220 37 216 353 354 355 196 133 356 132 215 216 298 344 182 133 182 357 216 358 347

Ref.

656

3,7,4’-triOMe

3,6,4’-triOMe

OMe-Substitution

TABLE 12.2 Flavonols and Their Methyl Ethers — continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 656 8.9.2005 10:37am

Flavonoids: Chemistry, Biochemistry, and Applications

(3,5,6,8,4’-pentaOH) (5,4’-diOH

(3,5,7,8,2’-pentaOH) 3,5,8,2’-tetraOH 5,2’-diOH 5-OH 3,5,7,8,4’-pentaOH 5,7,8,4’-tetraOH

3,5,8,4’-tetraOH 3,5,7,4’-tetraOH 3,5,7,8-tetraOH 5,8,4’-triOH 5,7,4’-triOH

5,7,8-triOH 3,5,4’-triOH 3,5,8-triOH 3,5,7-triOH 5,4’-diOH

5,8-diOH 5,7-diOH

88

89 90 91 92 93

94 95 96 97 98

99 100 101 102 103

104 105

3,7,4’triMe 3,8,4’-triOMe

3,4’-diOMe* 7,8-diOMe 7,4’-diOMe 8,4’-diOMe 3,7,8-triOMe

7-OMe 8-OMe 4’-OMe 3,7-diOMe 3,8-diOMe

3-OMe

7-OMe 3,7,8-triOMe 3,7,8,2’-tetraOMe

3,6,8-triOMe)

Prudomestin

Pollenitin Sexangularetin

Herbacetin

‘‘Candiron’’ —

Ozothamnus obcordatus Haplopappus deserticola

Calceolaria irazuensis Ozothamnus, 4 spp. Cleome spinosa Calceolaria chelidonioides, C. tripartita

Ozothamnus hookeri Baccharis pilularis Ozothamnus, 3 spp. Ephedra aphylla Ozothamnus, 3 spp. Pentagramma triangularis Ozothamnus hookeri Brachyglottis cassinoides Chrysothamnus nauseosus Haplopappus deserticola Ozothamnus, 3 spp. Cleome spinosa Calcolaria arachnoidea Pityrogramma triangularis Ozothamnus expansifolius, O. obcordatus

Ester only

Tephrosia candida

Grindelia glutinosa Parthenium incanum Aeonium, 3 spp. Drummondita hassellii

Asterac. Asterac.

Scrophul. Asterac. Capparid. Scrophul.

Asterac. Asterac. Asterac. Ephedrac. Asterac. Pteridac. Asterac. Asterac. Asterac. Asterac. Asterac. Capparid. Scrophul. Pteridac. Asterac.

Fabac.

Asterac. Asterac. Crassul. Rutac.

Aerial p., ext. Resin. exud.

Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial parts Aerial p., ext. Frond exudate Aerial p., ext. Leaf exudate Aerial p., ext. Resin. exud. Aerial p., ext. Aerial p., ext. Aerial p., ext. Frond exud. Aerial p., ext. Synthesis Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext.

Seed Synthesis

Leaf exudate Aerial p., ext. Aerial p., ext. Aerial parts

Flavones and Flavonols continued

197 361

197 196 197 40 197 359 197 360 199 361 197 321 108 362 197 313 108 197 321 108

51

c

344 182 216 358

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 657 8.9.2005 10:37am

657

112 113 114 115 116 117 118

109 110 111

3,5,7,3’,4’-pentaOH 5,7,3’,4’-tetraOH 3,7,3’,4’-tetraOH 3,5,3’,4’-tetraOH

(3,6,7,8,4’-pentaOH) 3,5,7,2’,4’-pentaOH 5,7-diOH (3,5,7,2’,5’-pentaOH) 3,5,2’-triOH 3,5,7,2’,6’-pentaOH

5-OH

107

3-OMe 5-OMe 7-OMe

3,5,7,2’,6’-pentaOMe

7,5’-diOMe

3,2’,4’-triOMe

3,6,7,8,4’-pentaOMe

3,5,7,8,4’-pentaOMe*

3,7,8,4’-tetraOMe

7,8,4’-triOMe

OMe-Substitution

Azaleatin Rhamnetin

Quercetin

Viscidulin I

Auranetin Morin

Flindulatin

Tambulin

Trivial Name

Artemisia campestris ssp. glutinosa Baccharis pilularis Baccharis pilularis Cassinia vauvilliersii Chromolaena odorata Chrysothamnus nauseosus

Many records Many records

Blumea balsamifera

Asterac. Asterac. Asterac. Asterac. Asterac. Asterac.

Asterac.

Fabac.

Asterac. Fagac. Pteridac. Scrophul. Asterac. Asterac. Rutac. Scrophul. Asterac. Asterac. Capparid. Fagac. Rutac.

Helichrysum foetidum Nothofagus, 3 spp. Currania robertiana Calceolaria chelidonioides Helianthus annuus Ozothamnus expansifolius, O. obcordatus Drummondita calida Calceolaria irazuensis Helichrysum foetidum Ozothamnus, 4 spp. Cleome spinosa Nothofagus menziesii, N. nervosa Drummondita calida

Millettia racemosa

Family

Plant Species

Aerial parts Aerial p., ext. Aerial p., ext. Aerial parts Aerial p., ext. Aerial p., ext.

Aerial parts

Leaf

Aerial p., ext. Aerial p., ext. Frond exud. Aerial p., ext. Leaf Aerial p., ext. Aerial parts Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial parts

Plant Organ

132 129 133 365 193 133

364

38

182 158 173 108 363 197 358 108 182 197 321 158 358

Ref.

658

108

3,5-diOH

OH-Substitution

106

No.

TABLE 12.2 Flavonols and Their Methyl Ethers — continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 658 8.9.2005 10:37am

Flavonoids: Chemistry, Biochemistry, and Applications

3,5,7,4’-tetraOH

3,5,7,3’-tetraOH

119

120

4’-OMe

3’-OMe

Tamarixetin

Isorhamnetin

Flourensia thurifera Madia elegans Ozothamnus expansifolius, O. scutellifolius Pulicaria dysenterica Heliotropium stenophyllum Capparis tweediana Aeonium, 3 spp. Nothofagus obliqua Vellozia streptophylla Viscum album, V. cruciatum Ambrosia ambrosioides Baccharis viminea Chrysothamnus nauseosus Ericameria linearifolia Eriophyllum staechadifolium Grindelia nana Haplopappus baylahuen Lychnophora diamantina Ozothamnus, 3 spp. Pulicaria dysenterica Pulicaria gnaphalodes Siegesbeckia jorullensis Capparis tweediana Aeonium decorum Nothofagus obliqua Eriodictyon sessilifolium Kitaibelia vitifolia Mirabilis viscosa Polygonum punctatum Vellozia conicostigma Viscum album, V. cruciatum Propolis from Arizona Chromolaena odorata Vellozia streptophylla Asterac. Velloziac.

Asterac. Asterac. Asterac. Asterac. Boragin. Capparid. Crassul. Fagac. Velloziac. Viscac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Capparid. Crassul. Fagac. Hydrophyll. Malvac. Nyctagin. Polygon. Velloziac. Viscac. Aerial p., ext. Leaf surface

Leaf resin Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Leaf Aerial p., ext. Aerial p., ext. Leaf surface Cut. wax Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Leaf and stem resin Aerial parts Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Leaf Aerial p., ext. Aerial p., ext. Leaf resin Aerial p., ext. Aerial p., ext. Aerial parts Leaf surfac Cut. wax

Flavones and Flavonols continued

366 201 197 182 36 311 216 158 105 318 133 129 133 133 133 133 223 367 197 182 220 182 311 216 158 135 226 43 368 105 318 305 193 105

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 659 8.9.2005 10:37am

659

OH-Substitution

7,3’,4’-triOH 5,3’,4’-triOH

5,7,4’-triOH

No.

121 122

123

Caryatin

Trivial Name Artemisia spp. Baccharis pilularis Chrysothamnus viscidiflorus Eirmocephala megaphylla Flourensia cernua Grindelia tarapacana Haplopappus taeda Holocarpha, 3 spp. Ozothamnus lycopodioides, O. scutellifolius Palafoxia sphacelata Siegesbeckia jorulensis., S. orientalis Heliotropium pycophyllum., H. stenophyllum Aeonium spp. Eucryphia milliganii, E. moorei Pelargonium fulgidum, P. quercifolium Mirabilis viscosa Rubus phoenicolasius Calceolaria, 4 spp. Petunia surfina Salpiglossis sinuata Lantana camara Viscum album Viscum cruciatum Anarthria scabra Heliotropium sinuatum Heliotropium stenophyllum Cleome amplyocarpa Eucryphia lucida Cyperus alopecuroides

Plant Species Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Boragin. Crassul. Cunoniac. Geraniac. Nyctagin. Rosac. Scrophul. Solanac. Solanac. Verbenac. Viscac. Viscac. Anarthriac. Boragin. Boragin. Capparid. Cunoniac. Cyperac.

Family Aerial parts Aerial p., ext. Aerial p., ext. Aerial parts Aerial p., ext. Aerial p., ext. Stems Leaf resin Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Leaf, bud, ext. Leaf exudate Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Cut. wax Leaf Leaf exudate Aerial p., ext. Exudate Leaf, bud, ext. Aerial parts

Plant Organ

132 133 199 369 182 298 370 371 197 182 182 36 216 165 142 43 18 108 214 214 228 44 318 554 310 36 372 165 217

Ref.

660

3,3’-diOMe

3,5-diOMe 3,7-diOMe

OMe-Substitution

TABLE 12.2 Flavonols and Their Methyl Ethers — continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 660 8.9.2005 10:37am

Flavonoids: Chemistry, Biochemistry, and Applications

5,7,3’-triOH

3,7,4’-triOH 3,7,3’-triOH

3,5,4’-triOH

124

125 126

127

7,3’-diOMe

5,3’-diOMe 5,4’-diOMe*

3,4’-diOMe

Rhamnazin

Nothofagus menziesii, N. nervosa Fouquieria splendens Mirabilis viscosa Cotoneaster microphylla Rubus phoenicolasius Barosma crenulata Melicope coodeana Calceolaria, 5 spp. Mimulus lewisii Viscum album Viscum cruciatum Propolis from Arizona Asteriscus graveolens Chrysothamnus viscidiflorus Calycadenia truncata Flourensia cernua Grindelia tarapacana Psiadia dentata Eucryphia milliganii Cyperus alopecuroides Petunia surfina Vellozia streptophylla Heliotropium stenophyllum Anarthria laevis Rhododendron ellipticum Ambrosia trifida Artemisia campestris Grindelia nana Heterotheca villosa Madia elegans Siegesbeckia jorullensis Stevia subpucescens Wedelia biflora Heliotropium stenophyllum Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Cunoniac. Cyperac. Solanac. Velloziac. Boragin. Anarthriac. Ericac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Boragin.

Fagac. Fouquierac. Nyctagin. Rosac. Rosac. Rutac. Rutac. Scrophul. Scrophul. Viscac. Viscac. Aerial parts Aerial p., ext. Leaf exudate Aerial p., ext. Aerial p., ext. Leaf Leaf, bud, ext. Aerial parts Aerial p., ext. Leaf surface Leaf ex. Leaf Leaf Aerial p., ext. Aerial parts Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Leaf Aerial p., ext.

Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Leaf Aerial p., ext. Leaf exudate Aerial p., ext. Cut. wax

Flavones and Flavonols continued

158 325 43 373 18 326 374 108 375 44 318 305 111 199 236 182 298 345 165 217 214 105 213 554 376 233 132 133 182 201 182 182 377 36

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 661 8.9.2005 10:37am

661

OH-Substitution

3,5,3’-triOH

3,5,7-triOH 7,4’-diOH 5,4’-diOH

No.

128

129 130 131

3’,4’-diOMe 3,5,3’-triOMe 3,7,3’-triOMe Pachypodol

Dillenetin

Ombuin

Trivial Name

Chrysothamnus viscidiflorus Flourensia cernua Grindelia robusta Grindelia tarapacana Grindelia squarrosa Heterotheca villosa Senecio viscosa Senecio viscosissimus Xanthocephalum gymnospermoides Heliotropium sinuatum Nothofagus cunninghamii Mirabilis viscosa Bosistoa floydii, B. medicinalis Melicope elleryana Melicope ternata

Capparis tweediana Aeonium, 3 spp. Eucryphia jinksii Nothofagus cunninghamii Kitaibelia vitifolia Mirabilis viscosa Polygonum punctatum Notholaena nivea Salpiglossis sinuata Viscum cruciatum Propolis from Arizona Chromolaena odorata Amomum koenigii Chromolaena odorata

Plant Species

Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Boragin. Fagac. Nyctagin. Rutac. Rutac. Rutac.

Aerial p., ext. Aerial p., ext. Leaf exudate Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. External Aerial p., ext. Leaf exudate Aerial p., ext. Aerial p., ext. Leaf Fruit Bark

Aerial p., ext. Fruit Aerial p., ext.

Leaf Aerial p., ext. Leaf, bud, ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial parts Frond exud. Aerial p., ext. Cut. wax

Capparid. Crassul. Cunoniac. Fagac. Malvac. Nyctagin. Polygon. Pteridaceae Solanac. Viscac. Asterac. Zingib. Asterac.

Plant Organ

Family

199 182 344 352 182 182 32 378 182 310 158 43 322 379 380

311 216 165 158 226 43 368 45 214 318 305 193 324 193

Ref.

662

7,4’-diOMe

OMe-Substitution

TABLE 12.2 Flavonols and Their Methyl Ethers — continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 662 8.9.2005 10:37am

Flavonoids: Chemistry, Biochemistry, and Applications

5,3’-diOH

5,7-diOH

3,7-diOH 3,5-diOH

132

133

134 135

5,3’,4’-triOMe* 7,3’,4’-triOMe

3,3’,4’-triOMe

3,7,4’-triOMe

Ayanin

Euodia merrillii Euodia viticina Adenosma capitatum Mimulus lewisii Petunia surfina Salpiglossis sinuata Viscum album Viscum cruciatum Bahia glandulosa Grindelia squarrosa, tenella Haplopappus hirtellus Ozothamnus scutellifolius Pisadia dentata Siegesbeckia jorullensis, orientalis Stevia subpubescens Heliotropium chenopodiaceum var. ericoideum Heliotropium pycnophyllum Eucryphia lucida, E. milliganii Petunia surfina Lantana camara Amomum koenigii Flourensia cernua Grindelia nana Grindelia robusta Siegesbeckia jorullensis Eucryphia lucida, E. milliganii Mimulus lewisii Petunia surfina Barbacenia rubro-virens Amomum koenigii Chrysothamnus viscidiflorus Chromolaena odorata Aeonium arboreum Kitaibelia vitifolia

Rutac. Rutac. Scrophul. Scrophul. Solanac. Solanac. Viscac. Viscac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Boragin. Boragin. Cunoniac. Solanac. Verbenac. Zingib. Asterac. Asterac. Asterac. Asterac. Cunoniac. Scrophul. Solanac. Velloziac. Zingib. Asterac. Asterac. Crassul. Malvac.

Fruit Fruit External? Leaf exudate Aerial p., ext. Aerial p., ext. Aerial p., ext. Cut. wax Aerial parts Aerial p., ext. Aerial parts Aerial p., ext. Leaf Aerial p., ext. Aerial p., ext. Exudate Aerial p., ext. Leaf, bud, ext. Aerial p., ext. Aerial p., ext. Fruit Aerial p., ext. Aerial p., ext. Leaf exudate Aerial p., ext. Leaf, bud, ext. Leaf exudate Aerial p., ext. Leaf surface Fruit Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext.

Flavones and Flavonols continued

323 381 382 375 214 214 44 318 221 182 327 197 345 182 182 35 36 165 214 228 324 182 133 344 182 165 375 214 105 324 199 193 216 226

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 663 8.9.2005 10:37am

663

3-OH

138 139

140 141 142 143 144 145 146

5-OH

137

3-OMe

3-OMe* 7-OMe* 3,6,3’,4’-tetraOMe)

3’,5’-diOMe

5,7,3’,4’-tetraOMe 3,5,7,3’,4’-pentaOMe

3,7,3’,4’-tetraOMe

3,5,7,3’-tetraOMe

OMe-Substitution

‘‘Santoflavone’’ Melanoxetin Transilitin

Morelosin Rhynchosin

Retusin

Trivial Name

Graziela mollissima Dalbergia odorifera Achillea santolina Acacia karroo, A. montana Acacia nigrescens

Amomum koenigii

Distemonanthus benthamianus Artemisia rupestris Brickellia eupatorioides Grindelia nana Grindelia tenella Siegesbeckia jorullensis, S.orientalis Urolepis hecatantha Xanthocephalum gymnospermoides Aeonium lindleyi Eucryphia lucida, E. milliganii Bridelia ferruginea Nothofagus cunninghamii Mirabilis viscosa Evodia merrillii Solanum plusodum Cryptomeria japonica Amomum koenigii

Mirabilis viscosa Amomum koenigii

Plant Species

Asterac. Fabac. Asterac. Mimosac. Mimosac.

Zingib.

Aerial parts Heartwood Aerial parts Heartwood Heartwood

Fruit

Heartwood Aerial parts Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial parts Aerial p., ext. Aerial p., ext. Leaf, bud, ext. Stem bark Aerial p., ext. Aerial p., ext. Fruit Aeiral parts Leaf Fruit

Aerial p., ext. Fruit

Nyctagin. Zingib. Fabac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Crassul. Cunoniac. Euphorb. Fagac. Nyctagin. Rutac. Solanac. Taxodiac. Zingib.

Plant Organ

Family

332 385

d

330 333

324

383 132 215 133 182 182 262 182 216 165 384 158 43 323 317 39 324

43 324

Ref.

664

(3,5,7,3’,5’-pentaOH) 3,5,7-triOH 3,6,7,3’,4’-pentaOH 6,7,3’,4’-tetraOH 3,6,3’,4’-tetraOH (7-OH 3,7,8,3’,4’-pentaOH 7,8,3’,4’-tetraOH

4’-OH

OH-Substitution

136

No.

TABLE 12.2 Flavonols and Their Methyl Ethers — continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 664 8.9.2005 10:37am

Flavonoids: Chemistry, Biochemistry, and Applications

3,7,2’,3’,4’-pentaOH (G) 3,7,3’,4’,5’-pentaOH 3,7,4’-triOH 4’,5’-diOH 3,4’-diOH 4’-OH Hexa-O-substituted flavonols (3,5,6,7,8,3’-hexaOH) 5-OH (3,5,6,7,8,4’-hexaOH) 5,7,8,4’-tetraOH 5,8,4’-triOH 5,7,4’-triOH 3,5,4’-triOH 5,7,8-triOH 5,4’-diOH 5,7-diOH

3,8-diOH 3,5-diOH

5-OH

150 151 152 153 154 155

157 158 159 160 161 162 163

164 165

166

156

3,7,3’,4’-tetraOH 3,7,8,4’-tetraOH 7,8,4’-triOH

147 148 149

3,6,7,8,4’-pentaOMe

5,6,7,4’-tetraOMe 6,7,8,4’-tetraOMe*

3,6-diOMe 3,6,7-triOMe 3,6,8-triOMe 6,7,8-triOMe 3,6,4’-triOMe 3,6,7,8-tetraOMe 3,6,8,4’-tetraOMe

3,6,7,8,3’-pentaOMe

3’,5’diOMe* 3,7,3’-triOMe* 7,3’,5’-triOMe* 3,7,3’,5’-tetraOMe*

8-OMe 3’-OMe* 3,3’-diOMe*

5-Hydroxy-auranetin

Eriostemin

Calycopterin Araneosol

Sarothrin

Emmaosunin

Robinetin Laurentinol*

Gnaphalium affine Cleome spinosa Nothofagus menziesii, N. nervosa Rosa centifolia cv. muscosa Drummondita calida Antirrhinum hispanicum

Helichrysum cassianum

Ester only Trixis vauthieri Nothofagus, 3 spp. Rosa centifolia Drummondita calida

Ester only

Millettia laurentii Duroia hirsuta Duroia hirsuta Duroia hirsuta

Acacia karroo ssp. montana Acacia nigrescens Acacia karroo ssp. montana

Asterac. Capparid. Fagac. Rosac. Rutac. Scrophul.

Asterac.

Asterac. Fagac. Rosac. Rutac.

Fabac. Rubiac. Rubiac. Rubiac.

Mimosac. Mimosac. Mimosac.

Leaf Aerial p., ext. Aerial p., ext. Aerial parts Synthesis Synthesis Aerial p., ext. Synthesis Aerial parts Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial parts Aerial p., ext. Synthesis

Synthesis

Heartwood Root Root Root

Heartwood Heartwood Heartwood

Flavones and Flavonols continued

353 158 18 358 335 336 387 336 314 321 158 18 358 108 336

335

386 31 31 31

332 385 332

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 665 8.9.2005 10:37am

665

3,5,6,3’,4’-pentaOH 3,5,6,7,4’-pentaOH 3,5,6,7,3’-pentaOH 5,7,3’,4’-tetraOH

175 176 177 178

169

168

170 171 172 173 174

OH-Substitution

(3,5,6,7,2’,3’-hexaOH) 5,2’,3’-triOH (3,5,6,7,2’,4’-hexaOH) 5,4’-diOH (3,5,6,7,2’,5’-hexaOH) 5-OH 3,5,6,7,3’,4’-hexaOH 5,6,7,3’,4’-pentaOH 3,6,7,3’,4’-pentaOH 3,5,7,3’,4’-pentaOH

167

No.

Axillarin

‘‘Allopatuletin’’ Patuletin

Grantioidin Quercetagetin

Chrysosplin

Trivial Name

Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Eriophyllum staechadifolium Gymnosperma glutinosa

Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac.

Verbenac.

Rutac.

Family

Glycoside only Glycoside only Ambrosia chamissonis Artemisia australis Asteriscus sericeus Bahia pringlei Calycadenia, 3 spp. Eriophyllum confertum

Tagetes patula Anthemis tinctoria Artemisia barrelieri Centaurea incana Chrysactinia mexicana Eriophyllum confertum Pallenis spinosa

Vitex rotundifolia

Drummondita calida

Plant Species

Aerial p., ext. Aerial p., ext.

Synthesis Synthesis Petals Flower Aerial parts Aerial parts Aerial p., ext. Aerial p., ext. Aerial parts Synthesis Synthesis Synthesis Synthesis Aerial p., ext. Aerial parts Aerial p., ext. Aerial parts Leaf exudate Aerial p., ext.

Fruit

Aerial parts Synthesis

Plant Organ

133 196

389 132 281 182 133 390 342 47 47 47 233 132 32 391 236 133

e

47 28

388

358 336

Ref.

666

7-OMe 3’-OMe 4’-OMe 3,6-diOMe

3-OMe 5-OMe 6-OMe

3,6,7,2’5’OMe*

3,6,7,2’-tetraOMe

3,6,7-triOMe*

3,5,6,7,8,4’-hexaOMe*

OMe-Substitution

TABLE 12.2 Flavonols and Their Methyl Ethers — continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 666 8.9.2005 10:37am

Flavonoids: Chemistry, Biochemistry, and Applications

5,6,3’,4’-tetraOH

5,6,7,4’-tetraOH 5,6,7,3’-tetraOH

3,5,3’,4’-tetraOH 3,5,7,4’-tetraOH

3,5,7,3’-tetraOH

5,3’,4’-triOH

179

180 181

182 183

184

185

3,6,7-triOMe

6,4’-diOMe

6,7-diOMe 6,3’-diOMe

3,3’-diOMe 3,4’-diOMe

3,7-diOMe

Chrysosplenol-D

Laciniatin

Eupatolitin Spinacetin

Tomentin

Achillea clusiana Artemisia australis, A. mongolica Brickellia eupatorioides Flourensia cernua Hemizonia lutescens Heterotheca villosa

Chromolaena odorata

Pulicaria gnaphaloides Anthemis tinctoria Eriophyllum confertum

Artemisia abrotanum

Gymnosperma glutinosum Helichrysum, 8 spp. Holocarpha heermannii Inula brittanica Inula germanica Madia sativa Madia, 4 spp. Oncosiphon grandiflorum Ozothamnus lycopodioides Tanacetum balsamita Tanacetum parthenium, T. vulgaris Xanthium strumarium Cleome amplyocarpa Ambrosia artemisifolia Artemisia abrotanum Holocarpha, 4 spp. Inula germanica Madia sativa Tanacetum parthenium

Asterac. Asterac. Asterac. Asterac. Asterac. Asterac.

Asterac.

Asterac. Asterac. Asterac.

Asterac.

Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Capparid. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac.

Aerial p., ext. Aerial p., ext. Leaf resin Aerial p., ext. Aerial p., ext. Leaf exudate Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Leaf Aerial p., ext. Exudate Aerial p., ext. Aerial parts Leaf resin Aerial p., ext. Aerial p., ext. Aieral parts synthesis Aerial parts synthesis Aerial p., ext. Flower Aerial p., ext. Synthesis Aerial p., ext. Synthesis Aerial p., ext. Aerial parts Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext.

Flavones and Flavonols continued

133 237 371 196 32 236 200 32 197 32 49 32 372 182 392 371 32 133 48 28 392 28 220 389 133 342 193 342 196 132 215 182 133 182

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 667 8.9.2005 10:37am

667

OH-Substitution

5,7,4’-triOH

5,7,3’-triOH

No.

186

187

Centaureidin

Jaceidin

Trivial Name

Plant Organ Aerial p., ext. Aerial p., ext. Leaf exudate Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial parts Aerial parts Aerial p., ext. Aerial parts Aerial p., ext. Aerial p., ext. Aerial parts Aerial p., ext. Aerial p., ext. Leaf exudate Aerial p., ext. Leaf Aerial parts Aerial p., ext. Leaf Aerial parts Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial parts Aerial parts Aerial parts

Family Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Rosac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Boragin. Nyctagin. Rutac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac.

Plant Species Inula brittanica Inula germanica Madia sativa Oncosiphon grandiflorum Pulicaria gnaphalodes Tanacetum polycephalum Rosa centifolia cv. muscosa Achillea clusiana Achillea micrantha Asteriscus graveolens Asteriscus sericeus Bahia pringlei Centaurea, 3 spp. Eriophyllum staechadifolium Eupatorium buniifolium Flourensia cernua Inula brittanica Lagophylla glandulosa Pulicaria gnaphalodes Tanacetum parthenium Alkanna orientalis Mirabilis viscosa Melicope coodeana Achillea atrata ssp. multifida Achillea multifida Ambrosia chamissonis Anthemis tinctoria Artemisia abrotanum Artemisia barrelieri Baccharis saligna

32 32 236 32 220 220 18 196 343 111 32 391 182 133 393 182 196 236 220 49 37 43 374 355 196 233 356 392 132 394

Ref.

668

3,6,4’-triOMe

3,6,3’-triOMe

OMe-Substitution

TABLE 12.2 Flavonols and Their Methyl Ethers — continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 668 8.9.2005 10:37am

Flavonoids: Chemistry, Biochemistry, and Applications

5,6,3’-triOH 3,5,4’-triOH 3,5,3’-triOH 3,5,7-triOH (3,5,6-triOH 7,4’-diOH 6,4’-diOH 5,4’-diOH

189 190 191 192

193 194 195

5,6,4’-triOH

188

3,7,4’-triOMe 6,7,3’-triOMe 6,7,4’-triOMe 6,3’,4’-triOMe 7,3’,4’-triOMe)* 3,5,6,3’-tetraOMe 3,5,7,3’-tetraOMe 3,6,7,3’-tetraOMe

3,7,3’-triOMe

Chrysosplenetin

Oxyayanin-B Veronicafolin Eupatin

Chrysosplenol-C

Achillea ageratum Artemisia clusiana Artemisia mongolica Artemisia nana Artemisia sieversii Grindelia robusta Grindelia tarapacana Haplopappus bezanillanus Inula brittanica Inula brittanica Parthenium incanum Pulicaria gnaphalodes Adenosma capitatum

Bahia xylopoda Centaurea jacea Eriophyllum confertum Eupatorium buniifolium Grindelia robusta Grindelia tarapacana Stevia berlandieri Asteriscus sericeus Tanacetum microphyllum Aeonium spp. Tanacetum parthenium Pterocaulon sphacelatum Pulicaria dysenterica Pulicaria dysenterica Arnica longifolia

Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Scrophul.

Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Crassul. Asterac. Asterac. Asterac. Asterac. Asterac.

Flavones and Flavonols continued

320 196 132 196 271 344 352 327 129 32 182 220 382

313

Only synth.

Aerial parts Aerial p., ext. Aerial parts Aerial p., ext. Aerial parts Leaf exudate Aerial p., ext. Aerial parts Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial p., ext. External?

391 182 133 393 344 352 182 32 395 216 48 396 347 182 210

Aerial parts Aerial p., ext. Aerial p., ext. Aerial parts Leaf exudate Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial parts Aerial p., ext. Aerial parts Aerial parts External Aerial p., ext. Flower

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 669 8.9.2005 10:37am

669

5,7-diOH 5,6-diOH 3,3’-diOH 3,5-diOH 3,5-diOH

4’-OH 7-OH

5-OH

3-OH — (3,5,6,8,3’,4’-hexaOH) (3,5,7,8,2’,3’-hexaOH) 5,2’,3’-triOH

197 198 199 200 201

202 203

204

205 206

3,7,8-triOMe

5,6,7,3’,4’-pentaOMe* 3,5,6,7,3’,4’-hexaOMe (7-chloro-derivative)

3,6,7,3’,4’-pentaOMe

3,5,6,7,3’-pentaOMe 3,5,6,3’,4’-pentaOMe*

3,6,3’,4’-tetraOMe 3,7,3’,4’-tetraOMe 5,6,7,4’-tetraOMe 6,7,3’,4’-tetraOMe 6,7,3’,4’-tetraOMe

3,6,7,4’-tetraOMe

OMe-Substitution

Marionol*

Artemetin

Eupatoretin

Bonanzin

Casticin

Trivial Name

Artemisia annua Baccharis saligna Parthenium incanum Pallemis spinosa Vigua spiralis Citrus sinensis Achillea conferta Achillea sibirica subsp.mongolica Artemisia annua Artemisia mongolica, A.verlotiorum Inula brittanica Inula brittanica Parthenium incanum Ficus altissima Adenosma capitatum Vitex rotundifolia Chromolaena odorata Pallemis spinosa

Achillea sibirica subsp.mongolica Artemisia abrotanum Lagophylla glandulosa Parthenium incanum Tanacetum polycephalum Vitex rotundifolia Bahia xylopoda Pulicaria dysenterica

Plant Species

Asterac. Asterac. Asterac. Asterac. Fabac. Rutac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Asterac. Morac. Scrophul. Verbenac. Asterac. Asterac.

Asterac. Asterac. Asterac. Asterac. Asterac. Verbenac. Asterac. Asterac.

Family

Aerial parts Aerial parts Aerial p., ext. Aerial parts Leaf and stem Fruit peel oil Aerial parts Aerial p., ext. Aerial parts Aerial parts Aerial p., ext. Aerial p., ext. Aerial p., ext. Aerial parts External? Fruit Aerial p., ext. Aerial parts

Aerial p., ext. Aerial parts Leaf exudate Aerial p., ext. Aerial parts Fruit Aerial parts Aerial p., ext.

Plant Organ

397 394 182 390 398 16 269 354 397 132 196 32 182 30 382 388 399 390

354 392 236 182 220 388 391 32

Ref.

670

207

5,3’-diOH

OH-Substitution

196

No.

TABLE 12.2 Flavonols and Their Methyl Ethers — continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 670 8.9.2005 10:37am

Flavonoids: Chemistry, Biochemistry, and Applications

3,5,3’,4’-tetraOH 5,7,8,4’-tetraOH 5,7,8,3’-tetraOH 3,5,8,3’-tetraOH 3,5,7,4’-tetraOH 3,5,7,3’-tetraOH 5,3’,4’-triOH

5,4’-diOH 5,7,4’-triOH

3,5,4’-triOH 3,5,7-triOH

228 229

230 231

(3,5,7,8,2’,4’-hexaOH) 3,5,2’-triOH 5,4’-diOH 5-OH (3,5,7,8,2’,5’-hexaOH) 5,2’,5’-triOH 5,5’-diOH 3,5,7,8,3’,4’-hexaOH 5,7,8,3’,4’-pentaOH 3,5,8,3’,4’-pentaOH 3,5,7,3’,4’-pentaOH 3,5,7,8,4’-pentaOH 7,8,3’,4’-triOH 5,8,3’,4’-tetraOH 5,7,3’,4’-tetraOH

221 222 223 224 225 226 227

211 212 213 214 215 216 217 218 219 220

208 209 210

7,8,3’-triOMe 8,3’,4’-triOMe

3,7,3’-triOMe 3,8,3’-triOMe

7,8-diOMe 3,3’-diOMe 3,4’-diOMe 7,4’-diOMe 8,3’-diOMe 8,4’-diOMe 3,7,8-triOMe

3-OMe 7-OMe 8-OMe 3’-OMe 3,5-diOMe* 3,7-diOMe 3,8-diOMe

3,7,8-triOMe 3,7,8,2’-tetraOMe

7,8,4’-triOMe 3,7,8,2’-tetraOMe 3,7,8,2’,4’-pentaOMe

Gossypetin

Asterac. Rutac. Scrophul.

Asterac. Asterac. Asterac. Scrophul.

Glycoside only Glycoside only Calycadenia ciliata, C. multiglandulosa Madia anomala Ozothamnus lycopodioides Calceolaria tenella Haplopappus deserticola Boronia coerulescens Calceolaria scabiosiifolia

Myrtac. Polygon. Asterac. Asterac. Asterac. Rutac.

Glycoside only Glycoside only Glycoside only Eugenia edulis Chorizanthe diffusa Madia sativa Madia, 4 spp. Ozothamnus hookeri Zanthoxylum alatum

Ester only

Resin. exud. Aerial parts Aerial p., ext. Synthesis

Leaf exudate Aerial p., ext. Aerial p., ext. Aerial p., ext.

Leaf Whole plant Aerial p., ext. Aerial p., ext. Aerial p., ext. Seed

continued

361 95 108 402

236 200 197 108

400 7 133 200 70 401

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Flavones and Flavonols 671

5,3’-diOH 5,8-diOH 5,7-diOH 7-OH 5-OH

— 3,6,7,8,3’,4’-hexaOH 3,5,7,2’,3’,4’-hexaOH 5,2’,3’-triOH 3,5,7,2’,4’,5’-hexaOH 5,7,4’,5’-tetraOH 5,7,2’,5’-tetraOH 5,2’,5’-triOH 3,5,7-triOH 2’,5’-diOH 5,2’-diOH 5’-OH 2’-OH 5-OH — (3,6,7,2’,4’,5’-hexaOH) 2’,5’-diOH

233 234 235 236 237

238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 3,6,7,4’-tetraOMe

3,2’-diOMe 3,4’-diOMe 3,7,4’-triOMe 2’,4’,5’-triOMe* 3,5,7,4’-tetraOMe 3,7,4’,5’-tetraOMe 3,5,7,2’,4’-pentaOMe 3,5,7,4’,5’-pentaOMe 3,7,2’,4’,5’-pentaOMe 3,5,7,2’,4’,5’-hexaOMe

3,7,4’-triOMe

3,5,7,8,3’,4’-hexaOMe

3,7,8,4’-tetraOMe 3,7,3’,4’-tetraOMe 3,8,3’,4’-tetraOMe 3,5,8,3’,4’-pentaOMe 3,7,8,3’,4’-pentaOMe

3,7,8,3’-tetraOMe

OMe-Substitution

Oxyayanin-A

Apuleidin 5’-Hydroxy-morin

Ternatin

Trivial Name

Psiadia punctulata

Glycoside only

Aerial parts

33

Asterac. Asterac. Rutac. Solanac. Rutac.

Helichrysum foetidum Ozothamnus lycopodioides Murraya paniculata Solanum paludosum Murraya paniculata

Asterac.

402 402 182 197 404 317 404

Synthesis Synthesis Aerial p., ext. Aerial p., ext. Fruit Aerial parts Fruit

Glycoside only

403 379 380 95 108 317

Ref.

Fruit Fruit Bark Aerial parts Aerial p., ext. Aerial parts

Plant Organ

Rutac. Rutac. Rutac. Rutac. Scrophul. Solanac.

Family

Euodia viticina Melicope elleryana Melicope simplex, M. ternata Boronia coerulescens Calceolaria tenella Solanum paludosum

Plant Species

672

253

5,4’-diOH

OH-Substitution

232

No.

TABLE 12.2 Flavonols and Their Methyl Ethers — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

6,5’-diOH 3,5,7,3’,4’,5’-hexaOH

5,7,3’,4’,5’-pentaOH 3,7,3’,4’,5’-pentaOH 3,5,3’,4’,5’-pentaOH 3,5,7,4’,5’-pentaOH 3,5,7,3’,5’-pentaOH 5,7,3’,5’-tetraOH 5,7,3’,4’-tetraOH 3,5,3’,5’-tetraOH 3,5,7,5’-tetraOH 3,5,7,4’-tetraOH 7,4’,5’-triOH 5,4’,5’-triOH 5,3’,5’-triOH 5,7,5’-triOH 5,7,4’-triOH 3,5,5’-triOH 5,7-diOH 5,5’-diOH

5,4’-diOH 5,7-diOH 3,5-diOH 5-OH

3-OH

254 255

256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273

274 275 276 277

278

5,7,3’,4’,5’-pentaOMe

3,7,3’,5’-tetraOMe 3,3’,4’,5’-tetraOMe 7,3’,4’,5’-tetraOMe* 3,7,3’,4’,5’-pentaOMe

3-OMe 5-OMe 7-OMe 3’-OMe 4’-OMe 3,4’-diOMe 3,5’-diOMe 7,4’-diOMe 3’,4’-diOMe 3’,5’-diOMe 3,5,3’-triOMe 3,7,3’-triOMe 3,7,4’-triOMe 3,3’,4’-triOMe 3,3’,5’-triOMe 7,3’,4’-triOMe 3’,4’,5’-triOMe* 3,7,3’,4’-tetraOMe

3,7,2’,4’-tetraOMe

Combretol

Ferrugin*

Syringetin

Europetin Laricytrin Mearnsetin

Annulatin

Myricetin

Euphorb. Boragin. Asterac. Crassul. Rutac. Rutac.

Stem bark Leaf exudate Aerial p., ext. Aerial p., ext. Leaf Leaf

Aerial p., ext. Stem bark Aerial p., ext. Aerial p., ext.

Crassul. Euphorb. Asterac. Brom. Aeonium sedifolium Bridelia ferruginea Xanthocephalum gymnospermum Tillandsia usneoides Bridelia ferruginea Heliotropium megalanthum Xanthocephalum gymnospermum Aeonium, 5 spp. Bosistoa floydii Murraya paniculata

Leaf Aerial p., ext. Aerial p., ext.

Stem bark Leaf Aerial p., ext. Aerial p., ext. Aerial parts Pollen Pollen

Myrtac. Crassul. Crassul.

Euphorb. Fabac. Fagac. Fagac. Myrtac. Myrtac. Myrtac.

Eugenia edulis Aeonium, 4 spp. Aeonium sedifolium

Glycoside only Glycoside only

Bridelia ferruginea Millettia racemosa Nothofagus antarctica Nothofagus antarctica Plinia pinnata Eucalyptus globulus Kunzea ericoides

Flavones and Flavonols continued

384 378 182 216 322 284

216 384 182 406

400 216 216

384 38 158 302 405 20 20

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673

5,6,3’,4’-tetraOH 3,5,3’,4’-tetraOH 3,5,7,4’-tetraOH 3,5,7,3’-tetraOH 5,3’,4’-triOH

5,7,4’-triOH 5,7,4’-triOH 5,7,3’-triOH

293 294 295 296 297

298

299

3,6,8,3’-tetraOMe 3,6,8,3’-tetraOMe 3,6,8,4’-tetraOMe

3,7,8-triOMe 6,7,8-triOMe 6,8,3’-triOMe 6,8,4’-triOMe 3,6,7,8-tetraOMe

3,6-diOMe 6,8-diOMe 3,6,8-triOMe

3,6,7,8,2,5’-hexa-OMe*

3,6,7,8-tetraOMe 3,6,7,8,2’-pentaOMe 3,6,7,8,4’-pentaOMe 3,6,7,8,2’,4’-hexaOMe

3,7,8,4’,5’-pentaOMe*

6,3’-diOMe*

3,5,7,3’,4’,5’-hexaOMe*

OMe-Substitution

Limocitrol Isolimocitrol

Grantiodinin*

Inucrithmin*

Trivial Name

Glycoside only Helichrysum, 8 spp. Madia, 3 spp. Rosa centifolia cv. Muscosa

Calycadenia, 3 spp. Madia, 3 spp.

Inula grantioides

Parkia clappertoniana

Inula crithmoides

Ficus altissima Murraya paniculata

Plant Species

Asterac. Asterac. Rosac.

Asterac. Asterac.

Asterac.

Fabac.

Asterac.

Morac. Rutac.

Family

Synthesis Synthesis Aerial parts, ext. Aerial p., ext. Aerial p., ext. Synthesis Synthesis

Synthesis Leaf exudate Aerial p., ext. Synthesis

Aerial parts

Leaf

Aerial parts

Aerial parts Flower

Plant Organ

335 335 237 200 18 335 335

335 236 200 335

34

331

407

30 61

Ref.

674

283 284 285 286

282

281

287 289 290 291 292

OH-Substitution

3,5,8,3’,4’,5’-hexaOH (3,6,7,3’,4’,5’-hexaOH) 3,7,4’,5’-tetraOH (3,7,8,2’,4’,5’-hexaOH) 2’-OH Hepta-O-substituted flavonols (3,5,6,7,8,2’,4’-OH) 5,2’,4’-triOH 5,4’-diOH 5,2’-diOH 5-OH (3,5,6,7,8,2’,5’-OH) 5-OH 3,5,6,7,8,3’,4’-heptaOH 5,7,8,3’,4’-pentaOH 3,5,7,3’,4’-pentaOH 5,7,3’,4’-tetraOH

280

279

No.

TABLE 12.2 Flavonols and Their Methyl Ethers — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

5,3’-diOH

5,7-diOH 3,5-diOH 7-OH 5-OH 3-OH

306

307 308 309 310 311 312 313

315 316 317 318 319 320 321 322 323 324

(3,5,6,7,2’,3’,4’-OH) 5,6,2’,3’-tetraOH (3,5,6,7,2’,4’,5’-OH) 5,7,4’,5’-tetraOH 5,7,2’,4’-tetraOH 5,7,2’,5’-tetraOH 5,2’,5’-triOH 5,7,5’-triOH 5,7,2’-triOH 5,6,5’-triOH 2’,5’-diOH 6,5’-diOH 6,2’-diOH

3,5,8-triOH 5,4’-diOH 5,4’-diOH

303 304 305

314

5,6,3’triOH 3,5,4’-triOH 3,5,3’-triOH

300 301 302

3,6,2’-triOMe 3,6,3’-triOMe 3,6,4’-triOMe 3,6,7,4’-tetraOMe 3,6,2’,4’-tetraOMe* 3,6,4’,5’-tetraOMe 3,7,2’,4’-tetraOMe 3,5,6,7,4’-pentaOMe 3,5,7,2’,4’-pentaOMe 3,5,7,4’,5’-pentaOMe

3,7,4’-triOMe

3,6,8,3’,4’-pentaOMe* 6,7,8,3’,4’-pentaOMe* 3,5,6,8,3’,4’-hexaOMe* 3,6,7,8,3’,4’-hexaOMe 5,6,7,8,3’,4’-hexaOMe 3,5,6,7,8,3’,4’-heptaOMe 3,5,6,7,8,3’,4’-heptaOMe

3,6,7,8,4’-pentaOMe

6,7,3’4’-tetraOMe* 3,6,7,8,3’-pentaOMe 3,6,7,8,3’-pentaOMe

3,7,8,4’tetraOMe* 6,7,8,3’-tetraOMe 6,7,8,4’-tetraOMe*

Apulein

Apuleisin

Natsudaidain ‘‘HEPTA’’

Eupatorium buniifolium

Calycadenia truncata, C. mollis Polanisia dodecandra Acronychia porteri Zieridium pseudobtusifolium Melicope coodeana Acronychia porteri Citrus sinensis Acronychia porteri Citrus hassaku, C. madurensis Citrus hassaku, C. madurensis Citrus sinensis

Asterac.

Asterac. Capparid. Rutac. Rutac. Rutac. Rutac. Rutac. Rutac. Rutac. Rutac. Rutac.

Rutac. Asterac. Asterac. Asterac. Capparid.

Rutac.

Zieridium pseudobtusifolium Murraya paniculata var. omphalocarpa Calycadenia ciliata, C. multiglandulosa Gnaphalium luteo-album Madia dissitiflora Polanisia dodecandra

Asterac.

Calycadenia ciliata

Leaf and stem

Leaf exudate Leaf exudate Aerial p., ext. Aerial parts Synthesis Leaf exudate Aerial parts Leaf Leaf Leaf Leaf Fruit peel oil Leaf Leaf Leaf Fruit peel oil

Leaf exudate Synthesis Leaf Synthesis

continued

412

236 336 408 335 409 236 315 200 410 336 236 410 408 408 374 408 16 408 410 410 16

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Flavones and Flavonols 675

350 351

349

(3,5,6,7,3’,4’,6’-heptaOH) 5,6’-diOH (3,5,7,8,2’,3’,4’-heptaOH) 5-OH (3,5,7,8,2’,4’,5’-heptaOH)

(3,5,6,7,3’,4’,5’-OH) 5,7,3’,4’,5’-pentaOH 5,6,7,3’,5’-pentaOH 3,5,7,3’,5’-pentaOH 5,7,4’,5’-tetraOH 5,7,3’,5’-tetraOH 5,6,7,4’-tetraOH 3,5,7,4’-tetraOH 5,3’,5’-triOH 5,7,5’-triOH 5,7,4’-triOH 5,6,5’-triOH 7,5’-diOH 5,5’-diOH 5,3’-diOH 3,5-diOH 4’-OH 5-OH

5,5’-diOH 5,2’-diOH 5,6-diOH 5-OH 3-OH

OH-Substitution

3,7,2’,3’,4’-pentaOMe

3,6,7,3’,4’-pentaOMe

3,6-diOMe 3,4’-diOMe 6,4’-diOMe 3,6,3’-triOMe 3,6,4’-triOMe 3,3’,5’-triOMe 6,3’,5’-triOMe 3,6,7,4’-tetraOMe 3,6,3’,4’-tetraOMe 3,6,3’,5’-tetraOMe 3,7,3’,4’-tetraOMe 3,5,7,3’,4’-pentaOMe 3,6,7,3’,4’-pentaOMe 3,6,7,4’,5’-pentaOMe 6,7,3’,4’,5’-pentaOMe 3,5,6,7,3’,5’-hexaOMe 3,6,7,3’,4’,5’-hexaOMe 3,5,6,7,3’,4’,5’-heptaOMe

3,6,7,2’,4’-pentaOMe 3,6,7,4’,5’-pentaOMe 3,7,2’,4’,5’-pentaOMe 3,6,7,2’4’5’hexaOMe* 5,6,7,2’,4’,5’-hexaOMe* 3,5,6,7,2’,4’,5’-heptaOMe

OMe-Substitution

Apuleitrin Apuleirin

6-Hydroxy-myricetin

Brickellin

Trivial Name

Ester only

Murraya paniculata Murraya paniculata

Rutac. Rutac.

Fruit Flower

Aerial parts

Asterac.

Eupatorium buniifolium

Glycoside only

Aerial parts

Plant Organ

Asterac.

Family

Glycoside only Eupatorium buniifolium

Plant Species

404 414

413

413

Ref.

676

331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348

325 326 327 328 329 330

No.

TABLE 12.2 Flavonols and Their Methyl Ethers — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

380 381

370 371 372 373 374 375 376 377 378 379

369

352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368

(3,5,6,7,8,3’,4’,5’-octaOH) 5,7,3’,4’,5’-pentaOH 5,7,3’,5’-tetraOH

(3,5,7,2’,3’,4’,6’-OH) 5-OH Octa-O-substituted flavonols (3,5,6,7,8,2’,4’,5’-octaOH) 5,7,4’,5’-tetraOH 5,7,2’,5’-tetraOH 5,7,2’,4’-tetraOH 5,6,2’,5’-tetraOH 5,4’,5’-triOH 5,7,5’-triOH 5,7,2’-triOH 5,2’-diOH 5,7-OH

5,7,2’,4’-tetraOH 5,3’,4’-triOH 5,7,3’-triOH 3,5,7,8,3’,4’,5’-heptaOH 3,5,7,3’,4’,5’hexaOH 5,8,3’,4’,5’-pentaOMe 3,5,7,3’4’-pentaOH 5,8,3’,5’-tetraOH 5,7,3’,5’-tetraOH 3,5,7,4’-tetraOH 5,3’,5’-triOH 5,7,3’-triOH 5,7-diOH 3,5-diOH 8-OH 5-OH

3,6,8,2’-tetraOMe 3,6,8,4’-tetraOMe 3,6,8,5’-tetraOMe 3,7,8,4’-tetraOMe 3,6,7,8,2’-pentaOMe 3,6,8,2’,4’-pentaOMe 3,6,8,4’,5’-pentaOMe 3,6,7,8,4’,5’-hexaOMe 3,6,8,2’,4’,5’-hexaOMe 3,5,6,7,8,2’,4’,5’-octaOMe – 3,6,8-triOMe 3,6,8,4’-tetraOMe

3,7,2’,3’,4’,6’-hexaOMe*

8-OMe 3,7-diOMe* 8,5’-diOMe 3,7,4’-triOMe 3,8,4’-triOMe 8,3’,5’-triOMe 3,7,8,4’-tetraOMe 3,8,4’,5’-tetraOMe 3,8,3’,4’,5’-pentaOMe 7,8,3’,4’,5’-pentaOMe 3,5,7,3’,4’,5’-hexaOMe* 3,7,8,3’,4’,5’-hexaOMe* 3,5,7,8,3’,4’,5’-heptaOMe

3,8,5’-triOMe 3,7,8,5’-tetraOMe 3,8,4’,5’-tetraOMe

Purpurascenin (6,8-Dihydroxy-myricetin)

Conyzatin

Hibiscetin

Zieridium pseudobtosifolium

Distemonanthus benthamianus

Murraya paniculata Murraya paniculata

Glycoside only

Glycoside only Chorizanthe diffusa Glycoside only

Rutac.

Fabac.

Rutac. Rutac.

Polygon.

Leaf

Heartwood

Fruit Fruit

408

29

404 404

7

continued

Whole plant

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Flavones and Flavonols 677

5,7,3’,4’-tetraOH 5,6,3’,5’-tetraOH 5,3’,5’-triOH 5,7,4’-triOH 5,7,3’-triOH 3,5,3’-triOH 3’,5’-diOH 5,3’-diOH 5,7-diOH 3’-OH 5-OH

382 383 384 385 386 387 388 389 390 391 392 393

3,6,8,5’-tetraOMe 3,7,8,4’-tetraOMe 3,6,7,8,4’-pentaOMe 3,6,8,3’,5’-pentaOMe 3,6,8,4’,5’-pentaOMe 6,7,8,4’,5’-pentaOMe* 3,5,6,7,8,4’-hexaOMe 3,6,7,8,4’,5’-hexaOMe 3,6,8,3’,4’,5’-hexaOMe 3,5,6,7,8,4’,5’-heptaOMe 3,6,7,8,3’,4’,5’-heptaOMe 3,5,6,7,8,3’,4’,5’-octaOMe

OMe-Substitution

Zieridium pseudobtusifolium Gymnosperma glutinosum

Digicitrin

Exoticin

Zieridium pseudobtusifolium

Plant Species

Desmethyl-digicitrin

Trivial Name

Rutac. Asterac.

Rutac.

Family

Leaf Aerial p., ext.

Leaf

Plant Organ

408 129

408

Ref.

678

*For explanation, please see text. a Revised to 3,5,7,8-tetraOH, see text. b Revised to 3,6,4’-triMe, see text. c Revised to 3,6,7-triMe, see text. d Revised to 5-OH-6,7,3’4’-tetraOMe, see text. e Revised to Queg-7-Me, see text.

OH-Substitution

No.

TABLE 12.2 Flavonols and Their Methyl Ethers — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

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Flavones and Flavonols

679

species of this genus. Single reports exist for families such as the Saxifragaceae42 or Nyctaginaceae43. New results on Rosaceae and Viscaceae deserve special consideration. A quite complex derivative (compound 298 in Table 12.2) was isolated from several Rosaceae. By contrast, rather simple derivatives were found in the leaf wax of Viscum spp.44 Particularly with the Rosaceae, more results in this direction are to be expected when more material is analyzed. Frond exudates of several ferns proved to be a rich source for various flavonol derivatives, which outnumber the few corresponding flavones.45 Several compounds were structurally revised. 6-Hydroxygalangin (compound 13 in Table 12.2), as reported from Platanus buds,46 was revised to 8-hydroxygalangin after synthesis (compound 23, Table 12.2).47 6-Hydroxykaempferol-3,7,4’-triMe had been reported as ‘‘tanetin’’ (compound 84, Table 12.2) from Tanacetum parthenium.48 Its structure was later revised to 6-hydroxykaempferol-3,6,4’-triMe ¼ santin (compound 83, Table 12.2).49 The name ‘‘tanetin‘‘is hence obsolete. 5,4-diOH-3,6,8-triOMe-flavone had been isolated from Tephrosia candida and named ‘‘candiron’’ (compound 88, Table 12.2).50 Synthesis revealed that the structure must be revised to 5,4’-diOH-3,6,7-triOMe-flavone ¼ penduletin (compound 82, Table 12.2).51 The name ‘‘candiron’’ must not be used, therefore. ‘‘Santoflavone,’’ a compound isolated from Achillea santolina and claimed to be 7-OH,3,6,3’,4’-tetramethoxyflavone (compound 144, Table 12.2),52 was later revised to 5-hydroxy-6,7,3’,4’-tetraOMe flavone (compound 170, Table 12.1).53 Bhardwaj et al. had reported ‘‘allopatuletin’’ to be a 3,6,7,3’,4’-pentahydroxy-5-methoxyflavone (compound 173, Table 12.2), from Tagetes pendula.54 After synthesis, revision of this structure to quercetagetin-7-Me is required (compound 175, Table 12.2).47 Zhang et al. reported ‘‘viscidulin III’’ from the roots of Scutellaria planipes.55 Unfortunately, it remains dubious whether the authors used the name in its initial meaning, that is, as 3,5,7,3’-tetraOH-2’,4’-diOMe flavone or as its revised structure 5,7,3’,6’tetraOH-8,2’-diOMe (for which the name ganhuangenin would apply).56 Since the authors did not answer relevant requests, this report has not been included in our tables.

12.5 FLAVONES WITH OTHER SUBSTITUENTS As already mentioned in Section 12.1, several biosynthetic trends are included in this section. These concern C-methylated as well as other C-substituted flavones, further methylenedioxy derivatives and structures resulting from prenylation and cyclization processes. Most of the prenyl side chains (C5, C10, or C15) are linked directly to the flavone molecule; rarely Oprenylation occurs. Extensive modification of the terpenoic side chain may occur by further oxidation, reduction, dehydration, and cyclization. In addition, cyclization of the terpenoid chains with an ortho-phenolic OH-group to give pyrano- or furano-derivatives is quite common. Apart from the flavanones, the flavones are the second most abundant class of isoprenylated flavonoids.3 Compounds which have not been included here are those resulting from Diels–Alder reaction, forming adducts (e.g., Brosimone D) or dimeric flavones (for these structures, see Ref. 3). Most reports concern a few genera of the Moraceae and Fabaceae, exhibiting quite diverse biosynthetic capacities in terms of complex substitution patterns, a phenomenon earlier also addressed by Barron and Ibrahim3. Thus, flavonoid profiles of some of these genera will be discussed separately.

12.5.1 C-METHYLFLAVONES AND C2/C3-SUBSTITUTED FLAVONES Direct methylation through C-bonds appears to be common in the positions 6 and 8 of the flavonoid molecule. Other positions are rarely C-methylated (C7, saltillin; C3, a glycoside only; compound 23, Table 12.3). Most reports concentrate on species from the family Myrtaceae, where C-methylflavones also occur externally.57 Desmos cochinchinensis (Annonaceae) was

5,7-diOMe 5-OH, 4’-OMe 5,7-diOH, 8-OMe 5,2’-diOH,7-OMe 5,7,4’-triOH

5,7,4’-triOH 5,7,4’-triOH 5,7,4’-triOH

5,4’-diOH, 7-OMe

5,4’-diOH, 7-OMe

5,7-diOH, 4’-OMe 5,7-diOH, 4’-OMe 5-OH, 7,4’-diOMe 5-OH, 7,4’-diOMe

5,7,3’,4’-tetraOH 5,7,3’,4’-tetraOH

6 7 8 9 10

11 12 13

14

15

16 17 18 19

20 21

3-Me 6-Me*

6-Me* 8-Me* 6-Me 6,8-diMe

6,8-diMe

6-Me

Glycoside only 6-Methylluteolin*

8-Desmethyleucalyptin Eucalyptin

Sideroxylin

8-Desmethyl-sideroxylin

8-Methyl-apigenin Glycoside only 6,8-Dimethyl-apigenin Syzalterin*

6-Methyl-apigenin

Saltillin

Desmosflavone

Strobochrysin Matteuorien*

Trivial Name

Salvia nemorosa

Callistemon, 5 spp. Callistemon lanceolatus Callistemon, 5 spp.

Callistemon, 9 spp. Eucalyptus saligna Leptospermum laevigatum

Callistemon, 5 spp. Pancratium maritimum Syzygium alternifolium Callistemon, 8 spp. Eucalyptus saligna

Trianthema portulacastrum Valeriana wallichii

Matteucia orientalis Leptospermum scoparium Leptospermum scoparium Desmos cochinchinensis Desmos chinensis Leptospermum scoparium

Plant Species

Lam.

Myrtac. Myrtac. Myrtac.

Myrtac. Myrtac. Myrtac.

Myrtac. Amaryllid. Myrtac. Myrtac. Myrtac.

Aizoaoac. Valerian.

Aspid. Myrtac. Myrtac. Annon. Annon. Myrtac.

Family

Aerial parts

External Bulb Leaf External Leaf wax Synthesis External Leaf wax Leaf wax Synthesis only Synthesis only External Leaf External

Whole plant Aerial parts Synthesis Synthesis

Seeds Leaf

Rhizome Leaf Leaf

Plant Organ

426

57 421 422 57 423 420 57 423 424 420 420 57 425 57

418 419 420 420

415 416 59 58 60 417

Ref.

680

8-Me* 3-Me 6,8-diMe*

6-Me* 7-Me 6-Me 6,8-diMe* 6-Me*

C-Methyl- and C2/C3-substituted flavones 5,7-diOH 6-Me 5,7-diOH 6,8-diMe* 5-OH, 7-OMe 6-Me 5-OH, 7-OMe 6,8-diMe* 5-OH, 7-OMe 6,8-diMe*

1 2 3 4 5

Other Substituents

OH- and OMe-Substitution

No.

TABLE 12.3 Flavones with Other Substituents

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Flavonoids: Chemistry, Biochemistry, and Applications

8-Me, 6-CHO 6,8-diCH3-5’-C5* 6-CH3, 4’,3’-ODmp* 6,8-diCH3, 4’,3’-ODmp* 6-C2* 6-CH2CHO, see Figure 1 6-Acrylic acid*, see Figure 1 6-Acrylic acid *, see Figure 1

6,7-OCH2O 3’,4’-OCH2O* 3’,4’-OCH2O* 5,6-/3’,4’-diOCH2O 3’,4’-OCH2O 3’,4’-OCH2O* 3’,4’-OCH2O* 3’,4’-OCH2O 3’,4’-OCH2O 6,7-OCH2O 4’, 5’-OCH2O* 3’,4’-OCH2O* 3’,4’-OCH2O* 3’,4’-OCH2O*

5-OH, 7-OMe 5,3’,4’-triOH-7-OMe 5,5’-diOH, 7-OMe 5,3’-diOH, 7-OMe 5,7,4’-triOH 5-OH, 7-OMe 5,7,3’,4’-tetraOH 5,7,3’-triOH, 4’-OMe

Methylendioxy-flavones 5-OH 7-OMe 7-OMe 7-OMe 5,6-diOMe 5-OH-7-OMe 5,7-diOMe 7-OH, 6-OMe 6,7-diOMe 5,4’-diOH 7,2’diOMe 7,8-diOMe 5-OH, 6,8-OMe 5,6,7-triOMe

27 28 29 30 31 32 33 34

35 36 37 38 39 40 41 42 43 44 45 46 47 48

6-Me, 8-CHO

5,7-diOH

26

6-Me* 6,8-diMe* 6-Me, 8-diMe, 7 ¼ O 8-Me, 6-CHO

5,3’,4’-triOH-7-OMe 5,3’,4’-triOH-7-OMe 5-OH 5,7-diOH

22 23 24 25

Ageconyflavon A*

Prosogerin-A Milletenin C Kanzakiflavon-2 Millettocalyxin A*

Unonal-7-Me Muxiangrine III* Muxiangrine II* Muxiangrine I* Drymariatin; glycoside only Hoslundal DeMe-torosaflavone D* Torosaflavone D*

Isounonal

Dasytrichone Unonal

Stem bark Stem bark Root bark Whole plant Whole plant

Fabac. Fabac. Fabac. (Mim.) Scroph. Ast. Millettia erythrocalyx Albizia odoratissima Limnophila indica Ageratum conyzoides

Stem bark Fruit

Fabac. Rutac. Millettia leucantha Neoraputia magnifica Millettia erythrocalyx

Leaf Stem bark

Fabac. Fabac.

Aerial parts Leaf

Fabac. Fabac.

Cassia nomane Cassia torosa

Millettia erythrocalyx Millettia leucantha

Aerial parts Aerial parts Aerial parts

Lam.. Lam.. Lam..

Elsholtzia stauntonii Elsholtzia stauntonii Elsholtzia stauntonii

428 174 430 268

428

429 286

428 429

68 67

65 65 65

64 60 62 58 64 60

427 427 63

Flavones and Flavonols continued

Stems Seeds Root

Annonac. Annonac. Annonac. Annonac. Annonac. Annonac.

Dasymascholon rostratum Desmos chinensis Desmos chinensis Desmos cochinchinensis Dasymaschalon rostratum Desmos chinensis Stem Seeds

Root Root Stems, leaves

Ranunculac. Ranunculac. Annonac.

Hydrastis canadensis Hydrastis canadensis Dasymaschalon trichophorum

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 681 8.9.2005 10:37am

681

6,7-O2CH2 3’,4’-OCH2O 3’,4’-OCH2O

7,8-di-C5* 8-C5-OH 6-C5 8-C5 8-C5 8-C5-OH 8-C5-OH 8-C5 6-C5* 8-C5 8-C5(OH)2* 3’-C5*

5,3’,4’,5’-tetraOMe 7-OH, 5,6,8,5’-OMe 5,6,7,8,5’-pentaOMe

C-Prenylflavones 5-OMe 7-OMe 5,7-diOH 5,7-diOH 5-OH, 7-OMe 5,7-diOMe 5,7-diOMe 5,7-diOMe 7,4’-diOH 7,4’-diOH 7,4’-diOH 7,4’-diOH

7,4’-diOH 7,4’-diOH 5,7-OH, 6OMe

55 56 57

58 59 60 61 62 63 64 65 66 67 68 69

70 71 72

Licoflavone B (Prenyllicoflavone A)

Brosimacutin F Kanzonol D

5-Methoxy-7,8-diprenylflavone trans-Lanceolatin; Lanceolatin A 6-Prenylchrysin 8-Prenylchrysin Tephrinone cis-Tephrostachin trans-Tephrostachin trans-Anhydrotephr Licoflavon A*

Eupalestin

Kanzakiflavon-1 Linderoflavone A Linderoflavone B

Trivial Name

Fabac. Fabac. Borag.

Fabac. Fabac. Morac. Fabac. Glycyrrhiza eurycarpa Glycyrrhiza echinata Brosimum acutifolium Glycyrrhiza eurycarpa Glycyrrhiza inflata Glycyrrhiza glabra Ehretia ovalifolia

Fabac.

Ast. Ast. Ast.

Ast. Morac. Rutac.

Rutac. Rutac.

Family

Tephrosia barbigera

Ageratum conyzoides Ageratum tomentosum var. bracteatum Ozothamnus lycopodioides#

Ozothamnus lycopodioides Ficus maxima Neoraputia paraensis

Neoraputia magnifica Neoraputia paraensis

Plant Species

Root Cell culture Bark Root Synthesis Root Root Leaves

Synthesis Synthesis

Seeds

Aerial parts Leaf þ flower Leaf exudate

Leaf exudate Leaf Aerial parts

Fruit Aerial parts

Plant Organ

17 3 433 17 434 74 75 78

432 432

4

27 431 69

69 77 285

286 285

Ref.

682

6,3’-diC5* 6,3’-diC5 3-C5

3’,4’-OCH2O* 3’,4’-OCH2O 6,7-O2CH2 3’,4’-OCH2O 3’,4’-OCH2O 3’,4’-OCH2O

5,7,4’triOMe 5,7,5’-triOMe 5,8-diOH, 4’-OMe 5,7-diOH, 6,8-diOMe 5,6,7,8-tetraOMe 5,6,7,5’-tetraOMe

49 50 51 52 53 54

Other Substituents

OH- and OMe-Substitution

No.

TABLE 12.3 Flavones with Other Substituents — continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 682 8.9.2005 10:37am

Flavonoids: Chemistry, Biochemistry, and Applications

5,7,4’-triOH

5,7,4’-triOH

5,7,4’-triOH

5,7,4’-triOH 5,7,4’-OH 5,7,4’-triOH 5,7,4’-triOH 5,7,4’-OH 5,7,4’-triOH 5,7,4’-triOH 5,7,4’-triOH 5,7,4’-triOH 5,7,4’-triOH 5,7,4’-triOH 5,7,4’-triOH 5,4’-diOH, 7-OMe 5,7-diOH, 4’-OMe 5,7-diOH, 4’-OMe 7,2’,4’-triOH 5,7,2’,4’-tetraOH 5,7,2’,4’-tetraOH

5,7,2’,4’-tetraOH 5,7,2’,4’-tetraOH 5,7,2’,4’-tetraOH

73

74

75

76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93

94 95 96

6-C5-OH 6-C10 8-C15

8-C5 8-C5-OH* 3’-C5 3’-C5-OH 6-C10 3’-C10 6,2’-diC5 6,3’-diC5 6,3’-diC5-OH 8,3’-diC5 3’,5’-diC5 3’-C5, 5’-C5-OH* 8-C5 8-C5 8,3’-diC5 3-C10 3-C5 6-C5

8-C5*

6-C5-OH*

6-C5*

Oxidihydroartocarpesin Albanin E, revised Moralbanone*

Rubraflavone A Albanin A Artocarpesin

Honyucitrin Yinyanghuo B* Artonin U

Albanin D, revised Kuwanon S Isoartocarpin Gancaonin Q

8-Prenylapigenin Ephedroidin Yinyanghuo D

Licoflavone C*, 8-prenylapigenin

Dinklagin C*

6-Prenyl-apigenin

Morus alba

Cudrania cochinchinensis Artocarpus elasticus Artocarpus heterophyllus Maclura pomifera

Morac.

Morac. Morac. Morac. Morac.

Berberidac. Morac.

Berberidac.

Vancouveria hexandra — Epimedium sagittatum Artocarpus heterophyllus

Morac. Morac.

Fabac. Berberidac. Berberidac.

Morac. Morac. Morac. Morac. Morac. Morac. Morac. Morac. Morac. Fabac.

Morus alba Artocarpus integrifolia

Genista ephedroides Epimedium sagittatum Vancouveria hexandra

Cudrania cochinchinensis Dorstenia ciliata Dorstenia kameruniana Maclura pomifera Dorstenia dinklagii Maclura pomifera Cudrania cochinchinensis Dorstenia ciliata Dorstenia poinsettifolia Glycyrrhiza inflata

Synthesis Root bark

Root Wood Heartwood Fruit

Leaf Bark

71 445

435 447 448 438

444 446

553

435 436 437 438 439 440 435 436 441 74 442 443 444 553 71 445 3

Flavones and Flavonols continued

Underground parts

Root Aerial parts Leaf Fruit Twigs Stem, leaf Root Twigs Leaf Root Synthesis Aerial parts Leaf Underground parts Synthesis Root bark Heartwood

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 683 8.9.2005 10:37am

683

5,7,2’,4’-tetraOH 5,7,2’,4’-tetraOH 5,7,2’,4’-tetraOH 5,7,2’,4’-tetraOH 5,7,2’,4’-tetraOH 5,7,2’,4’-tetraOH 5,7,2’,4’-tetraOH 5,7,2’,4’-tetraOH 5,7,2’,4’-tetraOH 5,2’,4’-triOH, 7-OMe 5,2’,4’-triOH,7-OMe 5,2’,4’-triOH, 7-OMe 5,2’,4’-triOH, 7-OMe 5,3’,4’-triOH-7-OMe 5,7,2’-triOH, 4’-OMe 5,4’-diOH, 7,2’-OMe 5,7,3’,4’-tetraOH 5,7,3’,4’-tetraOH 5,7,3’,4’-tetraOH 5,7,3’,4’-tetraOH 5,7,4’-triOH, 3’-OMe 5,7,4’-triOH, 3’-OMe 5,3’-diOH, 7,4’-diOMe 5,7,2’,5’-OH-4’-OMe 5,2’,5’-OH-7,4’-OMe 5,7,5’-OH-2’,4’-OMe 5,7,3’,4’,5’-pentaOH 5,7,4’-OH-3’,5’-OMe O-Prenylflavones 4’-OH, 5-OMe 4’-OH,7-OMe 7-O-C5 (epoxy) 7-O-C5 (epoxy)*

3,6-diC5 3,8-diC5 3-C10, 6-C5 8-C5, 3-C10* 6,5’-diC5 3,3’-diC5 3,6,8-triC5* 3,6,8-triC5 6,8,3’-triC5* 3-C5 8-C5 3,6-diC5 3-C5, 8-C10 6,8-diCH3, 5’-C5* 6,8-diC5 8-C5* 6-C5* 6-C5* 8-C5 8,5’-diC5 6-C5* 6-C10 6-C5 3,3’-diC5* 3-C5* 3-C5* 3-C5 8-C5

Other Substituents

Achyrocline flaccida Achyrocline flaccida

Root bark Heartwood Heartwood

Morac. Morac. Morac.

Aerial parts Aerial parts

Aerial parts Aerial parts

Berberidac. Morac.

Ast. Ast.

Root bark Aerial parts Callus

Root cortex Root bark Root bark Wood Root Root — Root ? — Aerial parts

Morac. Morac. Morac. Morac. Morac. Morac. — Morac. Morac. — Lam.

Artocarpus communis Cudrania tricuspidata Artocarpus heterophyllus Artocarpus elasticus Dorstenia psilurus Dorstenia psilurus — Artocarpus heterophylllus Clarisia racemosa — Elsholtzia stauntonii Morac. Fabac. Hypericaceae

Root bark Root bark

Plant Organ

Morac. Morac.

Family

Cudrania tricuspidata Morus australis

Plant Species

Artocarpetin B Artocarpus heterophyllus Gancaonin O*; 6-prenylluteolin Glycyrrhiza uralensis Hypericum peforatum 8-Prenylluteolin Epimedokoreanin B Epimedium koreanun 6-Prenylchrysoeriol Dorstenia mannii Cannflavin A Cannflavin B Heteroartonin A* Artocarpus heterophyllus Artoindonesianin Q* Artocarpus champeden Artoindonesianin R* Artocarpus champeden Asplenetin Baohuosu

Cudraflavone C Mulberrin, Kuwanon C Rubraflavone C Artocommunol CD* Cudraflavone D Kuwanon T Artelasticin* Dorsilurin D Dorsilurin A* Integrin Artocarpetin A Artocarpin Brosimone H Muxiangrine III*

Trivial Name

76 76

452 460 460

458 459

452 457 218

451 449 452 447 453 454 — 455 456 — 65

449 450

Ref.

684

125 126

97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124

No. OH- and OMe-Substitution

TABLE 12.3 Flavones with Other Substituents — continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 684 8.9.2005 10:37am

Flavonoids: Chemistry, Biochemistry, and Applications

5-OMe

6-OMe 2’-OH

5’-OMe 5,7-diOH

5,4’-diOH

5,4’-diOMe 5,4’-diOMe 5,4’-diOH 5,4’-diOH 5,4’-diOH

136

137 138

139 140

141

142 143 144 145 146

Isopongaflavon (Candidin)

Millettocalyxin B* Ugonine C Ovalifolin

7,6-ODmp-OH* 7,6-ODmp 7,8-ODmp 7,6-/3,6’-ODmp 7,8-/3,6’-ODmp

7,6-ODmp

Atalantoflavon Isocyclomorusin Cyclomorusin ¼ cyclomulberrochromene

Dinklagin B*

Carpachromene*

7,8-ODmp-diOAc, see Figure 12.2 7,8-ODmp* 4,3/6,5/7,8-triODmp, Dorsilurin E 4’ ¼ O see Figure 12.2 7,8-ODmp 4’,3’-ODmp* Yinyanghuo C*

7,8-ODmp 7,6-ODmp 7,8-ODmp

5-OH 5-OMe 5-OMe

133 134 135

5-O-allyl 4’-O-C5* 4’,5’-OCH2O* 7,8-fur 7,8-fur*

7,8-ODmp*

Pyranoflavones

6,7,4’-triOMe 5,6,7,3’,5’-OMe 7-OMe-6-OC5 5,4’-diOH, 6-OMe 6-O-C5

132

127 128 129 130 131

451

Root cortex Morac. Artocarpus communis

Flavones and Flavonols continued

471 445

444 553 434 469 437 440 470 439 469

464 453

465 297 466 467 468

463 464

77 461 462 297 461

Stem Root bark

Leaf Underground parts Synthesis Leaf Leaf Stem and leaf Leaf Twig Leaf

Root Root

Seed Root Root Synthesis Stem bark

Root Root

Leaf Stem bark Rhizome Root Leaf

Morac. Morac.

Fabac. Morac. Morac. Rutac. Morac. Fabac.

Berberidac. Berberidac.

Fabac. Morac.

Fabac.

Fabac. Fabac. Fabac.

Fabac. Fabac.

Morac. Fabac. Ophioglossac. Fabac. Fabac.

Artocarpus altilis Morus alba

Lonchocarpus xuul, L. yucatanensis Dorstenia kameruniana Maclura pomifera Atalantia monophylla Dorstenia dinklagii Lonchocarpus xuul, L. yucatanensis

Epimedium sagittatum Vancouveria hexandra

Lonchocarpus subglaucescens Dorstenia psilurus

Pongamia pinnata (syn. P- glabra)

Tephrosia praecans Pongamia pinnata Tephrosia tunicata

Dahlstedtia pentaphylla Lonchocarpus subglaucesc.

Ficus maxima Millettia erythrocalyx Helminthostachys zeylanica Pongamia pinnata Millettia erythrocalyx

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 685 8.9.2005 10:37am

685

5-OMe 6-OMe

8-OMe 2’-OMe

164 165

166 167

7,6-fur 7,8-fur

7,6-fur 7,8-fur

7,8-fur

5-OH

7,8-ODmp 2’,3-ODmp* 7,6-ODmp 5,6-ODmp 7,6-ODmp* 7,6-ODmp* 7,6-ODmp 5,6-ODmp 7,6-ODmp-C5* 7,8-ODmp-C5

163

5,4’-diOH, 3’-OMe 5,7,3’,4’-tetraOH 5,4’-diOH,3’,5’-diOMe5-OH, 7,8,3’,4’-OMe 5-OH-7,3’,4’,5’-OMe 5,4’-diOH,8,3’,5’-triOMe 5-OH, 8,3’,4’,5’-tetra-OMe 7,8,3’,4’,5’.pentaOMe 5,2’,4’-triOH 5,2’,4’-triOH Furanoflavones

152 153 154 155 156 157 158 159 160 161

5,6-ODmp 7,6-ODmp

7,8-fur

7,4’-diOH-3’-OMe 5,4’-diOH-3’-OMe

150 151

3,6’-ODmp* 4’,3’-ODmp* 7,6-ODmp

Other Substituents

Kanjone*

Pinnatin

Pongaglabol

Lanceolatin B

Australon A* Brosimone G

Racemoflavon Cyclochampedol*

Ciliatin B

Cyclocommunol* Yinyanghuo E Cycloartocarpesin

Trivial Name

Millettia peguensis Millettia sanagana Pongamia pinnata Millettia peguensis Tephrosia purpurea Millettia sanagana Pongamia glabra Millettia erythrocalyx Millettia peguensis Millettia sanagana Pongamia glabra Pongamia glabra

Fabac. Fabac. Fabac. Fabac. Fabac. Fabac. Fabac. Fabac. Fabac. Fabac. Fabac. Fabac.

Leaf, st. bark Root bark Root Leaf, st. bark Aerial parts Root bark Seed Root Leaf, st. bark Root bark Leaf Seed

Aerial parts Aerial parts Aerial parts Leaf Root bark Root Neoraputia paraensis Neoraputia paraensis

Rutac. Rutac. Rutac. Rutac. Neoraputia alba Morus australis Morac. Brosimopsis oblongifolia Morac.

Root bark Leaf Root bark Cell culture Aerial parts Leaf

Plant Organ

Bark Aerial parts

Morac. Berberidac. Morac. Morac. Morac. Fabac.

Family

Morac. Rutac.

Artocarpus champeden Neoraputia paraensis

Artocarpus communis Epimedium sagittatum Cudrania tricuspidata Maclura pomifera Dorstenia ciliata Lonchocarpus xuul, L. yucatanensis

Plant Species

478 79 297 478 479 79 480 461 478 79 480 481

285 475 285 476 450 477

474 475

472 444 449 473 436 469

Ref.

686

162

5,7,4’-triOH 5,7,5’-triOH 5,2’,4’-triOH

147 148 149

No. OH- and OMe-Substitution

TABLE 12.3 Flavones with Other Substituents — continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 686 8.9.2005 10:37am

Flavonoids: Chemistry, Biochemistry, and Applications

Fulvinervin B Fulvinervin C Kanzonol E*

Furano- and pyranosubstitution 6,5-ODmp, 7,8-fur* 5,3’,6’-triOH 7,6-ODmp, 4’,5’-dihydrofur-2’’-C3 5,3’,6’-triOH 7,6-ODmp, 4’,5’-dihydrofur-2’’-C3 5,3’,4’-triOH 7,6-ODmp, 6’,5’-dihydrofur-2’’-C3

C-prenyl- and C-pyranosubstitution 5-OH 6-C5, 7,8-ODmp 5-OH 6-C5-OH, 7,8-ODmp 7-OH 6-C5, 3’,4’-ODmp*

5,7-diOH 5,2’-diOH 5,2’-diOH 5,4’-diOH 5,4’-diOH *

184 185 186 187

188 189 190

191 192 193 194 195

5’-C5-OH, 4’,3’-ODmp 6-C5, 7,8/4’,5’-diODmp 8-C5, 7,6/4’,5’-diODmp 3-C5-OH, 7,8-ODmp 6-C5, 7,8-ODmp*

Sanaganone* Millettia sanagana* Dihydrofur-arto-bilichromene b1 Dihydrofur-arto-bilichromene b2 Dihydrofur-arto-bilichromene a

5,4’-diOH 4’-OH, 6-OMe 2’,5’-diOMe 5,3’,4’-triOH 5,3’-diOH, 4’-OMe

Artocommunol CC* Laxifolin*

Yinyanghuo A*

Artelastofuran* 6-OMe-isopongaglabol Millettocalyxin C* Demethyltorosaflavone C Torosaflavone C

Epimedokoreanin A*

Epimedium sagittatum Euchresta formosana Euchresta formosana Artocarpus communis Derris laxiflora Derris laxiflora

Tephrosia fulvinervis Tephrosia fulvinervis Glycyrrhiza eurycarpa

486 487 17 434 444 488 488 451 489 490

79

461 68 67

485

482 483 436 440 440 484

482

461

Flavones and Flavonols continued

Pods Seed Root Synthesis Berberidac. Leaf Fabac. Root Fabac. Root Morac. Root cortex Fabac. Root Fabac. Root

Fabac. Fabac. Fabac.

Root bark

Leaf Aerial parts Leaf

Morac. Fabac. Fabac.

Millettia erythrocalyx Cassia nomane Cassia torosa

Fabac.

Wood

Morac.

Artocarpus elasticus

Root Aerial parts Stem and leaf Stem and leaf Aerial parts

Fabac. Morac. Morac. Morac. Berberidac.

Derris mollis Dorstenia ciliata Maclura pomifera Maclura pomifera Epimedium koreanum

Ciliatin A* ‘‘Compound 8’’

Flower

Fabac.

Pongamia glabra

Leaf

Pongone Isopongaglabol Glabone

Fabac.

Millettia erythrocalyx

Pongol-Me

179 180 181 182 183

7,8-fur 7,8-fur 7,8-fur 7,6-fur 7,8-fur 7,6-fur 7,8-fur 7,6-dihydrofur-C3, see Figure 12.3 7,6-dihydrofur-C3-OH, see Figure 12.3 7,6-dihydrofurODmp-OH* 7,8-dihydrofur-2’’-C3/4’,5’-dihfurOH-5’’-C3-OH; see Figure 12.3 7,8-dihydrofurODmp-OH, see Figure 12.6 7,8-fur 7,8-fur* 7,6-bisfurano — see Figure 12.3 7,6- bisfurano — see Figure 12.3

2’-OMe 2’-OMe 3’-OH 3’-OMe 4’-OH 4’-OMe 4’-OMe 5,4’-diOH5,4’-diOH5,4’-diOH 5,3’-diOH

168 169 170 171 172 173 174 175 176 177 178

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c012 Final Proof page 687 8.9.2005 10:37am

687

5,2’,4’,5’-tetraOH 5,7,2’-triOH 5,7,2’-triOH

C-linked aromatic substituents 5,7-diOH 6-C-cinnamyl 5,7,4’-triOH 8-C-p-OH-benzyl* 5,7,3’,4’-tetraOH 8-C-p-OH-benzyl* 5,7,3’-OH-4’-OMe 8-C-p-OH-benzyl*

208 209 210

211 212 213 214

217

216

C-linked ketopyrano substituents 5-OH,7-OMe 6,5’’-Ketopyrano . . . 3’’-OH*, see Figure 12.4 5-OH, 7-OMe 6,5’’-Ketopyrano . . . 3’’-Me, see Figure 12.4 5,7-diOMe 6,5’’-Ketopyrano . . . 3’’-OH, see Figure 12.4

3-C5, 7,8-ODmp 3,8-diC5; 7,6-ODmp, see Figure 12.2 3’-C5, 7,6-ODmp 3-C5, 2’,3’-ODmp-C5 3-C5, 3’,4’-ODmp-C5

chinese propolis Thymus hirtus Thymus hirtus Thymus hirtus

Morus sp. Morus sp.

5-OMe-hoslundin

Hoslunda opposita

Lam.

Lam.

Lam. Lam. Lam.

Morac. Morac.

Twigs

Leaf

Aerial parts Aerial parts Aerial parts

Root bark Root bark

144

496

81 80 80 80

495 495

454 491 492 493 494 452

Root Root bark Shoot bark Stem bark Shoot bark Root bark

Morac. Morac. Morac. Morac. Morac. Fabac.

Dorstenia psiluris Morus insignis Artocarpus communis Artocarpus kemando Artocarpus communis Artocarpus heterophyllus

489 490

Ref.

553 450 445

Root Root

Plant Organ

Berberidac. Underground parts Morac. Root bark Morac. Root bark

Fabac. Fabac.

Family

Vancouveria hexandra Morus australis Morus alba

Derris laxiflora Derris laxiflora

Plant Species

Hosloppin Hoslunda opposita (3’’-O-demethylhoslundin)* Hoslundin

p-Hydroxybenzylluteolin p-Hydroxybenzyl-diosmetin

Artobilochromene Sanggenon K Sanggenon J

KB-2 Heterophyllin

Morusin; Mulberrochromene Oxydihydro-morusin Rubraflavone D Dorsilurin B* Morusignin L Artonin E; KB-3

Kuwanon B Cyclomulberrin

Isolaxifolin*

Trivial Name

688

215

5,2’4’,5’-tetraOH 5,2’,4’,5’-tetraOH

206 207

3-C5, 3’,4’-ODmp 8-C5, 2’,3-ODmp 3’-C5, 4’,5’-ODmp 3-C5, 7,8-ODmp 3-C5-OH, 7,8-ODmp 3-C10, 7,6-ODmp 3,6-diC5, 7,8-ODmpOH* 7,6-ODmp, 3-C5-OH 3-C5, 7,8-ODmp

5,7,2’-triOH 5,7,4’-triOH 5,7-diOH 5,2’,4’-triOH 5,2’,4’-triOH 5,2’,4’-triOH 5,2’,4’-triOH 5,2’,4’-triOH 5,2’4’,5’-tetraOH

197 198 199 200 201 202 203 204 205

8-C5, 7,6-ODmp*

5,4’-diOH

Other Substituents

196

No. OH- and OMe-Substitution

TABLE 12.3 Flavones with Other Substituents — continued

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7,8-bisfur –OH 7,8-bisfur –Oac — 7,8-bisfur —*, see Figure 12.5 7,8-bisfur — 7,8-bisfur — 7,8-pyr-fur (3’’-oxo) 7,8-pyr-fur (3’’-oxo-4’’-OAc) 7,8-fur-C4-diOAc 8-diMe-oxo-furano*, see Figure 12.5 7,8-oxofuryl*, see Figure 12.5 8-furyl (2’’,4’’-diOH) 8-furyl (4’’-oxo) 8-furyl (2’’ ¼ oxo), see Figure 12.5 8-furyl (2’’-oxo)

3,6’-cyclo C6-C3; 6-C5 3,6’-cyclo C6-C3* 3,6’-cyclo C6-C3* 3,6’cyclo-C6-diMe-fur* 3,6’-cyclo C6-5’-fur* 3,6’-cyclo C6-5’-fur*, see Figure 12.6 3,6’-cyclo-C6-5’-fur; 4’-C5* 3,6’-cyclo-C6-5’-fur; 4’-C5*

5-OMe 5-OMe 5-OMe 5-OMe 5-OMe 5-OMe 5,7-diOMe

5-OMe 7-OMe 7-OMe 7-OMe 5,7-diOMe

Artocarpus flavones 5,7,5’-triOH,4’-OMe 5,2’,5’-triOH,7,4’-diOMe 5,7,2’,5’-tetraOH, 4’-OMe 5,7,2’,4’,tetraOH 5,4’-diOH, 7,2’-diOMe 5,2’,4’-triOH, 7-OMe 5,7,2’,4’-tetraOH5,2’,4’-triOH,7-OMe

223 224 225 226 227 228 229 230 231

232 233 234 235 236

237 238 239 240 241 242 243 244

6,6’’-Ketopyrano . . . 3’’-OH*, see Figure 12.4 7,8-bisfur — 7,8-bisfur — 7,8- bisfur — 7,8- bisfur —

Tephrosia flavones

5,7-diOMe

219 220 221 222

218

Cycloaltilisin Artoindonesianin S* Artoindonesianin T* Artoindonesianin P* Artonin L* Artonin K* Artonin J* Artonin T*

Tephrorianin* Tepurindol Tephroglabrine Apollinine Tachrosin

Pseudosemiglabrinol Pseudosemiglabrin Enantiomultijugin Multijugin Multijuginol Stachyoidin Tephrodin Polystachin Hookerianin*

Glabratephrinol Glabratephrin Semiglabrinol Semiglabrin

Oppositin

apollinea semiglabra semiglabra semiglabra purpurea apollinea semiglabra viciodes multijuga multijuga polystachyoides polystachyoides polystachyoides hookeriana

Artocarpus altilis Artocarpus champeden Artocarpus champeden Artocarpus lanceifolius Artocarpus heterophyllus Artocarpus heterophyllus Artocarpus heterophyllus Artocarpus heterophyllus

Tephrosia hookeriana Tephrosia purpurea Tephrosia purpurea Tephrosia apollinea Tephrosia polystachyoides

Tephrosia Tephrosia Tephrosia Tephrosia Tephrosia Tephrosia Tephrosia Tephrosia Tephrosia Tephrosia Tephrosia Tephrosia Tephrosia Tephrosia

Bidens pilosa Hoslunda opposita

Morac. Morac. Morac. Morac. Morac. Morac. Morac. Morac.

Fabac. Fabac. Fabac. Fabac. Fabac.

Fabac. Fabac. Fabac. Fabac. Fabac. Fabac. Fabac. Fabac. Fabac. Fabac. Fabac. Fabac. Fabac. Fabac.

Ast. Lam.

Stem Heartwood Heartwood Tree bark Root bark Root bark Root bark Root bark

Pods Root Root Seed Leaf and stem

471 460 460 506 507 492 507 446

82 500 500 500 500

498 499 500 500 479 501 502 503 504 504 3 3 555 505

497 144

Flavones and Flavonols continued

Seed Aerial parts and root Aerial part. roots Aerial part. roots Aerial parts Aerial parts Aerial parts Aerial parts Aerial parts and root Aerial parts and root Not mentioned Not mentioned Aerial parts Root

Aerial parts Twigs

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689

5,2’4’,5’-tetra-OH 5-OH, 4’-OMe 5,2’,4’,5’-tetraOH

5,2’,5’-triOH, 4’-OMe 5,2’,4’,triOH

5,2’,4’-triOH 5,2’,4’-triOH 5,2’-diOH, 4’-OMe 5,2’-diOH, 4’-OMe 5,2’,5’-triOH, 7-OMe 5,7,2’,4’-tetraOH 5,2’,5’-triOH 5,7,4’-triOH, 3’,6’-di-oxo

5-OH; 2’,5’-di-oxo

5,4’-dOH, 2’,5’-di-oxo 5OH,7OMe 5,4’-diOH 5,4’diOH# 5-OH,4’OMe

5,7,4’-triOH

5,7,4’-triOH 5,7,4’-triOH

245 246 247

248 249

250 251 252 253 254 255 256 257

258

259 260 261 262 263

264

265 266

No. OH- and OMe-Substitution

6-C5, 3,6’-cycl-O-C5 6,8-diC5, 3,6’-cycl-O-C5

7,8-ODmp, 3’,4’-ODmp, 3,6’-cyclo-C6-C3*, see Figure 12.6 7,8-ODmp; 3,6’-cycloC6-C3, 2’,5’-epoxy* 6-C5, 3,6’-cyclo O-C6-C3* 8-C5, 7,6-ODmp, 3,6’-cycl-OC5* 8-C5-7,6-fur-C3-OH, 3,6’-cyclo-O-C6-C3-OH* 7,8-ODmp, C5-O-C5; 3,6’-cycl-O-C5*, see Figure 12.6 6-C5, 3,6’-cycl-O-C5*

Brosimone I Artelastin*

Cyclocommunin ¼ (isocyclomulberrin*)

Artonin P* Artoindonesianin B* Artelastochromene* Carpelastofuran* Artocommunol CA*

Artonol D*

Artonin M Artoindonesianin A* Cycloartomunoxanthone* Artonin F* Artonol E* Artonin N* Artonol C* Artonin O*

Artomunoxanthone Cycloartobiloxanthone

KB-1 Artomunoxanthentrione Artobiloxanthone

Trivial Name

Stem Root bark Wood Root Wood

Morac. Morac. Morac. Morac. Artocarpus communis Artocarpus elasticus Brosimopsis oblongifolia Artocarpus elasticus

Bark Root Wood Wood Root cortex

Shoot bark Root bark Bark Bark Root bark Bark Bark Bark Root Root bark Bark Bark Bark Bark Bark Stem bark Bark

472 485 477 447

471

552 510 447 513 451

494 508 509 492 3 509 492 552 510 511 512 492 552 492 552 493 492

Plant Organ Ref.

Morac.

Morac. Morac. Morac. Morac. Morac.

Morac. Morac. Morac. Morac. Morac. Morac. Morac. Morac. Morac. Morac. Morac. Morac. Morac. Morac. Morac. Morac. Morac.

Family

Artocarpus altifolius

Artocarpus rigida Artocarpus champeden Artocarpus elasticus Artocarpus elasticus Artocarpus communis

Artocarpus communis Artocarpus communis Artocarpus nobilis Artocarpus communis Artocarpus communis Artocarpus nobilis Artocarpus communis Artocarpus rigida Artocarpus champeden Artocarpus communis Artocarpus communis Artocarpus communis Artocarpus rigida Artocarpus communis Artocarpus rigida Artocarpus kemando Artocarpus communis

Plant Species

690

7,6-ODmp; 3,6’-cyclo C6-5’-fur 8-C10, 7,6-ODmp-3,6’ cyclo-C6-diMe-fur* 7,8-ODmp, 3,6’-cyclo C6-5’-fur* 6-C5; 7,8-ODmp, 3,6’-cyclo C6-5’-fur* 3’,4’-ODmp, 3,6’-cyclo-C6-C3*, see Figure 12.6 6-C5, 3’,4’-ODmp, 3,6’-cycloC6-C3* 7,8-ODmp, 3’,4’-ODmp, 3,6’-cyclo-C6-C3* 6,5’-C5; 3,6’-cycloC6-C3*

7,8-ODmp, 3,6’-cyclo C6 7,8-ODmp, 3,6’-cyclo-C6-diMe-fur

7,8-ODmp, 3,6’-cyclo-C6 7,8-ODmp; 3,6’-cyclo-C6-C3 7,8-ODmp, 3,6’-cyclo-C6-C3

Other Substituents

TABLE 12.3 Flavones with Other Substituents — continued

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6-(8’’-umbelliferyl)-*, see Figure 12.7 8-(6’’-umbelliferyl)-*, see Figure 12.7

Flavone–coumarin hybrids 5,7,4’-triOH 5,7,4’-triOH

275 276

Oxyisocyclointegrin* Cyclointegrin* Artonin S Cycloartocarpin Cycloheterophyllin Cycloartomunin Dihydro-isocycloartomunin*

Artelastocarpin

Root bark Root bark

Morac. Morac.

Artocarpus communis Artocarpus communis

Thymeleac. Thymeleac.

Wood Heartwood Heartwood Bark; shoot

Morac. Morac. Morac. Morac.

Artocarpus elasticus Artocarpus integrifolia Artocarpus integrifolia Artocarpus heterophyllus

Gnidia soccotrana Gnidia soccotrana

Wood

Morac.

Artocarpus elasticus

83 83

511 511

513 3 3 446

485

Notes: C5 means, e.g., Me2CH–CH¼¼CH– or Me2C ¼ CH–CH2–; C5-OH means, e.g., Me2C(OH)CH2–CH2–; C10 means, e.g., geranyl- or lavandulyl-. For further possibilities see Barron and Ibrahim.3 The pyrano ring is indicated by –ODmp for oxygen-linked dimethylallyl unit. For the meaning of C3, cyclo-C6, etc. see examples in figures, as indicated for related structures. *For explanation, please see text.

3,6’-cyclo O-C6* 3,6’-cyclo O-C7* 6-C5, 3,6’-cyclo O-C6-C3 6-C5, 3,6’-cycl-O-C5 8-C5, 7,6-ODmp, 3,6’-cycl-O-C5 7,8-ODmp, 3,6’-cycl-O-C5 8-C5, 3,6’-cycl-O-C5-ODmp*

5,4’-diOH, 7-OMe 5,4’-diOH, 7-OMe 5,4’-diOH, 7-OMe 5,4’-diOH, 7-OMe 5,4’,5’-triOH 5,5’-diOH, 4’-OMe 5,3’,4’-triOH,7-OMe

268 269 270 271 272 273 274

6,8-diC5, 3,6’-cyclo-O-C6-C3-OH, see Figure 12.6

5,7,4’-triOH

267

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reported as a new source for desmosflavone (5-OH-7OMe-6,8-diMe flavone),58 a compound already known from Leptospermum scoparium (Myrtaceae).59 C-Formylflavones, being substituted at the 6 and 8 position (unonal and related compounds), have been reported for species of the genus Desmos (Annonaceae).60–62 Another derivative with unusual substitution, dasytrichone, was isolated from two species of Dasymascholon (Annonaceae).63,64 Thus, the accumulation of these types of compounds in Annonaceae may be of chemosystematic significance. Muxiangrines I and II, comprising a pyrano structure and C-methyl substitution (compounds 28, 29, Table 12.3), have been isolated along with muxiangrine III (C-methyl- and prenyl-substitution; compound 30, Table 12.3) from the aerial parts of Elsholtzia stauntonii (Lamiaceae).65 Drymariatin, a C-2-substituted derivative, is known as glycoside only (Drymaria diandra, Caryophyllaceae).66 Another C-2-substituted flavone, hoslundal, was earlier reported from Hoslunda (Lamiaceae).6 From species of Cassia (Fabaceae), flavones with a C-6-acrylic acid substituent were isolated.67,68 This substitution pattern appears to be quite unique. Hoslundal, torosaflavone D, and its dimethyl derivative (for formulae see Figure 12.1) were all detected in either leaves or aerial parts, but not indicated as exudate compounds.

12.5.2 METHYLENEDIOXYFLAVONES Predominantly, this substitution occurs in the 3’,4’-position of ring B, rarely between neighboring OH-groups in ring A. Such compounds were reported from Fabaceae, Rutaceae, and some Asteraceae, from all parts of the plants. Only in rare cases, their accumulation as exudate constituents was documented (Ozothamnus, Asteraceae).69,70

12.5.3 C-PRENYLFLAVONES Linear substituted prenyl flavones exhibit a tendency towards prenylation at positions 3,6- and 8- of the flavonoid molecule. 3’-Prenylation of ring B occurs occasionally. The prenyl residue is mostly of the 3,3-dimethylallyl structure or the OH-equivalent of it. The prenyl residue ‘‘1,1-dimethylallyl’’ is rare. Geranylated flavones are also not very MeO

H

C

O

CH2 Hoslundal OH

O

O

OH 2⬘

8

HO

O

2

3⬘ 4⬘

1⬘

7 3

HOOC 3⬙

1⬙

5

2⬙

OH

FIGURE 12.1 C2/C3-substituted flavones.

4

6⬘

OR

5⬘

O R = Me: Torosaflavone D R = H: Demethyltorosaflavone D

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693

common (e.g., albanin D). For further types of substituents the reader may consult the review of Barron and Ibrahim.3 The 7,6-chromenoflavone carpachromene affords an example of a more widespread occurrence in species of Fabaceae, Moraceae, and Rutaceae (Table 12.3). Similar results may be expected for other complex flavones in the future. Some problematical structures and names should be mentioned here. Revised structures concern albanins D (compound 80, Table 12.3) and E (compound 95, Table 12.3) from Morus alba, which are not 8-geranyl-, but 6-geranyl-derivatives of 5,7,4’-triOH and 5,7,2’,4’-tetraOH flavone, respectively.71 The flavone lanceolatin A (compound 59, Table 12.3) is definitely a C-prenylated flavone, isolated originally from the stems of Tephrosia lanceolata.72 Thus, this name must not be used for a biflavone from Lophira lanceolata as Pegnyemb et al. have done later.73 The compound 7,4’-diOH-6,3’-diC5 flavone, isolated from the roots of Glycyrrhiza inflata and named ‘‘licoflavone B’’ by Kajiyamam et al.,74 was later isolated from the roots of G. glabra and named prenyllicoflavone A (compound 70, Table 12.3).75 Consequently, the latter name falls into the category of synonyms.

12.5.4 O-PRENYLFLAVONES Only very few flavones of this type exist, in most cases showing various other types of substituents as well. O-prenylation is known to occur at position 6, 7, or 4’-OH. Most of the substituents are 3,3-dimethylallyl structures. Whereas epoxyprenyl derivatives have been reported from the aerial parts of Achyrocline flaccida (Asteraceae),76 a new compound with 4’-O-dimethylallyl substitution was later reported from the leaves of Ficus maxima (compound 128, Table 12.3).77 There is no indication of external accumulation in any of the plants listed. Millettocalyxin B (compound 129, Table 12.3) from the stem bark of Millettia erythrocalyx represents an example of a mixed structure (methylenedioxy- and O-prenylsubstitution). Similarly, ovalifolin (compound 131, Table 12.3) has a furano-substitutent in addition and is being reported for two new sources of Fabaceae. The name ovalifolin (published 1974) has priority for this furanoflavone; its use for a structurally different compound from Ehretia ovalifolia78 is, therefore, obsolete.

12.5.5 PYRANOFLAVONES These types of flavones are characterized by cyclization between an OH-group with a prenyl residue to result in chromene or chromane structures, abbreviated as O-Dmp in Table 12.3. This section contains quite a large number of compounds and sources. Most cyclizations take place beween 7-OH and 6- or 8-position of ring A, particularly observed in species of Rutaceae and Fabaceae. Additional cyclization between 2’-OH and C-3 is mainly found in members of the Moraceae, whereas cyclization between 3’-OH or 4’-OH with the neighboring prenyl is reported from Berberidaceae (yinyanghuo C, E; compounds 140, 148, Table 12.3). Pyranoflavones are reported to occur in all parts of the plants, but there are no reports explicitly citing their external accumulation. Some special structures are illustrated in Figure 12.2, such as a flavone acetylated at the chromene residue from Pongamia pinnata (compound 136, Table 12.3) or the tri-ODmp-substituted dorsilurin E (compound 138, Table 12.3).

12.5.6 FURANOFLAVONES Cyclization resulting in furano-substitution is quite frequent between 7-OH and the neighboring 6 or 8-position of ring A. Most reports concentrate on Fabaceae and Moraceae, again from all parts of the plants, except external accumulation. The number of compounds known is smaller than that of the pyranoderivatives. Furano- substitution at ring B is rarely observed (e.g. epimedokoreanin A; compound 178, Table 12.3 and in Figure 12.3) from Epimedium

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OH

HO 19 O

20

O OH

18 17 16 O

OH

Heterophyllin

14

12

HO

O

4⬘

2⬘

11

O

2⬘

4⬘

OH

15 8

O 6

17

3

4

10

16

1⬘

O

21 22

O

O

20

24

Dorsilurin E 19

25

OAc OAc 2⬙

6⬘

3⬙ 8

O

4⬘

O 2

7

2⬘

4 5 OCH3

O

FIGURE 12.2 (Dihydro-) pyranoflavones.

(Berberidaceae). This compound exhibits a more complex furano-substitution, similar to ciliatin A (Figure 12.3) and ‘‘compound 8’’ (Figure 12.3) from species of Moraceae. Torosaflavone C and its demethyl derivative, both isolated from Cassia species67,68 are bisfuranosubstituted (compounds 182 and 183, Table 12.3 and in Figure 12.3), similar to compounds found in Tephrosia species (see Section 12.5.10). In Epimedium, there appears to be a strong tendency towards cyclization between 3’-position and 4’-OH, both in pyrano- and furanoderivatives. Further distribution studies are needed to confirm these biosynthetic trends and their possible chemosystematic significance.

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695

Flavones and Flavonols 8⬙ 7⬙

OH

6⬙ 5⬙

7⵮

O

4⬙

O

6⵮

5⵮ 4⵮

O

OH 8⵮

OH Epimedokoreanin A O

OH

OH H2C

O

O

Me Ciliatin A

O

OH

OH O O

2⬘

8

O

7

3⬘ 4⬘

2 1⬘

5⬙ 4⬙ 3⬙

1⬙ 6

4

5

3

6⬘

OR

5⬘

2⬙

HO

O

OH

R = Me: Torosaflavone C R = H: Demethyltorosaflavone C

Me

OH O

O HO

OH

O Compound 8

FIGURE 12.3 Furanoflavones.

12.5.7 FURANO- AND PYRANO-SUBSTITUTION With the exception of sanaganone, all other compounds listed in this section exhibit a chromeno-structure between 7-OH and C-6 of ring A, whereas the furano-substitution occurs on ring B. During the reporting period, only sanaganone is a newly described compound, occurring in the root bark of Millettia (Fabaceae).79

12.5.8 C-PRENYL- AND PYRANO-SUBSTITUTION This section comprises a series of flavones, mostly reported from genera of the Moraceae (Morus, Dorstenia, Artocarpus) and the Fabaceae (Derris, Tephrosia, Euchresta). Very few reports exist on Vancouveria and Epimedium (Berberidaceae). In contrast to most of the other

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reported structures, these Berberidaceae flavones are again B-ring-substituted only (e.g., Yinyanghuo A, compound 191, Table 12.3). The majority of the other flavones are cyclized to chromene structures between 7,6- or 7,8 of ring A, and C-5-substitution concentrates on positions 3, 6, and 8 (see heterophyllin, Figure 12.2). They have been reported from all parts of the plants, but there is a strong indication for roots and root barks as major sources. No reference exists on external accumulation of such compounds.

12.5.9 C-LINKED AROMATIC- AND KETOPYRANO-SUBSTITUTION C-Linked aromatic substituents are reported to occur in aerial parts of Thymus hirtus,80 along with one report on Chinese propolis.81 In aerial parts of some members of Asteraceae and Lamiaceae, flavones with a C-6-ketopyrano-substitution were reported (e.g., hosloppin, oppositin; see Figure 12.4). These aromatic substituents are positioned at the 6-, and rarely, at the 8-position of ring A. They are all reported from aerial parts, but no reference is made to their possible occurrence as exudates constituents.

12.5.10 TEPHROSIA FLAVONES The genus Tephrosia (Fabaceae) was selected to demonstrate the biosynthetic capacity of flavone substitution. In particular, there is a strong tendency towards formation of furanoresidues, linked through C-bonds on position 8 of the flavone nucleus (e.g., apollinine, hookerianin; Figure 12.5). The basic flavone structure is mostly 5- and 7-O-methylated. These compounds have been exclusively reported to occur in roots, leaf and stem as well as

OMe O

O

2

6

R1O

5⬙

3

5

3⬙ 2⬙ O

O

OR2

Me

R1 = R2 = H : Hosloppin R1 = Me, R2 = H : Hoslundin R1 = R2 = Me: 5-O-Methylhoslundin

H CH3O CH3

O

CH3O

4⬘

8

O

OCH3

O

6

O

FIGURE 12.4 Flavones with ketopyrano substitution.

Oppositin

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in seeds of Tephrosia species. Several compounds are 7,8-disubstituted (furanogroup between 7-OH and C-8; e.g., tephrorianin; Figure 12.5) isolated from pods.82 Aerial parts of Tephrosia spp. yielded primarily bisfurano structures, which are also 7,8-disubstituted, such as semiglabrin, multijugin, and enantiomultijugin (Figure 12.5). There is also a tendency observed towards acetylation on the bisfurano moiety. Even more complex structures arise by addition of bicyclic substituents, being combined from furano and pyrano residues (stachyoidin, tephrodin, compounds 228 and 229, Table 12.3). These structures have been known for a long time, their accumulation site, however, being not indicated.3 Only two pyranoflavones are accumulated: isopongaflavone and 5-OMe-7,6-(2,2-dimethylchromeno)-flavone (compounds 135 and 136, Table 12.3). Further compounds include C-prenylpyranoflavones such

4⬙

1⬙ 5⬙ O 2⬙

O

3⬙

MeO

O

R

R = Apollinine R = OCH3: Hookerianin

O

OAc 3⵮ 2⵮

O

8

1⬙ O

3⬘

1⵮

2⬙

2⬘ 1 O

4⬘ 5⬘

2

7

6⬘ 3

6

4

5 OCH3

Tephrorianin

O

Ac

O H

H O

O

Enantiomultijugin OMe

O

FIGURE 12.5 Furanoflavones from Tephrosia.

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Flavonoids: Chemistry, Biochemistry, and Applications

as fulvinervins (compounds 188 and 189, Table 12.3). Generally, the trend to 7-OH-C-8substitution is quite prominent in this genus. Altogether, the biosynthetic capacity of Tephrosia is remarkable.

12.5.11 ARTOCARPUS FLAVONES The genus Artocarpus (Moraceae) affords a prime example of biosynthetic activities to produce complex cyclized flavone structures, being primarily accumulated in addition to Cprenylated and pyrano-substituted flavones (see Table 12.3; Section 12.5.2 and Section 12.5.8). Apart from the pyrano substitution also encountered in other plants (see Section 12.5.5, Table 12.3), cyclization occurs between the 6’- and 3-position of the flavone molecule to yield xanthonoid structures (e.g., artonol E, D; Figure 12.6). A further and even more prominent tendency is represented by cyclization between the 2’-OH-group and the position 6 of the flavonoid nucleus. In this case, cyclization may lead to either six- or seven-membered rings including oxygen (see structures of artocommunol CA and artelastocarpin in Figure 12.6). Artonin K serves as another example of complex cyclization (Figure 12.6). Generally, cyclization between 7-OH and C-8 occurs in various flavone derivatives of Artocarpus (e.g., artonol D; artocommunol CA, artelastofuran; Figure 12.6.). However, A. rigida yielded both 7, 6- and 7, 8-cyclized compounds (artonin M, P; compounds 250 and 259, Table 12.3). In this section, compounds with pyranosubstitution at both ring A and B are listed, for example, artonol D (Figure 12.6). All of these compounds appear to be mainly accumulated in rather lignified parts of the plant, such as heartwood, bark, and shoot. It is hardly perceivable that such complex compounds could occur in exudates of aerial parts.

12.5.12 FLAVONE–COUMARIN HYBRIDS Only two flavones of this type are known so far. They were reported from Gnidia soccotrana (Thymeleaceae).83 For formula see Figure 12.7. Similarly, only a few flavonols are known as hybrid structures, but none of them with coumarins (see Table 12.4).

12.6 FLAVONOLS WITH OTHER SUBSTITUENTS Data on this type of flavonols are summarized in Table 12.4. In contrast to the corresponding flavones, the number and complexity of derivatives is smaller. This concerns particularly the formation of furano-, pyrano- and other cyclic flavonols. There is a remarkable number of O-prenylated flavonols known to date, contrasting to only very few flavones exhibiting this substitution pattern (see Table 12.3). Similar trends have been earlier documented in the review of Barron and Ibrahim.3 The occurrence of a series of glycosides based on C-prenylated structures is considerable.3 This substitution trend concerns also some of the dihydroflavonols, thus indicating specific enzyme activities probably dependent on the presence of a 3-OH group.

12.6.1 C-METHYLFLAVONOLS In this section, reports concentrate on genera from the families Caesalpiniaceae, Myrtaceae, and Velloziaceae. Apart from the Myrtaceae, no C-methylflavones have been reported to occur in the other two families as yet (see Table 12.3). In Myrtaceae, C-methylflavonols have been found also in exudates.57 Most of the other species listed here accumulate these flavonols in the leaves without further specification. Fungal sources include two species of Colletotrichum, where C-methylflavonols have been found in the culture filtrate.84 So far, no C2- or C3- C-linked flavonols have been reported as was the case with the flavones.

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699

Flavones and Flavonols 17

OH

15 14

21

OR

16

HO

20

18

O

19

O

O

CH3O

O OH

OR 9

OH

13

10

O

Artelastofuran

O

Artonol E

12

O

O

OH

11

O

OH

HO

O

CH3O

O

O O

OH

O

OH

O

Artonin K

Artonol D

4⬘

23

OCH3

22

21

OH 5⬘

8

O

8a

1⬘

O 3

6

4a

20

3⬘

2

7

6⬘

19

2⬘

1⬘

HO

O

7

5

6

OH

14

O

8

5

8a

O

4a

4

3⬘ 2⬘

2

O

3 9

10 11

18

Artocommunol CA

4⬘

15 16 17

OH

O 13

12

OH

Artelastocarpin

FIGURE 12.6 Flavones from Artocarus spp.

12.6.2 METHYLENEDIOXYFLAVONOLS The Rutaceae appear to be a rich source of flavonols with methylenedioxy substitution. Their main accumulation site is apparently bark tissue, followed by leaves. It may be assumed that some of these leaf constitutents are accumulated externally as was also the case with the corresponding flavone derivatives of other plant families. In general, the Rutaceae exhibit a

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Flavonoids: Chemistry, Biochemistry, and Applications OH

O HO O

7 6

8

1⬘

O 2 3

5

8⬙

OH

O

OH 6-(8⬙-Umbelliferyl)-apigenin

O

O

OH

6⬙

OH HO 8

OH

O

O

8-(6⬙-Umbelliferyl)-apigenin

FIGURE 12.7 Flavone–coumarin hybrids.

trend rather to produce flavonols of this type, whereas one corresponding flavone only (ageconyflavon A) is so far known from this family. Very few reports concern the genus Millettia (Fabaceae; stem bark)85 and some Amaranthaceae (aerial parts, whole plants).86

12.6.3 C-PRENYLFLAVONOLS Within the complex flavonols, C-5 substitution is by far the most prominent trend in terms of numbers of compounds and sources. Also, the number of structurally different C-5-residues is remarkable. Apart from the common ‘‘3,3-dimethylallyl’’ and the rarer ‘‘1,1-dimethylallyl,’’ several hydroxylated C-5-residues such as in topazolin hydrate, isolated from roots of Lupinus luteus (Fabaceae; compound 94 in Table 12.4). Another source of such compounds is the whole plant of Duranta repens (Verbenaceae).87,88 Plant organs accumulating C-prenylflavonols range from buds to leaves and from aerial parts to roots. Only the bud constituents may be considered as exudate compounds. From Lilium candidum, a more complex flavonol was reported (Figure 12.8).89 This genus also accumulates N-containing flavonoid derivatives discussed earlier.6 Some remarks should be made regarding structures revised during the reporting period. A flavonol isolated from Glycyrrhiza lepidota, named glepidotin, had been ascribed the structure of 8-C-prenylgalangin.90 Comparison with the synthetic product and its isomer revealed that it is, in fact, 6-C-prenylgalangin (compound 78, Table 12.4).91 Noricaritin

8-Me 6,8-diMe 8-Me 6,8-diMe 8-Me 6,8-diMe 8-Me 6-Me 6-Me 6-Me 8-Me 6-Me 6-Me 6,8-diMe 6-Me

5,4’-diOH, 3,7-diOMe 5-OH, 3,7,4’-triOMe 5-OH, 3,7,4’-triOMe 5,4’-diOH-3,6,7-triOMe 5,4’-diOH-3,6,7-triOMe

3,5,8,4’-OH, 7-OMe 5,8,4’-triOH, 3,7-OMe 5,4’-diOH-3,7,8-triOMe 3,5,7,3’,4’-pentaOH (3,5,7,3’,4’-pentaOH)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

16 17 18 19 20

21 22 23 24 25

6-Me 6-Me 6-Me* 6-Me 8-Me

6,8-diMe 6-Me 6,8-diMe 6-Me* 8-Me*

Other Substituents

O-Substitution

C-Methylflavonols 3,5,7-triOH 3,5,7-triOH 5,7-diOH, 3-OMe 5,7-diOH, 3-OMe 3,5-diOH, 7-OMe 3,5-diOH, 7-OMe 3,5,6,7-tetraOH 3,5,7,8-tetraOH 5,7,8-triOH, 3-OMe 3,5,7-triOH, 8-OMe 5,6,4’-triOH, 3-OMe 3,5,7,4’-tetraOH 5,7,4’-triOH, 3-OMe 5,7,4’-triOH, 3-OMe 5,4’-diOH-3,7-diOMe

No.

TABLE 12.4 Flavonols with Other Substituents

Pinoquercetin Glycoside only

Latifolin 8-Desmethylkalmiatin Kalmiatin

8-Desmethyllatifolin

Pityrogrammin Sylpin 6-Methylkaempferol

Isoplatanin Platanin

8-Methylgalangin

Trivial Name

Fungus!

(cult. filtr.)

(cult. filtr.) Leaf surface Leaf

Fungus! Velloz. Velloz. Colletotrichum dematium Vellozia laevis Vellozia nanuzae

Colletotrichum dematium

Leaf External Leaf wax Leaf

Plant Organ

Caesalpin. Myrt. Myrt. Caesalpin.

Family

Piliostigma thonningii Callistemon, 4 spp. Leptospermum laevigatum Piliostigma thinningii

Plant Species

continued

84

84 105 515

514 57 424 514

Ref.

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Flavones and Flavonols 701

6,8-diMe 6-Me* 8-Me* 8-Me* 8-Me*

8-Me* 6-Me 6-Me 6,8-diMe 6-Me 6,8-diMe 6-Me 6,8-diMe

5,4’-diOH, 3,7,3’-OMe 5-OH-3,7,3’,4’-OMe 5,3’,4’-OH-3,6,7-OMe 5,7,4’-OH-3,6,3’-OMe 5,4’-OH,3,6,7,3’-OMe*

5,3’-OH,3,6,7,4’-OMe 3,5,7,3’,4’,5’-hexaOH 5,7,3’,4’,5’-OH, 3-OMe 5,7,3’,4’,5’-OH, 3-OMe 3,5,7,3’,5’-OH, 4’-OMe 3,5,7,3’,5’-OH, 4’-OMe 5,7,3’,5’-OH, 3,4’-OMe 5,7,3’,5’-OH, 3,4’-OMe

34 35 36 37 38

39 40 41 42 43 44 45 46

6,8-diMe* 6-Me* 6,8-diMe* 6-Me 6,8-diMe 6-Me

5,7,3’,4’-tetraOH-3-OMe 5,3’,4’-triOH-3,7-diOMe 5,3’,4’-triOH-3,7-diOMe 5,7,4’-OH, 3,3’-diOMe 5,7,4’-OH, 3,3’-diOMe 5,4’-diOH, 3,7,3’-OMe

28 29 30 31 32 33

6,8-diMe 6-Me

Other Substituents

3,5,7,3’,4’-pentaOH 5,7,3’,4’-OH, 3-OMe

O-Substitution

26 27

No.

TABLE 12.4 Flavonols with Other Substituents — continued

Myrt. Velloz. Velloz. Velloz. Velloz. Velloz. Velloz. Velloz.

Leaf wax Leaf Leaf Whole plant Leaf Leaf Leaf Leaf

External Leaf wax Leaf

Myrt. Myrt. Caesalpin.

Callistemon salignus Leptospermum laevigatum Piliostigma thonningii Leptospermum laevigatum Vellozia epidendroides, V.llilacina* Vellozia nanuzae Vellozia stipitata Vellozia nanuzae Vellozia epidendroides, V.llilacina* Vellozia laaevis Vellozia laevis, V. phalocarpa

Leaf Leaf Leaf Leaf Leaf Leaf Leaf

Plant Organ

Caesalpin. Velloz. Velloz. Velloz. Caesalpin. Caesalpin. Caesalpin.

Family

Piliostigma thonningii Vellozia phalocarpus Vellozia phalocarpus Xerophyta retinervis Piliostigma thonningii Piliostigma thonningii Piliostigma thonningii

Plant Species

424 517 515 104 515 517 516 105

57 424 514

514 105 516 105 514 514 514

Ref.

702

Dumosol

Alluaudiol

Trivial Name

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Flavonoids: Chemistry, Biochemistry, and Applications

Methylendioxyflavonols 3,5-diOMe 3,5-diOMe

3,7-diOMe 5-OH,3,7-diOMe 3,5,7-triOMe 3,5,8-triOH 3,5,8-triOMe 3,5,8-triOMe 3,5,8-triOMe 3,5,3’-triOMe 3,5,4’-triOH 3,7,3’-triOMe 3,7-diOH,5,6-diOMe 5-OH, 3,6,7-triOMe 3,5,6,7-tetraOMe 5,7-diOH-3,8-diOMe 5-OH, 3,7,8-triOMe 7-OH,3,5,8-triOMe

3,5,7,8-tetraOMe 3,5,8,3’-tetraOMe 5,3’,4’-OH, 3-OMe 3,5,3’-triOH,4’-OMe 5,3’,4’-triOH, 3-OMe 5,4’-OH, 3,3’-diOMe 3,5,7-triOH, 6,8-diOMe 5,7-diOH-3,6,8-triOMe 3,5-diOH, 6,7,8-triOMe 7-OH-3,5,6,8-tetraOMe 5-OH, 3,6,7,8-tetraOMe

3,5,6,7,8-pentaOMe 3,5,8,3’,4’-pentaOMe

47 48

49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

65 66 67 68 69 70 71 72 73 74 75

76 77

3’,4’-OCH2O 6,7-OCH2O

3’,4’-OCH2O 6,7-/3’,4’-diOCH2O 6,7-OCH2O 6,7-OCH2O* 7,8-OCH2O 6,7-OCH2O 3’,4’-OCH2O 3’,4’-.OCH2O* 3’,4’-OCH2O 3’,4’-.OCH2O* 3’,4’-OCH2O

3’,4’-OCH2O 3’,4’-OCH2O 3’,4’-OCH2O 6,7-/3’,4’-diOCH2O 6,7-OCH2O 3’,4’-OCH2O 6,7-/3’,4’-diOCH2O 6,7-/4’,5’-diOCH2O 6,7-OCH2O 3’,4’-OCH2O 3’,4’-OCH2O 3’,4’-OCH2O 3’,4’-OCH2O 3’,4’-OCH2O* 3’,4’-OCH2O 3’,4’-OCH2O

6,7-OCH2O 6,7-/3’,4’-diOCH2O

5-Desmethylmelibentin Melibentin Melicophyllin

Melinervin

Wharangin

Meliternin

5-Desmethylmeliternin

Melisimplin Melisimplexin

Gomphrenol Kanugin

Isokanugin

Desmethylkanugin

Meliternatin

Melicope coodeana Melicope triphylla Comptonella microcarpa Melicope triphylla Melicope ternata Melicope ternata

Rut. Rut. Rut. Rut. Rut. Rut.

Amaranth.

Glycoside only Blutaparon portulacoides Glycoside only

Leaf (ext.?) Bark

Rut. Rut.

Comptonella microcarpa Melicope ternata

Leaf Leaf Leaf Leaf Bark Bark

Aerial parts

Bark Bark Leaf Bark

Bark Leaf (ext.?)

Whole plant Bark Leaf (ext.?) Stem bark

Rut. Rut. Rut. Rut.

Rut. Rut.

Amaranth. Rut. Rut. Fab.

Melicope simplex, M. ternata Melicope ternata Melicope coodeana Melicope simplex

Melicope simplex, M. ternata Comptonella microcarpa

Gomphrena martiana, G. boliviana Melicope simplex, M. ternata Comptonella microcarpa Millettia leucantha

Flavones and Flavonols continued

374 520 518 521 380 380

519

518 380

380 380 374 380

380 518

150 380 518 85

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703

C-Prenylflavonols 3,5,7-triOH 3,5,7-triOH 3,7,4’-triOH 3,5,7,8-tetraOH 3,5,7,4’-tetraOH

3,5,7,4’-tetraOH 3,5,7,4’-tetraOH

3,5,7,4’-tetraOH

3,5,7,4’-tetraOH 3,5,7,4’-tetraOH

3,5,7,4’-tetraOH 3,5,7,4’-tetraOH

3,5,7,4’-tetraOH 3,5,7,4’-tetraOH 3,5,7,4’-tetraOH 5,7,4’-triOH, 3-OMe 5,7,4’-triOH, 3-OMe 3,7,4’-triOH, 5-OMe 3,5,4’-triOH, 7-OMe 3,5,7-triOH, 4’-OMe 3,5,7-triOH, 4’-OMe 3,5,7-triOH, 4’-OMe 5,7,4’-triOH, 3,6-diOMe

83 84

85

86 87

88 89

90 91 92 93 94 95 96 97 98 99 100

O-Substitution

78 79 80 81 82

No.

6,8-diC5 6,3’-diC5 8,3’-diC5 6-C5 6-C5-OH 8-C5 8-C5 8-C5 8-C5-OH 8-C5-OMe* 3’-C5-OH

6-C5-OH 8-C-(3-methyl-succinoyl), see Figure 12.8 8-C10* 3’-C5 6,8-Diprenylkaempferol Glyasperin A; 6,3’-diprenylkaempferol Broussoflavonol F Topazolin Topazolin hydrate Sophoflavescenol Isoanhydroicaritin Anhydroicaritin Icaritin Brevicornin* Aliarin

Isomacarangin* Isolicoflavonol

Noranhydroicaritin 8-(1,1-dimethylallyl)-kaempferol Noricaritin, revised

Macarangin*

Platanetin Licoflavonol*

Glepidotin A; 6-prenylgalangin; revised 8-(1,1-dimethylallyl)-galangin

Trivial Name

Leaf Liquorice Bud Leaf Root Root bark Root Root Roots Aerial parts Aerial parts

Berb. Berb.

Epimedium koreanum Epimedium brevicornum

Leaf Leaf Leaf Aerial parts Bud —

Bud Root

Bud

Plant Organ

Euphorb. Fab. Platanac. Dipteroc. Fab. Morac. Fab. Fab. Fab.

Platanac. Fab. Synthesis Euphorb. Dipteroc. Euphorb. Berb. Platanac. — Liliac.

Synthesis Platanac.

Family

Macaranga schweinfurthii Glycyrrhiza spec. Platanus acerifolia Monotes africanus Glycyrrhiza aspera Broussonetia papyrifera Lupinus luteus Lupinus luteus Sophora flavescens

Macaranga vedeliana Monotes africanus Macaranga denticulata Epimedium koreanum Platanus acerifolia — Lilium candidum

Platanus acerifolia Glycyrrhiza spp.

Platanus acerifolius

Plant Species

279

527

528 334 46 525 529 93 530 530 531

46 523 91 524 525 526 527 46 91 89

91 522

Ref.

704

8-C5

6-C5-OH 6-C10*

6-C5 8-C5 8-C5-OH 6-C5 6-C5*

Other Substituents

TABLE 12.4 Flavonols with Other Substituents — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

8,2’,3’-triC5* 8,2’,6’-triC5 6-C5* 5’-C5 6,8-diC5 6,8-diC5* 6-C5* 6-C5* 6-C5* 8-C5 8-C5 2’-C5 2’-C5

4’-O-C5* 4’-O-C5 7-O-C5 (epoxy)

3,5,7,3’,4’-pentaOH 3,5,7,3’,4’-pentaOH 3,5,7,3’,4’-penta-OH

3,5,7,3’,4’-pentaOH 3,5,7,3’,4’-pentaOH 5,7,3’,4’-OH-3-OMe 5,7,3’,4’-tetraOH, 3-OMe 5,7,3’,4’-OH, 3-OMe 3,5,7,4’-tetraOH-3’-OMe 5,3’,4’-OH-3,7-OMe 5,7,4’-triOH-3,8-diOMe 3,5,3’-OH, 7,4’-diOMe 3,5,3’-OH, 7,4’-diOMe 5,4’-diOH, 3,7,3’-OMe 3,6,7,3’,4’-pentaOH 5,6,4’,5’-tetraOH-3OMe

O-Prenylflavonols 5,7-diOH,3-OMe 5,7-diOH, 3-OMe 5-OH, 3,8-diOMe

111 112 113

114 115 116 117 118 119 120 121 122 123 124 125 126

127 128 129

6,5’-diC5* 8,5’-diC5* 8,2’,6’-triC5

6-C5 6-C5-OH 5’-C5

3,5,7,4’-tetraOH, 3’-OMe 3,5,7,3’,4’-pentaOH 3,5,7,3’,4’-pentaOH

108 109 110

3’-C5-OH 3’-C5 3’-C5-OH* 3’-C5-OH 8-C10 8-C10-OH 6-C5*

3,7,4’-triOH, 5,6-diOMe 5,7-diOH, 3,6,4’-triOMe 5,7-diOH,3,6,4’-triOMe 3,7-diOH,5,6,4’-triOMe 3,5,7,2’,4’-pentaOH 3,5,7,2’,4’-pentaOH 3,5,7,3’,4’-pentaOH

101 102 103 104 105 106 107

7-Epoxyprenylgnaphaliin

6-Prenylherbacetin* Isorhynchospermin Rhynchospermin 8-Prenylpachypodol Neouralenol Uralene

Uralenol-3-Me Broussoflavonol B Dorsmanin D*

Broussoflavonol G* Broussoflavonol C

Broussonol E* Broussonol D* 8,2’,6’-Triprenylquercetin

Uralenol

Gancanonin P -3’-Me

Kushenol C Kushenol G Gancaonin P*

Viscosol

95 537

533 536

454 515 105 277

515 536

94

457 436 532 — 533 534 98 98 535

88 87

87

continued

Aerial parts Leaf

Leaves Leaves

Fab. Fab. Glycyrrhiza uralensis Glycyrrhiza uralensis

Rut. Rut.

Twigs Leaf surface Leaf surface Aerial parts

Morac. Velloz. Velloz. Ast. Dorstenia mannii Vellozia coronata Vellozia scoparia Artemisia campestris glutinosa

Boronia coerulescens Bosistoa brassii

Leaf surface Leaves

Leaf Leaf Root, may be artifact

— Leaves

Aerial parts Aerial parts

Whole plant Whole plant

Whole plant

Velloz. Fab.

Fab. Morac. Fab. — Fab. Morac. Morac. Morac. Fab.

Verben. Verben.

Verben.

Vellozia coronata, V. nanuzae Glycyrrhiza uralensis

renamed from Broussoflavonol ‘‘E’’

Glycyrrhiza uralensis Dorstenia ciliata Glycyrrhiza uralensis Glycoside only Glycyrrhiza uralensis Broussonetia papyrifera Broussonetia kazinoki Broussonetia kazinoki Petalostemum purpureum

Duranta repens Duranta repens

Duranta repens

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Flavones and Flavonols 705

3’,4’-OCH2O 7,6-ODmp 7,8-ODmp 7,8-ODmp* 7,8-ODmp

5,4’-diOH, 3,3’-diOMe 5,7-diOH, 3,3’-diOMe 5,3’-diOH, 3,4’-diOMe 4’-OH, 3,5,3’-triOMe 3,5,3’-triOH-6,7-diOMe 5,7-diOH, 3,8,3’-OMe* 3,5,4’-triOH-8,3’-diOMe* 5,4’-diOH, 3,8,3’-OMe 5,4’-diOH, 3,8,3’-OMe 4’-OH, 3,5,8,3’-tetraOMe 3,5,8,3’,4’-pentaOMe 5,4’-OH, 3,6,8,3’-OMe 3,5,8,4’-OH-7,3’-OMe 5-OH,3,8-diOMe,7-O-C5 3,5,8-triOMe, 7-O-C5

3,5,6,8-tetraOMe-7O-C5

Pyranoflavonols 3,5,4’-triOH 3-OMe 3,5-diOMe 3,6-diOMe

136 137 138 139 140 141 142 143 144 145 146 147 148 149 150

152

153 154 155 156

7-O-C5 (epoxy) 4’-O-C5 7-O-C5 7-O-C5 4’-O-C10-OH 4’-O-C5* 7-O-C5* 7-O-C5* 7-O-C5 7-O-C5* 7-O-C5 7-O-C5 6-O-C5 3’,4’-OCH2O 3’,4’-OCH2O

3,4’-di-O-C5* 4’-O-C5* 4’-O-C5* 4’-O-C5* 4’-O-C5* 7-O-C5

5,7-diOH,8-OMe* 3,5,7-OH,6-OMe 5,7-OH,3,6-OMe 3,5,7-triOH, 8-OMe* 5,7-diOH,3,8-diOMe* 5,4’-diOH, 3,3’-diMe

130 131 132 133 134 135

Other Substituents

O-Substitution

No.

TABLE 12.4 Flavonols with Other Substituents — continued

Lonchocarpus latifolius Lonchocarpus latifolius

Zanthoxylum alatum Boronia coerulescens Melicope micrococca Boronia coerulescens Melicope elleryana Melicope triphylla Melicope triphylla Boronia coerulescens Melicope micrococca Melicope triphylla Achyrocline flaccida Melicope triphylla Comptonella microcarpa Comptonella microcarpa

Bosistoa medicinalis Melicope elleryana

Boronia coerulescens Boronia coerulescens Boronia coerulescens Boronia coerulescens Boronia coerulescens Euodia glabra Melicope elleryana

Plant Species

Fab. Fab.

Rut. Rut. Rut. Rut. Rut. Rut. Rut. Rut. Rut. Rut. Ast. Rut. Rut. Rut.

Rut. Rut.

Rut. Rut. Rut. Rut. Rut. Rut. Rut.

Family

Root Root

Seed Aerial parts Aerial parts Aerial parts Fruit Leaf Leaf þ bark Aerial parts Aerial parts Leaf Aerial parts Leaf þ bark Leaf (ext.?) Leaf (ext.?)

Leaf Fruit

Aerial parts Aerial parts Aerial parts Aerial parts Aerial parts Shoot bark Fruit

Plant Organ

91 541 541

401 95 96 95 379 521 539 95 96 521 540 539 518 518

322 379

95 95 95 95 95 538 379

Ref.

706

Desmethyl-anhydroicaritin Karanjachromene

Geranioloxyalatum flavone

Trivial Name

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183

Prenyl- and pyrano-substitution 3,5-diOH 8-C5, 7,6-ODmp 3,5,7-triOH 6,8-diC5-4’,3’-ODMp* 3,3’,4’-triOH 7,6-ODmp, 8-C5 3’,4’-diOH, 3-OMe 7,6-ODmp, 8-C5 3,5,7,3’tetraOH 4’,5’ODmp-8-C5* 3,5,7,4’-tetraOH 3’,2’-ODmp-C6* 3,5,3’,4’-tetraOH 7,8-ODmp-6-C10* 5,3’,4’-OH, 3-OMe 8-C5, 7,6-ODmp 3,5,7,5’-tetraOH 8,2’-diC5, 3’,4’-ODmp, see Figure 12.9 3,5,7,5’-tetraOH 8,2’-diC5, 3’,4’-ODmp

7,6-fur* 7,8-fur 7,8-fur 7,8-fur 7,8-fur 7,8-fur 7,8-fur 5’-C5; 7,8-triMe-fur 7,8-triMe-fur*

Furanoflavonols 3-OMe 3-OMe 3,4’-diOMe 3,5,6-triOMe 3-OMe, 3’,4’-OCH2O 3,3’-diOMe, 4’,5’-OCH2O 3,5,6-triOMe, 3’,4’-O2CH2 3,5,3’,4’-tetraOH 3,5,3’triOH, 4’,5’-ODmp

165 166 167 168 169 170 171 172 173

174 175 176 177 178 179 180 181 182

7,6-ODmp* 7,8-ODmp-Me 7,8-ODmp 7,8-ODmp 4’,3’-cycl-OC5-OH*

5,3’,4’-OH, 3-OMe* 3,5,3’,4’-tetraOH 3,5-diOMe, 3’,4’-OCH2O 3,6-diOMe, 3’,4’-O2CH2 3,5,7-triOH

160 161 162 163 164

7,8-ODmp 7,8-ODmp* 7,8-ODmp, 6-C5*, see Figure 12.9

3,5,4’-triOH 4’-OH, 3,6-diOMe 3,5,3’,4’-tetraOH

157 158 159

Broussoflavonol E

Sericetin Dorsilurin C* Macaflavon I Macaflavon II Broussonol A* Petalopurpurenol* Dorsmanin C* Broussoflavonol A Broussoflavonol D

Pongapin 3’-OMe-pongapin 5,6-diOMe-pongapin Broussonol C Broussonol B*

Ponganone XI* Karanjin

Glycyrrhiza-flavonol A*

Pongachromene

Sarothranol*

Poinsettifolin A*

Citrusinol

Morac.

Root bark

Leaf Root Twigs Cortex

Morac. Fab. Morac. Morac. Broussonetia kazinoki Petalostemon purpureus Dorstenia mannii Broussonetia papyrifera

Broussonetia papyrifera

Root

Morac.

Root Leaf Leaf

Fab. Morac. Morac.

Derris araripensis Broussonetia kazinoki Broussonetia kazinoki

Dorstenia psilurus

Root Root Root Root Root

Fab. Fab. Fab. Fab. Fab.

546

98 99 454 545

453

544 98 98

297 463 483 544 541

436 97 543 541 544 334

542 441

Flavones and Flavonols continued

Aerial parts Whole plant Leaf Root Root Liquorice

Morac. Hyperic. Asclepiad. Fab. Fab. Fab.

Dorstenia ciliata Hypericum japonicum Asclepias syriaca Lonchocarpus latifolius Derris araripensis Glycyrrhiza sp.

Pongamia pinnata Dahlstedtia pentaphylla Derris mollis Derris araripensis Lonchocarpus latifolius

Fruit Leaves

Rut. Morac.

Citrus reticulata* Dorstenia poinsettifolia var. angusta

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7,4,5’-triOH

7,3’,4’-triOH 5-OH, 7-OMe, 3’,4’-O2CH2 5-OH, 6,7-diOMe 3’,4’-O2CH2 3,5-diOH 3,5,4’-triOH

Hybrid structures 3,5,7,4’-tetraOH

5’-OH, 3,5,2’-OMe

191

192 193 194 195 196

197

198

*For explanation, please see text. For abbreviations see footnote to Table 12.3.

Diterpene–flavonol, see Figure 12.9 Flavono-lignoid

3,2’-O-CH23,2’-O-CH23,2’-O-CH27,8-O-cycl-phenylethyl 7,8-O-cycl-phenylethyl

Denticulaflavonol

Calomelanol D

Mopanin Pulcherrimin 6-OMe-pulcherrimin

Peltogynin

Benthamianin Distemonanthin Fasciculiferin

Distemonanthus benthamianus

Macaranga denticulata

Acacia peuce, A. crombei, A. fasciculifera Colophospermum mopane Caesalpinia pulcherrima Caesalpinia pulcherrima Pityrogramma calomelanos Pityrogramma calomelanos

Acacia crombei, A. carnei Distemonanthus benthamianus Distemonanthus benthamianus Acacia fasciculifera

Thymus hirtus Thymus hirtus Haplopappus foliosus

Plant Species

Fab.

Euphorb.

Caesalpin. Caesalpin. Caesalpin. Pteridaceae Pteridaceae

Mimosac.

Mimosac. Fab. Fab. Mimosac.

Lam. Lam. Ast.

Family

Heartwood

Leaves

Stem Stem Frond exudate Frond exudate

Heartwood

Heartwood Heartwood Heartwood

Aerial parts Aerial parts

Plant Organ

102

526

549 550 550 121 122

548

547

80 80 100

Ref.

708

3,2’-O-CH23,2’-O-CH23,2’-O-CH23,2’-O-CH2-OH, see Figure 12.9 3,2’-O-CH2-

Various cyclo-flavonols 5,7,4,5’-tetraOH 5,7,3’,4’-tetraOH-6OMe 5,7,3’,4’-tetraOH-6OMe 7,4,5’-triOH

187 188 189 190

Trivial Name p-Hydroxybenzyl-kaempferol* p-Hydroxybenzyl-quercetin* Haplopappin

Other Substituents

Flavonols with aromatic substituents 3,5,7,4’-tetraOH 8-C-p-OH-benzyl* 3,5,7,3’,4’-pentaOH 8-C-p-OH-benzyl* 5,7-diOH, 3,4’-diOMe 8-C-p-OH-phenylethyl

O-Substitution

184 185 186

No.

TABLE 12.4 Flavonols with Other Substituents — continued

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Flavones and Flavonols 5⬙

Me CO - CH2 - CH - COOH 1⬙

2⬙

8

HO

3⬙

4⬙

O 4⬘

OH

3

6 5

OH

OH O

FIGURE 12.8 Flavonol from Lilium candidum.

(compound 86, Table 12.4), originally isolated from Bursera leptophloeos as 3,5,7,4’-tetraOH8-C-hydroxyprenylflavone,92 needs to be revised to the corresponding 6-C-derivative.91 Finally, the structure of broussoflavonol E (3,5,7,3’,4’-pentaOH-8,2’,6’-triprenylflavone) from Broussonetia papyrifera93 was later revised to 3,5,7,3’,4’-pentaOH-8,2’,3’-triprenylflavone and renamed broussoflavonol G (compound 114, Table 12.4).94

12.6.4 O-PRENYLFLAVONOLS These compounds are almost exclusively accumulated in aerial parts and leaves from genera of the Rutaceae such as Bosistoa, Boronia, and Melicope, and rarely in Euodia and Zanthoxylum. There is a strong tendency towards prenylation at the 7-OH or 4’-OH group. From aerial parts of Boronia coerulescens, a derivative with 3,4’-O-prenylation was also described (compound 130, Table 12.4).95 Similarly, only one C-6-O-derivative was reported from the aerial parts of Melicope.96 Two 7-epoxyderivatives have already been listed in the previous survey.6 Combination with methylenedioxy substitution is less frequent, concerning a few sources of Rutaceae and Asteraceae only. Probably, these constituents are partly accumulated externally.

12.6.5 PYRANOFLAVONOLS In contrast to corresponding flavones, only a few structures are reported with a pyranosubstitution, mostly of the chromeno-type between the 7-OH and the neighboring C-8. Major sources are roots, aerial parts, and leaves from Rutaceae, Moraceae, and Fabaceae. The earlier reported Asclepias syriaca (Asclepiadaceae) affords a rare source of such structures. So far, the corresponding 7,6-chromeno structures (sarothranol) are known only from whole plants of Hypericum japonicum (Hypericaceae).97 Poinsettifolin A serves as an example of a recently isolated flavonol with a C-5-unit attached to the chromene structure (Figure 12.9). Desmethylanhydroicaritin, isolated from Bursera leptophloea as 3,5,4’-trihydroxy-7,8-pyranoflavon,92 needs to be revised to 3,5,4’triOH-7,6-pyranoflavone (compound 157, Table 12.4).91

12.6.6 FURANOFLAVONOLS Major sources of the few flavonols with furano-substitution are roots of various Fabaceae genera. With exception of ponganone XI (7,6-furano-), all compounds listed here are furano-substituted between 7-OH and C-8 of ring A. Similarly, compounds exhibiting

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9⬙

7⬙

6⬙

OH

5⬙ 2⬙

4⬙

3⬘ 1⬙

3⬙ 10⬙

2⬘

8

O

1⬘

O

9

5⬘

2

7

OH 4⬘

6⬘

2⵮

5⵮

6 3⵮

4

10

3

4⵮

Poinsettifolin A

OH

5

1⵮

O

OH

OH HO

O Broussoflavonol D

O 11⬘ 7⬘

9⬘

OH OH

8⬘

10⬘

O OR1 OR1

1 2

R O

O

11a

10

A

3

B

12

11

1

12a

4

D

C

3⬘ 2⬘

9 8

6a

7

O

5

OR2

6

HO

8

9

7

O

2

OH 4⬘

1⬘

5⬘ 6⬘

O 14⬙

12⬙

3

13⬙

Fasciculiferin 20⬙

15⬙

17⬙

1⬙

16⬙

2⬙ 3⬙

4⬙

5

OH

10

4

OH

O

7⬙

5⬙ 6⬙

18⬙

6

Denticulaflavonol

19⬙

FIGURE 12.9 Complex flavonol structures.

additional substitution, such as methylenedioxy-, pyrano-, or C-prenylmoieties, are of limited number. During the reporting period, roots of Lonchocarpus latifolius (Fabaceae) were described as new source for pongapin, a methylendioxyfuranoflavonol. Leaves of Broussonetia kazinoki (Moraceae) represent a new source for mixed furanoflavonols such as broussonol C and B, respectively, with no indication as to possible external accumulation.98

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12.6.7 C-PRENYL- AND PYRANO-SUBSTITUTION Flavonols with this substitution pattern occur mainly in species of Moraceae. A related structure, petalopurpurenol was found in roots of Petalostemon purpureus (Fabaceae).99 Cyclization into chromene structures may occur between 7-OH and C-6 or 7-OH and C-8, but substitution between 3’-OH and C-4’ is also encountered (e.g., broussoflavonol D; Figure 12.9).

12.6.8 FLAVONOLS

WITH

AROMATIC SUBSTITUENTS

As with the corresponding flavones, aerial parts of Thymus hirtus (Lamiaceae) afforded p-OH-benzyl derivatives of kaempferol and quercetin, respectively.80 Earlier, Haplopappus foliosus (Asteraceae) was reported to accumulate haplopappin, a phenylethyl substituted quercetin derivative.100 Similar substituted flavones have also been found mainly to occur in members of Lamiaceae and Asteraceae (see Table 12.3), thus being probably chemosystematically significant accumulation trends. Frond exudates of the genus Pityrogramma (Pteridaceae) afforded calomelanol D and a related structure (compounds 195, 196, Table 12.4), being cyclized between 7-OH and C-8, whereby a phenylethyl unit is further attached to the 7,8-chromene unit. A corresponding flavone derivative was also isolated.101 By comparison with flavanone and chalcone analogues, Iinuma et al. suggested nonenzymatical processes upon which linear and angular calomelanols should be formed and hence coined the term ‘‘tertiary metabolites’’ for such compounds.101 This could possibly apply also to some of the other complex flavone and flavonol derivatives presented in this chapter.

12.6.9 VARIOUS CYCLOFLAVONOLS This section comprises a series of structurally different flavonols, with specific cyclization not falling in any of the other categories listed. These include the so-called ‘‘peltogynoids,’’ which are cyclized between 3-OH and C-2’- of ring B (as in fasciculiferin, Figure 12.9). They were reported from heartwood and stems of some Fabaceae and Caesalpiniaceae, respectively. 6-Methoxypulcherrimin bears a methylenedioxy group in addition. No new source has been published during the reporting period.

12.6.10 HYBRID STRUCTURES Only two compounds are listed here, in which a flavonol molecule is linked to a biosynthetically different product such as a terpenoid (denticulaflavonol; Figure 12.9) and a flavonollignoid structure isolated from heartwood of Distemonanthus benthamianus (Fabaceae).102 In addition, the latter taxon accumulates derivatives with a 3-OH-2’-cyclization as mentioned before (see previous section). Earlier, similar substituted flavone-lignoid derivatives named scutellaprostins were reported from Scutellaria spp. (for references see Wollenweber6).

12.6.11 FURANOFLAVONOLS

OF

VELLOZIA

Species of the genus Vellozia have been extensively studied for their flavonoid complement in relation to chemosystematics.103–107 In addition to a series of C-methylflavonols and two C-prenylated flavonols, derivatives of vellokaempferol and velloquercetin are accumulated in whole plants, leaves, and leaf exudates. The basic structure of these compounds is characterized by 7,6-isopropenylfurano substitution, based upon kaempferol, quercetin, and their O-methyl ethers. In addition, 8-C-methyl derivatives of these compounds were also identified from leaves of V. stipitata.104 So far, species of this genus are the only reported sources of these compounds, which in parts have been proved to be accumulated externally.104–106 Structures are exemplified by Figure 12.10.

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R

3

OR

O

2

O

OR HO

1

O

1

2

1

2

3

R = R = R : Vellokaempferol 3

R = R = H, R = OH: Velloquercetin

FIGURE 12.10 Furanoflavonols from Vellozia.

12.7 FLAVONE AND FLAVONOL ESTERS The occurrence of acylated flavones and flavonols still appears interesting enough to justify a short paragraph on this subject (for compilation see Table 12.5). Of the flavones, only three compounds are known to date, with one newly reported isobutyrate flavone from leaf exudates of Asarina procumbens (Scrophulariaceae).108 One further compound, the 5’-benzoate of 8,2’,5’-trihydroxyflavone, was isolated recently from the exudate of Primula palinuri (Iinuma and Wollenweber, unpublished). By comparison, a series of mostly monoacylated flavonols is known to date and recent reports increased the number slightly. Four new products came from Pseudognaphalium robustum and Tanacetum microphyllum (both Asteraceae), and from Adina cordifolia (Rubiaceae). A diacetylated compound (3,5-diacetyltambulin) was recently isolated from the bark of Zanthoxylum integrifoliolum (Rutaceae).109 Since most of the flavonols are monoacylated, the accumulation of quercetin tetraacetate in Adina cordifolia110 is a remarkable result. Altogether, the newly reported compounds occur scattered in the plant kingdom; their occurrence is so far of little chemosystematic value. Aerial parts of Tanacetum microphyllum (Asteraceae) yielded a derivative, which is structurally not an ester. It is, indeed, a carbomethoxy derivative of 6-hydroxyluteolin-4’-methyl ether (compound 34 in Table 12.5). No other flavonoid of this type is known so far. Several of these compounds are accumulated externally as was proven for the farinose exudates of ferns, the flavonoid aglycones from Primula species, or those washed from the surface leaves and stems from Asteraceae. Heartwood (Adina cordifolia) also is a well-known accumulation site for lipophilic products. In this case, the occurrence of a natural tetraacetylflavonol is of particular interest. However, the accumulation site of the angelate of tri-O-methylgossypetin from Polygonum flaccidum111 is unclear. Since it was isolated along with caryophyllenexpoxide, borneol, sitosterin, and stigmasterol, it might well be present in some lipophilic epicuticular material. Generally speaking, the production of acylated flavonoids still is a rare phenomenon, and so far Cheilanthoid ferns are the most important source of such products.

12.8 CHLORINATED FLAVONOIDS These are extremely rare natural products. Among the flavones, 6-chloroapigenin is the only compound of this type occurring naturally. It had been isolated in 1980 from an Equisetum species.112 The flavonol chlorflavonin (5,2’-diOH-3,7,8-triOMe-3’-chloroflavone) had been isolated from Aspergillus candidus already in 1969.113 Since then, only the 7-chloroderivatives

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TABLE 12.5 Flavone and Flavonol Esters No.

OH-Substitution

1 2 3

Flavon-ester 5-diOH 2’-diOH 5,4’-diOH

4

OMeSubstitution

Plant Species

7,8-diOMe

7-O-benzoate 5’-O-acetate 6-O-isobutyrate*

Asarina procumbens

Scroph.

Leaf exudate

108

Flavonol-ester 5,7-diOH

3-OMe

8-O-butyrate*

Pseudognaphalium robustum

Ast.

Resinous exudate

551

5 6 7 8 9 10

5,7-diOH 3,5-diOH 3,5-diOH 5-OH 5-OH 5,7-diOH

3-OMe 7-OMe 7-OMe 3,7-diOMe 3,7-diOMe 3,6-diOMe

8-Me-butenoate 8-O-acetate 8-O-butyrate 8-O-acetate 8-O-butyrate 8-O-butyrate*

Pseudognaphalium robustum

Ast.

Resinous exudate

551

11 12 13 14 15 16

3,5,2’-triOH 3,5,4’-triOH 3,5,4’-triOH 3,5-diOH 3,5-diOH

7-OMe 7-OMe 7-OMe 7,4’-diOMe 7,4’-diOMe 7,8,4’-triOMe

8-O-acetate 8-O-acetate 8-O-butyrate 8-O-acetate 8-O-butyrate 3,5-di-O-acetate*

Zanthoxylum integrifolium

Rutac.

Fruit

109

17 18 19 20

5,7,3’,4’-tetraOH 3,5,7,4’-tetraOH 3,5,7,3’-tetraOH 3’-OH

(Quercetin) (Quercetin) (Quercetin) (Quercetin)

Adina cordifolia

Naucleac.

Heartwood

110

21 22 23 24 25

5,7-diOH 5,7-diOH 5,7-diOH 5,4’-diOH 3,5,6,3’-tetraOH

3,3’-diOMe 3,3’-diOMe 3,6,4’-triOMe 3,6,7-triOMe 4’-OMe

3-O-isobutyrate 3’-O-isobut. 4’-O-isobut. 3,5,7,4’-tetraO-acetate* 4’-O-Me-butyrate 4’-O-isovalerate 8-O-tigliate 8-O-Me-butyrate 7-O-acetate*

Tanacetum microphyllum

Ast.

Aerial parts

395

26 27 28 29 30 31 32 33

5,5’-diOH 3,5,3’-triOH 3,5,3’-triOH 5,4’-diOH 5,7-diOH 5,7,2’-triOH 5,7,3’-triOH 5-OH

Tanacetum microphyllum

Ast.

Aerial parts

395

34

3,7,8-triOMe 7,4’-diOMe 7,4’-diOMe 3,7,3’-triOMe 8,3’,4’-triOMe 3,4’-diOMe 3,4’-diOMe 3,7,2’,3’,4’pentaOMe Carbomethoxy-flavonol 3,5,3’-OH 4’-OMe

Family

Plant Organ

Acyl Moiety

Ref.

2’-O-acetate 8-O-butyrate 8-O-butyrate 8-O-acetate 3-O-angelate 5’-O-acetate 5’-O-acetate 8-O-acetate

7-COOCH3*

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of 3,5,6,8,4’-pentamethoxyflavone and of 3,5,6,8,3’,4’-hexamethoxyflavone, both isolated from leaves of Citrus ‘‘Dancy tangerine,’’114 were reported as new chloroflavonols. The earlier expectation that such compounds might be found in Asteraceae, which are known for the production of other chlorinated natural products, was not fulfilled.

12.9 FLAVONOIDS OF HELMINTHOSTACHYS Rhizomes of Helminthostachys zeylanica (Ophioglossaceae) yielded a series of complex flavone and flavonol derivatives with singular structures. They were named ugonins A–I. Whereas some flavones of this medicinally used plant are known for a long time,115 new data include also a series of flavonols.116 The complexity of these compounds is remarkable. Some of the structures are depicted in Figure 12.11.

12.10 COMMENTS ON DISTRIBUTION AND ACCUMULATION In a compilation such as the present one, it is tempting to interpret the data regarding substitution patterns and distribution within the plant kingdom. However, the data presented here only comprise those not included in previous editions (e.g., Wollenweber6), hence the distribution picture sure is somewhat distorted. The new entries concern not only several families of the Angiosperms, but include also results on ferns and mosses. Although not from a plant source in the strict sense, the C-methylflavonols from fungi such as Colletotrichum dematium84 were also included (Table 12.4). This organism is pathogenic to Epilobium angustifolium. The possible uptake of these compounds by the fungus from the plant can be excluded since substitution patterns of the fungal flavonols and the flavonoids from Epilobium do not coincide.117 Another fungus, Aspergillus flavus, proved to be able to synthesize prenylated naringenin derivatives from supplied flavanones.118 Apparently, these fungi are able to metabolize flavonoids from precursors, but nothing is known about the basic biosynthesis of flavonoids in these organisms. One of the hypotheses regarding evolutionary aspects of flavonoid diversification concerns the concept of flavonol accumulation in basal Angiosperms versus flavone accumulation in advanced families. Recently, some further efforts have been made towards defining the flavone/flavonols ratio in Dicotyledonae and their relation to lignification,119 indicating an increased tendency towards flavonol accumulation in lignified plants, whereas herbaceous species tend to accumulate more of the flavones. From the presented entries, it appears that flavone derivatives are more abundant in Lamiaceae than flavonols. In the Asteraceae, however, more data concern the flavonols. Both families are more or less herbaceous and members of the more advanced Angiosperms. It might be of more value to check the substitution patterns for their chemosystematic significance, as had been done earlier in frequency analysis.56 According to current data, 6-substitution, both OH and OMe, appears to be more frequent than the corresponding 8-substitution in flavones. The number of their 6,8-diOMe derivatives is quite considerable though. By comparison, the number of the related 6,8-OH-flavones is restricted to a few compounds reported from natural sources (compounds 136, 222, 227, and 262 in Table 12.1). All of the other polyhydroxylated structures have so far not been found as natural products. A similar ratio between 6- and 8-substitution was found with the flavonols, but the number of naturally occurring 6,8-diOH flavonols is limited to two compounds only (compounds 239 and 289 in Table 12.2). Further accumulation trends of possible chemosystematic relevance have been discussed in the respective sections. Aspects on substitution patterns of prenylated flavonoids and their derivatives including the frequency of occurrence have been discussed in detail.3 Thus, these aspects will not be

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11

12

OH

13

9

10

8

O

O

13

7

14

12

16

18

OH

11

15

OH 17

O

10

O

H

OH

Ugonin F 2⬘

HO

O

5⬘ 6⬘

OH HO

OCH3 OH

O

O Ugonin I

6

OH

9 16

H 15

10

18

OH

O

OH

OH

11

17 12

14

H3CO

Ugonin G

13

O

6

H

9

16 10 17

13 14

O

11

15

O

Ugonin L

18

12 12

16

11

15

13 18

17

10

H

OH OH

9 2⬘

HO

O

5⬘ 6⬘

OCH3 OH

O

Ugonin H

FIGURE 12.11 Flavonoids from Helminthostachys.

covered here. From the present data, the tendency to produce complex flavones is predominant. Such products are of limited distribution in few genera of some families only, as exemplified in the respective sections of this chapter (e.g., Artocarpus-Moraceae; TephrosiaFabaceae). The degree of complexity differs between flavones and flavonols. Thus, the flavones outnumber the flavonols, both in number and complexity. Interestingly, the number of O-prenylated flavonols is much higher than that of the corresponding flavones. The

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occurrence of complex flavones and flavonols in various Pteridophyta and Hepaticae is further remarkable. Apparently, various evolutionary independent groups in the plant kingdom are able to synthesize biosynthetically complex products. Some general comments on the external accumulation and excretion of flavonoid aglycones should be made. In most cases, flavone and flavonol methyl ethers contribute to the exudates, sometimes including methylenedioxy derivatives, C-methylderivatives, and flavone and flavonol esters. Complex structures, however, are rarely reported to occur in exudates, as for example, C-prenylflavonols in Velloziaceae,105 or 7,8-cycloflavonols from frond exudates of Pteridaceae.120–122 The most complex structures found in Artocarpus spp. are not known to be excreted, for reasons unknown. Maybe the responsible enzymes cannot be compartimented in the cells of, for example, glandular hairs, which are frequently the accumulation site of lipophilic material. For flavonoid aglycones, this was established for instance in a study on Mentha.123 Several other studies are similarly conclusive (e.g., Heinrich et al.124). The presence of the basic enzymes for flavonoid production in head cells of glands was reported for Primula kewensis.125 Primula species are widely known for their production of flavonoid exudates. Afolayan and Meyer126 hypothesized that exudate flavonoids of Helichrysum aureonitens were probably produced by the endoplasmatic reticulum in the secreting trichomes. There would be many more interesting aspects to be discussed, such as ecological significance (e.g., Tattini et al.127) or ontological differentiation during plant development,128 which would be beyond the scope of this review. Ecological and other aspects not fully discussed here have been addressed in previous publications.6,129,130 It is hoped that the aspects discussed here will stimulate further research outside the flavonoid community as well.

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APPENDIX Trivial Name Trivial Name Abrectorin Acacetin Acerosin Ageconyflavon A Ageconyflavon B Ageconyflavon C Agecorynin F Agecorynin G Agecorynin-C Agecorynin-D Agehoustin A Agehoustin B Agehoustin C Agehoustin D Agehoustin E Agehoustin F Albanin A Albanin D, revised Albanin E, revised Aliarin ‘‘Allopatuletin’’ — obsolete Alluaudiol Alnetin Alnusin Alnustin Altisin Anhydroicaritin Annulatin Apigenin Apollinine Apometzgerin Apuleidin Apulein Apuleirin Apuleisin Apuleitrin Araneol Araneosol Arcapillin Arteanoflavon Artelasticin Artelastin Artelastocarpin Artelastochromene Artelastofuran Artemetin Artobilochromene

Substitution 7,3’-diOH, 6,4’-diOMe — flavone 5,7-diOH, 4’-OMe — flavone 5,7,3’-triOH, 6,8,4’-triOMe — flavone 5,6,7-triOMe, 3’,4’-OCH2O — flavone 4’-OH, 5,6,7,3’-tetraOMe — flavone 4’-OH, 5,6,7,3’,5’-OMe — flavone 5-OH, 6,7,2’,3’,4’,5’-hexaOMe — flavone 3’-OH, 5,6,7,2’,4’,5’-hexaOMe — flavone 5,6,7,8,2’,4’,5’-heptaOMe — flavone 5,2’,4’-triOH, 6,7,8,5’-tetraOMe — flavone 5,6,7,8,2’,3’,4’,5’-octaOMe — flavone 5,6,7,2’,3’,4’,5’-heptaOMe — flavone 3’-OH, 5,6,7,8,2’,4’,5’-heptaOMe — flavone 5,3’-diOH, 6,7,8,2’,4’,5’-hexaOMe — flavone 5-OH, 6,7,8,2’,4’,5’-hexaOMe — flavone 5,2’-diOH, 6,7,8,4’,5’-pentaOMe — flavone 5,7,2’,4’-tetraOH, 3-C5 — flavone 5,7,4’-OH, 6-C10 — flavone 5,7,2’,4’-tetraOH, 6-C10 — flavone 5,7,4’-triOH, 3,6-diOMe, 3’-C5-OH — flavonol 5,7,3’,4’,5’-OH, 3-OMe, 6-Me — flavonol 5-OH, 6,7,8-triOMe — flavone 3,5,7-triOH, 6-OMe — flavonol 5-OH, 3,6,7-triOMe — flavonol 5-OH, 7,8,2’,6’-tetraOMe — flavone 3,5,7-triOH, 4’-OMe, 8-C5 — flavonol 5,7,3’,4’,5’-pentaOH, 3-OMe — flavonol 5,7,4’-triOH — flavone 7-OMe, 8-furyl (2’’ ¼ oxo) — flavone, see Figure 12.5 5,7,5’-triOH, 3’,4’-diOMe — flavone 5,2’,3’-triOH, 3,7,4’-triOMe — flavonol 2’,5’-diOH, 3,5,6,7,4’-pentaOMe — flavonol 7,5’-diOH, 3,5,7,3’,4’-pentaOMe — flavonol 5,6,2’,3’-tetraOH, 3,7,4’-triOMe — flavonol 5,6,5’-triOH, 3,7,3’,4’-tetraOMe — flavonol 5,7-diOH, 3,6,8-triOMe — flavonol 5,7-diOH, 3,6,8,4’-tetraOMe — flavonol 5,2’,5’-triOH, 6,7,5’-triOMe — flavone 5,7-diOH, 6,3’,4’,5’-tetraOMe — flavone 5,7,2’,4’-tetraOH, 3,6,8-triC5 — flavone 5,7,4’-triOH, 6,8-diC5, 3,6’-cycl-OC5 — flavone 5,7,4’-triOH, 6,8-diC5, 3,6’-cyclo-O-C6-C3-OH — flavone, see Figure 12.6 5,4’-diOH, 8-C5, 7,6-ODmp, 3,6’-cycl-OC5 — flavone 5,4’-diOH, 7,8-dihydrofurODmp-OH — flavone, see Figure 12.6 5-OH, 3,6,7,3’,4’-pentaOMe — flavonol 5,2’,4’,5’-tetraOH, 3’-C5, 7,6-ODmp — flavone continued

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APPENDIX Trivial Name — continued Trivial Name Artobiloxanthone Artocarpesin Artocarpetin Artocarpetin A Artocarpetin B Artocarpin Artocommunol CA Artocommunol CC Artocommunol CD Artoindonesianin A Artoindonesianin B Artoindonesianin P Artoindonesianin Q Artoindonesianin R Artoindonesianin S Artoindonesianin T Artomunoxanthentrione Artomunoxanthone Artonin E (‘‘KB-3’’) Artonin F Artonin J Artonin K Artonin L Artonin M Artonin N Artonin O Artonin P Artonin S Artonin T Artonin U Artonol C Artonol D Artonol E Asplenetin Atalantoflavon Auranetin Australon A Axillarin Ayanin Azaleatin Baicalein Baohuosu Benthamianin Betuletol Bonanzin Brevicornin Brickellin (revised) Brosimacutin F

Substitution 5,2’,4’,5’-tetraOH, 7,8-ODmp, 3,6’-cyclo-C6-C3 — flavone 5,7,2’,4’-tetraOH, 6-C5 — flavone 5,2’,4’-triOH, 7-OMe — flavone 5,2’,4’-triOH,7-OMe, 8-C5 — flavone 5,4’-diOH, 7,2’-OMe, 8-C5 — flavone 5,2’,4’-triOH, 7-OMe, 3,6-diC5 — flavone 5-OH,4’OMe, 7,8-ODmp, C5-O-C5; 3,6’-cycl-O-C5 — flavone, see Figure 12.6 5,4’-diOH, 3-C5-OH, 7,8-ODmp — flavone 5,7,2’,4’-tetraOH, 8-C5, 3-C10 — flavone 5,2’,4’-triOH, 8-C10, 7,6-ODmp-3,6’ cyclo-C6-diMe-fur — flavone 5-OH, 7OMe, 6-C5, 3,6’-cyclo O-C6-C3 — flavone 5,7,2’,4’-tetraOH, 3,6’cyclo-C6-diMe-fur — flavone 5,2’,5’-OH, 7,4’-OMe, 3-C5 — flavone 5,7,5’, OH-2’,4’-OMe, 3-C5 — flavone 5,2’,5’-triOH, 7,4’-diOMe, 3,6’-cyclo C6-C3 — flavone 5,7,2’,5’-tetraOH, 4’-OMe, 3,6’-cyclo C6-C3 — flavone 5-OH, 4’-OMe, 7,8-ODmp; 3,6’-cycloC6-C3 — flavone 5,2’,5’-triOH, 4’-OMe, 7,8-ODmp, 3,6’-cyclo C6 — flavone 5,2’4’,5’-tetraOH, 3-C5, 7,8-ODmp — flavone 5,2’-diOH, 4’-OMe, 6-C5;7,8-ODmp, 3,6’-cyclo C6-5’-fur — flavone 5,7,2’,4’-tetraOH, 3,6’-cycloC6-5’-fur; 4’-C5 — flavone 5,2’,4’-triOH, 7-OMe, 3,6’-cyclo C6-5’-fur — flavone, see Figure 12.6 5,4’-diOH, 7,2’-diOMe, 3,6’-cyclo C6-5’-fur — flavone 5,2’,4’-triOH, 7,6-ODmp; 3,6’-cyclo C6-5’-fur — flavone 5,7,2’,4’-tetraOH, 6-C5, 3’,4’-ODmp, 3,6’-cycloC6-C3 — flavone 5,7,4’-triOH, 3’,6’-di-oxo, 6,5’-C5; 3,6’-cycloC6-C3 — flavone 5,4’-dOH, 2’,5’-di-oxo, 7,8-ODmp; 3,6’-cycloC6-C3, 2’,5’-epoxy — flavone 5,4’-diOH, 7-OMe, 6-C5, 3,6’-cyclo O-C6-C3 — flavone 5,2’,4’-triOH, 7-OMe, 3,6’-cycloC6-5’-fur; 4’-C5 — flavone 5,4’-diOH, 7-OMe, 8-C5 — flavone 5,2’,5’-triOH, 7,8-ODmp, 3’,4’-ODmp, 3,6’-cyclo-C6-C3 — flavone 5-OH, 2’,5’-di-oxo, 7,8-ODmp, 3’,4’-ODmp, 3,6’-cyclo-C6-C3 — flavone, see Figure 12.6 5,2’,5’-triOH, 7-OMe, 3’,4’-ODmp, 3,6’-cyclo-C6-C3 — flavone, see Figure 12.6 5,7,3’,4’,5’-pentaOH, 3-C5 — flavone 5,4’-diOH, 7,8-ODmp — flavone 3,6,7,8,4’-pentaOMe — flavonol 5,2’,4’-triOH, 7,6-ODmp-C5 — flavone 5,7,3’,4’-tetraOH, 3,6-diOMe — flavonol 5,3’-diOH, 3,7,4’-triOMe — flavonol 3,7,3’,4’-tetraOH, 5-OMe — flavonol 5,6,7-triOH — flavone 5,7,4’-OH. 3’,5’-OMe, 8-C5 — flavone 5,7,3’,4’-tetraOH, 6OMe, 3,2’-O-CH2 — flavonol 3,5,7-triOH, 6,4’-diOMe — flavonol 5,7-diOH, 3,6,3’,4’-tetraOMe — flavonol 3,5,7-triOH, 4’-OMe, 8-C5-OMe — flavone 5,2’-diOH, 3,6,7,4’,5’-pentaOMe — flavonol 7,4’-diOH, 8-C5(OH)2 — flavone

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APPENDIX Trivial Name — continued Trivial Name Brosimone G Brosimone H Brosimone I Broussoflavonol A Broussoflavonol B Broussoflavonol C Broussoflavonol D Broussoflavonol E Broussoflavonol F Broussoflavonol G Broussonol A Broussonol B Broussonol C Broussonol D Broussonol E Bucegin Calomelanol D Calycopterin Candidin (syn.: Isopongaflavone) Candidol ‘‘Candiron’’ — obsolete Cannflavin A Cannflavin B Carajuflavone Carpachromene Carpelastofuran Caryatin Casticin Centaureidin Cerosillin Cerosillin B Chlorflavonin 6-Chloroapigenin Chrysin Chrysoeriol Chrysosplenetin Chrysosplenol-C Chrysosplenol-D Chrysosplin Ciliatin A Ciliatin B Cirsilineol Cirsiliol Cirsimaritin Citrusinol Combretol

Substitution 5,2’,4’-triOH, 7,8-ODmp-C5 — flavone 5,2’,4’-triOH, 7-OMe, 3-C5, 8-C10 — flavone 5,7,4’-triOH, 6-C5, 3,6’-cycl-O-C5 — flavone 5,3’,4’-OH, 3-OMe, 8-C5, 7,6-ODmp — flavonol 5,7,3’,4’-OH, 3-OMe, 6,8-diC5 — flavonol 3,5,7,3’,4’-pentaOH, 8,2’,6’-triC5 — flavonol 3,5,7,5’-tetraOH, 8,2’-diC5, 3’,4’-ODmp — flavonol, see Figure 12.9 3,5,7,5’-tetraOH, 8,2’-diC5, 3’,4’-ODmp — flavonol 3,5,7,4’-tetraOH, 8,3’-diC5 — flavonol 3,5,7,3’,4’-pentaOH, 8,2’,3’-triC5 — flavonol 3,5,7,3’tetraOH, 4’,5’ODmp-8-C5 — flavonol 3,5,3’triOH, 4’,5’-ODmp, 7,8-triMe-fur — flavonol 3,5,3’,4’-tetraOH, 5’-C5; 7,8-triMe-fur — flavonol 3,5,7,3’,4’-pentaOH, 8,5’-diC5 — flavonol 3,5,7,3’,4’-pentaOH, 6,5’-diC5 — flavonol 5,7-diOH, 8,4’-diOMe — flavone 3,5,4’-triOH, 7,8-O-cycl-phenylethyl — flavonol 5,4’-diOH, 3,6,7,8-tetraOMe — flavonol 3,4’-diOH, 5,6,7-triOMe — flavonol 5,7,4’-triOH, 3’-OMe, 6-C10 — flavone 5,3’-diOH, 7,4’-diOMe, 6-C5 — flavone 6,7,3’,4’-tetraOH, 5-OMe — flavone 5,4’-diOH, 7,6-ODmp — flavone 5,4’diOH, 8-C5-7,6-fur-C3-OH, 3,6’-cyclo-O-C6-C3-OH — flavone 7,3’,4’-triOH, 3,5-diOMe — flavonol 5,3’-diOH, 3,6,7,4’-tetraOMe — flavonol 5,7,3’-triOH, 3,6,4’-triOMe — flavonol 5,6,3’,5’-tetraOMe — flavone 5,6,3’,4’,5’-pentaOMe — flavone 5,2’-diOH, 3,7,8-triOMe, 3’-chloro — flavonol 5,7,4’-triOH, 6-chloro — flavone 5,7-diOH — flavon 5,7,4’-triOH, 3’-OMe — flavone 5,4’-diOH, 3,6,7,3’-tetraOMe — flavonol 5,6,4’-triOH, 3,7,3’-triOMe — flavonol 5,3’,4’-triOH, 3,6,7-triOMe — flavonol 5,4’-diOH, 3,6,7,2’-tetraOMe — flavonol 5,4’-diOH, 7,6-dihydrofur-C3 — flavone, see Figure 12.3 7,4’-diOH, 3’-OMe, 5,6-ODmp — flavone 5,4’-diOH, 6,7,3’-triOMe — flavone 5,3’,4’-triOH, 6,7-diOMe — flavone 5,4’-diOH, 6,7-diOMe — flavone 3,5,4’-triOH, 7,8-ODmp — flavonol 5-OH, 3,7,3’4’5’-pentaOMe — flavonol continued

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APPENDIX Trivial Name — continued Trivial Name Conyzatin Corymbosin Cudraflavone C Cudraflavone D Cycloaltilisin Cycloartobiloxanthone Cycloartocarpesin Cycloartocarpin Cycloartomunin Cycloartomunoxanthone Cyclochampedol Cyclocommunin (syn.: Isocyclomulberrin) Cyclocommunol Cycloheterophyllin Cyclointegrin Cyclomorusin (syn.: Cyclomulberrochromene) Cyclomulberrin Cyclomulberrochromene (syn.: Cyclomorusin) Dasytrichone Datin Datiscetin Demethyltorosaflavone C Demethyltorosaflavone D Denticulaflavonol Desmethylcentaureidin Desmethylsudachitin Desmethylanhydroicaritin Desmethyldigicitrin 8-Desmethyleucalyptin 8-Desmethylkalmiatin Desmethylkanugin 8-Desmethyllatifolin 5-Desmethylmelibentin 5-Desmethylmeliternin 5-Desmethylnobiletin 8-Desmethylsideroxylin Desmosflavone Digicitrin Dihydrofuranoartobilichromene a Dihydrofuranoartobilichromene b1 Dihydrofuranoartobilichromene b2 Dillenetin 5,6-Dimethoxypongapin Dihydroisocycloartomunin 8-(1,1-Dimethylallyl)-galangin 8-(1,1-Dimethylallyl)-kaempferol 6,8-Dimethylapigenin Diosmetin

Substitution 5,7-diOH, 3,8,3’,4’,5’-pentaOMe — flavonol 5-OH, 7,3’,4’,5’-tetraOMe — flavone 5,7,2’,4’-tetraOH, 3,6-diC5 — flavone 5,7,2’,4’-tetraOH, 6,5’-diC5 — flavone 5,7,5’-triOH,4’-OMe, 3,6’-cyclo C6-C3; 6-C5 — flavone 5,2’,4’,triOH, 7,8-ODmp, 3,6’cyclo-C6-diMe-fur — flavone 5,2’,4’-triOH, 7,6-ODmp — flavone 5,4’-diOH, 7-OMe, 6-C5, 3,6’-cycl-O-C5 — flavone 5,5’-diOH, 4’-OMe, 7,8-ODmp, 3,6’-cycl-O-C5 — flavone 5,2’-diOH, 4’-OMe, 7,8-ODmp, 3,6’-cyclo C6-5’-fur — flavone 5,7,3’,4’-tetraOH, 2’,3-ODmp — flavone 5,7,4’-triOH, 6-C5, 3,6’-cycl-O-C5 — flavone 5,7,4’-triOH, 3,6’-ODmp — flavone 5,4’,5’-triOH, 8-C5, 7,6-ODmp, 3,6’-cycl-O-C5 — flavone 5,4’-diOH, 7-OMe, 3,6’-cyclo O-C7 D202 — flavone 5,4’-diOH, 7,8-/3,6’-ODmp — flavone 5,7,4’-triOH, 8-C5, 2’,3-ODmp — flavon 5-OH, 6-Me, 8-diMe, 7 ¼ O — flavone 3,5,2’-triOH, 7-OMe — flavonol 3,5,7,2’-tetraOH — flavonol 5,3’,4’-triOH, 7,6- bisfurano — flavone, see Figure 12.3 5,7,3’,4’-tetraOH, 6-acrylic acid — flavone, see Figure 12.1 3,5,7,4’-tetraOH, diterpene-flavonol — flavonol, see Figure 12.9 5,7,3’-triOH, 6,4’-diOMe — flavone 5,7,4’-triOH, 6,8-diOMe — flavone 3,5,4’-triOH, 7,6-ODmp — flavonol 3,5,3’-triOH, 6,7,8,4’,5’-pentaOMe — flavonol 5-OH, 7,4’-diOMe, 6-Me — flavone 5-OH, 3,7,4’-triOMe, 6-Me — flavonol 3,7-diOMe, 3’,4’-OCH2O — flavonol 5,4’-diOH, 3,7-diOMe, 6-Me — flavonol 5-OH, 3,6,7,8-tetraOMe, 3’,4’-O2CH2 — flavonol 5-OH, 3,7,8-triOMe, 3’,4’-OCH2O — flavonol 5-OH, 6,7,8,3’,4’-pentaOMe — flavone 5,4’-diOH, 7-OMe, 6-Me — flavone 5-OH, 7-OMe, 6,8-diMe — flavone 5,3’-diOH, 3,6,7,8,4’,5’-hexaOMe — flavonol 5,3’,4’-triOH, 7,6-ODmp, 6’,5’-dihydrofur-2’’-C3 — flavone 5,3’,6’-triOH, 7,6-ODmp, 4’,5’-dihydrofur-2’’-C3 — flavone 5,3’,6’-triOH, 7,6-ODmp, 4’,5’-dihydrofur-2’’-C3 — flavone 3,5,7-triOH, 3’,4’-diOMe — flavonol 3,5,6-triOMe, 3’,4’-O2CH2, 7,8-fur — flavonol 5,3’,4’-triOH,7-OMe, 8-C5, 3,6’-cycl.-O-C5-ODmp — flavone 3,5,7-triOH, 8-C5 — flavonol 3,5,7,4’-tetraOH, 8-C5 — flavonol 5,7,4’-triOH, 6,8-diMe — flavone 5,7,3’-triOH, 4’-OMe — flavone

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APPENDIX Trivial Name — continued Trivial Name 6,8-Diprenylkaempferol Dinklagin B Distemonanthin Dorsilurin A Dorsilurin B Dorsilurin C Dorsilurin D Dorsilurin E Dorsmanin C Dorsmanin D Dumosol Echioidinin Emmaosunin Enantiomultijugin Ephedroidin Epimedokoreanin A Epimedokoreanin B 7-Epoxyprenylgnaphaliin Eriostemin Ermanin Eucalyptin Eupalestin Eupalitin Eupatilin Eupatin Eupatolitin Eupatoretin Eupatorin Europetin Exoticin Farnisin Fasciculiferin Ferrugin Fisetin Flindulatin Fulvinervin B Fulvinervin C Galangin Gancaonin O Gancaonin P Gancaonin Q Ganhuangenin Gardenin A Gardenin B Gardenin C Gardenin D

Substitution see Glyasperin A 5,4’-diOMe, 7,6-ODmp-OH — flavone 5,7,3’,4’-tetraOH, 6-OMe, 3,2’-O-CH2 — flavonol 5,7,2’,4’-tetraOH, 6,8,3’-triC5 — flavone 5,2’,4’-triOH, 3,6-diC5, 7,8-ODmpOH — flavone 3,5,7-triOH, 6,8-diC5-4’,3’-ODMp — flavonol 5,7,2’,4’-tetraOH, 3,6,8-triC5 — flavone 2’-OH, 4,3/6,5/7,8-triODmp, 4’ ¼ O . . . — flavone, see Figure 12.2 3,5,3’,4’-tetraOH, 7,8-ODmp-6-C10 — flavonol 3,5,7,4’-tetraOH, 3’-OMe, 6,8-diC5 — flavonol 3,5,7,3’,5’- pentaOH, 4’-OMe, 6-Me — flavonol 5,2’-diOH, 7-OMe — flavone 5-OH, 3,6,7,8,3’-pentaOMe — flavonol 5-OMe, 7,8-bisfur — flavone, see Figure 12.5 5,7,4’-OH, 8-C5-OH — flavone 5,3’-diOH, 7,8-dihydrofur-2’’-C3/4’,5’-dihfur-OH-5’’-C3-OH . . . — flavone, see Figure 12.3 5,7,3’,4’-tetraOH, 8,5’-diC5 — flavone 5-OH, 3,8-diOMe, 7-O-C5 (epoxy) — flavonol 3,8-diOH, 5,6,7,4’-tetraOMe — flavonol 5,7-diOH, 3,4’-diOMe — flavonol 5-OH, 7,4’-diOMe, 6,8-diMe — flavone 5,6,7,8,5’-pentaOMe, 3’,4’-OCH2O — flavone 3,5,4’-triOH, 6,7-diOMe — flavonol 5,7-diOH, 6,3’,4’-triOMe — flavone 3,5,3’-triOH, 6,7,4’-triOMe — flavonol 3,5,3’,4’-tetraOH, 6,7-diOMe — flavonol 3,3’-diOH, 5,6,7,4’-tetraOMe — flavonol 5,3’-diOH, 6,7,4’-triOMe — flavone 3,5,3’,4’,5’-pentaOH, 7-OMe — flavonol 3,5,6,7,8,3’,4’,5’-octaOMe — flavonol 7,3’-diOH, 4’-OMe — flavone 7,4,5’-triOH, 3,2’-O-CH2-OH — flavonol, see Figure 12.9 5,7-diOH, 3’,4’,5’-triOMe — flavonol 3,7,3’,4’-tetraOH — flavonol 5-OH, 3,7,8,4’-tetraOMe — flavonol 5-OH, 6-C5, 7,8-ODmp — flavone 5-OH, 6-C5-OH, 7,8-ODmp — flavone 3,5,7-triOH — flavonol 5,7,3’,4’-tetraOH, 6-C5 — flavone 3,5,7,3’,4’-pentaOH, 6-C5 — flavonol 5,7,4’-triOH, 6,3’-diC5 — flavone 5,7,3’,6’-tetraOH, 8,2’-diOMe — flavone 5-OH, 6,7,8,3’,4’,5’-hexaOMe — flavone 5-OH, 6,7,8,4’-tetraOMe — flavone 5,3’-diOH, 6,7,8,4’,5’-pentaOMe — flavone 5,3’-diOH, 6,7,8,4’-tetraOMe — flavone continued

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APPENDIX Trivial Name — continued Trivial Name Gardenin E Genkwanin Geraldol Geraldone Geranioloxyalatum flavone Glabone Glabratephrin Glabratephrinol Glepidotin A Glyasperin A Glycyrrhiza-flavonol A Gnaphalin Gomphrenol Gossypetin Grantiodinin Grantioidin Grantionin Haplopappin Herbacetin Heteroartonin A Heterophyllin Hibiscetin Hispidulin Honyucitrin Hookerianin Hosloppin Hoslundin 5-Hydroxyauranetin 6-Hydroxygalangin 8-Hydroxygalangin 5’-Hydroxymorin 6-Hydroxykaempferol 6-Hydroxyluteolin 6-Hydroxymyricetin 4’-Hydroxywogonin Hymenoxin Hypolaetin Icaritin Integrin Inucrithmin Isoanhydroicaritin Isoartocarpin Isocyclomorusin Isocyclomulberrin (syn.: Cyclocommunin) Isoetin Isognaphalin Isokaempferide Isokanugin

Substitution 5,3’,5’-triOH, 6,7,8,4’-tetraOMe — flavone 5,4’-diOH, 7-OMe — flavone 3,7,4’-triOH, 3’-OMe — flavonol 7,4’-diOH, 3’-OMe — flavone 3,5,3’-triOH-6,7-diOMe, 4’-O-C10-OH — flavonol 4’-OMe, 7,6-fur — flavone 7,8-bisfur — flavone 7,8-bisfur — flavone 3,5,7-triOH, 6-C5 — flavonol 3,5,7,4’-tetraOH, 6,3’-diC5 — flavonol 3,5,7-triOH, 4’,3’-cycl-OC5-OH — flavonol 5,7-diOH, 3,8-diOMe — flavonol 3,5,4’-triOH, 6,7-OCH2O — flavonol 3,5,7,8,3’,4’-hexaOH — flavonol 5-OH, 3,6,7,8,2,5’-hexa-OMe — flavonol 5-OH, 3,6,7,2’5’pentaOMe — flavonol 7-OH, 6,3’,5’-triOMe — flavone 5,7-diOH, 3,4’-diOMe, 8-C-p-OH-phenylethyl — flavonol 3,5,7,8,4’-pentaOH — flavonol 5,7,2’,5’-OH-4’, OMe, 3,3’-diC5 — flavone 5,2’,4’,5’-tetraOH, 3,8-diC5; 7,6-ODmp — flavone, see Figure 12.2 3,5,7,8,3’,4’,5’-heptaOH — flavonol 5,7,4’-triOH, 6-OMe — flavone 5,7,4’-triOH, 3’,5’-diC5 — flavone 5,7-diOMe, 8-diMe-oxo-furano — flavone, see Figure 5 5-OH,7-OMe, 6,5’’-Ketopyrano. . . . 3’’-OH — flavone, see Figure 12.4 5-OH, 7-OMe, 6,5’’-Ketopyrano. . . . 3’’-Me — flavone, see Figure 12.4 5-OH, 3,6,7,8,4’-pentaOMe — flavonol 3,5,6,7-tetraOH — flavonol 3,5,7,8-tetraOH — flavonol 3,5,7,2’,4’,5’-hexaOH — flavonol 3,5,6,7,4’-pentaOH — flavonol 5,6,7,3’,4’-pentaOH — flavone 3,5,6,7,3’,4’,5’-OH — flavonol 5,7,4’-triOH, 8-OMe — flavone 5,7-diOH, 6,8,3’,4’-tetraOMe — flavon 5,7,8,3’,4’-pentaOH, — flavone 3,5,7-triOH, 4’-OMe, 8-C5-OH — flavonol 5,2’,4’-triOH, 7-OMe, 3-C5 — flavone 3,7,4’,5’-tetraOH, 6,3’-diOMe — flavonol 3,5,4’-triOH, 7-OMe, 8-C5 — flavonol 5,7,4’-triOH, 6,2’-diC5 — flavone 5,4’-diOH, 7,6-/3,6’-ODmp — flavone 5,7,2’,4’,5’-pentaOH — flavone 5,8-diOH, 3,7-diOMe — flavonol 5,7,4’-triOH, 3-OMe — flavonol 3,5,7-triOMe, 3’,4’-OCH2O — flavonol

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APPENDIX Trivial Name — continued Trivial Name Isolaxifolin Isolicoflavonol Isolimocitrol Isomacarangin Isoplatanin Isopongaflavone (syn.: Candidin) Isopongaglabol Isopratol Isorhamnetin Isorhynchospermin Isoscutellarein Isosinensetin Isothymusin Isounonal Izalpinin Jaceidin Jaceosidin Kaempferide Kaempferol Kalmiatin Kanjone Kanugin Kanzakiflavon-1 Kanzakiflavon-2 Kanzonol D Kanzonol E Karanjachromene Karanjin KB-1 KB-2 Kumatakenin Kushenol C Kushenol G Kuwanon B Kuwanon C (syn.: Mulberrin) Kuwanon S Kuwanon T Laciniatin Ladanein Lanceolatin A Lanceolatin B Laricitrin Latifolin Laurentinol Laxifolin Lethedocin

Substitution 5,4’-diOH, 8-C5, 7,6-ODmp — flavone 3,5,7,4’-tetraOH, 3’-C5 — flavonol 3,5,7,3’-tetraOH, 6,8,4’-triOMe — flavonol 3,5,7,4’-tetraOH, 8-C10 — flavonol 3,5,6,7-tetraOH, 8-Me — flavonol 5-OMe, 7,8-ODmp — flavone 4’-OH, 7,8-fur — flavone 4’-OH, 7-OMe — flavone 3,5,7,4’-tetraOH, 3’-OMe — flavonol 3,5,3’-OH, 7,4’-diOMe, 6-C5þD348 — flavonol 5,7,8,4’-tetraOH — flavone 5,7,8,3’,4’-pentaOMe — flavone 5,8,4’-triOH, 6,7-diOMe — flavone 5,7-diOH, 6-Me, 8-CHO — flavone 3,5-diOH, 7-OMe — flavonol 5,7,4’-triOH, 3,6,3’-triOMe — flavonol 5,7,4’-triOH, 6,3’-diOMe — flavone 3,5,7-triOH, 4’-OMe — flavonol 3,5,7,4’-tetraOH — flavonol 5-OH, 3,7,4’-triOMe, 6,8-diMe — flavonol 6-OMe, 7,8-fur — flavone 3,7,3’-triOMe, 3’,4’-OCH2O — flavonol 5,8-diOH, 4’-OMe, 6,7-O2CH2 — flavone 5,4’-diOH, 6,7-OCH2O — flavone 7,4’-diOH, 3’-C5 — flavone 7-OH, 6-C5, 3’,4’-ODmp — flavone 3-OMe, 7,8-ODmp — flavonol 3-OMe, 7,8-fur — flavonol 5,2’4’,5’-tetra-OH, 7,8-ODmp, 3,6’-cyclo C6 — flavone 5,2’4’,5’-tetraOH, 3-C5, 7,8-ODmp — flavone 5,4’-diOH, 3,7-diOMe — flavonol 3,5,7,2’,4’-pentaOH, 8-C10 — flavonol 3,5,7,2’,4’-pentaOH, 8-C10-OH — flavonol 5,7,2’-triOH, 3-C5, 3’,4’-ODmp — flavone 5,7,4’-triOH, 3’-C10 — flavone 5,7,2’,4’-tetraOH, 3,3’-diC5 — flavone 3,5,7,3’-tetraOH, 6,4’-diOMe — flavonol 5,6-diOH, 7,4’-diOMe — flavone 7-OMe, 8-C5-OH — flavone 7,8-fur — flavone 3,5,7,4’,5’-pentaOH, 3’-OMe — flavonol 5,4’-diOH, 3,7-diOMe, 6,8-diMe — flavonol 3,7,4’-triOH, 3’,5’diOMe — flavone 5,4’-diOH, 6-C5, 7,8-ODmp — flavone 5,5’-diOH, 7,3’,4’-triOMe — flavone continued

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APPENDIX Trivial Name — continued Trivial Name Licoflavone A Licoflavone B Licoflavone C Licoflavonol Limocitrin Limocitrol Linderoflavone A Linderoflavone B Luteolin Macaflavone I Macaflavone II Macarangin Marionol Matteuorien Mearnsetin Melanoxetin Melibentin Melicophyllin Melinervin Melisimplexin Melisimplin Meliternatin Meliternin 6-Methylapigenin 8-Methylapigenin 8-Methylgalangin Methylgnaphalin 6-Methylkaempferol 6-Methylluteolin 7-Methyltricin 7-Methylwogonin Mikanin Milletenin C Millettocalyxin A Millettocalyxin B Millettocalyxin C Mopanin Moralbanone Morelosin Morin Morusignin L Morusin (syn.: Mulberrochromene) Mosloflavone Moslosooflavone Mulberrin (syn.: Kuwanon C) Mulberrochromene (syn.: Morusin) Multijugin Multijuginol

Substitution 7,4’-diOH, 6-C5 — flavone 7,4’-diOH, 6,3’-diC5 — flavone 5,7,4’-triOH, 8-C5 — flavone 3,5,7,4’-tetraOH, 6-C5 — flavonol 3,5,7,4’-tetraOH, 8,3’-diOMe — flavonol 3,5,7,4’-tetraOH, 6,8,3’-triOMe — flavonol 5,7-diOH, 6,8-diOMe, 3’,4’-OCH2O — flavone 5,6,7,8-tetraOMe, 3’,4’-OCH2O — flavone 5,7,3’,4’-tetraOH — flavone 3,3’,4’-triOH, 7,6-ODmp, 8-C5 — flavonol 3’,4’-diOH, 3-OMe, 7,6-ODmp, 8-C5 — flavonol 3,5,7,4’-tetraOH, 6-C10 — flavonol 3-OH, 5,6,7,3’,4’-pentaOMe — flavonol 5,7-diOH, 6,8-diMe — flavon 3,5,7,3’,5’-pentaOH, 4’-OMe — flavonol 3,7,8,3’,4’-pentaOH — flavonol 3,5,6,7,8-pentaOMe, 3’,4’-OCH2O — flavonol 3,5,8,3’,4’-pentaOMe, 6,7-OCH2O — flavonol 3,5,7-triOH, 6,8-diOMe, 3’,4’-OCH2O — flavonol 3,5,6,7-tetraOMe, 3’,4’-OCH2O — flavonol 5-OH, 3,6,7-triOMe, 3’,4’-OCH2O — flavonol 3,5-diOMe, 6,7-/3’,4’-diOCH2O — flavonol 3,5,7,8-tetraOMe, 3’,4’-OCH2O — flavonol 5,7,4’-triOH, 6-Me — flavone 5,7,4’-triOH, 8-Me — flavone 3,5,7-triOH, 8-Me — flavonol 5-OH, 3,7,8-triOMe — flavonol 3,5,7,4’-tetraOH, 6-Me — flavonol 5,7,3’,4’-tetraOH, 6-Me — flavone 5,4’-diOH, 7,3’,5’-triOMe — flavone 5-OH, 7,8-diOMe — flavone 3,5-diOH, 6,7,4’-triOMe — flavonol 6,7-diOMe, 3’,4’-OCH2O — flavone 7,2’diOMe, 4’, 5’-OCH2O — flavone 7-OMe-6-OC5, 4’,5’-OCH2O — flavone 2’,5’-diOMe, 7,8-furþD426 — flavone 7,3’,4’-triOH, 3,2’-O-CH2 — flavonol 5,7,2’,4’-tetraOH, 8-C15 — flavone 3,5,7-triOH, 3’,5’-diOMe — flavonol 3,5,7,2’,4’-pentaOH — flavonol 5,2’,4’-triOH, 7,6-ODmp, 3-C5OH — flavone 5,2’,4’-triOH, 3-C5, 7,8-ODmp — flavone 5-OH, 6,7-diOMe — flavone 5-OH, 7,8-diOMe — flavone 5,7,2’,4’-tetraOH, 3,8-diC5 — flavone 5-OMe, 7,8-bisfur — flavone 5-OMe, 7,8-bisfur — flavone

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APPENDIX Trivial Name — continued Trivial Name Murrayanol Muxiangrine I Muxiangrine II Muxiangrine III Myricetin Natsudaidain Negletein Neouralenol Nepetin Nevadensin Nobiletin Nodifloretin Noranhydro-icaritin Norartocarpetin Norartocarpin (syn.: Mulberrrin) Noricaritin (revised) Norwightin Norwogonin Ombuin Onopordin Oppositin Oroxylin Ovalifolin Oxidihydroartocarpesin Oxyayanin-A Oxyayanin-B Oxydihydromorusin Oxyisocyclointegrin Pachypodol Patuletin Pectolinarigenin Pedalitin Pediflavone ‘‘Pedunculin’’ — obsolete Peltogynin Penduletin Petalopurpurenol p-Hydoxybenzylluteolin p-Hydroxybenzyldiosmetin p-Hydroxybenzylkaempferol p-Hydroxybenzylquercetin Pilloin Pilosin Pinnatin Pinoquercetin Pityrogrammin

Substitution 5,4’-diOH, 3,6,7,3’,5’-pentaOMe — flavonol 5,3’-diOH, 7-OMe, 6,8-diCH3, 4’,3’-ODmp — flavone 5,5’-diOH, 7-OMe, 6-CH3, 4’,3’-ODmp — flavone 5,3’,4’-triOH-7-OMe, 6,8-diCH3-5’-C5 — flavone 3,5,7,3’,4’,5’-hexaOH — flavonol 3-OH, 5,6,7,8,3’,4’-hexaOMe — flavonol 5,6-diOH, 7-OMe — flavone 3,6,7,3’,4’-pentaOH, 2’-C5 — flavonol 5,7,3’,4’-tetraOH, 6-OMe — flavone 5,7-diOH, 6,8,4’triOMe — flavone 6,6,7,8,3’4’-hexaOMe — flavone 5,6,7,4’-tetraOH, 3’OMe — flavone 3,5,7,4’-tetraOH, 8-C5 — flavonol 5,7,2’4’-tetraOH — flavone 3,5,7,4’-tetraOH, 6-C5-OH — flavonol 5,7,8,2’,3’-pentaOH — flavone 5,7,8-triOH — flavone 3,5,3’-triOH, 7,4’-diOMe — flavonol 5,7,3’4’-tetraOH, 8-OMe — flavone 5,7-diOMe, 6,6’’-Ketopyrano. . . . 3’’-OH — flavone, see Figure 12.4 5,7-diOH, 6-OMe — flavone 6-O-C5, 7,8-fur — flavone 5,7,2’,4’-tetraOH, 6-C5-OH — flavone 5,2’,5’-triOH, 3,7,4’-triOMe — flavonol 5,6,3’-triOH, 3,7,4’-triOMe — flavonol 5,2’,4’-triOH, 3-C5-OH, 7,8-ODmp — flavone 5,4’-diOH, 7-OMe, 3,6’-cyclo O-C6 — flavone 5,4’-diOH, 3,7,3’-triOMe — flavone 3,5,7,3’,4’-pentaOH, 6-OMe — flavone 5,7-diOH, 6,4’-diOMe — flavone 5,6,3’,4’-tetraOH, 7-OMe — flavone 5,8-diOH, 7-OMe — flavone 7,4,5’-triOH, 3,2’-O-CH2 — flavonol 5,4’-diOH, 3,6,7-triOMe — flavone 3,5,7,4’-tetraOH, 3’,2’-ODmp-C6 — flavonol 5,7,3’,4’-tetraOH, 8-C-p-OH-benzyl — flavone 5,7,3’-OH, 4’-OMe, 8-C-p-OH-benzyl — flavone 3,5,7,4’-tetraOH, 8-C-p-OH-benzyl — flavonol 3,5,7,3’,4’-pentaOH, 8-C-p-OH-benzyl — flavonol 5,3’-diOH, 7,4’-diOMe — flavone 5,7,8-triOH, 6,4’-diOMe — flavone 5-OMe, 7,6-fur — flavone 3,5,7,3’,4’-pentaOH, 6-Me — flavonol 3,5,7-triOH, 8-OMe, 6-Me — flavonol continued

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APPENDIX Trivial Name — continued Trivial Name Platanetin Platanin Poinsettifolin A Pollenitin Polystachin Pongachromene Pongaglabol Ponganone XI Pongapin Pongone Pratensin A Pratensin B Pratoletin 6-Prenylapigenin 8-Prenylapigenin, see Licoflavone C 6-Prenylchrysin 8-Prenylchrysin 6-Prenylchrysoeriol 6-Prenylgalangin, see Glepidotin A 6-Prenylherbacetin Prenyllicoflavone A (syn.: licoflavone B) 6-Prenylluteolin, see Gancaonin O 8-Prenylluteolin 8-Prenylpachypodol Primetin Primuletin Prosogerin A Prosogerin C Prosogerin D Prosogerin E Prudomestin Pseudosemiglabrin Pseudosemiglabrinol Psiadiarabicin Ptaeroxylol Pulcherrimin Purpurascenin Quercetagetin Quercetin Racemoflavon Rehderianin I Retusin Rhamnazin Rhamnetin Rhamnocitrin Rhynchosin Rhynchospermin Rivularin

Substitution 3,5,7,8-tetraOH, 6-C5 — flavonol 3,5,7,8-tetraOH, 6-Me — flavonol 3,5,3’,4’-tetraOH, 7,8-ODmp, 6-C5 — flavonol, see Figure 12.9 3,5,8,4’-tetraOH, 7-OMe — flavonol 5-OMe, 7,8-fur-C4-diOAc — flavone 3,5-diOMe, 3’,4’-OCH2O, 7,8-ODmp — flavonol 5-OH, 7,8-fur — flavone 3-OMe, 7,6-fur — flavonol 3-OMe, 3’,4’-OCH2O, 7,8-fur — flavonol 3’-OMe, 7,6-fur — flavone 5,7-diOH, 3,6,4’-triOMe, 8-tigliat — flavonol 5,4’-diOH, 3,6,7-triOMe, 8-Me-but — flavonol 3,5,8,4’-tetraOH — flavonol 5,7,4’-triOH, 6-C-5 — flavone 5,7-diOH, 6-C5 — flavone 5,7-diOH, 8-C5 — flavone 5,7,4’-triOH, 3’-OMe, 6-C5 — flavone 5,7,4’-triOH, 3,8-diOMe, 6-C5 — flavonol

5,7,3’,4’-tetraOH, 8-C5 — flavone 5,4’-diOH, 3,7,3’-OMe, 8-C5 — flavonol 5,8-diOH — flavone 5-OH — flavone 7-OH, 6-OMe, 3’,4’-OCH2O — flavone 6,7,3’,4’,5’-pentaOMe — flavone 7-OH, 6,3’,4’,5’-tetraOMe — flavone 6,7-diOH, 3’,4’,5’-triOMe — flavone 3,5,7-triOH, 8,4’-diOMe — flavonol 7,8-bisfur -OAc — flavone 7,8-bisfur -OH — flavone 5,3’-diOH, 6,7,2’,4’,5’-pentaOMe — flavone 3,5,7-triOH, 2’-OMe — flavonol 5-OH, 7-OMe, 3’,4’-O2CH2, 3,2’-O-CH2 — flavonol 3,5,6,7,8,2’,4’,5’-octaOMe — flavonol 3,5,6,7,3’,4’-hexaOH — flavonol 3,5,7,3’,4’-pentaOH — flavonol 5,4’-diOH, 3’-OMe, 7,8-ODmp — flavone 5,2’,5’-triOH, 7,8-diOMe — flavone 5-OH, 3,7,3’,4’-tetraOMe — flavonol 3,5,4’-triOH, 7,3’-diOMe — flavonol 3,5,3’,4’-tetraOH, 7-OMe — flavonol 3,5,4’-triOH, 7-OMe — flavonol 3,6,7,3’,4’-pentaOH — flavonol 3,5,3’-OH, 7,4’-diOMe, 8-C5 — flavonol 5,2’-diOH, 7,8,6’-triOMe — flavone

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APPENDIX Trivial Name — continued Trivial Name Robinetin Rubraflavone A Rubraflavone C Rubraflavone D Saltillin Salvigenin Sanaganone Sanggenon J Sanggenon K Santin ‘‘Santoflavone’’ — obsolete Sarothranol Sarothrin Scaposin Scutellarein Scutevulin Selgin Semiglabrin Semiglabrinol Sericetin Serpyllin Sexangularetin Sideritiflavon Sideroxylin Sinensetin Skullkapflavone I Skullcapflavone II Sophoflavescenol Sorbifolin Spinacetin Stachyoidin Strobochrysin Sudachitin Sylpin Syringetin Syzalterin Tabularin Tachrosin Takakin Tamadone Tamaridone Tamarixetin Tambulin ‘‘Tanetin’’ — obsolete Tangeretin Tectochrysin

Substitution 3,7,3’,4’,5’-pentaOH — flavonol 7,2’,4’-triOH, 3-C10 — flavone 5,7,2’,4’-tetraOH, 3-C10, 6-C5 — flavone 5,2’,4’-triOH, 3-C10, 7,6-ODmp — flavone 5-OH, 4’-OMe, 7-Me — flavone 5-OH, 6,7,4’-triOMe — flavone 6,5-ODmp, 7,8-fur — flavone 5,7,2’-triOH, 3-C5, 3’,4’-ODmp-C5 — flavone 5,7,2’-triOH, 3-C5, 2’,3’-ODmp-C5 — flavone 5,7-diOH, 3,6,4’-triOMe — flavonol 5,3’,4’-OH, 3-OMe, 7,6-ODmp — flavonol 5,7,4’-triOH, 3,6,8-triOMe — flavonol 5,7,5’-triOH, 6,8,3’,4’-tetraOMe — flavone 5,6,7,4’-OH — flavone 5,7,2’-triOH, 8-OMe — flavone 5,7,4’,5’-tetraOH, 3’-OMe — flavone 7,8- bisfur — flavone 7,8- bisfur — flavone 3,5-diOH, 8-C5, 7,6-ODmp — flavonol 5-OH, 7,8,2’,3’,4’-pentaOMe — flavone 3,5,7,4’-tetraOH, 8-OMe — flavonol 5,3’,4’-triOH, 6,7,8-triOMe — flavone 5,4’-diOH, 7-OMe, 6,8-diMe — flavone 5,6,7,3’,4’-pentaOMe — flavone 5,2’diOH, 7,8-diOMe — flavone 5,2’-diOH, 6,7,8,6’-tetraOMe — flavone 3,7,4’-triOH, 5-OMe, 8-C5 — flavonol 5,6,4’-triOH, 7-OMe — flavone 3,5,7,4’-tetraOH, 6,3’-diOMe — flavonol 5-OMe, 7,8-pyr-fur (3’’-oxo) — flavone 5,7-diOH, 6-Me — flavone 5,7,4’-triOH, 6,8,3’-triOMe — flavone 5,6,4’-triOH, 3-OMe, 8-Me — flavonol 3,5,7,4’-tetraOH, 3’,5’-diOMe — flavonol 5,7,4’triOH, 6,8-diMe — flavone 5,7-diOH, 6,2’,4’,5’-tetraOMe — flavone 5,7-diOMe, 8-furyl (2’’-oxo) — flavon 5,7,8-triOH, 4’-OMe — flavone 5,2’,4’-triOH, 6,7,8-triOMe — flavon 5,7,2’-triOH, 6,4’-diOMe — flavone 3,5,7,3’-tetraOH, 4’-OMe — flavonol 3,5-diOH, 7,8,4’-triOMe — flavonol 5,6,7,8,4’-pentaOMe — flavone 5-OH, 7-OMe — flavone continued

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APPENDIX Trivial Name — continued Trivial Name Tenaxin 1 Tephrinone Tephrodin Tephroglabrine Tephrorianin cis-Tephrostachin Tepurindol Ternatin Thevetiaflavon Thymonin Thymusin Tithonine Tomentin Topazolin Topazolin hydrate Torosaflavone C Torosaflavone D trans-Anhydrotephronin Transilitin trans-Lanceolatin (syn.: Lanceolatin A) trans-Tephrostachin Tricetin Tricin Trimethylwogonin 8,2’,6’-Triprenylquercetin Ugonine C Umhugengerin Unonal Uralene Uralenol Velutin Veronicafolin Viscidulin I Viscidulin III Viscosol Wharangin Wightin Wogonin Xanthomicrol Yinyanghuo A Yinyanghuo B Yinyanghuo C Yinyanghuo D Yinyanghuo E Zapotin Zapotinin

Substitution 5,2’-diOH, 6,7,8-triOMe — flavone 5-OH, 7-OMe, 8-C5 — flavone 5-OMe, 7,8-pyr-fur (3’’-oxo-4’’-OAc) — flavone 7-OMe, 8-furyl (4’’-oxo) — flavone 5-OMe, 7,8-oxofuryl — flavone, see Figure 5 5,7-diOMe, 8-C5-OH — flavone 7-OMe, 8-furyl (2’’,4’’-diOH) — flavone 5,4’-diOH, 3,7,8,3’-tetraOMe — flavonol 7,4’-diOH, 5-OMe — flavone 5,6,4’-triOH, 7,8,3’-triOMe — flavone 5,6,4’-triOH, 7,8-diOMe — flavone 3’-OH, 7,4’-diOMe — flavone 5,6,3’,4’-tetraOH, 3,7-diOMe — flavonol 5,7,4’-triOH, 3-OMe, 6-C5 — flavonol 5,7,4’-triOH, 3-OMe, 6-C5-OH — flavonol 5,3’-diOH, 4’-OMe, 7,6- bisfurano — flavone, see Figure 12.3 5,7,3’-triOH, 4’-OMe, 6-acrylic acid — flavone, see Figure 12.1 5,7-diOMe, 8-C5 — flavone 7,8,3’,4’-tetraOH, 3-OMe — flavonol 5,7-diOMe, 8-C5-OH — flavone 5,7,3’,4’,5’-pentaOH — flavone 5,7,4’-triOH, 3’,5’-diOMe — flavone 5,6,7-triOH, 8,3’,4’,5’-tetraOMe — flavone 3,5,7,3’,4’-penta-OH, 8,2’,6’-triC5 — flavonol 5, 4’-diOH, 6-OMe, 7,8-fur — flavone 5-OH, 6,7,3’,4’,5’-pentaOMe — flavone 5,7-diOH, 8-Me, 6-CHO — flavone 5,6,4’,5’-tetraOH, 3OMe, 2’-C5 — flavonol 3,5,7,3’,4’-pentaOH, 5’-C5 — flavonol 5,4’-diOH, 7,3’-diOMe — flavone 3,5,4’-triOH, 6,7,3’-triOMe — flavonol 3,5,7,2’,6’-pentaOH — flavonol 3,5,7,3’-tetraOH, 2’,4’-diOMe — flavon 5,7-diOH, 3,6,4’-triOMe, 3’-C5 — flavonol 5,3’,4’-triOH, 3-OMe, 7,8-OCH2O — flavonol 5,3’-diOH, 7,8,2’-triOMe — flavone 5,7-diOH, 8-OMe — flavone 5,4’-diOH, 6,7,8-triOMe — flavone 5,7-diOH, 5’-C5-OH, 4’,3’-ODmp — flavone 5,7,4’-triOH, 3’-C5, 5’-C5-OH — flavone 5,7-diOH, 4’,3’-ODmp — flavone 5,7,4’-triOH, 3’-C5 — flavone 5,7,5’-triOH, 4’,3’-ODmp — flavone 5,6,2’,6’-tetraOMe — flavone 5-OH, 6,2’,6’-triOMe — flavone

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Flavone and Flavonol O-Glycosides Christine A. Williams

CONTENTS 13.1 13.2 13.3

Introduction ............................................................................................................. 749 Separation, Purification, and Identification ............................................................. 751 New Flavone and Flavonol O-Glycosides ............................................................... 751 13.3.1 Monosaccharides....................................................................................... 751 13.3.2 Disaccharides ............................................................................................ 760 13.3.3 Trisaccharides ........................................................................................... 781 13.3.4 Tetrasaccharides........................................................................................ 782 13.3.5 Sulfate Conjugates .................................................................................... 783 13.3.6 Acylated Derivatives ................................................................................. 785 13.3.7 New Flavone Glycosides — Further Considerations................................ 786 13.3.8 New Flavonol Glycosides — Further Considerations .............................. 787 13.3.9 Glycosides of Prenylated Flavones and Flavonols, and of Pyrano and Methylenedioxyflavonols ................................................................... 787 13.4 Distribution Patterns................................................................................................ 788 References .......................................................................................................................... 790 Appendix A ........................................................................................................................ 808 Appendix B ........................................................................................................................ 824

13.1 INTRODUCTION Flavone and flavonol O-glycosides make up one of the largest classes of flavonoid constituents with over 2000 known structures. There are 279 glycosidic combinations of the most common flavonol aglycone, quercetin, and 347 kaempferol O-glycosides listed in the check list (Appendix B) for the period ending December 2003.The group includes any bound form of flavone or flavonol such as acylated and sulfated derivatives and not only those with just sugar. Thus, the number of possible combinations is enormous because of the wide structural variation, i.e., in (1) the hydroxylation and methoxylation pattern of the aglycone; (2) the number and nature of sugars and their position of attachment through hydroxyl groups to the aglycone; (3) the nature of the sugar linkage to the aglycone, different interglycosidic linkages and whether the sugars are in the pyranose or furanose form; (4) the nature, number, and position of attachment of aliphatic or aromatic acyl groups to one or more sugars or directly through a hydroxyl group to the aglycone; and (5) the presence and position of attachment of one or more sulfate groups through a hydroxyl group of the aglycone or that of a sugar. Sugars can also be attached through a carbon bond but these compounds, the C-glycosylflavonoids, are dealt within Chapter 14. 749

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The monosaccharides most frequently found in O-combination with flavone and flavonols are glucose and rhamnose and less frequently arabinose, xylose, and glucuronic acid. These sugars are usually present in the expected pyranose form and with the appropriate linkage, i.e., b for glucose, galactose, xylose, and glucuronic acid and a for rhamnose. Arabinose can occur in either the pyranose or furanose form and with an a- or b-linkage. Seven other monosaccharides have been found occasionally linked to flavones or flavonols (see Section 13.3.1). The most usual place of sugar attachment in flavonols is at the 3-hydroxyl and at the 7-hydroxyl in flavones but sugars have been found at all the other possible positions. In the first edition of The Flavonoids,1 published in 1975, 134 flavone glycosides and 252 flavonol glycosides were listed. The original intent of this first edition was to compile an updated version of the classic monograph edited by the late Ted Geissman, entitled The Chemistry of Flavonoid Compounds, which was published in 1962, in which only 30 flavone and 54 flavonol glycosides were described.2 The glycosides listed in the monograph included the best-known flavonol glycoside, quercetin 3-rhamnosyl(1 ! 6)glucoside (rutin) and the common flavone glycoside, luteolin 7-glucoside (glucoluteolin), but did not include any acylated or sulfated derivatives. Thirteen years later, in the first edition of The Flavonoids,1 nine of the listed 134 flavone glycosides and 18 of the 247 recorded flavonol glycosides were found to be acylated with acids such as p-coumaric, caffeic, ferulic, sinapic, gallic, benzoic, phydroxybenzoic, acetic, and malonic. However, the most exciting find of this review period was the discovery that flavonoid conjugates are not such a rarity in the plant kingdom as once thought and that they are in fact frequent constituents of many salt-tolerant and water-stress resilient plants. At this stage, only 11 had been fully characterized but many more had been detected and flavonoid sulfates were regularly recorded on a presence or absence basis. The second edition of The Flavonoids, which covered the new compounds found between 1975 and 1980,3 showed a large increase in the number of both acylated and sulfated glycosides bringing the total number of flavone glycosides in that check list to 271 and flavonol glycosides to 486. Both the third edition, covering the years 1981 to 1985,4 and the fourth edition5 (1986 to 1991) of The Flavonoids showed a steady increase in the number of flavone and flavonol glycosides to 345 and 647 and 463 and 906, respectively, but with comparatively small increases in the number of new acylated and sulfated glycosides. No trisaccharides were reported in association with flavones or flavonols in Geissman’s monograph2 and only a small number of flavonol triosides, some with linear and some with branched sugars, were recorded in book one1 of The Flavonoids. It is not until book four5 that there is a marked increase in the number of trisaccharides with 4 new linear and 11 new branched structures recorded. Flavone triosides continued to be of rare occurrence in books three4 and four.5 However, the first known tetrasaccharide, [rhamnosyl(1 ! 4)glucosyl]sophorose, was recorded in 1987 (book four)5 in combination with the flavone acacetin (apigenin 4’-methyl ether) at the 7-position with an acetyl group at the 6’’-position of the sophorose in leaves of Peganum harmala (Zygophyllaceae).6 The main remit of this chapter is to provide reference and plant source details of new flavone and flavonol O-glycosides discovered since 1991, i.e., covering the years 1992 to 2003. A checklist of all (as far as possible) known structures is also included in Appendices A and B. A series of reviews, which include most of the data on new O-glycosylflavones and flavonols presented here, have appeared in Natural Product Reports and cover the years 1992 to 1994,7 1995 to 1997,8 and 1998 to 2000,9 and with a fourth (2001 to 2003)10 in press. Other useful sources of data are The Phytochemical Dictionary,11 The Handbook of Natural Flavonoids,12 and for general background reading Jeffrey Harborne’s Comparative Biochemistry of the Flavonoids.13

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13.2 SEPARATION, PURIFICATION, AND IDENTIFICATION The traditional methods of separation, purification, and identification of flavone and flavonol O-glycosides, including paper, column, and thin layer chromatography and UV spectral analysis of pure compounds, acid, alkaline, and enzyme hydrolysis, and identification of the resulting aglycones and sugars are well described by Mabry et al.,14 by Markham,15,16 and by Harborne.17 High-performance liquid chromatography (HPLC) is now a standard technique used in all phytochemistry laboratories. HPLC with UV detection is an established method for separating and detecting flavonoid glycosides in complex mixtures, for comparing flavonoid profiles of related plant taxa and for identifying known compounds. However, it has been recently superceded by HPLC–mass spectrometry (MS) techniques such as liquid chromatography (LC)–MS, which gives the molecular weight of the glycoside and LC–MS– MS, which also gives the mass spectrum of the fragmentation ions. Atmospheric pressure chemical isolation (APCI) is especially useful for obtaining the molecular weight of the glycoside, together with the molecular ions for the aglycone and any intermediate sugars or acylated sugars from very small amounts (~0.1 mg) of pure compound. In their paper in Phytochemical Analysis, Grayer et al.18 describe the application of APCI to a chemotaxonomic study of the flavonoids in the genus Ocimum. Fast atom bombardment MS gives a strong molecular ion, which indicates the number and type of sugar units present and useful fragmentation patterns with obvious loss of sugars and any methoxyls from the aglycone. This method has tended to be replaced by electrospray MS, which is less costly but does not give so much fragmentation data, although MS–MS on the resulting product ions can give further useful fragmentation ions. However, the techniques of choice for flavonoid glycoside identification are 1H NMR, 13C NMR, and two-dimensional nuclear magnetic resonance (NMR), which allow complete characterization including details of form and linkage of the sugars, the nature and position of acyl groups, and number of sulfate groups. For more detailed information on HPLC, MS, NMR, and other recent separation, purification, and identification techniques see Chapters 1 and 2.

13.3 NEW FLAVONE AND FLAVONOL O-GLYCOSIDES Some 228 new flavone O-glycosides and over 500 new flavonol O-glycosides have been reported in the period 1992 to 2003. This brings the number of known structures listed in the check lists (Appendix A) to 679 flavone and 1331 flavonol glycosides. (Appendix B) The new glycosides are listed in Table 13.119–164 and Table 13.2,23,107,165–479 respectively. In all these entries and in later tables the sugars are assumed to be in the pyranose form and to have the appropriate linkage, i.e., b for glucose, a for rhamnose, etc. except where otherwise stated. Reports of new monosaccharides, disaccharides, trisaccharides, tetrasaccharides, acylating agents, and sulfate conjugates will be considered first.

13.3.1 MONOSACCHARIDES A list of all the monosaccharides that have been found in O-combination with flavones or flavonols are given in Table 13.3. These include five sugars, fructose, allulose, lyxose, fucose, and glucosamine, which have been recorded since 1992. a-D-Fructofuranose has been reported from leaves of Crataegus pinnatifida (Rosaceae)41 linked to both the C-8 position and the 7-hydroxyl of apigenin. Here, the C- and O-glycosidic linkages to the sugar form a unique ring structure (Pinnatifinoside A, 13.1). There has been one previous report of fructose, as a tricin fructosylglucoside in Hyacinthus orientalis (Liliaceae),480 but the structure of this glycoside was never confirmed. An acetylated derivative, Pinnatifinoside B (13.2), and

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TABLE 13.1 New Flavone Glycosides Glycoside 5,7-Dihydroxyflavone (chrysin) 7-(4’’-Acetylglucoside) 7-(6’’-Acetylglucoside) 5,6,7-Trihydroxyflavone (baicalein) 7-(6’’-Malonylglucoside) Baicalein 5-methyl ether 7-Glucoside Baicalein 6-methyl ether (oxoxylin A) 5-Rhamnoside 7-Glucosyl(1 ! 3)rhamnoside Baicalein 7-methyl ether (negletein) 6-Xyloside 6-Glucoside 6-Rhamnoside(1 ! 2)fucoside 5,7,8-Trihydroxyflavone (norwogonin) 5-Glucoside 7-Galactoside 7-Hydroxy-5,8-dimethoxyflavone 7-Glucoside 7-Glucuronide 5,7,2’-Trihydroxyflavone 7-Glucoside 2’-Glucoside 5,2’-Dihydroxy-7-methoxyflavone (echioidinin) 5-Glucoside 2’-(6’’-Acetylglucoside) 5,7,4’-Trihydroxyflavone (apigenin) 7-Apiofuranosyl(1 ! 6)glucoside 7-Cellobioside 7-Sophorotrioside 7-(2G-Rhamnosyl)rutinoside 7-(2G-Rhamnosyl)gentiobioside 7-Rhamnoside-4’-glucosylrhamnoside 7-Cellobioside-4’-glucoside 7-Glucosyl(1 ! 2)glucuronide-4’-glucuronide Pinnatifinoside A (13.1) Pinnatifinoside B (13.2) Pinnatifinoside C (13.3) Pinnatifinoside D (13.4) 7-(2’’-E-p-Coumaroylglucoside) 7-(3’’-p-Coumaroylglucoside) 7-(6’’-E-p-Coumarylgalactoside) 7-(6’’-E-Caffeoylglucoside)

Source

Family

Ref.

Calicotome villosa Aerial parts

Leguminosae

19

Cephalocereus senilis suspension cultures

Cactaceae

20

Cephalocereus senilis chitin-treated cell suspension cultures

Cactaceae

21

Trichosanthes anguina seeds Eupatorium africanum whole plant

Cucurbitaceae Compositae

22 23

Bauhinia purpurea stems Colebrookea oppositifolia bark Origanum vulgare

Leguminosae Labiatae Labiatae

24 25 26

Pyracantha coccinea roots Scutellaria ocellata and S. nepetoides

Rosaceae Labiatae

27 28

Scutellaria immaculate aerial parts Scutellaria rivularis roots

Labiatae Labiatae

29 30

Scutellaria ramosissima aerial parts

Labiatae

31

Andrographis alata whole plant Andrographis affinis whole plant

Acanthaceae Acanthaceae

32 33

Gonocaryum calleryanum leaves Salvia uliginosa petals Leptostomum macrocarpon gametophyte Ligustrum vulgare leaves Lonicera gracilepes var. glandulosa leaves Asplenium normale Salvia uliginosa petals Medicago sativa aerial parts Crataegus pinnatifida var. major leaves

Icacinaceae Labiatae Bryales Oleaceae Caprifoliaceae Aspleniaceae Labiatae Leguminosae Rosaceae

34 35 36 37 38 39 35 40 41

Echinops echinatus flowers Stachys aegyptiaca aerial parts Lagopsis supina whole plant Bellis perennis flowers

Compositae Labiatae Labiatae Compositae

42 43 44 45

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TABLE 13.1 New Flavone Glycosides — continued Glycoside 7-[6’’-(3-Hydroxy-3-methylglutaryl)glucoside] 7-(3’’,6’’-Di-E-p-coumaroylgalactoside) 7-(3’’-Acetyl-6’’-E-p-coumaroylglucoside) 7-Rhamnosyl(1 ! 6)(4’’-E-pmethoxylcinnamoylglucoside) 4’-(2’’-Feruloylglucuronosyl)(1 ! 2)glucuronide 7-Glucuronosyl(1 ! 3)[(2’’-pcoumaroylglucuronosyl)(1 ! 2)glucuronide] 7-Glucuronosyl(1 ! 3)[(2’’’-feruloylglucuronosyl) (1 ! 2) glucuronide] 7-(2’’-Feruloylglucuronosyl)(1 ! 2) glucuronide-4’-glucuronide 7-Glucuronide-4’-(2’’’-E-p-coumaroylglucuronosyl) (1 ! 2)glucuronide 7-Glucuronide-4’-(2’’’-feruloylglucuronosyl) (1 ! 2) glucuronide Apigenin 7-methyl ether (genkwanin) 4’-a-L-Arabinopyranosyl (1 ! 6)galactoside 4’-Rhamnosyl(1 ! 2)[rhamnosyl (1 ! 6)galactoside] Apigenin 4’-methyl ether (acacetin) 7-Rhamnoside 7-Glucosyl(1 ! 4)xyloside 7-Apiosyl(1 ! 6)glucoside 7-(2G-Rhamnosyl)rutinoside 7-Rhamnosyl(1 ! 2)glucosyl(1 ! 2)glucoside 7-Rhamnosyl(1 ! 2)glucosyl (1 ! 2)glucosyl(1 ! 2)glucoside 7-(4’’’-Acetylrutinoside) 7-Rhamnosyl(1 ! 6)[2’’-acetylglucosyl (1 ! 2)glucoside] 7-[6’’’-Acetylglucosyl(1 ! 2)]rhamnosyl (1 ! 6)glucoside 7-Glucosyl(1 ! 6)[3’’’-acetylrhamnosyl (1 ! 2)glucoside] 7-(4’’’’-Acetylrhamnosyl)(1 ! 6) glucosyl(1 ! 3)(6’’-acetylglucoside) 6-Hydroxyapigenin (scutellarein) 7-Xylosyl(1 ! 2)xyloside 7-Xylosyl(1 ! 2)glucoside 7-Xylosyl(1 ! 6)galactoside 7-Glucuronosyl(1 ! 2)glucuronide 7-[6’’-(3-Hydroxy-3-methylglutaryl)glucoside] Scutellarein 6-methyl ether (hispidulin) 7-Rhamnoside 7-Methylglucuronide

Source

Family

Ref.

Chamaemelum nobile flowers Lagopsis supina whole plant Blepharis ciliaris aerial parts Chrozophora oblongifolia aerial parts Medicago sativa aerial parts Medicago sativa aerial parts

Compositae Labiatae Acanthaceae Euphorbiaceae

46 44 47 48

Leguminosae Leguminosae

49 40

Medicago sativa aerial parts

Leguminosae

49

Salvia moorcroftiana whole plant

Labiatae

50

Peganum harmalai Centratherum anthelminticum seeds Crotalaria podocarpa aerial parts Buddleia officinalis flowers Peganum harmala leaves Peganum harmala leaves

Zygophyllaceae Compositae Leguminosae Loganiaceae Zygophyllaceae Zygophyllaceae

51 52 53 54 51 55

Thalictrum przewalskii aerial parts Dendranthema lavandulifolium whole plant Calamintha glandulosa leaves

Ranunculaceae Compositae

56 57

Labiatae

58

Peganum harmala leaves

Zygophyllaceae

51

Thalictrum przewalskii aerial parts

Ranunculaceae

56

Hebe stenophyllum leaves

Scrophulariaceae

59

Semecarpus kurzii leaves Perilla ocimoides leaves Frullania muscicola whole plant

Anacardiaceae Labiatae Frullaniaceae

60 61 62

Picnomon acarna aerial parts Centaurea furfuracea aerial parts

Compositae Compositae

63 64 continued

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TABLE 13.1 New Flavone Glycosides — continued Glycoside 4’-Glucoside 7-Xylosyl(1 ! 2)xyloside 7-Neohesperidoside 7-(6’’-E-p-Coumaroylglucoside) Scutellarein 4’-methyl ether 7-Rutinoside 7-(2’’,6’’-Diacetylalloside) Scutellarein 5,4’-dimethyl ether 7-Glucoside 7-(4Rha-Acetylrutinoside) Scutellarein 6,7-dimethyl ether 4’-Glucuronide Scutellarein 6,4’-dimethyl ether (pectolinarigenin) 7-(6’’-Acetylglucoside) 7-(2’’’-Acetylrutinoside) 7-(3’’’-Acetylrutinoside) 7-(4’’’-Acetylrutinoside) Scutellarein 7,4’-dimethyl ether 6-Xylosyl(1 ! 2)glucoside 6-Neohesperidoside Scutellarein 6,7,4’-trimethyl ether (salvigenin) 5-[6’’-Acetylglucosyl (1 ! 3)galactoside] 8-Hydroxyapigenin (isoscutellarein) 7-Glucosyl(1 ! 2)xyloside 8-Sophoroside 8-(6’’-E-p-Coumaroylglucoside) 8-(2’’-Sulfatoglucuronide) 8-(2’’,4’’-Disulfatoglucuronide) Isoscutellarein 4’-methyl ether 8-Glucoside 8-(6’’-n-butylglucuronide) 7-Allosyl(1 ! 2)glucoside 8-(2’’-Sulfatoglucuronide) 8-(2’’,4’’-Disulfatoglucuronide) 6,8-Dihydroxy-7,4’-dimethoxyflavone 6-Rutinoside 6-(4’’-Acetylrhamnosyl)(1 ! 6)glucoside 5,7,2’-Trihydroxy-6-methoxyflavone 7-Glucoside 7-Methylglucuronide 5,7,2’,6’-Tetrahydroxyflavone 2’-Glucoside

Source

Family

Ref.

Cirsium oligophyllum leaves Chirita fimbrisepala roots Ipomoea purpurea flowers Eriocaulon buergerianum capitula

Compositae Gesneriaceae Convolvulaceae Eriocaulaceae

65 66 67 68

Teucridium parvifolium leaves, stems, and fruits Sideritis perfoliata

Labiatae

69

Labiatae

70

Striga passargei whole plant

Scrophulariaceae

71

Conyza linifolia

Compositae

72

Lantana camara aerial parts Linaria japonica whole plant

Verbenaceae Scrophulariaceae

73 74

Linaria haelava whole plant

Scrophulariaceae

75

Gelonium multiflorum seeds

Euphorbiaceae

76

Striga aspera

Scrophulariaceae

77

Sideritis spp. aerial parts Gratiola officinalis leaves Stachys aegyptiaca whole plant Helicteres angustifolia root bark Helicteres isora fruit

Labiatae Scrophulariaceae Labiatae Sterculiaceae Sterculiaceae

78 79 80 81 82

Glossostemon bruguieri roots Helicteres isora fruit Sideritis javalambrensis aerial parts Helicteres angustifolia root bark Helicteres isora fruit

Sterculiaceae Sterculiaceae Labiatae

83 82 84

Sterculiaceae Sterculiaceae

81 82

Dicliptera riparia whole plant

Acanthaceae

85

Scutellaria amoena roots

Labiatae

86

Scutellaria baicalensis hairy root cultures

Labiatae

87

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Flavone and Flavonol O-Glycosides

TABLE 13.1 New Flavone Glycosides — continued Glycoside 5,2’,6’-Trihydroxy-7-methoxyflavone 2’-Glucoside 5,7,8,2’-Tetrahydroxyflavone 7-Glucuronide 5,2’-Dihydroxy-7,8-dimethoxyflavone (skullcapflavone 1) 2’-Glucoside 2’-(2’’-E-Cinnamoylglucoside) 2’-(3’’-E-Cinnamoylglucoside) 2’-(4’’-E-Cinnamoylglucoside) 5,7,3’,4’-Tetrahydroxyflavone (luteolin) 5-Glucuronide-6’’-methyl ester 5-Rutinoside 7-Glucosyl(1 ! 4)-a-L-arabinopyranoside 7-Xylosyl(1 ! 6)glucoside (primeveroside) 7-Apiosyl(1 ! 6)glucoside 7-Rhamnosyl(1 ! 6)galactoside (7-robinobioside) 7-Sophoroside 7-Galactosyl(1 ! 6)galactoside 7-Galactosylglucuronide 7-Glucoside-3’-glucuronide 3’-Xylosyl(1 ! 2)glucoside 4’-Rutinoside 7-Sophorotrioside 7-(6’’-p-Benzoylglucoside) 7-[6’’-(2-Methylbutyryl)glucoside] 7-[6’’-(3-Hydroxy-3-methylglutaryl)glucoside] 3’-(3’’-Acetylglucuronide) 3’-(4’’-Acetylglucuronide) 7-Glucosyl(1 ! 6)(4’’’-caffeoylglucoside) 7-Glucoside-4’-(Z-2-methyl-2-butenoate) (7-glucoside-4’-angelate) 7-Apiosyl(1 ! 2)[glucosyl (1 ! 4)(6-malonylglucoside)] 7-(Acetylsophorotrioside) 7-(6’’’’-Acetylallosyl)(1 ! 3)glucosyl (1 ! 2)glucoside (veronicoside A) 7-(2’’-Feruloylglucuronosyl) (1 ! 2)glucuronide-4’-glucuronide 7-(2’’-Sulfatoglucoside) Luteolin 5-methyl ether 7-Xylosyl(1 ! 6)glucoside Luteolin 7-methyl ether

Source

Family

Ref.

Andrographis alata whole plant

Acanthaceae

88

Scutellaria rivularis roots

Labiatae

30

Andrographis paniculata roots Andrographis serpyllifolia whole plant

Acanthaceae Acanthaceae

89 90

Andrographis elongata whole plant

Labiatae

91

Dumortiera hirsuta gametophytes Salvia lavandulifolia ssp. oxyodon aerial parts Cassia glauca seeds Halenia corniculata whole plant Phlomis nissolii aerial parts Pteris cretica fronds

Hepaticae Labiatae

92 93

Leguminosae Gentianaceae Labiatae Adiantaceae

94 95 96 97

Pteris cretica aerial parts Anogeissus latifolia Andryala reguisina aerial parts Melissa officinalis leaves Viburnum grandiflorum leaves Dalbergia stipulacea leaves Leptostomum macrocarpon gametophytes Vitex agnus-castus root bark Arnica chamissonis flowers Frullania muscicola whole plant Rosmarinus officinalis leaves

Adiantaceae Combretaceae Compositae Labiatae Caprifoliaceae Leguminosae Bryales

98 99 100 101 102 103 36

Verbenaceae Compositae Frullaniaceae Labiatae

104 105 62 106

Lonicera implexa leaves Polygonum aviculare whole plant

Caprifoliaceae Polygonaceae

107 108

Capsicum anuum fruit

Solanaceae

109

Leptostomum macrocarpon gametophytes Veronica didyma

Bryales

Medicago sativa aerial parts

Leguminosae

Thalassia testudinum leaves

Hydrocharitaceae

111

Dirca palustris twigs

Thymelaeaceae

112

36

Scrophulariaceae

110 40

continued

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TABLE 13.1 New Flavone Glycosides — continued Glycoside 3’-Glucoside 3’-Galactoside Luteolin 3’-methyl ether (chrysoeriol) 7-a-L-Arabinofuranosyl(1 ! 6)glucoside 7-Apiosyl(1 ! 6)glucoside 7-Neohesperidoside 7,4’-Diglucuronide 7-(3’’-Z-p-coumaroylglucoside) 7-(3’’,6’’-di-E-p-coumaroylglucoside) 7-(2’’’-Feruloylglucuronosyl) (1 ! 2)glucuronide 7-[Glucuronosyl(1 ! 3)(2’’’-feruloylglucuronosyl)] (1 ! 2)glucuronide Luteolin 4’-methyl ether (diosmetin) 3’-Glucoside 7-Arabinosyl(1 ! 6)glucoside 7-Xylosyl(1 ! 6)glucoside (as a mixture) 7-Xylosyl(1 ! 6)glucoside 7-Neohesperidoside (neodiosmin) 7-(2’’,6’’-Dirhamnosyl)glucoside 7-Apiosyl(1 ! 2)(6’’-acetylglucoside) Luteolin 5,3’-dimethyl ether 7-Glucoside 4’-Glucoside Luteolin 5,4’-dimethyl ether 7-Xylosyl(1 ! 6)glucoside Luteolin 7,3’-dimethyl ether 4’-Apiosyl(1 ! 2)glucoside Luteolin 5,3’,4’-trimethyl ether 7-Xylosyl(1 ! 6)glucoside 7-Rutinoside Luteolin 7,3’,4’-trimethyl ether 5-Glucoside 5-Xylosyl(1 ! 6)glucoside 6-Hydroxyluteolin 6-Rhamnoside 7-Xylosyl(1 ! 2)xyloside 7-Xylosyl(1 ! 6)glucoside 7-Sambubioside 7-[3’’-(3-Hydroxy-3-methylglutaryl)glucoside] 7-[4’’-(3-Hydroxy-3-methylglutaryl)glucoside] 7-[6’’-(3-Hydroxy-3-methylglutaryl)glucoside] 7-(6’’-E-Caffeoylglucoside)

Source

Family

Ref.

Avicennia marina aerial parts

Avicenniaceae

113

Tagetes patula whole plant Phlomis nissolii aerial parts Morinda morindoides leaves Medicago sativa aerial parts Ballota acetabulosa flowering aerial parts Marrubium velutinum aerial parts Medicago sativa aerial parts

Compositae Labiatae Rubiaceae Leguminosae Labiatae

114 96 115 116 117

Labiatae

118

Leguminosae

116

Cassia torosa leaves Galium palustre

Leguminosae Rubiaceae

119 120

Hebe parviflora and H. traversii leaves Citrus aurantium leaves Buddleia madagascariensis leaves Paullinia pinnata leaves

Scrophulariaceae Rutaceae Loganiaceae Sapindaceae

121 122 123

Pyrus serotina leaves

Rosaceae

124

Dirca palustris dried twigs

Thymelaeaceae

112

Viscum alniformosanae leaves and stems

Loranthaceae

125

Dirca palustris dried twigs

Thymelaeaceae

112

Lethedon tannaensis leaves

Thymelaeaceae

126

Erythroxylum leal-costae leaves Hebe stenophylla aerial parts Hebe stenophylla aerial parts Hebe stricta leaves Frullania muscicola whole plant

Erythroxylaceae Scrophulariaceae Scrophulariaceae Scrophulariaceae Frullaniaceae

127 128 59 129 62

Veronica liwanensis and V. longifolia aerial parts

Scrophulariaceae

130

59

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Flavone and Flavonol O-Glycosides

TABLE 13.1 New Flavone Glycosides — continued Glycoside 6-Glucoside-7-[6’’’-(3-hydroxy-3methylglutaryl)glucoside] 7-[6’’-(3-Hydroxy-3-methylglutaryl) glucoside]-3-glucuronide 6-Methoxyluteolin (nepetin, eupafolin) 7-Glucuronide 7-Methylglucuronide 4’-Glucoside 7-Rhamnoside-3’-xyloside 7-[6’’-(2-Methylbutyryl)glucoside] 6-Hydroxyluteolin 3’-methyl ether (nodifloretin) 7-[6’’-(3-Hydroxy-3-methylglutaryl)glucoside] 6-Hydroxyluteolin 4’-methyl ether 7-Rhamnosyl(1 ! 2)(6’’-acetylglucoside) 6-Hydroxyluteolin 6,3’-dimethyl ether 5-Rhamnoside 7-Rutinoside 6-Hydroxyluteolin 5,6,3’,4’-tetramethyl ether 7-Cellobioside 8-Hydroxyluteolin (hypolaetin) 8-Rhamnoside 7-Sophoroside 8-Glucoside-3’-rutinoside 7-Sulfatoglucoside 7-Sulfatogalactoside 7-Sulfatoglucuronide 7-Sulfate-8-glucoside Hypolaetin 7-methyl ether 3’-Sulfatogalactoside 3’-Sulfatoglucuronide Hypolaetin 3’-methyl ether 8-Glucuronide 7-Sophoroside Hypolaetin 4’-methyl ether 7-(6’’’-Acetylallosyl)(1 ! 2)(6’’-acetylglucoside) Hypolaetin 7,3’-dimethyl ether 4’-Glucoside 5,6,4’-Trihydroxy-7,8-dimethoxy flavone (thymusin) 6-Isobutyrate 5,8,4’-Trihydroxy-6,7-dimethoxy flavone (isothymusin) 8-Glucoside 5,7-Dihydroxy-6,8,4’-trimethoxy flavone (nevadensin)

Source

Family

Ref.

Frullania teneriffae

Hepaticae

131

Frullania cesatiana

Hepaticae

131

Digitalis lanata leaves

Scrophulariaceae

132

Cirsium oligophyllum leaves Chenopodium ambrosioides Arnica chamissonis flowers

Compositae Chenopodiaceae Compositae

65 133 105

Frullania polysticta whole plant

Frullaniaceae

Veronica liwanensis and V. longifolia aerial parts

Scrophulariaceae

130

Tridax procumbens leaves Kichxia elatine aerial parts

Compositae Scrophulariaceae

134 135

Sphaeranthus indicus stems

Compositae

136

Erythroxylum leal-costae leaves Gratiola officinalis leaves Cornulaca monacantha aerial parts Leptocarpus elegans culm

Erythroxylaceae Scrophulariaceae Chenopodiaceae

127 79 137

Restionaceae

138

Meeboldina thysanantha culm Hypolaena fastigiata culm

Restionaceae Restionaceae

138 138

Leptocarpus tenax culm Leptocarpus elegans culm

Restionaceae Restionaceae

138 138

Gratiola officinalis leaves

Scrophulariaceae

Sideritis syriaca and S. scardica

Labiatae

139

Leptocarpus elegans culm

Restionaceae

138

Asarina procumbens aerial parts

Scrophulariaceae

140

Becium grandiflorum leaves

Labiatae

141

62

79

continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 758 6.10.2005 10:36am

758

Flavonoids: Chemistry, Biochemistry, and Applications

TABLE 13.1 New Flavone Glycosides — continued Glycoside 5-Glucoside 7-Glucoside 5-Gentiobioside 7-Rutinoside 5,8-Dihydroxy-6,7,4’-trimethoxyflavone (8-hydroxysalvigenin) 8-Glucoside 5,6,7,8,3’,4’-Hexahydroxyflavone 7-Glucoside 5,6,7,3’,4’-Pentahydroxy-8-methoxyflavone 7-Glucoside 5,6,3’,4’-Tetrahydroxy-7,8-dimethoxyflavone (pleurostimin 7-methyl ether) 6-Glucoside 5,2’,6’-Trihydroxy-6,7-dimethoxyflavone 2’-Glucoside 5,2’,6’-Trihydroxy-7,8-dimethoxyflavone 2’-Glucuronide 5,2’-Dihydroxy-7,8,6’-trimethoxyflavone 2’-Glucuronide 5,7,2’,4’,5’-Pentahydroxyflavone (isoetin) 4’-Glucuronide 5,7,3’,4’,5’-Pentahydroxyflavone (tricetin) 3’-Rhamnosyl(1 ! 4)rhamnoside 3’-Glucoside-5’-rhamnoside 7-Glucoside-3’-[6’’-(3-hydroxy-3-methylglutaryl) glucoside] Tricetin 7-methyl ether 3’-Glucoside-5’-rhamnoside Tricetin 3’-methyl ether 7-Glucuronide Tricetin 4’-methyl ether 7-Apiosyl(1 ! 2)(6’’-acetylglucoside) Tricetin 3’,5’-dimethyl ether (tricin) 7-b-D-Arabinopyranoside (setaricin) 4’-Apioside 7-(2’’-p-Coumaroylglucuronosyl) (1 ! 2)glucuronide 7-(2’’-Feruloylglucuronosyl)(1 ! 2)glucuronide 7-(2’’-Sinapoylglucuronosyl)(1 ! 2)glucuronide 7-[Glucuronosyl(1 ! 3)(2’’’-feruloylglucuronosyl) (1 ! 2)glucuronide] 7-[X’’-(3-Hydroxy-3-methylglutaryl)glucoside] Tricetin 7,3’,4’-trimethyl ether 5-Glucoside Tricetin 7,3’,4’,5’-tetramethyl ether 5-Glucoside

Source

Family

Ref.

Lysionotus pauciflorus aerial parts Lysionotus pauciflorus aerial parts Lysionotus pauciflorus aerial parts Lysionotus pauciflorus aerial parts

Gesneriaceae Gesneriaceae Gesneriaceae Gesneriaceae

142 143 142 143

Isodon erianderianus leaves

Labiatae

144

Juniperus zeravschanica fruits

Cupressaceae

145

Vellozia nanuzae leaves

Velloziaceae

146

Vellozia nanuzae leaves

Velloziaceae

146

Scutellaria baicalensis roots

Labiatae

147

Scutellaria rivularis roots

Labiatae

30

Scutellaria rivularis roots

Labiatae

30

Adonis aleppica whole plant

Ranunculaceae

148

Mentha longifolia aerial parts

Labiatae

149

Frullania polysticta whole plant

Frullaniaceae

Mentha longifolia aerial parts

Labiatae

149

Medicago sativa aerial parts

Leguminosae

116

Paullinia pinnata leaves

Sapindaceae

123

Setaria italica leaves Salsola collina aerial parts Medicago sativa aerial parts

Gramineae Chenopodiaceae Leguminosae

150 151 116

Frullania polysticta whole plants

Frullaniaceae

Lethedon tannaensis leaves

Thymelaeaceae

126

Lethedon tannaensis leaves

Thymelaeaceae

126

62

62

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 759 6.10.2005 10:36am

759

Flavone and Flavonol O-Glycosides

TABLE 13.1 New Flavone Glycosides — continued Glycoside 5-Xylosyl(1 ! 2)rhamnoside 5-Xylosyl(1 ! 6)glucoside 6-Hydroxytricetin 6,3’,5’-trimethyl ether 7-a-L-Arabinosyl(1 ! 6)glucoside 6-Hydroxytricetin 6,4’,5’-trimethyl ether 3’-Rhamnoside 6-Hydroxytricetin 6,7,3’,5’-tetramethyl ether 5-Robinobioside 8-Hydroxytricetin 5-Rhamnoside 5-Glucoside 5,6,7,8,3’,4’- Hexahydroxyflavone 7-Glucoside 5,7,2’,5’-Tetrahydroxy-8,6’-tetrahydroxy-8, 6’-dimethoxyflavone (viscidulin III) 2’-Glucoside 5,2’,6’-Trihydroxy-6,7,8-trimethoxyflavone 2’-Glucoside 5,7-Dihydroxy-6-C-methylflavone 7-Xylosyl(1 ! 3)xyloside 5,7-Dihydroxy-6,8-di-C-methylflavone (matteuorien) 7-[6’’-(3-Hydroxy-3-methylglutaryl)glucoside] Stachysetin (13.5) 8-Prenylapigenin 4’-Rutinoside 3’-Prenylapigenin 7-Rutinoside 8-C-Prenyl-5,7,4’-trihydroxy-3’-methoxyflavone (8-C-prenylchrysoeriol) 7-Glucosyl(1 ! 3)-a-L-arabinopyranoside

Source

Family

Ref.

Bauhinia variegata seeds Lethedon tannaensis leaves

Leguminosae Thymelaeaceae

152 126

Mimosa rubicaulis roots

Leguminosae

153

Mimosa rubicaulis roots

Leguminosae

154

Aloe barbadensis leaves

Liliaceae

155

Argyreia speciosa leaves

Convolvulaceae

156

Juniperus seravschanica fruits

Cupressaceae

157

Scutellaria baicalensis roots

Labiatae

158

Scutellaria baicalensis roots

Labiatae

147

Mosla chinensis

Labiatae

159

Matteuccia orientalis rhizomes Stachys aegyptiaca aerial parts

Aspleniaceae Labiatae

160 161

Desmodium gangeticum stems

Leguminosae

162

Pithecellobium dulce stems

Leguminosae

163

Erythrina indica seeds

Leguminosae

164

two related nonacetylated glycosides, Pinnatifinosides C and D (13.3 and 13.4), in which the fructose has been replaced by the sugars b-D-allulofuranose and a-D-allulofuranose, respectively, co-occurred with Pinnatifinoside A.41 A second pentose sugar, a-D-lyxose, was found attached to the 8-hydroxyl of gossypetin (8-hydroxyquercetin) in the aerial parts of Orostachys japonicus,422 a member of the Crassulaceae. This is an unexpected discovery as the 2epimer of xylose is very rare in nature. Fucose, a characteristic constituent of algal and plant polysaccharides, has been found in combination with 5,6-dihydroxy-7-methoxyflavone (negletein) as the 6-rhamnosyl(1 ! 2)fucoside in Origanum vulgare.26 Glucosamine (2amino-2-deoxyglucose) is the only amino sugar to have been found in combination with flavones or flavonols. This sugar is important in animal physiology as a component of chitin, mucoproteins, and mucopolysaccharides. The presence of a-D-glucosamine in the aerial parts of Halocnemum strobilaceum (Chenopodiaceae)377 at the 7-hydroxyl of isorhamnetin is totally unexpected and should be further investigated to establish its exact location in the plant and to screen related plants for similar structures.

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 760 6.10.2005 10:36am

760

Flavonoids: Chemistry, Biochemistry, and Applications

H

O

CH2OR

HO H

O

H

O O

O

OH

OH H OH H H

H3CCOH2C H

OH

H

H HO O

H

O

OH

O

13.1 R = H 13.2 R = Acetyl

OH

O

13.3

O H HO H

CH2OCCH3 O

H

OH

H

HO H O

O

OH

O

13.4

13.3.2 DISACCHARIDES Twenty-one new disaccharides have been found in combination with flavones or flavonols since 1992. These are listed with previously known disaccharides in Table 13.4. Four of the new structures are novel sugar combinations: xylose–xylose, rhamnose–fucose, apiosyl–rhamnose, and glucose–arabinose. Both xylosyl(1 ! 2)xylose and xylosyl(1 ! 3)xylose have been found, the former at the 7-hydroxyl of scutellarein 6-methyl ether (patuletin) from roots of Chirita fimbrisepala (Gesneriaceae)66 and its 1 ! 3 isomer from Mosla chinensis (Labiatae)159 at the 7-hydroxyl of 5,7,-dihydroxy-6-C-methylflavone. Rhamnosyl(1 ! 2)fucose has already been dealt with under monosaccharides above. Apiofuranosyl(1 ! 4)rhamnose has been recorded from Chenopodium murale198 in combination with kaempferol at the 3-position and with rhamnose at the 7-hydroxyl. Five new glucosylarabinose isomers have been recorded during the review period. This is not surprising as arabinose can occur in either the pyranose or furanose form, with a or b linkage and with five possible linkage positions, which can all now be easily distinguished by modern NMR techniques. Glucosyl(1 ! 4)-a-L-arabinopyranose was found at the 7-position of the flavone luteolin in seed of Cassia glauca94 and its 1 ! 5 linked furanose isomer in aerial parts of the legume, Retama sphaerocarpa,402 at the 3hydroxyl of quercetin 7,3’-dimethyl ether (rhamnazin). Glucosyl(1 ! 3)-a-L-arabinopyranose occurs at the 7-hydroxyl of 8-prenylchysoeriol in seeds of Erythrina indica164.The other two isomers were present only in acylated form. Thus, glucosyl(1 ! 2)-b-arabinopyranose was recorded at the 3-hydroxyl of quercetin with glucose at the 7-hydroxyl and a feruloyl group at the 6-position of the glucose in a whole plant extract of Carrichtera annua (Cruciferae),357 while the remaining isomer, glucosyl(1 ! 2)-a-L-arabinofuranose, from Euphorbia pachyrhiza,340 was found attached to the 3-hydroxyl of quercetin with a galloyl group at the 2-hydroxyl of the glucose.

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 761 6.10.2005 10:36am

761

Flavone and Flavonol O-Glycosides

TABLE 13.2 New Flavonol Glycosides Glycoside 3,5,7-Trihydroxyflavone (galangin) 3-Glucoside-8-sulfate 3,7-Dihydroxy-8-methoxyflavone 7-Rhamnoside 7-Rhamnosyl(1 ! 4) rhamnosyl(1 ! 6)glucoside 5,7-Dihydroxy-3,6-dimethoxyflavone 5-a-L-Arabinosyl(1 ! 6)glucoside 3,6,7-Trihydroxy-4’-methoxyflavone 7-Rhamnoside Kaempferol 3-a-D-Arabinopyranoside 5-Glucuronide 7-Alloside 3-Rhamnosyl(1 ! 2)-a-L-arabinofuranoside (arapetaloside B) 3-Xylosyl(1 ! 2)glucoside 3-Rhamnoside(1 ! 2)rhamnoside 3-Glucosyl(1 ! 2)rhamnoside 7-Glucosyl(1 ! 4)xyloside 7-Neohesperidoside 7-Glucosyl(1 ! 3)rhamnoside 7-Sophoroside 3,5-Diglucoside 3,7-Diarabinoside 3,4’-Diglucoside 7-Rhamnoside-4’-glucoside 7,4’-Diglucoside 3-Xylosyl(1 ! 3)rhamnosyl(1 ! 6)galactoside 3-Xylosyl(1 ! 6)glucosyl(1 ! 2)rhamnoside 3-Rhamnosyl(1 ! 3)rhamnosyl(1 ! 6)glucoside 3-Rhamnosyl(1 ! 2)glucosyl(1 ! 6)galactoside 3-Rhamnosyl(1 ! 6)glucosyl(1 ! 6)galactoside 3-Glucosyl(1 ! 4)rhamnosyl(1 ! 2)glucoside 3-Glucosyl(1 ! 2)galactosyl(1 ! 2)glucoside 3-Rhamnosyl(1 ! 2)[glucosyl(1 ! 3)glucoside] 3-Rhamnosyl(1 ! 2)[glucosyl(1 ! 4)glucoside] 3-Glucosyl(1 ! 2)[glucosyl(1 ! 3)rhamnoside] 7-(3G-Glucosylgentiobioside) 3-Rhamnosyl(1 ! 2)galactoside-7-a-Larabinofuranoside 3-Robinobioside-7-a-L-arabinofuranoside 3-Xylosyl(1 ! 4)rhamnoside-7-rhamnoside 3-Rhamnoside-7-xylosyl(1 ! 2)rhamnoside 3-Apiosyl(1 ! 4)rhamnoside-7-rhamnoside

Source

Family

Ref.

Phyllanthus virgatus whole plant

Euphorbiaceae

165

Butea superba stems Shorea robusta seeds

Leguminosae Dipterocarpaceae

166 167

Acacia catechu stems

Leguminosae

168

Setaria italica leaves

Gramineae

169

Persea americana leaves Leucanthemum vulgare leaves Indigofera hebepetala leaves Artabotrys hexapetalus leaves

Lauraceae Compositae Leguminosae Annonaceae

170 171 172 173

Galium sinaicum aerial parts Cassia hirsuta flowers Ginkgo biloba leaves

Rubiaceae Leguminosae Ginkgoaceae

Crotalaria laburnifolia Caralluma tuberculata Rhodiola crenulata roots Crocus sativus stamens (saffron) Dryopteris dickinsii fronds Indigofera hebepetala leaves Picea abies needles Pteridium aquilinum aerial parts Cassia javanica Astragalus caprinus leaves Helicia nilagirica leaves Camellia sinensis green tea Cassia marginata stems Albizia lebbeck leaves Allium neapolitanum whole plant Nigella sativa seeds Impatiens balsamina petals Allium neapolitanum whole plant Crocus speciosus and C. antalyensis flowers Brassica juncea leaves

Leguminosae Asclepiadaceae Crassulaceae Iridaceae Aspleniaceae Leguminosae Pinaceae Dennstaedtiaceae Leguminosae Leguminosae Proteaceae Theaceae Leguminosae Leguminosae Liliaceae Ranunculaceae Balsaminaceae Liliaceae Iridaceae

174 175 176, 177 178 179 180 181 182 172 183 184 185 186 187 188 189 190 191 192 193 194 195

Cruciferae

196

Indigo hebepetala flowers Chenopodium murale whole plant Chenopodium murale aerial parts Chenopodium murale whole plant

Leguminosae Chenopodiaceae Chenopodiaceae Chenopodiaceae

197 198 199 198

continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 762 6.10.2005 10:36am

762

Flavonoids: Chemistry, Biochemistry, and Applications

TABLE 13.2 New Flavonol Glycosides — continued Glycoside 3-Neohesperidoside-7-rhamnoside

Source

Sedum telephium subsp. maximum leaves 3-Rhamnoside-7-glucosyl(1 ! 2)rhamnoside Siraita grosvenori fresh fruit 3-Glucosyl(1 ! 4)galactoside-7-a-L-arabinofuranoside Corchorus depressus whole plant 3-Glucosyl(1 ! 6)galactoside-7-a-L-arabinofuranoside 3-Apioside-7-rhamnosyl(1 ! 6)galactoside Silphium perfoliatum leaves 3-Glucosyl(1 ! 2)rhamnoside-7-glucoside Crocus chrysanthus-biflorus cvs ‘‘eye-catcher’’ and ‘‘spring pearl’’ flowers 3-Gentiobioside-7-rhamnoside Arabidopsis thaliana leaves 3-Glucosyl(1 ! 2)galactoside-7-glucoside Nicotiana spp. flowers 3-Sophoroside-7-glucuronide Allium cepa guard cells 3-Neohesperidoside-4’-glucoside Pseuderucaria clavata aerial parts 3-Neohesperidoside-7,4’-diglucoside Minus flowers 3-Gentiobioside-4’-glucoside Asplenium incisum fronds 3-Galactoside-3’,4’-dirhamnoside Astragalus tana aerial parts 3-Rhamnoside-7,4’-digalactoside Warburgia ugandensis leaves 4’-Rhamnosyl(1 ! 3)rhamnosyl(1 ! 6)galactoside Rhamnus thymifolius fruits 3-Rhamnosyl(1 ! 2)[xylosyl Astragalus caprinus leaves (1 ! 3)rhamnosyl(1 ! 6)galactoside] 3-Glucosyl(1 ! 3)rhamnosyl(1 ! 2) Maytenus aquifolium leaves [rhamnosyl(1 ! 6) galactoside] 3-Rhamnosyl(1 ! 4)rhamnosyl Vigna spp. whole plant (1 ! 6)galactoside-7-rhamnoside (3-isorhamninoside-7-rhamnoside) 3-Rutinoside-7-sophoroside Equisetum spp. 3-Sophoroside-7-cellobioside Brassica oleracea leaves Sophora japonica seeds 3-(2G-Glucosylrutinoside)-7-rhamnoside Alangium premnifolium leaves 3-(2G-Rhamnosylrutinoside)-7-glucoside (mauritianin 7-glucoside) 3-Rhamnosyl(1 ! 6)[rhamnosyl(1 ! 2) Astragalus shikokianus aerial parts galactoside]-7-rhamnoside 3-Glucosyl(1 ! 2)[rhamnosyl(1 ! 6) Cephalocereus senilis whole young galactoside]-7-rhamnoside plants 3-[6’’-(3-Hydroxy-3-methylglutaryl)glucoside] Citrus aurantifolia callus cultures 3-(6’’-p-Hydroxybenzoylgalactoside) Persicaria lapathifolia whole plants 3-(2’’-Galloylarabinoside) Eucalyptus rostrata leaves 3-(6’’-Galloylgalactoside) Pemphis acidula leaves 3-(2’’,6’’-Digalloylglucoside) Loropetalum chinense leaves Prunus spinosa flowers 3-(2’’-E-p-Coumaroyl-a-L-arabinofuranoside) 3-(2’’-E-p-Coumaroylrhamnoside) Platanus orientalis buds Platanus acerifolia buds 3-(2’’-Z-p-Coumaroylrhamnoside) Platanus acerifolia buds 3-(2’’-Z-p-Coumaroylglucoside) Eryngium campestre aerial parts 3-(4’’-p-Coumaroylglucoside) Elaeagnus bockii whole plant

Family

Ref.

Crassulaceae

200

Cucurbitaceae Tiliaceae

201 202

Compositae Iridaceae

203 204

Cruciferae Solanaceae Alliaceae Cruciferae

205 206 207 208

Aspleniaceae Leguminosae Rubiaceae Rhamnaceae Leguminosae

209 210 211 212 213

Celestraceae

214

Leguminosae

215

Equisetaceae Cruciferae Leguminosae Alangiaceae

216 217 218 219

Leguminosae

220

Cactaceae

221

Rutaceae Polygonaceae Myrtaceae Lythraceae Hamamelidaceae Rosaceae Platanaceae Platanaceae Platanaceae Umbelliferae Elaeagnaceae

222 223 224 225 226 227 228 229 229 230 231

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 763 6.10.2005 10:36am

763

Flavone and Flavonol O-Glycosides

TABLE 13.2 New Flavonol Glycosides — continued Glycoside 3-(6’’-Caffeoylglucoside) 3-(5’’-Feruloylapioside) 3-(6’’-Feruloylglucoside) 3-(6’’-Acetylglucoside) 7-(6’’-p-Coumaroylglucoside) 3-(2’’,3’’-di-E-p-Coumaroylrhamnoside) 3-(2’’,4’’-di-E-p-Coumaroylrhamnoside) 3-(2’’,4’’-di-Z-p-Coumaroylrhamnoside) 3-(2’’,6’’-di-E-p-Coumaroylglucoside) 3-(2’’-Z-p-Coumaroyl-6’’-E-p-coumaroylglucoside) 3-(3’’,6’’-di-Z-p-Coumaroylglucoside) (stenopalustroside A) 3-(3’’-Z-p-Coumaroyl-6’’-E-feruloylglucoside) (stenopalustroside B) 3-(3’’-Z-p-Coumaroyl-6’’-E-p-coumaroylglucoside) (stenopalustroside C) 3-(3’’-E-p-Coumaroyl-6’’-Z-p-coumaroylglucoside) (stenopalustroside D) (isolated as a mixture) 3-(3’’-E-p-Coumaroyl-[6’’-(4-O-(4-hydroxy-3methoxyphenyl-1,3-dihydroxyisopropyl-feruloyl)] glucoside (stenopalustroside E) 3-(2’’-E-p-Coumaroyl-6’’-acetylglucoside) 3-(3’’-Acetyl-6’’-p-coumaroylglucoside) 3-(3’’,4’’-Diacetylglucoside) 3-(6G-Malonylneohesperidoside) 3-(2’’’-E-Feruloylgalactosyl(1 ! 4)glucoside) 3-(2’’’-E-Feruloylgalactosyl(1 ! 6)glucoside) 3-(2G-E-p-Coumaroylrutinoside) 3-(6’’’-Caffeoylglucosyl)(1 ! 4)rhamnoside 3-(6’’’-E-Feruloylglucosyl)(1 ! 2)galactoside 3-(6’’’-Sinapoylglucosyl)(1 ! 2)galactoside 3-(3’’’-Acetyl-a-L-arabinopyranosyl)(1 ! 6)glucoside 3-(6’’’-Acetylglucosyl)(1 ! 3)galactoside 3-(2’’’-Feruloylglucosyl)(1 ! 2)(6’’-malonylglucoside) 3-[6’’-(3-Hydroxy-3-methylglutaryl)glucoside]-7glucoside 3-(6’’-Malonylglucoside)-7-glucoside 3-(2’’-E-p-Coumaroyl-a-L-arabinofuranoside)-7rhamnoside 3-(3’’-p-Coumaroylrhamnoside)-7-rhamnoside 3-(6’’-E-p-Coumaroylglucoside)-7-glucoside 3-(2’’,3’’-Diacetylrhamnoside)-7-rhamnoside 3-(2’’,4’’-Diacetylrhamnoside)-7-rhamnoside 3-(3’’,4’’-Diacetylrhamnoside)-7-rhamnoside

Source

Family

Ref.

Pteridium aquilinum aerial parts Pteridium aquilinum aerial parts Polylepis incana leaves Picea abies needles Buddleia coriacea aerial parts Platanus orientalis buds Pentachondra pumila leaves and stems Laurus nobilis leaves Quercus canariensis

Dennstaedtiaceae Dennstaedtiaceae Rosaceae Pinaceae Loganiaceae Platanaceae Epacridaceae

232 233 234 235 236 228 237

Lauraceae Fagaceae

238 239

Stenochlaena palustris leaves

Pteridaceae

240

Quercus dentata leaves Anaphalis aurea-punctata whole plant Minthostachys spicata aerial parts Clitoria teratea petals Allium porrum bulbs

Fagaceae Compositae

241 242

Labiatae Leguminosae Alliaceae

243 244 245

Alibertia sessilis leaves Rorippa indica whole plant Hedyotis diffusa whole plant Thevetia peruviana leaves Thalictrum atriplex aerial parts Ricinus communis roots Petunia cv ‘‘Mitchell’’ and its LC transgenic leaves Citrus aurantifolia callus cultures

Rubiaceae Cruciferae Rubiaceae Apocynaceae Ranunculaceae Euphorbiaceae Solanaceae

246 247 248 249 250 251 252

Rutaceae

222

Equisetum spp. Prunus spinosa leaves

Equisetaceae Rosaceae

216 253

Cheilanthes fragrans aerial parts Lotus polyphyllus whole plant Dryopteris crassirhizoma rhizomes

Sinopteridaceae Leguminosae Filicales

254 255 256

continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 764 6.10.2005 10:36am

764

Flavonoids: Chemistry, Biochemistry, and Applications

TABLE 13.2 New Flavonol Glycosides — continued Glycoside 3-(4’’,6’’-Diacetylglucoside)-7-rhamnoside 3-(2’’’,3’’’,4’’’-Triacetyl-a-L-arabinopyranosyl)(1 ! 6) glucoside 3-[6’’-(7’’’’-Glucosyl-p-coumaroyl)glucosyl](1 ! 2)rhamnoside 3-Rhamnosyl(1 ! 3)(4’’’-acetylrhamnosyl)(1 ! 6)glucoside 3-[2Gal-(6’’’-Feruloylglucosyl)robinobioside] 3-Rhamnosyl(1 ! 3)(4’’’-acetylrhamnosyl(1 ! 6)galactoside) 3-Glucosyl(1 ! 4)[(6’’’-sinapoylglucosyl)(1 ! 2)galactoside] 3-(2’’’’-Sinapoylglucosyl(1 ! 4)[(6’’’-sinapoylglucosyl) (1 ! 2)galactoside] 3-[2Gal(4’’’-Acetylrhamnosyl)robinobioside] 3-[2’’-(4’’’-Acetylrhamnosyl)sophoroside] 3-Neohesperidoside-7-(6’’-malonylglucoside)

3-Neohesperidoside-7-(6’’-acetylglucoside) 3-Neohesperidoside-7-(2’’-E-p-coumaroylglucoside) 3-Neohesperidoside-7-(2’’-E-feruloylglucoside) 3-(4’’’-p-Coumaroylglucosyl)(1 ! 2)rhamnoside-7-glucoside

Source

Family

Ref.

Delphinium formosum flowers Ranunculaceae 257 Calluna vulgaris flowers Ericaceae 258 Ginkgo biloba leaves Camellia sinensis green tea Brunfelsia grandiflora ssp. grandiflora aerial parts Rhamnus thymifolius fruits Thevetia peruviana leaves

Ginkgoaceae Theaceae Solanaceae

177 259 260

Rhamnaceae Apocynaceae

212 249

Galega officinalis aerial parts Ammi majus aerial parts Crocus chrysanthus biflorus cvs ‘‘eye catcher’’ and ‘‘spring pearl’’ flowers

Leguminosae Umbelliferae Iridaceae

261 262 204

Allium ursinum whole plant

Liliaceae

263

Mentha lavandulacea aerial parts

Labiatae

264

3-(6’’’-p-Coumaroylglucosyl)(1 ! 2)rhamnoside-7-glucoside 3-(6’’’-p-Coumaroylglucosyl)(1 ! 2)rhamnoside-7-glucoside Ginkgo biloba leaves 3-Glucosyl(1 ! 2)rhamnoside-7-(6’’-E-p-coumaroylglucoside) Reseda muricata leaves 3-(6’’’-E-p-Coumaroylglucosyl)(1 ! 2)glucoside-7-rhamnoside Aconitum napellus ssp. tauricum flowers 3-(6’’’-E-Caffeoylglucosyl)(1 ! 2)glucoside-7-rhamnoside 3-Glucoside-7-(6’’’-E-p-coumaroylglucosyl)(1 ! 3) Aconitum napellus ssp. neomontanum rhamnoside 3-Glucoside-7-(6’’’-E-caffeoylglucosyl)(1 ! 3)rhamnoside 3-(2’’’-E-p-Coumaroylsophoroside)-7-glucoside Brassica oleracea leaves 3-(2’’’-E-Caffeoylsophoroside)-7-glucoside 3-(2’’’-E-Feruloylsophoroside)-7-glucoside 3-Apioside-7-rhamnosyl(1 ! 6)(2’’-E-caffeoylgalactoside) Silphium perfoliatum leaves 3-Xylosyl(1 ! 2)rhamnoside-7-(4’’-acetylrhamnoside) Kalanchoe streptantha leaves 3-Glucosyl(1 ! 2)(6’’-acetylgalactoside)-7-glucoside Trigonella foenum graecum 3-Rhamnosyl(1 ! 2)[glucosyl(1 ! 3)(4’’’-pLysimachia capillipes coumaroylrhamnosyl)(1 ! 6)galactoside] whole plant 3-Rhamnosyl(1 ! 2)[xylosyl(1 ! 3)rhamnosyl(1 ! 6) Astragalus caprinus leaves (3’’-p-coumaroylgalactoside)] 3-Rhamnosyl(1 ! 2)[xylosyl(1 ! 3)rhamnosyl(1 ! 6) (4’’-p-coumaroylgalactoside)] 3-Rhamnosyl(1 ! 2)[xylosyl(1 ! 3)rhamnosyl(1 ! 6) (3’’-feruloylgalactoside)] 3-Rhamnosyl(1 ! 2)[xylosyl(1 ! 3)rhamnosyl(1 ! 6) (4’’-feruloylgalactoside)] 3-Neohesperidoside-7-[2’’-E-p-coumaroyllaminaribioside] Allium ursinum whole plant

Ginkgoaceae 265 Resedaceae 266 Ranunculaceae 267

Ranunculaceae 268

Cruciferae

269

Compositae Crassulaceae Leguminosae Primulaceae

203 270 271 272

Leguminosae

213

Liliaceae

263

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 765 6.10.2005 10:36am

765

Flavone and Flavonol O-Glycosides

TABLE 13.2 New Flavonol Glycosides — continued Glycoside 3-(2’’’-E-Caffeoylglucosyl)(1 ! 2) glucoside-7-cellobioside 3-(2’’’-E-Feruloylglucosyl)(1 ! 2) glucoside-7-cellobioside 3-(2’’-E-Sinapoylglucosyl)(1 ! 2) glucoside-7-cellobioside 3-Glucosyl(1 ! 6)[rhamnosyl(1 ! 3)(2’’-E-pcoumaroylglucoside)]-7-rhamnosyl(1 ! 3) rhamnosyl (1 ! 3)(4’’-E-p-coumaroylrhamnoside) 3-Glucosyl(1 ! 6)[rhamnosyl(1 ! 3)(2’’-E-pcoumaroylglucoside)]-7-rhamnosyl(1 ! 3) rhamnosyl(1 ! 3)(4’’-Z-p-coumaroylrhamnoside) 3-Rhamnosyl(1 ! 6)[rhamnosyl(1 ! 3)(2’’-E-pcoumaroylglucoside)]-7-rhamnosyl(1 ! 3) rhamnosyl (1 ! 3)rhamnosyl(1 ! 3) (4’’-E-p-coumaroylrhamnoside) 3-Sulfate-7-a-arabinopyranoside 8-C-Sulfate Kaempferol 3-methyl ether 7-Glucuronide Kaempferol 7-methyl ether (rhamnocitrin) 4’-Glucoside 3-Xylosyl(1 ! 2)[rhamnosyl(1 ! 6)glucoside] 3-Rhamnosyl(1 ! 3)[apiosyl(1 ! 6)glucoside] 3-Apiosyl(1 ! 5)apioside-4’-glucoside 3-Neohesperidoside-4’-glucoside 3-Apiosyl(1 ! 5)apiosyl(1 ! 2) [rhamnosyl(1 ! 6)glucoside] 3-[3-Hydroxy-3-methylglutaryl(1 ! 6)][apiosyl (1 ! 2)galactoside] 3-[5’’’-p-Coumaroylapiosyl(1 ! 2)glucoside] 3-[5’’’-Feruloylapiosyl(1 ! 2)glucoside] 3-glucoside-4’-(3’’’-dihydrophaseoylglucoside) 3-(6-E-3,5-Dimethoxy-4-hydroxycinnamoylglucosyl) (1 ! 2)[rhamnosyl(1 ! 6)glucoside] Kaempferol 4’-methylether (kaempferide) 3-Rhamnoside 3-Neohesperidoside 3-Rhamnoside-7-xyloside 3-(4Rha-Rhamnosylrutinoside) 3-(2Glc-Glucosylrutinoside) 3-[6’’’-Acetyl(4’’-a-methylsinapoylneohesperido-side)] Kaempferol 3,5-dimethyl ether 7-Glucoside

Source

Family

Ref.

Brassica oleracea leaves

Cruciferae

217

Planchonia grandis

Lecythidaceae

273

Atriplex hortensis leaves Phyllanthus virgatus whole plant

Chenopodiaceae Euphorbiaceae

274 165

Centaurea bracteata aerial parts

Compositae

275

Cotoneaster simonsii leaves Cestrum nocturnum leaves Mosla soochouensis stem wood Mosla chinensis Cadaba glandulosa aerial parts Viscum angulatum whole plant

Rosaceae Solanaceae Labiatae Labiatae Capparidaceae Viscaceae

276 277 278 279 280 281

Astragalus caprinus leaves

Leguminosae

186

Astragalus complanatus seeds

Leguminosae

282

Cestrum nocturnum leaves

Solanaceae

277

Agrimonia eupatoria aerial parts Costus spicatus leaves Cassia biflora leaves Sageretia filiformia leaves Dianthus caryophyllus cv. ‘‘Novada’’ leafy stems and roots Aerva tomentosa

Rosaceae Costaceae Leguminosae Rhamnaceae Caryophyllaceae

283 284 285 286 287

Amaranthaceae

288

Nitraria tangutorum leaves

Nitrariaceae

289 continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 766 6.10.2005 10:36am

766

Flavonoids: Chemistry, Biochemistry, and Applications

TABLE 13.2 New Flavonol Glycosides — continued Glycoside Kaempferol 3,7-dimethyl ether 4’-Glucoside Kaempferol 7,4’-dimethyl ether 3-Glucoside 3-Neohesperidoside 6-Hydroxykaempferol 3-Glucoside 7-Alloside 3-Rutinoside 3,6-Diglucoside 3,6,7-Triglucoside 3-Rutinoside-6-glucoside 7-(6’’-Caffeoylglucoside) 6-Hydroxykaempferol 6-methyl ether (eupafolin) 3-(6’’-p-Coumaroylglucoside)

6-Hydroxykaempferol 4’-methyl ether 7-Glucoside 7-Galactoside 6-Hydroxykaempferol 6,4’-dimethyl ether 3-Glucoside 6-Hydroxykaempferol 3,5,7,4’-tetramethyl ether 6-Rhamnoside 8-Hydroxykaempferol (herbacetin) 3-b-D-Glucofuranoside 3-Rhamnoside-8-glucoside Herbacetin 7-methyl ether 8-Sophoroside 3-(2’’-E-Feruloylglucoside) Herbacetin 8-methyl ether (sexangularetin) 3-Neohesperidoside Herbacetin 7,8,4’-trimethyl ether (tambulin) 3,5-Diacetate 5,7,8-Trihydroxy-3-methoxyflavone 8-(E-2-Methylbut-2-enoate) 5,7,8-TriOH-3,6-dimethoxyflavone 8-(E-2-Methylbut-2-enoate) 6,8-Dihydroxykaempferol 3-Rutinoside Quercetin 3-a-D-Arabinopyranoside 5-Glucuronide 4’-Galactoside

Source

Family

Ref.

Lantana camara leaves

Verbenaceae

290

Gymnotheca involucrata whole plant Costus spiralis leaves

Saururaceae

291

Costaceae

292

Carthamnus tinctorius petals Tagetes erecta flowers Daphniphyllum calycinum leaves Carthamnus tinctorius petals

Compositae Compositae Daphniphyllaceae Compositae

293 294 295 293

Eupatorium glandulosum leaves

Compositae

296

Paepalanthus polyanthus, P. hilairei, P. robustus, P. ramosus, and P. denudatus capitulae

Eriocaulaceae

297

Serratula strangulata whole plant

Compositae

298

Arnica montana flowers

Compositae

299

Pterocarpus marsupium roots

Leguminosae

300

Jungia paniculata whole plant Ephedra aphylla aerial parts

Compositae Ephedraceae

301 302

Ranunculus sardous pollen Ranunculus sardous pollen

Ranunculaceae Ranunculaceae

303 304

Crateagus monogyna pollen

Rosaceae

305

Zanthoxylum integrifolium fruits

Rutaceae

306

Pseudognaphalium robustum and P. cheirantifolium whole plant

Compositae

307

Pseudognaphalium robustum and P. cheirantifolium whole plant

Compositae

307

Withania somnifera leaves

Solanaceae

308

Persea americana leaves Leucanthemuum vulgare leaves Cornulaca monacantha aerial parts

Lauraceae Compositae Chenopodiaceae

170 171 309

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 767 6.10.2005 10:36am

767

Flavone and Flavonol O-Glycosides

TABLE 13.2 New Flavonol Glycosides — continued Glycoside 4’-Glucuronide 3-Rhamnosyl(1 ! 2)-a-L-arabinofuranoside (arapetaloside A) 3-a-L-Arabinofuranosyl(1 ! 2)glucoside 3-Xylosyl(1 ! 6)glucoside 3-Rhamnosyl(1 ! 2)rhamnoside 3-Glucosyl(1 ! 2)rhamnoside 3-Galactosyl(1 ! 2)rhamnoside 3-Laminaribioside 3-Glucosyl(1 ! 3)galactoside 3-Glucosyl(1 ! 4)galactoside 3-Glucosyl(1 ! 2)glucuronide 3-Rhamnoside-3’-glucoside 3-Xylosyl(1 ! 2)rhamnosyl(1 ! 6)glucoside 3-Xylosyl(1 ! 2)rhamnoside 3-Apiosyl(1 ! 2)rhamnosyl(1 ! 6)glucoside 3-(6’’’-Rhamnosylgentiobioside) 3-Rhamnosyl(1 ! 2)glucosyl(1 ! 6)galactoside 3-Rhamnosyl(1 ! 6)glucosyl(1 ! 6)galactoside 3-Glucosyl(1 ! 2)galactosyl(1 ! 2)glucoside 7-(2G-Xylosylrutinoside) 3-Glucosyl(1 ! 2)[rhamnosyl(1 ! 6)galactoside] 3-Rhamnosyl(1 ! 2)-a-L-arabinopyranoside-7glucoside 3-Xylosyl(1 ! 2)glucoside-7-rhamnoside 3-Galactoside-7-glucosyl(1 ! 4)rhamnoside 3-Neohesperidoside-7-rhamnoside 3-Rhamnosyl(1 ! 4)rhamnoside-7-galactoside 3-Neohesperidoside-7-glucoside 3-Glucosyl(1 ! 2)rhamnoside-7-glucoside

3-Glucosyl(1 ! 2)galactoside-7-glucoside 3-Sophoroside-7-glucuronide 3-Rutinoside-3’-apioside 3,3’,4’-Triglucoside 3-Xylosyl(1 ! 4)[xylosyl(1 ! 6)glucosyl (1 ! 2)rhamnoside] 3-Xylosyl(1 ! 3)rhamnosyl(1 ! 6) [apiosyl(1 ! 2)galactoside] 3-Glucosyl(1 ! 4)rhamnoside-7-rutinoside 3-Rhamnosyl(1 ! 6)[glucosyl(1 ! 2) glucoside]-7-rhamnoside 7-[Xylosyl(1 ! 2)rhamnosyl(1 ! 2) rhamnosyl](1 ! 6)glucoside

Source

Family

Ref.

Psidium guaijava leaves Artabotrys hexapetalus leaves

Myrtaceae Annonaceae

310 173

Prunus spinosa leaves Cistus ladanifer pollen Centaurea horrida aerial parts Ginkgo biloba leaves Embelia schimperi leaves Pteridium aquilinum aerial parts Filipendula formosa aerial parts Rumex chalepensis leaves Cordia macleodii leaves and flowers Myrsine seguinii leaves Camellia saluensis leaves Helicia nilagirica leaves Baccharis thesioides aerial parts Capparis spinosa aerial parts Cassia marginata stems Albizia lebbeck leaves Nigella sativa seeds Bidens andicola aerial parts Thevetia peruviana leaves Putoria calabrica aerial parts

Rosaceae Cistaceae Compositae Ginkgoaceae Myrsinaceae Dennstaedtiaceae Rosaceae Polygonaceae Boraginaceae Myrsinaceae Theaceae Proteaceae Compositae Capparidaceae Leguminosae Leguminosae Ranunculaceae Compositae Apocynaceae Rubiaceae

253 311 312 177 313 314 315 316 317 318 319 187 320 321 189 190 192 322 323 324

Lathyrus chrysanthus and L. chloranthus flowers

Leguminosae

325

Sedum telephium subsp. maximum leaves Maesa lanceolata leaves Nicotiana spp. flowers Crocus chrysanthus-biflorus cvs ‘‘eye catcher’’ and ‘‘spring pearl’’ flowers Trigonella foenum-graecum stems Allium cepa guard cells Plantago ovata and P. psyllium seeds Eruca sativa leaves Helicia nilagirica leaves

Crassulaceae

200

Myrsinaceae Solanaceae Iridaceae

326 206 204

Leguminosae Alliaceae Plantaginaceae Cruciferae Protaceae

271 207 327 328 187

Astragalus caprinus leaves

Leguminosae

213

Myrsine africana leaves Warburgia ugandensis leaves

Myrsinaceae Rubiaceae

329 211

Bidens andicola aerial parts

Compositae

322

continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 768 6.10.2005 10:36am

768

Flavonoids: Chemistry, Biochemistry, and Applications

TABLE 13.2 New Flavonol Glycosides — continued Glycoside 3-(4’’-Malonylrhamnoside) 3-(2’’-Caffeoylglucuronide) 3-(6’’-Feruloylgalactoside) 3-(2’’-Acetylrhamnoside) 3-(2’’-Acetylgalactoside) 3-(6’’-n-Butylglucuronide) (parthenosin) 7-(6’’-Galloylglucoside) 7-(6’’-Acetylglucoside) 4’-(6’’-Galloylglucoside) 3-(2’’,6’’-Digalloylgalactoside) 3-(3’’,6’’-Diacetylgalactoside) 3-(2’’,3’’,4’’-triacetylgalactoside) 3-(2’’’-Galloylglucosyl)(1 ! 2)-a-L-arabinofuranoside 3-(2’’-Galloylglucoside)-4’-vinylpropionate 3-(2’’-Galloylrutinoside) 3-(6G-Malonylneohesperidoside) 3-a-L-Arabinopyranosyl(1 ! 6) (2’’-E-p-coumaroylglucoside) 3-a-L-Arabinopyranosyl(1 ! 6) (2’’-E-p-coumaroylgalactoside) 3-(2G-E-p-Coumaroylrutinoside) 3-(2’’’-E-Caffeoyl-a-L-arabinopyranosyl) (1 ! 6)glucoside 3-(2’’’-E-Caffeoyl-a-L-arabinopyranosyl) (1 ! 6)galactoside 3-(6’’-Caffeoylgentiobioside) 3-(6’’-Caffeoylsophoroside) 3-(6’’-Feruloylsophoroside) 3-(2’’’-Feruloylsophoroside) 3-(6’’’-Sinapoylglucosyl)(1 ! 2)galactoside 3-Rhamnosyl(1 ! 6)(2’’-acetylglucoside) 3-(6’’-Acetylglucosyl)(1 ! 3)galactoside (euphorbianin) 3-(2’’-Caffeoylglucoside)(1 ! 2) (6’’-malonylglucoside) 3-(3’’,4’’-Diacetylrhamnosyl)(1 ! 6)glucoside 3-[2’’’,3’’’,4’’’-Triacetyl-a-L-arabinopyranosyl (1 ! 6)glucoside] 3-[2’’’,3’’’,4’’’-Triacetyl-a-L-arabinopyranosyl (1 ! 6)galactoside] 3-[2’’’,3’’’,5’’’-Triacetyl-a-L-arabinopyranosyl (1 ! 6)glucoside] 3-[2’’,6’’-{-p-(7’’’-Glucosyl)coumaroyl} glucosyl]rhamnoside

Source

Family

Ref.

Ribes alpinum leaves Scolymus hispanicus Persicaria lapathifolia aerial parts Nymphaea caerulea blue flowers Hypericum perforatum dried crude drug Parthenocissus tricuspidata leaves Acacia farnesiana pods Carthamnus tinctorius leaves Eucalyptus rostrata leaves Acer okamotanum leaves Tagetes elliptica aerial parts

Grossulariaceae Compositae Polygonaceae Nymphaeaceae Guttiferae

330 331 332 333 334

Vitaceae Leguminosae Compositae Myrtaceae Aceraceae Compositae

335 336 337 224 338 339

Euphorbia pachyrhiza Psidium guaijava seeds Euphorbia ebractedata aerial parts Clitoria ternatea petals Vicia angustifolia leaves and stems

Euphorbiaceae Myrtaceae Euphorbiaceae Leguminosae Leguminosae

340 341 342 244 343

Alibertia sessilis leaves Morina nepalensis var. alba whole plant

Rubiaceae Morinaceae

246 344

Lonicera implexa leaves Bassia muricata aerial parts

Caprifoliaceae Chenopodiaceae

107 345

Petunia cv ‘‘Mitchell’’ and its LC transgenic leaves Thevetia peruviana leaves Prunus mume flowers Euphorbia hirta leaves

Solanaceae

252

Apocynaceae Rosaceae Euphorbiaceae

249 346 347

Petunia cv. ‘‘Mitchell’’ and its LC transgenic leaves Tordylium apulum aerial parts Calluna vulgaris flowers

Solanaceae

252

Umbelliferae Ericaceae

348 349

Calluna vulgaris flowers

Ericaceae

350

Calluna vulgaris flowers

Ericaceae

258

Ginkgo biloba leaves

Ginkgoaceae

177

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 769 6.10.2005 10:36am

769

Flavone and Flavonol O-Glycosides

TABLE 13.2 New Flavonol Glycosides — continued Glycoside 3-(6’’-Malonylglucoside)-7-glucoside 3-(6’’-E-p-Coumaroylglucoside)-7-glucoside 3-(6’’’’-p-Coumaroylsophorotrioside) 3-(6’’’’-Caffeoylsophorotrioside) 3-(6’’’’-Feruloylsophorotrioside) 3-(6’’’’- Sinapoylsophorotrioside) 3-(6’’’’-Feruloylglucosyl)(1 ! 2) galactosyl(1 ! 2)glucoside 3-Rutinoside-7-(6’’-benzoylglucoside) 3-(p-Coumaroylsambubioside)-7-glucoside 3-(6’’’-p-Coumaroylglucosyl)(1 ! 2)rhamnoside7-glucoside 3-(6’’-E-p-Coumaroylsophoroside)-7-rhamnoside 3-(p-Coumaroylsophoroside)-7-glucoside 3-(Caffeoylarabinosylglucoside)-7-glucoside 3-(2’’’-Caffeoylsambubioside)-7-glucoside 3-(Feruloylsambubioside)-7-glucoside 3-(4’’’-Caffeoylrhamnosyl)(1 ! 2)-a-Larabinopyranoside-7-glucoside 3-Glucosyl-7-(6’’-E-caffeoylglucosyl)(1 ! 3) rhamnoside 3-(6’’-Caffeoylsophoroside)-7-rhamnoside 3-Sophoroside-7-(6’’-trans-caffeoylglucoside) 3-(2’’’-E-Caffeoylsophoroside)-7-glucoside 3-(2’’’-E-Feruloylsophoroside)-7-glucoside 3-[(6’’-Feruloylglucosyl)(1 ! 2)-b-arabinopyranoside]7-glucoside 3-(6’’-E-Sinapoylsophoroside)-7-rhamnoside 3-Caffeoylsophoroside-7-caffeoylglucoside 3-Caffeoylsophoroside-7-feruloylglucoside 3-(2’’-Sinapoylglucoside)-3’-(6’’-sinapoylglucoside)4’-glucoside 3,4’-Diglucoside-3’-(6’’-sinapoylglucoside) 3-Rhamnosyl(1 ! 6)[rhamnosyl(1 ! 2)(3’’-E-pcoumaroylgalactoside)]-7-rhamnoside 3-Rhamnosyl(1 ! 6)[rhamnosyl(1 ! 2)(4’’-E-pcoumaroylgalactoside)]-7-rhamnoside 3-Rhamnosyl(1 ! 2)[glucosyl(1 ! 3)(4’’’-pcoumaroylrhamnosyl)(1 ! 6)galactoside] Diquercetin 3-galactoside ester of tetrahydroxym-truxinic acid (monochaetin, 13.6) 3-Sulfate-7-a-arabinopyranoside 3-Rhamnoside-3’-sulfate 3-Glucoside-3’-sulfate

Source

Family

Ref.

Ranunculus fluitans leaves Lotus polyphyllus whole plant Pisum sativum shoots

Ranunculaceae Leguminosae Leguminosae

351 255 352

Nigella sativa seeds

Ranunculaceae

192

Canthium dicoccum leaves Ranunculus spp. leaves Ginkgo biloba leaves

Rubiaceae Ranunculaceae Ginkgoaceae

353 354 177

Aconitum napellus ssp. tauricum flowers Ranunculus spp. leaves

Ranunculaceae

267

Ranunculaceae

354

Putoria calabrica aerial parts

Rubiaceae

324

Aconitum napellus ssp. neomontanum flowers Aconitum baicalense aerial parts Symplocarpus renifolius leaves Brassica oleracea leaves

Ranunculaceae

268

Ranunculaceae

355

Araceae Cruciferae

356 269

Carrichtera annua whole plant

Cruciferae

357

Elaeagnus bockii leaves Ranunculus fluitans leaves

Elaeagnaceae Ranunculaceae

358 351

Eruca sativa leaves

Cruciferae

328

Rhazya orientalis aerial parts

Apocynaceae

359

Lysimachia capillipes whole plant Monochaetum multiflorum leaves Atriplex hortensis leaves Leea guineensis leaves Centaurea bracteata aerial parts

Primulaceae

272

Melastomataceae

360

Chenopodiaceae Leeaceae Compositae

274 361 275

continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 770 6.10.2005 10:36am

770

Flavonoids: Chemistry, Biochemistry, and Applications

TABLE 13.2 New Flavonol Glycosides — continued Glycoside 7,4’-Disulfate Quercetin 3-methyl ether 5-Glucoside 7-a-L-Arabinofuranosyl(1 ! 6)glucoside 7-Rutinoside 7-Gentiobioside 7-Galactosyl(1 ! 4)glucoside 5-Glucoside-3’-sulfate Quercetin 7-methyl ether (rhamnetin) 3-a-L-Arabinopyranosyl(1 ! 3)galactoside 3-Robinobioside 3-Laminaribioside 3-Gentiobioside 3-a-L-Arabinopyranosyl(1 ! 3) [galactosyl(1 ! 6)galactoside] 3-[3-Hydroxy-3-methylglutaryl(1 ! 6)] [apiosyl (1 ! 2)galactoside] 3-(3’’’’-p-Coumaroylrhamnoside) 3,3’-Disulfate 3,3’,4’-Trisulfate Quercetin 3’-methyl ether 3-Rhamnoside 5-Galactoside 7-a-D-Glucosaminopyranoside 3-a-Arabinopyranosyl(1 ! 6)galactoside

Source

Family

Ref.

Alchornea laxiflora whole plant

Euphorbiaceae

362

Asplenium trichomanes-ramosum fronds Lepisorus ussuriensis whole plant Bidens leucantha leaves Lonicera implexa leaves Acacia catechu stems Calorphus elongatus culms

Aspleniaceae Polypodiaceae Compositae Caprifoliaceae Leguminosae Restionaceae

363 364 365 107 366 367

Pongamia pinnata seeds Cassia siamea stem bark Pteridium aquilinum aerial parts Cassia fistula roots Pongamia pinnata seeds

Leguminosae Leguminosae Dennstaedtiaceae Leguminosae Leguminosae

368 369 370 371 368

Astragalus caprinus leaves

Leguminosae

186

Rhamnus petiolaris fruit Argyreia mollis roots Tamarix amplexicaulis leaves

Rhamnaceae Convolvulaceae Tamaricaceae

372 373 374

Leguminosae Rosaceae Chenopodiaceae Liliaceae

375 376 377 378

Leguminosae

325

Cistaceae Asclepiadaceae Compositae

311 379 380

Compositae

381

Oxytropis lanata aerial parts Pyrus bourgaeana aerial parts Halocnemum strobilaceum aerial parts Trillium apeton and T. kamtechaticum leaves 3-Xylosyl(1 ! 2)glucoside Lathyrus chrysanthus and L. chloranthus flowers 3-Xylosyl(1 ! 6)glucoside Cistus ladanifer pollen 3-Xylosyl(1 ! 2)galactoside Asclepias syriaca flowers 3-Apiosyl(1 ! 2)glucoside Vernonia galamensis ssp. galamensis var. petitiana whole plant 3-Apiosyl(1 ! 2)galactoside Vernonia galamensis spp. nairobiensis leaves 3-Laminaribioside Pteridium aquilinum aerial parts 3-Glucosyl(1 ! 3)galactoside Achlys triphylla underground parts 3-Galactoside-7-rhamnoside Lathyrus chrysanthus and L. chloranthus flowers 4’-Rhamnosyl(1 ! 2)glucoside (crosatoside A) Crocus sativus pollen 3-Xylosyl(1 ! 3)rhamnosyl(1 ! 6)glucoside Hamada scoparia leaves 3-Xylosylrobinobioside Nitraria retusa leaves and young stems 3-Apiosyl(1 ! 2)[rhamnosyl(1 ! 6)glucoside] Pituranthos tortuosus shoots 3-Rhamnosyl(1 ! 2)[glucosyl(1 ! 6)glucoside Allium neapolitanum whole plant Nitraria retusa leaves and young stems 3-(4Rha-Galactosylrobinobioside) 3-Galactosyl(1 ! 2)[rhamnosyl(1 ! 6)glucoside]) Calotropis gigantean aerial parts 3-Xylosyl(1 ! 2)glucoside-7-rhamnoside Lathyrus chrysanthus and L. chloranthus flowers

Dennstaedtiaceae 314 Berberidaceae 382 Leguminosae 325 Iridaceae Chenopodiaceae Nitrariaceae Umbelliferae Liliaceae Nitrariaceae Asclepiadaceae Leguminosae

383 384 385 386 191 385 387 325

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 771 6.10.2005 10:36am

771

Flavone and Flavonol O-Glycosides

TABLE 13.2 New Flavonol Glycosides — continued Glycoside 3-Glucosyl(1 ! 6)galactoside-7-glucoside 3-Rhamnosyl(1 ! 2)gentiobiosyl (l ! 6)glucoside 3-Rhamnosyl(1 ! 2)gentiobioside-7-glucoside 3-(2G-Rhamnosylrutinoside)-7-rhamnoside 3-[6’’-(2-E-Butenoyl)glucoside] 3-(2’’,3’’,4’’-Triacetylglucoside) 7-(6’’-p-Coumaroylglucoside) 3-(6’’’-p-Coumaroylglucosyl)(1 ! 2)rhamnoside 3-(3’’’-Feruloylrhamnosyl)(1 ! 6)galactoside 3-(6’’-E-Sinapoylsophoroside) 3-(2’’’-Acetyl-a-arabinopyranosyl)(1 ! 6) galactoside 3-Rhamnosyl(1 ! 6)(2’’-acetylglucoside) 3-(6’’-Acetylglucosyl)(1 ! 3)galactoside 3-(4’’,6’’-Diacetylglucosyl)(1 ! 3)galactoside 3-(6’’-E-p-Coumaroylglucoside)-7-glucoside 3-[2’’-(4’’’-Acetylrhamnosyl)gentiobioside] 3-Rhamnosyl(1 ! 6)[rhamnosyl(1 ! 2) (3’’’-E-p-coumaroylgalactoside]-7-rhamnoside 3-Rhamnosyl(1 ! 6)[rhamnosyl(1 ! 2) (4’’-p-coumarylgalactoside)]-7-rhamnoside 3-Rhamnosyl(1 ! 6)[rhamnosyl(1 ! 2) (4’’-Z-p-coumaroylgalactoside)] 3-Rhamnosyl(1 ! 6)[rhamnosyl(1 ! 2) (4’’-E-feruloylgalactoside)]-7-rhamnoside 3-(4’’-Sulfatorutinoside) Quercetin 4’-methyl ether (tamarixetin) 3-Galactoside 3-Neohesperidoside 3-Glucosyl(1 ! 2)galactoside 3,7-Diglucoside 3-Rutinoside-7-rhamnoside 3-Glucoside-7-sulfate Quercetin 3,5-dimethyl ether (caryatin) 7-Glucoside Quercetin 3,7-dimethyl ether 3’-Neohesperidoside 3’-(6G-Rhamnosylneohesperidoside) 4’-Sulfate Quercetin 3,3’-dimethyl ether 7-Rutinoside Quercetin 3,4’-dimethyl ether 7-Glucoside 7-a-L-Arabinofuranosyl(1 ! 6)glucoside 7-Rutinoside 7-Rutinoside

Source

Family

Ref.

Heterotropa aspera leaves Allium neopolitanum whole plant

Aristolochiaceae Liliaceae

388 191

Coleogyne ramosissima aerial parts Zygophyllum simplex aerial parts Warburgia stuhlmanii leaves Buddleia coriacea aerial parts Ginkgo biloba leaves Allium neopolitanum whole plant Cassia marginata stems Trillium apetalon and T. kamtschaticum leaves Prunus mume flowers Achlys triphylla underground parts

Rosaceae Zygophyllaceae Cannellaceae Loganiaceae Ginkgoaceae Liliaceae Leguminosae Liliaceae

389 390 391 236 265 191 189 378

Rosaceae Berberidaceae

346 382

Lotus polyphyllus whole plant Ammi majus aerial parts Rhazya orientalis aerial parts

Leguminosae Umbelliferae Apocynaceae

255 262 359

Zygophyllum dumosum aerial parts

Zygophyllaceae

392

Cynanchum thesioides whole plant Costus spicatus leaves Cynanchum thesioides whole plant Zanthoxylum bungeanum pericarps Cassia italica aerial parts Polygonum hydropiper leaves

Asclepiadaceae Costaceae Asclepiadaceae Rutaceae Leguminosae Polygonaceae

393 284 393 394 395 396

Eucryphia glutinosa twigs

Eucryphiaceae

397

Dasymaschalon sootepense leaves

Annonaceae

398

Ipomoea regnelli

Convolulacaeae

373

Bidens pilosa roots

Compositae

399

Zanthoxylum bungeanum pericarps Punica granatum bark Bidens pilosa var. radiata aerial parts Bidens leucantha leaves

Rutaceae Punicaceae Compositae Compositae

394 400 401 365 continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 772 6.10.2005 10:36am

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Flavonoids: Chemistry, Biochemistry, and Applications

TABLE 13.2 New Flavonol Glycosides — continued Glycoside

Source

Family

Ref.

G

7-(2 -Rhamnosylrutinoside) 7-(2G-Glucosylrutinoside) Quercetin 7,3’-dimethyl ether (rhamnazin) 3-Glucosyl(1 ! 5)-a-L-arabinofuranoside 3-Xylosyl(1 ! 2)glucoside 3-Glucosyl(1 ! 5)[apiosyl(1 ! 2)-a-Larabinofuranoside] Quercetin 7,4’-dimethyl ether (ombuin) 3-Arabinofuranoside 3-Glucoside Quercetin 3’,4’-dimethyl ether 3-Neohesperidoside 3,7-Diglucoside Quercetin 3,7,4’-trimethyl ether 3-Sulfate Quercetin 5,3’,4’-trimethyl ether 3-Galactosyl(1 ! 2)rhamnoside-7-rhamnoside Quercetin 5,7,3’,4’-tetramethyl ether 3-Galactoside 6-Hydroxyquercetin (quercetagetin) 6-Glucoside 7-(6’’-Isobutyrylglucoside) 7-(6’’-Isovalerylglucoside) 7-[6’’-(2-Methylbutyryl)glucoside] 7-(6’’-E-Caffeoylglucoside) 7-(6’’-Acetylglucoside) Quercetagetin 6-methyl ether (patuletin) 3,7-Diglucoside 3-(6’’-p-Coumaroylglucoside)

3-(6’’-E-Feruloylglucoside) 7-(6’’-Isobutyrylglucoside) 7-[6’’-(2-Methylbutyryl)glucoside] 7-(6’’-Isovalerylglucoside) 3-Rhamnoside-7-(2’’-acetylrhamnoside) 3-(4’’-Acetylrhamnoside)-7-rhamnoside 3-(4’’-Acetylrhamnoside)-7-(2’’’-acetylrhamnoside) 3-(2’’-Feruloylglucosyl)(1 ! 6) [apiosyl(1 ! 2)glucoside] Quercetagetin 7-methyl ether 6-Glucoside 4’-Glucoside

Retama sphaerocarpa aerial parts Albizzia julibrissin seeds Retama sphaerocarpa aerial parts

Leguminosae Leguminosae Leguminosae

402 403 404

Coccinia indica roots Gynostemma yixingense

Cucurbitaceae Cucurbitaceae

405 406

Crotalaria verrucosa stems Calamintha grandiflora leaves and flowers

Leguminosae Labiatae

407 408

Ipomoea regnelli

Convolvulaceae

373

Alhagi persarum aerial parts

Leguminosae

409

Sesbania aculeata

Leguminosae

410

Tagetes mandonii aerial parts Buphthalmum salicifolium flowers

Compositae Compositae

411 412

Eupatorium glandulosum leaves

Compositae

413

Arnica montana flowers Paepalanthus polyanthus, P. hilairei, P. robustus, P. ramosus, and P. denudatus capitulae Paepalanthus polyanthus aerial parts Buphthalmum salicifolium flowers Inula britannica flowers Inula britannica flowers

Compositae Eriocaulaceae

299 297

Eriocaulaceae Compositae Compositae Compositae

414 412 415 415

Kalanchoe brasiliensis stems and leaves

Crassulaceae

416

Spinacia oleracea leaves

Chenopodiaceae

417

Tagetes mandonii aerial parts Paepalanthus latipes leaves and scapes

Compositae Eriocaulaceae

418 419

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 773 6.10.2005 10:36am

773

Flavone and Flavonol O-Glycosides

TABLE 13.2 New Flavonol Glycosides — continued Glycoside 3-Neohesperidoside 3-Cellobioside 3-(2’’’-Caffeoylglucosyl)(1 ! 2)glucuronide Quercetagetin 3,6-dimethyl ether (axillarin) 5-a-L-Arabinosyl(1 ! 6)glucoside 7-Sulfate Quercetagetin 6,3’-dimethyl ether (spinacetin) 3-(2’’-Apiosylgentiobioside) 3-(2’’’-Feruloylgentiobioside) 3-(2’’-p-Coumaroylglucosyl)(1 ! 6) [apiosyl(1 ! 2)glucoside] 3-(2’’-Feruloylglucosyl)(1 ! 6) [apiosyl(1 ! 2)glucoside] Quercetagetin 7,3’-dimethyl ether 6-Glucoside Quercetagetin 3,6,3’-trimethyl ether (jaceidin) 5-Glucoside Quercetagetin 6,7,3’-trimethyl ether (veronicafolin) 3-Glucosyl(1 ! 3)galactoside Quercetagetin 6,3’,4’-trimethyl ether 3-Glucoside 8-Hydroxyquercetin (gossypetin) 8-a-D-Lyxopyranoside Gossypetin 8-methyl ether 3-Xylosyl(1 ! 2)rhamnoside Gossypetin 3,8-dimethyl ether 5-Glucoside Gossypetin 7,8-dimethyl ether 3-Glucoside 4’-Glucoside 3,3’-Disulfate Gossypetin 8,3’-dimethyl ether (limocitrin) 3-Rutinoside-7-glucoside 3,5,7,3’,4’,5’-Hexahydroxyflavone (myricetin) 3’-Rhamnoside 3-Xylosyl(1 ! 3)rhamnoside 3-Rhamnosyl(1 ! 2)rhamnoside 3-Neohesperidoside 3-Robinobioside 3-Rhamnoside-3’-glucoside 3-Galactoside-3’-rhamnoside 3,4’-Dirhamnoside 3,4’-Diglucoside 3-Rhamnosyl(1 ! 3)glucosyl(1 ! 6)glucoside

Source

Family

Ref.

Eriocaulaceae

419

Eriocaulaceae

419

Eriocaulaceae

419

Acacia catechu stems Centaurea bracteata roots

Legumnosae Compositae

420 421

Spinacia oleracea leaves

Chenopodiaceae

417

Tagetes mandonii aerial parts

Compositae

418

Eucryphia glutinosa twigs

Eucryphiaceae

397

Eupatorium africanum

Compositae

23

Arnica montana

Compositae

299

Orostachys japonicus aerial parts

Crassulaceae

422

Butea superba stems

Leguminosae

423

Eugenia edulis leaves

Myrtaceae

424

Erica cinerea flowers

Ericaceae

425

Erica cinerea flowers

Ericaceae

426

Coleogyne ramosissima aerial parts

Rosaceae

389

Davilla flexuosa leaves Maesa lanceolata leaves Licania densiflora leaves Physalis angulata leaves Nymphae´a  Marliacea leaves Myrsine seguinii leaves Buchanania lanzan leaves Myrsine seguinii leaves Picea abies needles Oxytropis glabra

Dilleniaceae Myrsinaceae Chrysobalanaceae Solanaceae Nymphaceae Myrsinaceae Anacardiaceae Myrsinaceae Pinaceae Leguminosae

427 326 428 429 430 318 431 318 432 433

Paepalanthus vellozioides leaves and scapes Paepalanthus latipes and P. vellozioides leaves and scapes Paepalanthus latipes leaves and scapes

continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 774 6.10.2005 10:36am

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Flavonoids: Chemistry, Biochemistry, and Applications

TABLE 13.2 New Flavonol Glycosides — continued Glycoside G

3-(2 -Rhamnosylrutinoside) 3-Glucosyl(1 ! 2)rhamnoside-7-glucoside

3-(4’’-Malonylrhamnoside) 3-(2’’-p-Hydroxybenzoylrhamnoside) 3-(3’’-Galloylrhamnoside) 3-(3’’-Galloylgalactoside) 3-(2’’-Galloylglucoside) 3-(6’’-p-Coumaroylglucoside) Nympholide A

Source

Family

Ref.

Clitoria ternatea petals Crocus chrysanthus-biflorus cvs ‘‘eye catcher’’ and ‘‘spring pearl’’ flowers Ribes alpinum leaves Limonium sinense aerial parts Myrica esculenta bark

Leguminosae Iridaceae

244 204

Grossulariaceae Plumbaginaceae Myricaceae

330 434 435

Geranium pratense aerial parts Nymphae´a lotus leaves

Geraniaceae Nymphaeaceae

436 437

Nymphae´a caerulea blue flowers Eugenia jambola leaves Acacia farnesiana pods Acacia confusa leaves Myrsine africana leaves Maesa lanceolata leaves Eugenia jambolana leaves Maesa lanceolata leaves

Nymphaeaceae Myrtaceae Leguminosae Leguminosae Myrsinaceae Myrsinaceae Myrtaceae Myrsinaceae

333 438 336 439 440 326 441 326

Acacia confusa leaves

Leguminosae

439

Lysimachia congestiflora whole plant

Primulaceae

442

CH2

HO

O

HO O

HO

O

O

OH OH

H HO

O OH OH OH

O

13.7 CH2

Nympholide B

HO

O

HO O

HO

O

O

OH OH

H HO

O OH OH OH

O

13.8 3-(2’’-Acetylrhamnoside) 3-(4’’-Acetylrhamnoside) 7-(6’’-Galloylglucoside) 3-(2’’,3’’-Digalloylrhamnoside) 3-(3’’,4’’-Diacetylrhamnoside) 3-(2’’,3’’,4’’-Triacetylxyloside) 3-(4’’-Acetyl-2’’-galloylrhamnoside) 3-(3’’’-6’’’-Diacetylglucosyl)(1 ! 4) (2’’,3’’-diacetylrhamnoside) Myricetin 7-methyl ether 3-(2’’-Galloylrhamnoside) 3-(3’’-Galloylrhamnoside) Myricetin 3’-methyl ether (larycitrin) 3-a-L-Arabinofuranoside

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 775 6.10.2005 10:36am

775

Flavone and Flavonol O-Glycosides

TABLE 13.2 New Flavonol Glycosides — continued Glycoside 3-(4’’-Malonylrhamnoside) Myricetin 4’-methyl ether 3-Galactoside 3-(4’’-Acetylrhamnoside) Myricetin 3’,4’-dimethyl ether 3-Rhamnoside 3-Glucoside Myricetin 3’,5’-dimethyl ether (syringetin) 3-Rhamnosyl(1 ! 5)-a-L-arabinofuranoside 3-Robinobioside 3-(2’’,3’’-Diacetylglucoside) 3-(6’’-Acetylglucosyl)(1 ! 3)galactoside 8-Hydroxymyricetin 8-methyl ether 3-Rhamnoside 8-Hydroxymyricetin 8,5’-dimethyl ether 3-Rhamnoside 8-Hydroxymyricetin 8,3’,5’-trimethyl ether 3-Rhamnoside 3,7,3’,4’,5’-Pentalhydroxyflavone (5-deoxymyricetin, robinetin) 7-Glucoside 3-Rutinoside 3,4’-Dihydroxy-7,3’,5’-trimethoxyflavone 3-Galactosyl(1 ! 4)xyloside 5,7,8-Trihydroxy-3,6,4’-trimethoxyflavone 8-Tiglate (pratensin A) 3,5,2’-Trihydroxy-7,8,4’-trimethoxyflavone 5-Glucosyl(1 ! 2)galactoside 3,5,6,7,8,4’-Hexahydroxy-3’-methoxyflavone 3-Rhamnosyl(1 ! 4)rhamnosyl(1 ! 6)glucoside 3,5,7,4’-Tetrahydroxy-6,8,3’-trimethoxyflavone 3-a-L-Arabinopyranosyl(1 ! 3)galactoside 3-a-L-Arabinopyranosyl(1 ! 3)[galactosyl (1 ! 6)galactoside] 3,6,7,8,3’,4’-Hexahydroxy-5’-methoxyflavone 7-Neohesperidoside 5,7,2’,3’,4’-Pentahydroxy-3,6-dimethoxyflavone 7-Glucoside 5,2’-Dihydroxy-3,6,7,4’,5’-pentamethoxyflavone (brickellin) 2’-Glucoside 3,5,7,2’,6’-Pentahydroxyflavone 2’-Glucoside 5,7-Dihydroxy-3,6,8,4’-tetramethoxyflavone 7-Glucosyl(1 ! 3)galactoside 7,4’-Dihydroxy-3,5,6,8-tetramethoxyflavone 4’-Glucosyl(1 ! 3)galactoside

Source

Family

Ref.

Ribes alpinum leaves

Grossulariaceae

330

Licania heteromorpha var. heteromorpha aerial parts Eugenia jambolana leaves

Chrysobalanaceae

443

Myrtaceae

441

Clausena excavata aerial parts Licania densiflora

Rutaceae Chrysobalanaceae

444 429

Lysimachia congestiflora whole plant Catharanthus roseus stems Warburgia stuhlmannii leaves Achlys triphylla underground parts

Primulaceae Apocynaceae Canellaceae Berberidaceae

442 445 391 382

Erica verticillata aerial parts

Ericaceae

446

Erica verticillata aerial parts

Ericaceae

446

Erica verticillata aerial parts

Ericaceae

446

Alternanthera sessilis Ateleia Herbert-smithii leaves

Amaranthaceae Leguminosae

447 448

Abrus precatorius seeds

Leguminosae

449

Galeana pratensis aerial parts

Compositae

450

Cassia occidentalis whole plant

Leguminosae

451

Eschsholtzia californica aerial parts

Papaveraceae

452

Pongamia pinnata heartwood

Leguminosae

453

Hibiscus vitifolius

Malvaceae

454

Tridax procumbens aerial parts

Compositae

455

Chrysosplenium grayanum

Saxifragaceae

456

Scutellaria amoena roots

Labiatae

457

Aspilia africana whole plant

Compositae

458

Centaurea senegalensis whole plant

Compositae

459 continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 776 6.10.2005 10:36am

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Flavonoids: Chemistry, Biochemistry, and Applications

TABLE 13.2 New Flavonol Glycosides — continued Glycoside 5,8-Dihydroxy-3,6,7,4’-tetramethoxyflavone 8-Neohesperidoside 5,4’-Dihydroxy-6,7,8,3’-tetramethoxyflavone (africanutin) 4’-Galactoside 3,5,7,2’,3’,4’-Hexahydroxyflavone 3-Glucoside 5,7,2’-Trihydroxy-3,6,4’-trimethoxyflavone 7-Glucoside 5,2’,4’-Trihydroxy-3,7,5’-trimethoxyflavone 2’-Galactosyl(1 ! 4)glucoside Methylenedioxyflavonol glycosides 3-Methoxy-5-hydroxy-6,7-methylenedioxyflavone 4’-Glucuronide 3-Hydroxy-5,4’-dimethoxy-6,7-methylenedioxyflavone 3-Xyloside (viviparum A) 3,3’-Dihydroxy-5,4’-dimethoxy-6,7methylenedioxyflavone 3-Xyloside (viviparum B) Prenyl- and pyranoflavonol glycosides 8-Prenylkaempferol[noranhydroicaritin, 3,5,7,4’tetrahydroxy-8-(3’’,3’’-dimethylallyl)flavone] 3,7-Diglucoside 8-Prenylkaempferol 7-methyl ether 3-Rhamnosyl(1 ! 3)[apiosyl(1 ! 6)glucoside] 8-Prenylkaempferol 4’-methyl ether (anhydroicarinin) 7-Glucosyl(1 ! 4)glucoside (cuhuoside, 7-cellobioside) 3-Rhamnosyl(1 ! 6)galactoside-7-galactoside 3-Glucosyl(1 ! 3)rhamnoside-7-glucoside

Source

Family

Ref.

Peperomia pellucida

Piperaceae

460

Eupatorium africanum whole plant Eupatorium sternbergianum whole plant

Compositae

23

Compositae

461

Tridax procumbens whole plant

Compositae

462

Albizzia procera stems

Leguminosae

463

Spinacia oleracea leaves

Chenopodiaceae 464

Polygonum viviparum

Polygonaceae

465

Polygonum viviparum

Polygonaceae

465

Vancouveria hexandra underground and aerial parts

Berberidaceae

466

Mosla soochouensis stem wood

Labiatae

278

Epimedium acuminatum Sesbania grandiflora bark Vancouveria hexandra underground and aerial parts Epimedium acuminatum aerial parts Berberis dictyota aerial parts Epimedium koreanum aerial parts

Berberidaceae Leguminosae Berberidaceae

467 468 466

Berberidaceae

469

Berberidaceae Berberidaceae

470 471

Berberidaceae

472

Berberidaceae

473

Berberidaceae

474

Berberidaceae

475

3-Rhamnosyl(1 ! 2)rhamnoside-7-sophoroside (acuminatoside) 3-[4’’’-,6’’’-Diacetylglucosyl(1 ! 3)-4’’-acetylrhamnoside] 3-[2’’’,6’’’-Diacetylglucosyl(1 ! 3)-4’’-acetylrhamnoside]7-glucoside (epimedin K) 3’’-[4’’’,6’’’-Diacetylglucosyl(1 ! 3)-4’’-acetylrhamnoside]- Epimedium koreanum aerial parts 7-glucoside 8-(3’’-Hydroxy-3’’-methylbutyl)kaempferol 4’-methyl ether (icaritin) 3-Rhamnosyl(1 ! 2)rhamnoside (wanepimedoside A) Epimedium wanshanense whole plant 8-(g-Methoxy-gg-dimethyl)propylkaempferol 4’-methyl ether 7-Glucoside (caohuoside D) Epimedium koreanum aerial parts 8-Prenylquercetin 4’-methyl ether 3-Rhamnoside (caohuoside C) Epimedium koreanum aerial parts

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 777 6.10.2005 10:36am

777

Flavone and Flavonol O-Glycosides

TABLE 13.2 New Flavonol Glycosides — continued Glycoside

Source

8-Prenylquercetin 7,4’-dimethyl ether 3-Rhamnosyl(1 ! 4)rhamnoside 6’’,6’’-Dimethylpyrano(2’’,3’’:7,8)-4’-methoxykaempferol 3-Rhamnoside C-Methylated flavonol glycosides 5,7-Dihydroxy-6,8-di-C-methyl-3-methoxyflavone 7-Galactosyl(1 ! 2)rhamnoside 2’-C-Methylmyricetin 3-Rhamnoside-5’-gallate

Family

Ref.

Butea monosperma stems

Leguminosae

476

Epimedium acuminatum

Berberidaceae

477

Cotula anthemoides seeds Syzygium samarangense leaves

478 Myrtaceae

479

All the other new disaccharides are new isomers of known sugar combinations. Among the pentose–pentose sugars are three rhamnosylarabinoses. A rhamnosyl(1 ! 2)arabinose was listed in the fourth edition of The Flavonoids5 but no details of form or stereochemistry were given. The new sugars include a rhamnosyl(1 ! 2)-a-L-arabinopyranose, which was identified in the aerial parts of Putoria calabrica (Rubiaceae)324 in combination with quercetin at the 3-hydroxyl and its furanose isomer at the 3-hydroxyl of kaempferol in leaves of Artabotrys hexapetalus (Annonaceae).173 The report of myricetin 3’,5’-dimethyl ether (syringetin) 3-rhamnosyl(1 ! 5)arabinofuranoside from the whole plant of Lysimachia congestiflora442 provides the third new isomer. Xylosyl(1 ! 4)rhamnose, found at the 3-position of kaempferol with rhamnose at the 7-hydroxyl in Chenopodium murale,198 is an expectable new isomer of the known 1 ! 2 and 1 ! 3 linked sugars. There are three new isomers of pentose–hexose disaccharides in Table 13.4. These include a-L-arabinopyranosyl(1 ! 3)galactose found in combination with 3,5,7,4’-tetrahydroxy6,8,3’-flavone at the 3-hydroxyl in the heartwood of the legume, Pongamia pinnata.453 Lathyrose, xylosyl(1 ! 6)galactose was found in a member of the Anacardiaceae, Semecarpus kurzii,60 at the 7-hydroxyl of scutellarein (6-hydroxyapigenin). The third new isomer in this

TABLE 13.3 Monosaccharides of Flavone and Flavonol Glycosides Pentoses

Hexoses

D-Apiose

Uronic Acids acida a D-Glucuronic acid

D-Allose b

D-Galacturonic

c,d

L-Arabinose c D-Fructose c D-Lyxose

D-Allulose c D-Fucose

L-Rhamnose

D-Glucosamine

D-Xylose

D-Glucose

D-Galactose c

D-Mannose a

Also reported to occur as the methyl and ethyl ethers. Known to occur in both pyranose and furanose forms; all other sugars (except apiose, fructose, and allulose) are normally in the pyranose form. c Newly reported since 1992. d Recorded as D-allulose but preferred name is D-psicose or D-ribo-2-hexulose. b

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 778 6.10.2005 10:36am

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Flavonoids: Chemistry, Biochemistry, and Applications

group is apiosyl(1 ! 6)glucose found at the 7-position of three different flavones: luteolin and its 3’-methyl ether (chrysoeriol) in Phlomis nissolii (Labiatae)96 and acacetin (apigenin 4’methyl ether) in Crotalaria podocarpa (Leguminosae).53 There are two further new hexose– pentoses: glucosyl(1 ! 4)xylose has been isolated at the 7-hydroxyl of kaempferol from Crotalaria laburnifolia178 and galactosyl(1 ! 2)rhamnose at the 3-position of quercetin from Embelia schimperi (Myrsinaceae).313 Noteworthy is the first record of the hexose–hexose, cellobiose (glucosyl(1 ! 4)glucose) from Epimedium acuminatum,467 which was present at the 7-hydroxyl of 8-prenylkaempferol 4’-methyl ether. Cellobiose has the same sugar linkage as cellulose and has been found in a further four families in combination with two flavones and two flavonols during the review period. Thus, 6-hydroxyluteolin 5,6,3’,4’-tetramethyl ether 7cellobioside has been isolated from stems of the Composite Sphaeranthus indicus136 and apigenin 7-cellobioside and 7-cellobioside-4’-glucoside from petals of Salvia uliginosa (Labiatae).35 Quercetagetin 3-cellobioside has been reported in stems and scapes of Paepalanthus latipes and P. vellozioides,419 from the monocot family Velloziaceae. Kaempferol 3-sophoroside-7-cellobioside and three acylated kaempferol 3-diglycosides, the 3-(2-E-caffeoylsophoroside)-7-cellobioside and the corresponding feruoyl and sinapoyl isomers, were found in leaves of Brassica oleracea (Cruciferae).217 Two further glucosylgalactose isomers are listed in Table 13.4. Glucosyl(1 ! 3)galactose was present in underground parts of Achlys triphylla (Berberidaceae),382 in acetylated form attached to the 3-hydroxyls of both isorhamnetin and syringetin, while its 1 ! 4 isomer was found at the 3-hydroxyl of quercetin in leaves of Rumex chalepensis (Polygonaceae).316

TABLE 13.4 Disaccharides of Flavone and Flavonol Glycosides Structure

Trivial Name

Pentose–pentose O-b-D-Xylosyl(1 ! 2)xylosea,66 O-b-D-Xylosyl(1 ! 3)xylosea,159 O-a-L-Apiofuranosyl(1 ! 2)xylose O-a-L-Apiofuranosyl(1 ! 4)rhamnosea,198 O-a-L-Rhamnosyl(1 ! 5)arabinofuranosea,442 O-a-L-Rhamnosyl(1 ! 2)-a-L-arabinopyranosea,324 O-a-L-Rhamnosyl(1 ! 2)-a-L-arabinofuranosea,b,173 O-a-L-Rhamnosyl(1 ! 2)rhamnose O-a-L-Rhamnosyl(1 ! 3)rhamnose O-a-L-Rhamnosyl(1 ! 4)rhamnose O-a-L-Rhamnosyl(1 ! 4)xylose O-b-D-Xylosyl(1 ! 2)rhamnose O-b-D-Xylosyl(1 ! 3)rhamnose O-b-D-Xylosyl(1 ! 4)rhamnosea,198 Pentose–hexose O-a-L-Arabinosyl(1 ! 6)glucose O-a-L-Arabinopyranosyl(1 ! 3)galactosea,453 O-a-D-Arabinosyl(1 ! 6)galactose O-b-D-Xylosyl(1 ! 2)glucose O-b-D-Xylosyl(1 ! 6)glucose O-b-D-Xylosyl(1 ! 2)galactose O-b-D-Xylosyl(1 ! 6)galactosea,60 O-b-D-Apiosyl(1 ! 2)glucose

Vicianose

Sambubiose

Lathyrose

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TABLE 13.4 Disaccharides of Flavone and Flavonol Glycosides — continued Structure

Trivial Name a,53,96

O-b-D-Apiosyl(1 ! 6)glucose O-b-D-Apiosyl(1 ! 2)galactose O-a-L-Rhamnosyl(1 ! 2)glucose O-a-L-Rhamnosyl(1 ! 3)glucose O-a-L-Rhamnosyl(1 ! 6)glucose O-a-L-Rhamnosyl(1 ! 2)galactose O-a-L-Rhamnosyl(1 ! 6)galactose O-a-L-Rhamnosyl(1 ! 2)fucosea,26

Neohesperidose Rungiose Rutinose Robinobiose

Hexose–pentose O-b-D-Glucosyl(1 ! 2)-b-arabinopyranosea,357 O-b-D-Glucosyl(1 ! 2)-a-L-arabinofuranosea,c,340 O-b-D-Glucosyl(1 ! 3)-a-L-arabinopyranosea,164 O-b-D-Glucosyl(1 ! 4)-a-L-arabinopyranosea,94 O-b-D-Glucosyl(1 ! 5)-a-L-arabinofuranosea,402 O-b-D-Glucosyl(1 ! 2)rhamnose O-b-D-Glucosyl(1 ! 3)rhamnose O-a-L-Glucosyl(1 ! 4)rhamnose O-b-D-Glucosyl(1 ! 2)xylose O-b-D-Glucosyl(1 ! 4)xylosea,178 O-b-D-Galactosyl(1 ! 2)rhamnosea,313 O-b-D-Galactosyl(1 ! 3)rhamnose O-b-D-Galactosyl(1 ! 4)rhamnose Hexose–hexose O-b-D-Glucosyl(1 ! 2)glucose O-b-D-Glucosyl(1 ! 3)glucose O-b-D-Glucosyl(1 ! 4)glucosea,467 O-b-D-Glucosyl(1 ! 6)glucose O-b-D-Glucosyl(1 ! 2)galactose O-b-D-Glucosyl(1 ! 3)galactosea,382 O-b-D-Glucosyl(1 ! 4)galactosea,316 O-b-D-Galactosyl(1 ! 4)glucose O-b-D-Galactosyl(1 ! 6)glucose O-b-D-Galactosyl(1 ! 4)galactose O-b-D-Galactosyl(1 ! 6)galactose O-b-D-Allosyl(1 ! 2)glucose O-b-D-Mannosyl(1 ! 2)allose

Sophorose Laminaribiose Cellobiose Gentiobiose

Lactose

Pentose–uronic acid O-a-L-Rhamnosyl(1 ! 2)galacturonic acid Uronic acid–uronic acid O-b-D-Glucuronosyl(1 ! 2)glucuronic acid a

Disaccharides newly reported since 1992 with reference number. Except where otherwise stated, sugars are assumed to be in the pyranose form and to have the appropriate linkage, i.e., b for glucosides, a for rhamnosides, etc. b Reported only at the 3-hydroxyl of quercetin with glucose at the 7-position. c Reported only in acylated form.

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TABLE 13.5 Trisaccharides of Flavonol Glycosides Structure Linear O-b-Glucosyl(1 ! 4)-O-a-arabinofuranosyl(1 ! 2)arabinopyranose O-b-D-Xylosyl(1 ! 2)-O-a-L-rhamnosyl(1 ! 6)glucosea,319 O-b-D-Xylosyl(1 ! 3)-O-a-L-rhamnosyl(1 ! 6)glucosea,384 O-b-D-Xylosyl(1 ! 6)-O-b-D-glucosyl(1 ! 2)rhamnosea,187 O-b-D-Xylosyl(1 ! 3)-O-a-L-rhamnosyl(1 ! 6)galactosea,186 O-a-L-Rhamnosyl(1 ! 3)-O-a-L-rhamnosyl(1 ! 3)rhamnosea,b,273 O-a-L-Rhamnosyl(1 ! 2)-O-a-L-rhamnosyl(1 ! 6)glucose O-a-L-Rhamnosyl(1 ! 3)-O-a-L-rhamnosyl(1 ! 6)glucosea,188 O-a-L-Rhamnosyl(1 ! 4)-O-a-L-rhamnosyl(1 ! 6)glucosec O-a-L-Rhamnosyl(1 ! 2)-O-b-D-glucosyl(1 ! 3)glucose O-a-L-Rhamnosyl(1 ! 3)-O-b-D-glucosyl(1 ! 6)glucosea,433 O-b-D-Glucosyl(1 ! 3)-O-a-L-rhamnosyl(1 ! 6)glucose O-b-D-Glucosyl(1 ! 4)-O-a-L-rhamnosyl(1 ! 2)glucosea,191 O-b-D-Glucosyl(1 ! 2)-O-b-D-glucosyl(1 ! 2)rhamnose O-b-D-Glucosyl(1 ! 6)-O-b-D-glucosyl(1 ! 4)rhamnose O-b-D-Glucosyl(1 ! 2)-O-b-D-glucosyl(1 ! 2)glucose O-b-D-Glucosyl(1 ! 2)-O-b-D-glucosyl(1 ! 6)glucose O-b-D-Glucosyl(1 ! 4)-O-b-D-glucosyl(1 ! 6)glucose O-b-D-Glucosyl(1 ! 6)-O-b-D-glucosyl(1 ! 4)glucose O-a-L-Rhamnosyl(1 ! 3)-O-a-L-rhamnosyl(1 ! 6)galactose O-a-L-Rhamnosyl(1 ! 4)-O-a-L-rhamnosyl(1 ! 6)galactose O-a-L-Rhamnosyl(1 ! 2)-O-b-D-glucosyl(1 ! 6)galactosea,189 O-a-L-Rhamnosyl(1 ! 6)-O-b-D-glucosyl(1 ! 6)galactosea,190 O-b-D-Glucosyl(1 ! 3)-O-a-L-rhamnosyl(1 ! 6)galactosed O-b-D-Glucosyl(1 ! 2)-O-b-D-galactosyl(1 ! 2)glucosea,192 Branched O-a-L-Arabinopyranosyl(1 ! 3)-O-[b-D-galactosyl(1 ! 6)galactose]a,453 O-b-D-Apiosyl(1 ! 2)-O-[a-L-rhamnosyl(1 ! 4)glucose] O-b-D-Apiosyl(1 ! 2)-O-[a-L-rhamnosyl(1 ! 6)galactose] O-b-D-Glucosyl(1 ! 5)-O-[b-D-apiosyl(1 ! 2)-a-L-arabinofuranose]a,404 O-a-L-Rhamnosyl(1 ! 3)-O-[b-D-apiosyl(1 ! 6)glucose]a,278 O-b-D-Xylosyl(1 ! 2)-O-[a-L-rhamnosyl(1 ! 6)glucose] O-a-L-Rhamnosyl(1 ! 2)-O-[a-L-rhamnosyl(1 ! 6)glucose] O-a-L-Rhamnosyl(1 ! 4)-O-[a-L-rhamnosyl(1 ! 2)glucose] O-b-D-Glucosyl(1 ! 2)-O-[b-D-apiosyl(1 ! 2)glucose] O-a-L-Rhamnosyl(1 ! 6)-O-[b-D-glucosyl(1 ! 2)glucose] O-a-L-Rhamnosyl(1 ! 2)-O-[b-D-glucosyl(1 ! 4)glucose]a,194 O-a-L-Rhamnosyl(1 ! 2)-O-[b-D-glucosyl(1 ! 6)glucose] O-b-D-Glucosyl(1 ! 2)-O-[a-L-rhamnosyl(1 ! 6)glucose] O-b-D-Glucosyl(1 ! 3)-O-[a-L-rhamnosyl(1 ! 2)glucose] O-b-D-Glucosyl(1 ! 2)-O-[b-D-glucosyl(1 ! 3)rhamnose]a,195 O-a-L-Rhamnosyl(1 ! 2)-O-[b-D-glucosyl(1 ! 6)galactose] O-b-D-Glucosyl(1 ! 2)-O-[a-L-rhamnosyl(1 ! 6)galactose] O-b-D-Galactosyl(1 ! 2)-O-[a-L-rhamnosyl(1 ! 6)glucose] O-b-D-Glucosyl(1 ! 2)-O-[b-D-glucosyl(1 ! 6)glucose]

Trivial Name

Primflasin

2’-Rhamnosylrutinoside

3’-Rhamnosyllaminaribiose 3’-Glucosylrutinoside

Sophorotriose 2’-Glucosylgentiobiose 6’-Maltosylglucose Sorborose Rhamninose Isorhamninose

Sugar of faralatroside

2G-Apiosylrutinose 2Gal-Apiosylrobinobiose

2G-Xylosylrutinose 2G-Rhamnosylrutinose 4G-Rhamnosylneohesperidose 6G-Rhamnosylsophorose 2G-Rhamnosylcellobiose 2G-Rhamnosylgentiobiose 2G-Glucosylrutinose 3G-Glucosylneohesperidose

2G-Glucosylrobinobiose 2G-Galactosylrutinose 2G-Glucosylgentiobiose

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TABLE 13.5 Trisaccharides of Flavonol Glycosides — continued Structure

Trivial Name a,196

O-b-D-Glucosyl(1 ! 3)-O-[b-D-glucosyl(1 ! 6)glucose] O-a-L-Rhamnosyl(1 ! 2)-O-[a-L-rhamnosyl(1 ! 6)galactose] O-a-L-Rhamnosyl(1 ! 4)-O-[a-L-rhamnosyl(1 ! 6)galactose] O-a-L-Rhamnosyl(1 ! 6)-O-[a-L-rhamnosyl(1 ! 2)galactose]a,220 O-b-D-Glucosyl(1 ! 4)-O-[b-D-glucosyl(1 ! 2)galactose]a,e,249

G

3 -Glucosylgentiobiose 2Gal-Rhamnosylrobinobiose 4Gal-Rhamnosylrobinobiose

a

Newly reported since 1992 with reference number. Present at the 7-position of kaempferol with a p-coumaric acid attached at the 4-hydroxyl of the first rhamnose and a known acylated branched trisaccharide at the 3-hydroxyl of the aglycone. c Only present with a caffeyl or p-coumaryl group at the 6-hydroxyl of the second glucose. d Only present with an acetyl group at the 4-hydroxyl of the rhamnose. e Present at the 3-hydroxyl of kaempferol in mono- or diacylated form with sinapic acid. b

13.3.3 TRISACCHARIDES Some 11 new linear and 8 new branched trisaccarides have been discovered in combination with flavonols since 1992. These are presented in Table 13.5 together with previously known trisaccharides. Among the linear trisaccharides are seven novel sugar combinations. The most interesting are four structures with xylose as the terminal sugar. The only previously known trisaccharide containing xylose is the branched sugar, 2G-xylosylrutinose. The linear trisaccharide, xylosyl(1 ! 2)rhamnosyl(1 ! 6)glucose was found attached to the 3-hydroxyl of quercetin in leaves of Camellia saluensis (Theaceae),319 while its isomer, xylosyl(1 ! 3)rham3)rhamnosyl(1 ! 6)glucose, was found at the 3-position of isorhamnetein in Hamada scoparia (Chenopodiaceae).384 The other two structures were both found in combination with kaempferol at the 3-position, xylosyl(1 ! 6)glucosyl(1 ! 2)rhamnose from Helicia nilagirica (Proteaceae)187 and xylosyl(1 ! 3)rhamnosyl(1 ! 6)galactose from the legume Astragalus caprinus.186 The former was also present in similar combination with quercetin. The first linear trirhamnose, rhamnosyl(1 ! 3)rhamnosyl(1 ! 3)rhamnose, has been recorded from

TABLE 13.6 Trisaccharides of Flavone Glycosides Structure

Trivial Name

Linear O-a-L-Rhamnosyl(1 ! 2)-O-b-D-glucosyl(1 ! 2)glucosea,51 O-b-D-Allosyl(1 ! 3)-O-b-D-glucosyl(1 ! 2)glucosea,110 Branched O-a-L-Rhamnosyl(1 ! 2)-O-[a-L-rhamnosyl(1 ! 6)galactose]b O-b-D-Glucosyl(1 ! 2)-O-[a-L-rhamnosyl(1 ! 6)glucose]b,c O-b-D-Apiosyl(1 ! 2)-O-[b-D-glucosyl(1 ! 4)glucose]a,c,109 O-b-D-Glucuronosyl(1 ! 3)-O-[b-D-glucuronosyl(1 ! 2)glucuronic acid]a,c,40,116 a

Newly reported trisaccharides with reference number. Found previously only attached to flavonols. c Present only in acylated form (see Table 13.1) b

2Gal-Rhamnosylrobinobiose 2G-Glucosylrutinose 2G-Apiosylcellobiose

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Planchonia grandis (Lecythidaceae).273 This sugar occurred at the 7-hydroxyl of kaempferol acylated with p-coumaric acid at the 4-position of the first rhamnose and with a known acylated branched trisaccharide at the 3-hydroxyl. Two further acylated kaempferol glycosides with known trisaccharides at both the 3- and 7-hydroxyls were also present in this plant. This is the first record of flavonol (or flavone) glycosides containing six sugars. The three other new linear combinations were isolated as kaempferol 3-rhamnosyl(1 ! 2)glucosyl (1 ! 6)galactoside from Cassia marginata,189 kaempferol and quercetin 3-rhamnosyl(1 ! 6) glucosyl(1 ! 6)galactoside from Albizia lebbeck190 (both legumes), and kaempferol and quercetin 3-glucosyl(1 ! 2)galactosyl(1 ! 2)glucosides from seeds of Nigella sativa (Ranunculaceae).192 The remaining new linear trisaccharides in Table 13.2: rhamnosyl(1 ! 3) rhamnosyl(1 ! 6)glucose,192 rhamnosyl(1 ! 3)glucosyl(1 ! 6)glucose,433 and glucosyl (1 ! 4)rhamnosyl(1 ! 2)glucose191 are all new isomers of known structures. Details will not be given here but these sugars are marked as new in Table 13.6 and with a reference number, which relates both to the main reference list and to the reference numbers in Table 13.2. Among the eight new branched trisaccharides are five new sugar combinations, including the first to contain arabinose. Thus, a-L-arabinopyranosyl(1 ! 3)[galactosyl(1 ! 6) galactose] was found at the 3-hydroxyl of 3,5,7,4’-tetrahydroxy-6,8,3’-trimethoxyflavone in the heartwood of Pongamia pinnata (Leguminosae)453 and glucosyl(1 ! 5)[apiosyl(1 ! 2)-aL-arabinofuranose] at the 3-hydroxyl of quercetin 7,3’-dimethyl ether in another legume, Retama sphaerocarpa.404 Another novel apiose containing sugar, rhamnosyl(1 ! 3)[apiosyl (1 ! 6)glucose], present at the 3-hydroxyls of kaempferol 7-methyl ether and 8-prenylrhamnetin, was isolated from stemwood of the Labiate, Mosla soochouensis.278 The remaining new combinations include kaempferol 3-glucosyl(1 ! 2)[glucosyl(1 ! 3)rhamnoside] from flowers of Crocus speciosus and C. antalyensis195 and glucosyl(1 ! 4)[glucosyl(1 ! 2)galactose], which was found attached to the 3-position of kaempferol in mono- and diacylated forms with sinapic acid, in Thevetia peruviana (Apocynaceae).249 Details of three new isomers of known sugar combinations, rhamnosyl(1 ! 2)[glucosyl(1 ! 4)glucose],194 glucosyl(1 ! 3)[glucosyl (1 ! 6)glucose],196 and rhamnosyl(1 ! 6)[rhamnosyl(1 ! 2)galactose]220 are given in Table 13.2 and Table 13.5. It is of some note that trisaccharides have been found in combination with flavones for the first time. Six structures have been identified since 1992; two linear and four branched trisaccharides are listed in Table 13.6. However, flavone trioses are still of rare occurrence compared with the large number of known flavonol trisaccharide combinations. Rhamnosyl(1 ! 2)glucosyl(1 ! 2)glucose was found at the 7-hydroxyl of acacetin in aerial parts of Peganum harmala (Zygophyllaceae)51 and allosyl(1 ! 3)glucosyl(1 ! 2)glucose, acetylated at the 6-position of the allose and attached to luteolin at the 7-hydroxyl, in Veronica didyma.110 These are both new trisaccharides that have not been found in association with flavonols. Two of the branched sugars are also novel structures, apiosyl(1 ! 2)[glucosyl(1 ! 4)glucose] and glucuronosyl(1 ! 3)[glucuronosyl(1 ! 2)glucuronic acid]. The former was discovered in fruits of Capsicum annum (Solanaceae)109 at the 7-hydroxyl of luteolin and the latter, in acylated form, attached to the 7-hydroxyls of apigenin,40 chrysoeriol,116 and tricin,116 in aerial parts of Medicago sativa (Leguminosae). The remaining two branched trisaccharides have been found previously in combination with flavonols.

13.3.4 TETRASACCHARIDES Only one branched tetrasaccharide was listed in the last edition of The Flavonoids:5 [rhamnosyl(1 ! 4)glucosyl(1 ! 6)]sophorose, which was present at the 7-hydroxyl of acacetin and acetylated at the 6’’-position of the sophorose in leaves of Peganum harmala (Zygophyllaceae).6 Since then some eight new branched tetrasaccharides have been reported, all attached

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783

to flavonols and all with unique sugar combinations. Details of the new structures together with the known tetrasaccharide are given in Table 13.7. No linear tetrasaccharide has yet been recorded. Apiosyl(1 ! 5)apiosyl[rhamnosyl(1 ! 6)glucose], which was found at the 7-hydroxyl of kaempferol 7-methyl ether in the mistletoe, Viscum angulatum,281 is the first report of any sugar to contain two linked apiose moieties. There are three new structures with xylose as the terminal sugar. Two were found in combination with quercetin at the 3-position. Thus, xylosyl(1 ! 3)rhamnosyl(1 ! 6)[apiosyl(1 ! 2)galactose] was present in leaves of Astragalus caprinus213 and xylosyl(1 ! 4)[xylosyl(1 ! 6)glucosyl(1 ! 2)rhamnose] in leaves of Helicia nilagirica.187 The third sugar, xylosyl(1 ! 2)[rhamnosyl(1 ! 2)rhamnosyl (1 ! 6)glucose], was attached to the 7-hydroxyl of both quercetin 3-methyl ether and 7-methyl ether in Bidens andicola (Compositae).322 Three of the remaining structures were found attached to the 3-hydroxyl of kaempferol. These are: glucosyl(1 ! 3)rhamnosyl(1 ! 2) [rhamnosyl(1 ! 6)galactose], which was isolated from leaves of Maytenus aquifolium,214 rhamnosyl(1 ! 2)[xylosyl(1 ! 3)rhamnosyl(1 ! 6)galactose] from leaves of Astragalus caprinus,213 and rhamnosyl(1 ! 2)[glucosyl(1 ! 3)rhamnosyl(1 ! 6)galactose] present in acylated form, together with the corresponding quercetin glycoside, in Lysimachia capillipes (Primulaceae).272 The eighth new sugar, rhamnosyl(1 ! 2)[gentiobiosyl(1 ! 6)glucose] was discovered at the 3-hydroxyl of isorhamnetin in Allium neapolitanum.191

13.3.5 SULFATE CONJUGATES Only a comparatively small number of new flavonoid sulfate conjugates have been recorded between 1993 and 2003. Eleven flavone derivatives are recorded in Table 13.1 and 15 flavonol derivatives in Table 13.2, mostly from plants that grow in water-stress conditions. Amongst the flavones the most notable are six sulfate conjugates discovered in some Australian species of the monocot family, the Restionaceae. These plants are unusual in having no true leaves so that the compounds were isolated from culm tissue. Four are hypolaetin (8-hydroxyluteolin) derivatives: the 7-sulfatoglucoside and 7-sulfatoglucuronide from Leptocarpus elegans,138 the 7-sulfatoglucuronide from Meeboldina thysanantha,138 and the 7-sulfate-8-glucoside from Hypolaena fastigiata.138 The other two flavone sulfates are hypolaetin 7-methyl ether 3’-sulfatogalactoside from Leptocarpus tenax138 and the corresponding 3’-sulfatoglucuronide

TABLE 13.7 Tetrasaccharides of Flavone and Flavonol O-Glycosides Structure Flavone tetrasaccharide [O-a-L-Rhamnosyl(1 ! 4)-O-b-D-glucosyl(1 ! 6)]-O-sophorose Flavonol tetrasaccharides O-b-D-Apiosyl(1 ! 5)-O-b-D-apiosyl(1 ! 2)-O-[a-L-rhamnosyl(1 ! 6)glucose]a O-b-D-Xylosyl(1 ! 3)-O-a-L-rhamnosyl(1 ! 6)-O-[b-D-apiosyl(1 ! 2)galactose]a O-b-D-Xylosyl(1 ! 4)-O-[b-D-xylosyl(1 ! 6)-O-b-D-glucosyl(1 ! 2)rhamnose]a O-b-D-Xylosyl(1 ! 2)-O-[a-L-rhamnosyl(1 ! 2)-O-a-L-rhamnosyl(1 ! 6)glucose]a O-a-L-Rhamnosyl(1 ! 2)-O-[b-D-xylosyl(1 ! 3)-O-a-L-rhamnosyl(1 ! 6)galactose]a,b O-a-L-Rhamnosyl(1 ! 2)-O-[b-D-glucosyl(1 ! 3)-O-a-L-rhamnosyl(1 ! 6)galactose]a,b O-b-D-Glucosyl(1 ! 3)-O-a-L-rhamnosyl(1 ! 2)-O-[a-L-rhamnosyl(1 ! 6)galactose]a O-a-L-Rhamnosyl(1 ! 2)[gentiobiosyl(1 ! 6)glucose]a a

Newly reported since 1992. Present only in acylated form.

b

Ref.

6 281 213 187 322 213 272 214 191

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from L. elegans.138 Flavonoid sulfates were found to be characteristic constituents of the Restionaceae being detected in 27% of the 115 taxa surveyed. The first report of a sulfate 2’’linked to glucose is from the water plant, Thalassia testudinum,111 another monocot, where it is found in association with luteolin at the 7-position. The other flavone sulfates are 8hydroxyapigenin (isoscutellarein) 8-(2’’-sulfatoglucuronide)81 and 8-(2’’,4’’-disulfatoglucuronide) and the corresponding isoscutellarein 4’-methyl ether conjugates from fruits of Helicteres isora (Sterculiaceae).82 Among the more interesting new flavonol conjugates are three sulfates linked directly to the aglycone via a carbon rather than an oxygen atom. Compounds such as these have previously only been recorded from synthesis. Thus, galangin 3-glucoside-8-C-sulfate and 8-C-sulfate and kaempferol 8-C-sulfate have been characterized from a whole plant extract of Phyllanthus virgatus,165 a member of the Euphorbiaceae. Two new sulfated flavonols recorded from Centaurea bracteata275 are quercetin 3-glucoside-3’-sulfate and quercetagetin (6-hydroxyquercetin) 3,6-dimethyl ether 7-sulfate. Another quercetin conjugate, the 3-rhamnoside-3’-sulfate, has been isolated from leaves of Leea guineensis (Leeaceae),361 a monogeneric family close to the vines (Vitaceae). Quercetin 7-methyl ether 3,3’-disulfate from roots of Argyreia mollis373 and quercetin 3,7-dimethyl ether 4’-sulfate and quercetin 3,7,4’-trimethyl ether 3-sulfate from aerial parts of Ipomoea regnelli373 are the first sulfated flavonoids to be isolated from Convolulaceae species. Most of the other new flavonol sulfates are all single family occurrences: quercetin 7,4’-disulfate from Alchornea laxiflora,362 another member of the Euphorbiaceae, and the 3,3’,4’-trisulfate from leaves of Tamarix amplexicaulis (Tamarixaceae),374 isorhamnetin 3-(4’’-sulfatorutinoside) from aerial parts of Zygophyllum dumosum (Zygophyllaceae),392 quercetin 4’-methyl ether 3-glucoside-7-sulfate from Polygonum hydropiper (Polygonaceae)396 leaves, and gossypetin 7,8-dimethyl ether 3,3’-disulfate from flowers of the bell heather, Erica cinerea (Ericaceae).426 The structure of quercetin 5-glucoside-3’-

TABLE 13.8 Acylating Acids and Alcohol and a Lignan Found in Flavone and Flavonol Derivatives Aliphatic Acids and Alcohol Acetic Malonic Lactic (2-hydroxypropionic) Vinylpropionica, 341 Succinic Butyric Isobutyric 3-Methylbutyric Crotonic (E-2-butenoic) 2-Methyl-2-butenoic n-Butanoica, 335 Isovaleric (isopentanoic)a, 412, 417 Tiglic (E-2-methyl-2-butenoic) 3-Hydroxy-3-methylglutaric Quinic 4-Hydroxy-3-methoxyphenyl-1, 3-dihydroxypropan-2-ola, 240 a

Aromatic Acids Benzoic p-Hydroxybenzoic Gallic Cinnamic p-Coumaric Caffeic Ferulic Isoferulic Sinapic a-Methylsinapica, 288

Newly reported since 1992 with reference numbers.

Sesquiterpene Acid Dihydrophaseic

Lignans m-Truxillic acid360 p,p-Dihydroxytruxillic acid161

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sulfate from another restionad, Calorphus elongatus,367 has not been completely established. However, the possibility that it might be the corresponding 5-sulfate-3’-glucoside seems unlikely since it co-occurs with quercetin 5-glucoside.

13.3.6 ACYLATED DERIVATIVES Some 77 new acylated flavone and 224 new acylated flavonol derivatives are included in Table 13.1 and Table 13.2, respectively. Only one new acylating acid has been found in combination with flavones and three new aliphatic acids, a new aliphatic alcohol, a lignan, and a new aromatic acid have been discovered in association with flavonols. These are listed with previously recorded structures in Table 13.8. Thus, the lignan, p,p-dihydroxytruxillic acid has been found linked to two molecules of apigenin 7-glucoside through the 6-positions of the two sugar moieties in the biflavone glycoside, stachysetin (13.5), from Stachys aegyptiaca.161 m-Truxillic acid has been identified more recently in the biflavonol glycoside, monochaetin (13.6). Here, two molecules of quercetin 3-galactoside are attached through the 6-hydroxyls of the two galactoses to the carboxyl groups of the m-truxillic acid. Monochaetin was isolated from a leaf extract of the Columbian species Monochaetum multiflorum (Melastomataceae).360

OH OH O O

CH2

O

O HO HO

CH2

O O

HO HO O

OH O

OH

O OH

O O

OH

OH

HO

13.5

O

OH OH OH HO

O

OH OH HO O

OH

O OH

OH O O

O OH

HO

O

OH OH HO O

OH

O O

O

O 13.6

OH HO

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The aliphatic acid, vinylpropionic, has been found in seeds of Psidium guaijava (Myrtaceae)341 directly attached to the 4’-hydroxyl of quercetin 3-(3’’-galloylglucoside) and n-butanoic acid as quercetin 3-(6’’-n-butylglucuronide) in leaves of the vine, Parthenocissus tricuspidata.335 There are two independent reports of isovaleric (isopentanoic) acid, the first as quercetagetin 7-(6’’-isovalerylglucoside) in flowers of Buphthalmum salicifolium412 and the corresponding patuletin glycoside in flowers of another Composite, Inula Britannica.415 The new aliphatic alcohol, 4-hydroxyl-3-methoxyphenyl-1,3-dihydroxypropan-2-ol, has been found, in combination with two additional aromatic acylating acids, p-coumaric and ferulic, attached to kaempferol 3-glucoside (stenopalustroside E) in the fern, Stenochlaena palustris.240 Three new related kaempferol glycosides, the 3-(3’’-Z-p-coumaroyl-6’’-feruloylglucoside) (stenopalustroside B), 3-(3-Z-p-coumaroyl-6’’-E-p-coumaroylglucoside) (stenopalustroside C), and its stereoisomer, stenopalustroside D, were also present in this plant. The only new aromatic acid, a-methylsinapic, was found in Aerva tomentosa (Amaranthaceae),288 attached to kaempferol 4’-methyl ether 3-(6’’’-acetyl neohesperidoside) at the 4-position of the glucose moiety. Among the new reports of previously known acylating agents attached to flavonols, p-coumaric and acetic acids are the most common with 61 and 50 entries, respectively. Malonic acid, a frequent acylating agent in anthocyanins (see Chapter 10), is rarely found in association with flavones and flavonols. The one new flavone entry is of luteolin 7apiosyl(1 ! 2)[glucosyl(1 ! 4)(malonylglucoside)] from fruits of Capsicum annum109 and there are some six malonated flavonol glycosides listed in Table 13.2.7,38,51,82,168,185 Reports of unusual known acylating acids include 12 new entries for 3-hydroxy-3methylglutaric acid, ten are in combination with glycosides of scutellarein, tricetin, luteolin, 6-hydroxyluteolin, and its 3-methyl ether, from four species of the liverwort genus, Frullania.62,131 The other reports are of the 7-[6’’-(3-hydroxy-3-methylglutaryl)glucoside] of apigenin from Chamaemelum nobile (Compositae)46 and of 5,7-dihydroxy-6,8-di-Cmethylflavone from the fern, Matteuccia orientalis.160 There are also new reports of 2-methyl butyric acid and 2-methyl-butenoic (angelic) acid, the former occurs as luteolin 7-[6’’-(2methylbutryl)glucoside] in flowers of Arnica chamissonis (Compositae)105 and the latter as luteolin 7-glucoside-4’-angelate in Polygonum aviculare.108 Tiglic acid (E-2-methyl-2-butenoic acid) has been found, attached to the 8-hydroxyl of 5,7,8-trihydroxy-3,6,4’-trimethoxyflavone, in Galeana pratensis,450 another Composite.

13.3.7 NEW FLAVONE GLYCOSIDES — FURTHER CONSIDERATIONS Some 228 new flavone glycosides are listed in Table 13.1 with details of plant source and references. This increases the total of known glycosides by some third to 700 and includes 26 new apigenin, 25 new luteolin, 8 new chrysoeriol, and 2 new tricin glycosides bringing their totals to, 99, 111, 44, and 44, respectively. A complete check list of all the known flavone glycosides is given in Appendix A. There are a small number of new monoglycosides still discovered. Among the most interesting finds are three 5-glycosides of simple flavones, i.e., baicalein 6-methyl ether 5-rhamnoside from seeds of Trichosanthes anguina (Cucurbitaceae),22 and the 5-glucosides of 5,7,8-trihydroxyflavone (norwogonin) and 5,2’-dihydroxy-7methoxyflavone from Pyracantha coccinea (Rosaceae)27 and Andrographis alata (Acanthaceae),32 respectively. The new structures in Table 13.1 also include 32 flavone aglycones that have been found in glycosidic combination for the first time. For example, scutellarein 5,4’dimethyl ether as the 7-glucoside and 7-(4Rha-acetylrutinoside) from Striga passargei (Scrophulariaceae)71 and four new luteolin methyl ethers, the 5,3’-dimethyl ether as the 7-glucoside and 4’-glucoside from Pyrus serotina,124 the 5,4’-di- and 5,3’,4’-trimethyl ether as their 7xylosyl(1 ! 6)glucosides from Dirca palustris (Thymelaeaceae),112 and the 7,3’,4’-trimethyl ether as the 5-glucoside and 5-xylosyl(1 ! 6)glucoside in Lethedon tannaensis,126 another

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member of the Thymelaeaceae. Among the 8-hydroxyluteolin (hypolaetin) derivatives are three glycosides from the Restionaceae: hypolaetin 7-methyl ether 3’-sulfatoglucuronide and 3’-sulfatogalactoside and hypolaetin 7,3’-dimethyl ether 4’-glucoside from three Leptocarpus species.138 Four glycosides, the 5- and 7-glucosides, the 5-gentiobioside, and the 7-rutinoside, of the trimethylated flavone, nevadensin (5,7-dihydroxy-6,8,4’-trimethoxyflavone), have been reported from Lysionotus pauciflorus (Gesneriaceae).142,143 2’-Methylation and 2’-glycosylation are characteristic features of Scutellaria and other Labiate species. Therefore, it is not surprising to find reports of further 2’,6’-hydroxylated flavones in glycosidic combination in Scutellaria baicalensis147 and S. rivularis.30 Glycosides of several new methyl ethers of tricetin and 6-hydroxytricetin have also been discovered (see Table 13.1). These include further glycosides from Lethedon tannaensis,126,127 namely, tricetin 7,3’,4’-trimethyl ether 5-glucoside and tricetin 7,3’,4’,5’-tetramethyl ether 5-glucoside and 5-xylosyl(1 ! 6)glucoside. Two C-methylated flavones have been found in glycosidic combination for the first time bringing the total number of known structures to five. One of the novel glycosides, 5,7-dihydroxy-6,8di-C-methylflavone 7-[6’’-(3-methylglutaryl)glucoside], was isolated from the rhizomes of the fern, Matteuccia orientalis160 and the other, 5,7-dihydroxy-6-C-methylflavone 7-xylosyl(1 ! 3)xyloside, from the Labiate, Mosla chinensis.159

13.3.8 NEW FLAVONOL GLYCOSIDES — FURTHER CONSIDERATIONS There has been a very large increase in the number of flavonol glycosides discovered, especially kaempferol derivatives. Thus, over 500 new structures have been listed in Table 13.2 bringing the total number of known flavonol glycosides to 1333. These are included with previously known flavonol glycosides in Appendix B. There are some 140 new kaempferol, 107 quercetin, and 28 new myricetin glycosides. Half of all the new flavonol glycosides are acylated, often with two or more acyl groups (see Section 13.3.6). A number of new acylated kaempferol glycosides have been isolated from ferns, for example, the 3-(6’’-caffeoylglucoside) and 3-(5’’-feruloylapioside) from Pteridium aquilinum232,233 and three 3-(diacetylrhamnoside)-7-rhamnoside isomers (2,’3’-, 2’,4’-, and 3’,4’-diacetyl) from Dryopteris crasssirhizoma.256 Thirty-four known flavonol aglycones have been found in combination with sugars for the first time. These include three interesting new methylated 8-hydroxymyricetin derivatives, the 3-rhamnosides of the 8-mono-, 8,5’-di-, and 8,3’,5’-trimethyl ethers, from Erica verticillata.446 Also two glycosides of 5-deoxymyricetin (robinetin) have been reported, the 7-glucoside from Alternanthera sessilis (Amaranthaceae)447 and the 3-rutinoside from Ateleia herbert-smithii,448 a member of the Leguminosae, a family rich in 5-deoxy and 5-methylated flavonoids. The first reported glycosides of gossypetin 3,8-dimethyl ether and its 7,8-isomer have been identified in Eugenia edulis (Myrtaceae)424 and Erica cinerea,425,426 respectively. There are six new records of 2’- or 2’,6’hydroxylated flavonols in glycosidic combination including one from the roots of another Scutellaria species, S. amoena,457 but most of the reports are from members of the Compositae. Two further C-methylated flavonols have been found in glycosidic combination, the 3-rhamnoside-5’-gallate of 2’-C-methyl myricetin from Syzgium samarangense (Myrtaceae)479 and the 7-galactosyl(1 ! 2)rhamnoside of 5,7-dihydroxy-6,8-di-C-methyl-3-methoxyflavone from Cotula anthemoides (Compositae).478 The only previous entry was of 8-C-methylkaempferol 7-glucoside from roots of Sophora leachiana (Leguminosae).481

13.3.9 GLYCOSIDES OF PRENYLATED FLAVONES AND FLAVONOLS, PYRANO AND METHYLENEDIOXYFLAVONOLS

AND OF

No prenylated flavone glycosides were recorded in the last edition of The Flavonoids. Therefore, it is significant that the present list in Table 13.1 should contain three such compounds, all isolated from members of the Leguminosae. They include 8-C-prenylapigenin 4’-rutinoside

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from Desmodium gangeticum,162 3’-C-prenylapigenin 7-rutinoside from Pithecellobium dulce163 (both from stem tissue), and 8-C-prenylchrysoeriol 7-glucosyl(1 ! 3)-a-L-arabinopyranoside from seeds of Erythrina indica.164 Thirteen new prenylated flavonol glycosides have been discovered during the review period, all but three of them from species of the Berberidaceae. There are four new aglycone sugar combinations including the first prenylated quercetin glycosides, i.e., 8-prenylquercetin 4’-methyl ether 3-rhamnoside from Epimedium koreanum (Berberidaceae)475 and 8-prenylquercetin 7,4’-dimethyl ether 3-rhamnosyl(1 ! 4)rhamnoside from Butea monosperma (Leguminosae).476 6,6’’-Dimethylpyrano(2’’,3’’:7,8)-4’-methoxykaempferol 3-rhamnoside was also present in Epimedium acuminatum.477 This is only the second occurrence of a pyranoflavonol glycoside. Three new methylenedioxyflavonol glycosides have been reported bringing the total number of known structures to four. They include two glycosides, viviparum A and B from Polygonum viviparum465 and 3-methoxy-5-hydroxy-6,7-methylenedioxyflavone 4’-glucuronide from spinach, Spinacia oleracea (Chenopodiaceae).464

13.4 DISTRIBUTION PATTERNS Flavone and flavonol O-glycosides are widely distributed in the angiosperms and gymnosperms, mosses, liverworts, and ferns. However, in some monocot families they are largely replaced by or co-occur with flavone C-glycosides, for example, in the grasses, palms, Cyperaceae, and Iridaceae. In the dicots the more evolutionary advanced families tend to accumulate flavone O-glycosides and complex methylated or extra hydroxylated flavonoid aglycones, while the more primitive families produce flavonol O-glycosides, especially myricetin derivatives, together with proanthocyanins. Gymnosperms are characterized by the presence of flavonol O-glycosides, flavone C-glycosides, and biflavonoids. Flavonoid O- and C-glycosides also occur in mosses, liverworts, and ferns. Biflavonoids are important constituents of the bryophytes but are rare in ferns, where flavonol and flavone O-glycosides, glycoflavones, and dihydroflavonols are the most frequent components. There have been no major reviews of the distribution of flavonoids in lower plants, gymnosperms, or the dicotyledons since those by Markham, Niemann, and Giannasi in the third edition of The Flavonoids,4 Chapters 12 to 14, respectively. However, the chapter by Williams and Harborne on the distribution of flavonoids in the monocotyledons was updated in 1994.482 Undoubtedly, the current emphasis on molecular taxonomy has led to a reduction in research in chemotaxonomy with most flavonoid projects now based on a search for biologically active or medicinally useful secondary constituents. Space does not allow a complete review of flavonoid distribution here but some of the more interesting findings and the more extensive surveys will be mentioned. Among the bryophytes, ten new flavone glycosides, all acylated with 3-hydroxy-3-methylglutaric acid, have been reported from three Frullania species.62,131 In another liverwort, Dumortiera hirsuta,92 luteolin 5-glucuronide-6’’-methyl ether has been identified and apigenin and luteolin 7-sophorotrioside and luteolin 7-(acetylsophorotrioside) have been characterized from gametophytes of the moss, Leptostomum macrocarpon.36 There are reports of new flavone O-glycosides from two ferns, luteolin 7-robinobioside97 and 7-sophoroside98 from Pteris cretica and 5,7-dihydroxy-6,8-di-C-methylflavone 7-[6’’-(3-hydroxy-3-methylglutaryl)glucose] from Matteuccia orientalis.160 The other novel fern glycosides are all flavonol and include the unusual quercetin 3-methyl ether 5-glucoside from Asplenium trichomanes-ramosum,363 four acylated kaempferol glycosides, stenopalustrosides B–E from Stenochlaena palustris,240 which were discussed in Section 13.3.6 and quercetin 3-methyl ether 7-a-Larabinofuranosyl(1 ! 6)glucoside from Lepisorus ussuriensis.364 Six further flavonol glycosides have been recorded for brachen, Pteridium aquilinum184,232,233,314 (Table 13.2).

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Reports of flavonoid O-glycosides from the gymnosperms include the unusual 5,6,7,8,3’,4’-hexahydroxyflavone 7-glucoside from fruits of Juniperus zeravschanica (Cupressaceae)145 and kaempferol 3,4’-diglucoside from needles of the common spruce, Picea abies.183 Five further glycosides have been identified in leaves of the Maidenhair tree, Ginkgo biloba,176,177,265 including the unusual acylated glycosides, kaempferol and quercetin 3-[2’’6’’’{-p-(7’’’-glucosyl)coumaroyl}glucosyl]rhamnosides,177 in which the p-coumaric acid moiety is linked in a linear fashion to the 6’’’- and 4’’’’-hydroxyls of the two glucose molecules. There have been three major flavonoid surveys of monocot families since 1991. Thus, 115 Restionaceae species483 endemic to Australia were analyzed for their culm flavonoids. The data are mainly of flavonoid aglycones but a variety of new glycosides were also characterized, including six new flavone sulfate conjugates (discussed in Section 13.3.5). The aglycones were determined after acid hydrolysis and hypolaetin (found in 23 of 34 genera), luteolin (in 25 genera), flavone C-glycosides (in 13 genera), and sulfates (in 15 genera) were found to be the most typical flavonoid constituents. Gossypetin (in seven genera), tricin (in seven genera), and myricetin (in two genera) were relatively rare in these plants. A survey of three families related to Restionaceae, the Anarthriaceae, Ecdeiocoleaceae, and Lygineaceae,484 which are endemic to South Western Australia, showed the regular presence of myricetin, quercetin, and isorhamnetin with only traces of kaempferol. These flavonols were present mainly as 3-Oglycosides but some unknown conjugates were found to be characteristic of the genus Anarthria. In a further flavonoid survey of Velloziaceae taxa two new unusual flavone glycosides, 5,6,7,3’.4’-pentahydroxy-8-methoxyflavone 7-glucoside and 5,6,3’,4’-tetrahydroxy-7,8-dimethoxyflavone 6-glucoside, have been identified in Vellozia nanza.146 However, most genera of the Velloziaceae are characterized by the presence of lipophilic, prenyl-, pyrano-, or C-methylated flavonols, with some simple flavones and flavanones. Flavonol O-glycosides are common in Aylthonia, Barbacenia, and Xerophyta but most Vellozia species accumulate flavone C-glycosides. The lipophilic and vacuolar flavonoid data for Vellozia species are summarized by Harborne et al.485 and the data for all the genera of the Velloziaceae by Williams et al.486 A flavonoid survey of Iris species487 showed the characteristic constituents were glycoflavones but here they co-occur with isoflavones and the xanthone mangiferin and its derivatives. Among the dicotyledons three of the larger families will be considered, Compositae, Labiatae, and Leguminosae. The Compositae is very rich in flavonoids and there have been a number of recent surveys of tribes or genera but nearly all are confined to or concentrate on the lipophilic surface constituents. There is one useful new book by Bohm and Stuessy entitled Flavonoids of the Sunflower Family (Asteraceae), published in 2001,488 which after a general introduction to the family and to flavonoids, summarizes all the then known flavonoid data for each tribe and considers the efficacy of flavonoids at different taxonomic levels. However, it is not always reader friendly with many back references to previous sections or chapters so that access to the reference information is not as easy as it might be. The genus Tanacetum489 and other members of the tribe Anthemideae171 have been surveyed for both surface lipophilic and vacuolar flavonoids. In Tanacetum species, apigenin and luteolin 7-glucuronides are the characteristic vacuolar flavonoids. However, 6-hydroxyluteolin 7-glucoside was found in T. corymbosum, chrysoeriol 7-glucuronide in T. parthenium, T. macrophyllum, and T. cinerariifolium, and quercetin 7-glucuronide in T. parthenium, T. corymbosum, and T. cinerariifolium.489 The lipophilic flavonoids are based mainly on 6-hydroxykaempferol 3,6,4’-trimethyl ether and quercetagetin 3,6,3’-trimethyl ether with methyl ethers of scutellarein and 6-hydroxyluteolin in some species. Both lipophilic and polar flavonoids were isolated from leaf, ray, and disc florets of other Anthemideae, Anthemis, Chrysanthemum, Cotula, Ismelia, Leucanthemim, and Tripleuropermum.171 Anthemis species characteristically produced flavonol glycosides in the leaves while in the other taxa

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flavone O-glycosides were more usual. Two flavonol glycosides, quercetin and kaempferol 5-glucuronides, were identified in leaves of Leucanthemum vulgare.171 In most of these plants ray and disc florets had noticeably different flavonoid patterns, the former based on apigenin or luteolin 7-glucoside or glucuronide and the latter having additional flavonol glycosides such as quercetin and patuletin 7-glucosides and quercetin 7-glucuronide. A similar flavonoid survey of Pulicaria species (tribe Inulae)490 has also been published. There have been a considerable number of chemotaxonomic studies of Labiate taxa since 1991. These include a survey of flavonoid aglycones and glycosides in Sideritis species491 from the Canary Islands and Madeira and the discovery of a new flavone glycoside, isoscutellarein 7-glucosyl(1 ! 2)xyloside, from Sideritis luteola and 15 other Spanish Sideritis species.78 A review of the polyphenolics of the genus Salvia492 includes flavonoid O-glycoside data and Toma´s-Barbera´n et al.493 have determined the distribution of flavonoid p-coumaroylglucoside and 8-hydroxyflavone allosylglucosides in the Labiatae. Five other studies concern leaf flavonoid glycosides as taxonomic characters in the genera Ocimum,494 Calamintha and Micromeria,495 Teucridium and Tripora,496 Oxera and Faradaya,497 and Lavandula and Sabaudia.498 The Leguminosae is phytochemically one of the most diverse families and contains a wealth of flavonoid constituents. A review of the seed polysaccharides and flavonoids, which includes flavonoid O-glycosides, provides a useful chemical overview of the family.499 However, the definitive publications on the chemistry of the family are undoubtedly the three latest Leguminosae volumes (11a–11c) of Robert Hegnauer’s Chemotaxonomie der Pflanzen.500 A more recent review of the phytochemistry of the large and taxonomically difficult genus Acacia has been published by Seigler.501

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APPENDIX A CHECKLIST

OF

KNOWN FLAVONE GLYCOSIDES 3⬘ 2⬘ 8 7

4⬘

O

5⬘ 6⬘

6

3 5 O

13.9

5,7-Dihydroxyflavone (chrysin) 1. 5-Xyloside 2. 5-Glucoside (toringin) 3. 7-Glucoside 4. 7-Galactoside 5. 7-Glucuronide 6. 7-Rutinoside 7. 7-Gentiobioside 8. 7-Benzoate 9. 7-(4’’-Acetylglucoside)* 10. 7-(6’’-Acetylglucoside)* 6-Hydroxy-4’’-methoxyflavone 11. 6-Arabinoside 7,2’-Dihydroxyflavone 12. 7-Glucoside 7,4’-Dihydroxyflavone 13. 7-Glucoside 14. 4’-Glucoside 15. 7-Rutinoside 3’,4’-Dihydroxyflavone 16. 4’-Glucoside 2’,5’-Dihydroxyflavone 17. 5’-Acetate 5,6,7-Trihydroxyflavone (baicalein) 18. 6-Glucoside 19. 6-Glucuronide 20. 7-Rhamnoside 21. 7-Glucuronide 22. 7-(6’’-Malonylglucoside)*

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Flavone and Flavonol O-Glycosides

Baicalein 5-methyl ether 23. 7-Glucoside* Baicalein 6-methyl ether (oroxylin A) 24. 5-Rhamnoside* 25. 7-Glucoside 26. 7-Glucuronide 27. 7-Glucosyl(1 ! 3)rhamnoside* Baicalein 7-methyl ether (negletein) 28. 5-Glucuronide 29. 5-Glucuronosylglucoside 30. 6-Xyloside* 31. 6-Glucoside* 32. 6-Rhamnosyl(1 ! 2)fucoside* Baicalein 5,6-dimethyl ether 33. 7-Glucoside 5,7,8-Trihydroxyflavone (norwogonin) 34. 5-Glucoside* 35. 7-Galactoside* 36. 7-Glucuronide 37. 8-Glucuronide 5,7-Dihydroxy-8-methoxyflavone (wogonin) 38. 5-Glucoside 39. 7-Glucoside 40. 7-Glucuronide 7-Hydroxy-5,8-dimethoxyflavone 41. 7-Glucoside* 42. 7-Glucuronide* 5-Hydroxy-7,8-dimethoxyflavone 43. 5-Glucoside 7,3’,4’-Trihydroxyflavone 44. 7-Glucoside 45. 7-Galactoside 46. 7-Rutinoside 7,4’-Dihydroxy-3’-methoxyflavone 47. 7-Glucoside 5,7,2’-Trihydroxyflavone 48. 7-Glucoside* 49. 7-Glucuronide 50. 2’-Glucoside* 5,2’-Dihydroxy-7-methoxyflavone (echioidin) 51. 5-Glucoside* 52. 2’-Glucoside (echioidin) 53. 2’-(6’’-Acetylglucoside)* 7,8,4’-Trihydroxyflavone 54. 8-Neohesperidoside 5,7,4’-Trihydroxyflavone (apigenin) 55. 5-Glucoside 56. 5-Galactoside 57. 7-Arabinoside 58. 7-Xyloside

809

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810

59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108.

Flavonoids: Chemistry, Biochemistry, and Applications

7-Rhamnoside 7-Glucoside (cosmosiin) 7-Galactoside 7-Glucuronide 7-Galacturonide 7-Methylglucuronide 7-Methylgalacturonide 7-(6’’-Ethylglucuronide) 4’-Arabinoside 4’-Glucoside 4’-Glucuronide 7-Arabinofuranosyl(1 ! 6)glucoside 7-Arabinopyranosyl(1 ! 6)glucoside 7-Xylosyl(1 ! 2)glucoside 7-Xylosyl(1 ! 6)glucoside 7-Apiofuranosyl(1 ! 6)glucoside (apiin)* 7-Rutinoside 7-Neohesperidoside 7-Rhamnosylglucuronide 7-Dirhamnoside 7-Glucosylrhamnoside 7-Cellobioside* 7-Allosyl(1 ! 2)glucoside 7-Galactosyl(1 ! 4)mannoside 7-Xylosylglucuronide 7-Rhamnosylglucuronide 7-Rhamnosyl(1 ! 2)galacturonide 7-Digalacturonide 7-Galacturonylglucoside 7-Glucuronosyl(1 ! 2)glucuronide 7,4’-Diglucoside 7,4’-Dialloside 7,4’-Diglucuronide 7-Glucuronide-4’-rhamnoside 4’-Diglucoside 7-Sophorotrioside* 7-(2G-Rhamnosyl)rutinoside* 7-(2G-Rhamnosyl)gentiobioside* 7-Rhamnoside-4’-glucosylrhamnoside* 7-Rutinoside-4’-glucoside 7-Neohesperidoside-4’-glucoside 7-Cellobioside-4’-glucoside* 7-Rhamnoside-4’-rutinoside 7-Neohesperidoside-4’-sophoroside 7-Glucosyl(1 ! 2)glucuronide-4’-glucuronide* 7-Digalacturonide-4’-glucoside 7-Diglucuronide-4’-glucuronide Pinnatifinoside A (13.1) Pinnatifinoside B (13.2) Pinnatifinoside C (13.3)

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Flavone and Flavonol O-Glycosides

109. Pinnatifinoside D (13.4) 110. 7-(2’’-E-p-Coumaroylglucoside)* 111. 7-(3’’-p-Coumaroylglucoside)* 112. 7-(4’’-Z-p-Coumaroylglucoside) 113. 7-(4’’-E-p-Coumaroylglucoside) 114. 7-(6’’-p-Coumaroylglucoside) 115. 7-(6’’-E-p-Coumaroylgalactoside)* 116. 7-(6’’-E-Caffeoylglucoside)* 117. 5-(6’’-Malonylglucoside) 118. 7-(6’’-Malonylglucoside) 119. 7-[6’’-(3-Hydroxy-3-methylglutaryl)glucoside]* 120. 7-(2’’-Acetylglucoside) 121. 7-(6’’-Acetylglucoside) 122. 7-(6’’-Crotonylglucoside) 123. 7-(2’’-Acetyl-6’’-methylglucuronide) 124. 7-Lactate 125. 7-(2’’-Glucosyllactate) 126. 7-(2’’-Glucuronosyllactate) 127. 7-Glucoside-4’-p-coumarate 128. 7-Glucoside-4’-caffeate 129. 7-(2’’,6’’-Di-p-coumaroylglucoside) 130. 7-(3’’,6’’-Di-p-coumaroylglucoside) 131. 7-(3’’,6’’-Di-E-p-coumaroylgalactoside)* 132. 7-(4’’,6’’-Di-p-coumaroylglucoside) 133. 7-(2’’,3’’-Diacetylglucoside) 134. 7-(3’’,4’’-Diacetylglucoside) 135. 7-(3’’-Acetyl-6’’-E-p-coumaroylglucoside)* 136. 5-Rhamnosyl(1 ! 2)(6’’-acetylglucoside) 137. 7-Rhamnosyl(1 ! 6)(4’’-E-p-methoxycinnamoylglucoside)* 138. 4’-(2’’-Feruloylglucuronosyl(1 ! 2)glucuronide)* 139. 7-(6’’’-Acetylallosyl)(1 ! 2)glucoside 140. 7-(6’’’-Malonylneohesperidoside) 141. 7-(Malonylapiosyl)glucoside 142. 7-Rutinoside-4’-caffeate 143. 7-(6’’-Acetylalloside)-4’-alloside 144. 7-(4’’,6’’-Diacetylalloside)-4’-alloside 145. 7-Glucuronide-4’-(6’’-malonylglucoside) 146. 7-Glucuronosyl(1 ! 3)[(2’’-p-coumaroylglucuronosyl)(1 ! 2)glucuronide]* 147. 7-Glucuronosyl(1 ! 3)[(2’’-feruloylglucuronosyl)(1 ! 2)glucuronide]* 148. 7-(2’’-Ferulylglucuronosyl)(1 ! 2)glucuronide-4’-glucuronide* 149. 7-Glucuronide-4’-(2’’’-E-p-coumaroylglucuronosyl)(1 ! 2)glucuronide* 150. 7-Glucuronide-4’-(2’’’-feruloylglucuronosyl)(1 ! 2)glucuronide* 151. 7-Sulfatoglucoside 152. 7-Sulfatogalactoside 153. 7-Sulfatoglucuronide 154. 7-Sulfate Apigenin 7-methyl ether (genkwanin) 155. 5-Glucoside 156. 4’-Glucoside 157. 5-Xylosylglucoside

811

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812

Flavonoids: Chemistry, Biochemistry, and Applications

158. 4’-a-L-Arabinopyranosyl(1 ! 6)galactoside* 159. 4’-Glucosylrhamnoside 160. 4’-Rhamnosyl(1 ! 2)[rhamnosyl(1 ! 6)galactoside]* 161. 5-(6’’-Malonylglucoside) Apigenin 4’-methyl ether (acacetin) 162. 7-Rhamnoside* 163. 7-Glucoside (tilianine) 164. 7-Galactoside 165. 7-Glucuronide 166. 7-(6’’-Methylglucuronide) 167. 7-Arabinosylrhamnoside 168. 7-Glucosyl(1 ! 4)xyloside* 169. 7-Apiosyl(1 ! 6)glucoside* 170. 7-Rutinoside (linarin) 171. 7-Neohesperidoside (fortunellin) 172. 7-Diglucoside 173. 7-Rhamnosylgalacturonide 174. 7-Glucuronosyl(1 ! 2)glucuronide 175. 7-(2G-Rhamnosylrutinoside)* 176. 7-Rhamnosyl(1 ! 2)glucosyl(1 ! 2)glucoside* 177. 7-Rhamnosyl(1 ! 2)glucosyl(1 ! 2)glucosyl(1 ! 2)glucoside* 178. 7-(2’’-Acetylglucoside) 179. 7-(6’’-Acetylglucoside) 180. 7-(4’’-Acetylrutinoside) 181. 7-(4’’’-Acetylrutinoside)* 182. 7-[2’’’-(2-Methylbutyryl)rutinoside] 183. 7-[3’’’-(2-Methylbutyryl)rutinoside] 184. 7-Rhamnosyl(1 ! 6)[2’’-acetylglucosyl(1 ! 2)glucoside]* 185. 7-[6’’’-Acetylglucosyl(1 ! 2)][rhamnosyl(1 ! 6)glucoside]* 186. 7-Glucosyl(1 ! 6)[3’’’-acetylrhamnosyl(1 ! 2)glucoside]* 187. 7-(4’’’’-Acetylrhamnosyl)(1 ! 6)glucosyl(1 ! 3)(6’’-acetylglucoside)* 188. 7-[Rhamnosyl(1 ! 4)glucosyl(1 ! 6)](6’’’-acetylsophoroside) 189. Di-6’’-(acacetin-7-glucosyl)malonate Apigenin 5,7-dimethyl ether 190. 4’-Galactoside Apigenin 7,4’-dimethyl ether 191. 5-Xylosylglucoside 6-Hydroxyapigenin (scutellarein) 192. 5-Glucuronide 193. 6-Xyloside 194. 6-Glucoside 195. 7-Rhamnoside 196. 7-Glucoside 197. 7-Glucuronide 198. 4’-Arabinoside 199. 7-Xylosyl(1 ! 2)xyloside* 200. 7-Xylosyl(1 ! 4)rhamnoside 201. 7-Xylosyl(1 ! 2)glucoside* 202. 7-Xylosyl(1 ! 6)galactoside* 203. 7-Glucosyl(1 ! 4)rhamnoside

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Flavone and Flavonol O-Glycosides

204. 7-Rutinoside 205. 7-Neohesperidoside 206. 7-Rhamnosyl(1 ! 2)galactoside 207. 7-Diglucoside 208. 7-Glucuronosyl(1 ! 2)glucuronide* 209. 6-Xyloside-7-rhamnoside 210. 7,4’-Dirhamnoside 211. 7-(6’’-Malonylglucoside) 212. 7-[6’’-(3-Hydroxy-3-methylglutaryl)glucoside]* 213. 7-(6’’-Feruloylglucuronide) 214. 7-(Sinapoylglucuronide) Scutellarein 6-methyl ether (Hispidulin) 215. 7-Rhamnoside* 216. 7-Glucoside (homoplantaginin) 217. 7-Glucuronide 218. 7-Methylglucuronide* 219. 4’-Glucoside* 220. 7-Xylosyl(1 ! 2)glucoside* 221. 7-Rutinoside 222. 7-Neohesperidoside* 223. 7-(6’’-E-p-Coumaroylglucoside)* 224. 7-Sulfate 225. 4’-Sulfate 226. 7,4’-Disulfate Scutellarein 7-methyl ether 227. 6-Glucoside 228. 6-Galactoside 229. 7-Glucoside 230. 6-Rhamnosylxyloside Scutellarein 4’-methyl ether 231. 6-Glucoside 232. 7-Glucoside 233. 7-Glucuronide 234. 7-Rutinoside* 235. 7-Sophoroside 236. 7-(2’’,6’’-Diacetylalloside)* 237. 7-(p-Coumaroylglucosyl)(1 ! 2)mannoside Scutellarein 5,4’-dimethyl ether 238. 7-Glucoside* 239. 7-(4Rha-Acetylrutinoside)* Scutellarein 6,7-dimethyl ether 240. 4’-Glucoside 241. 4’-Glucuronide* 242. 4’-Rutinoside Scutellarein 6,4’-dimethyl ether (pectolinarigenin) 243. 7-Rhamnoside 244. 7-Glucoside 245. 7-Glucuronide 246. 7-Glucuronic acid methyl ether 247. 7-Rutinoside

813

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814

Flavonoids: Chemistry, Biochemistry, and Applications

248. 7-(6’’-Acetylglucoside)* 249. 7-(2’’’-Acetylrutinoside)* 250. 7-(3’’’-Acetylrutinoside)* 251. 7-(4’’’-Acetylrutinoside)* Scutellarein 7,4’-dimethyl ether 252. 6-Glucoside 253. 6-Xylosyl(1 ! 2)glucoside* 254. 6-Neohesperidoside* Scutellarein 6,7,4’-trimethyl ether (salvigenin) 255. 5-Glucoside 256. 5-(6’’-Acetylglucosyl)(1 ! 3)galactoside* 8-Hydroxyapigenin (isoscutellarein) 257. 7-Xyloside 258. 7-Glucoside 259. 7-Glucosyl(1 ! 2)xyloside* 260. 8-Glucuronide 261. 7-Neohesperidoside 262. 7-Allosyl(1 ! 2)glucoside 263. 8-Sophoroside* 264. 8-(6’’-E-p-Coumaroylglucoside)* 265. 7-(6’’-Acetylallosyl)(1 ! 2)glucoside 266. 7-[6’’’-Acetylallosyl(1 ! 2)6’’-acetylglucoside] 267. 8-(2’’-Sulfatoglucuronide)* 268. 8-(2’’,4’’-Disulfatoglucuronide)* 8-Hydroxyapigenin 4’-methyl ether 269. 8-Glucoside* 270. 8-Glucuronide 271. 8-(6’’-n-butylglucuronide)* 272. 7-Allosyl(1 ! 2)glucoside* 273. 8-Xylosylglucoside 274. 7-(6’’’-Acetylallosyl)(1 ! 2)glucoside 275. 8-(2’’-Sulfatoglucoside) 276. 8-(2’’Sulfatoglucuronide)* 277. 8-(2’’,4’’-Disulfatoglucuronide)* 8-Hydroxyapigenin 8,4’-dimethyl ether 278. 7-Glucuronide 6,8-Dihydroxy-7,4’-dimethoxyflavone 279. 6-Rutinoside* 280. 6-(4’’-Acetylrhamnosyl)(1 ! 6)glucoside* 7,3’,4’,5’-Tetrahydroxyflavone 281. 7-Rhamnoside 282. 7-Glucoside 5,6,7,2’-Tetrahydroxyflavone 283. 7-Glucuronide 5,7,2’-Trihydroxy-6-methoxyflavone 284. 7-Glucoside* 285. 7-Methylglucuronide* 5,7,2’,6’-Tetrahydroxyflavone 286. 2’-Glucoside* 5,2’,6’-Trihydroxy-7-methoxyflavone

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Flavone and Flavonol O-Glycosides

287. 2’-Glucoside* 5,7,8,2’-Tetrahydroxyflavone 288. 7-Glucuronide* 5,7,2’-Trihydroxy-8-methoxyflavone 289. 7-Glucuronide 5,2’-Dihydroxy-7,8-dimethoxyflavone (skullcapflavone 1) 290. 2’-Glucoside* 291. 2’-(2’’-E-Cinnamoylglucoside)* 292. 2’-(3’’-E-Cinnamoylglucoside)* 293. 2’-(4’’-E-Cinnamoylglucoside)* 5,7-Dihydroxy-8,2’-dimethoxyflavone 294. 7-Glucuronide 5-Hydroxy-7,8,2’-trimethoxyflavone 295. 5-Glucoside 5,7,3’,4’-Tetrahydroxyflavone (luteolin) 296. 5-Glucoside (galuteolin) 297. 5-Galactoside 298. 5-Glucuronide 299. 5-Glucuronide-6’’-methyl ester* 300. 7-Xyloside 301. 7-Rhamnoside 302. 7-Glucoside 303. 7-Galactoside 304. 7-Glucuronide 305. 7-Galacturonide 306. 7-Methylglucuronide 307. 3’-Xyloside 308. 3’-Rhamnoside 309. 3’-Glucoside 310. 3’-Glucuronide 311. 3’-Galacturonide 312. 4’-Arabinoside 313. 4’-Glucoside 314. 4’-Glucuronide 315. 5-Rutinoside* 316. 7-Dirhamnoside 317. 7-Arabinofuranosyl(1 ! 6)glucoside 318. 7-Arabinopyranosyl(1 ! 6)glucoside 319. 7-Glucosyl(1 ! 4)a-L-arabinopyranoside* 320. 7-Xylosyl(1 ! 6)glucoside (primeveroside)* 321. 7-Apiosyl(1 ! 6)glucoside* 322. 7-Sambubioside 323. 7-Apiosylglucoside 324. 7-Rutinoside 325. 7-Neohesperidoside (veronicastroside) 326. 7-Glucosylrhamnoside 327. 7-Robinobioside* 328. 7-Sophoroside* 329. 7-Gentiobioside 330. 7-Laminaribioside

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816

331. 332. 333. 334. 335. 336. 337. 338. 339. 340. 341. 342. 343. 344. 345. 346. 347. 348. 349. 350. 351. 352. 353. 354. 355. 356. 357. 358. 359. 360. 361. 362. 363. 364. 365. 366. 367. 368. 369. 370. 371. 372. 373. 374. 375. 376. 377. 378. 379. 380.

Flavonoids: Chemistry, Biochemistry, and Applications

7-Glucosylgalactoside 7-Galactosyl(1 ! 6)galactoside* 7-Allosyl(1 ! 2)glucoside 7-Glucosylglucuronide 7-Galactosylglucuronide* 7-Glucuronosyl(1 ! 2)glucuronide 7-Glucoside-3’-xyloside 7,3’-Diglucoside 7-Glucoside-3’-glucuronide* 7-Glucuronide-3’-glucoside 7,3’-Diglucuronide 7,3’-Digalacturonide 7,4’-Diglucoside 7-Galactoside-4’-glucoside 7-Glucuronide-4’-rhamnoside 7-Galacturonide-4’-glucoside 7,4’-Diglucuronide 3’-Xylosyl(1 ! 2)glucoside* 4’-Rutinoside* 4’-Neohesperidoside 3’,4’-Diglucoside 3’,4’-Diglucuronide 3’,4’-Digalacturonide 7-Rhamnosyldiglucoside 7-Sophorotrioside* 7-Glucosylarabinoside-4’-glucoside 7-Rutinoside-3’-glucoside 7-Rutinoside-4’-glucoside 7-Neohesperidoside-4’-glucoside 7-Glucoside-4’-neohesperidoside 7-Gentiobioside-4’-glucoside 7-Glucuronide-3’,4’-dirhamnoside 7,4’-Diglucuronide-3’-glucoside 7-Glucuronosyl(1 ! 2)glucuronide-4’-glucuronide 7,3’,4’-Triglucuronide 7-Neohesperidoside-4’-sophoroside 7-(6’’-E-Cinnamoylglucoside) 7-(2’’-p-Coumaroylglucoside) 7-(6’’-p-Coumaroylglucoside) 7-Caffeoylglucoside 7-(6’’-Feruloylglucoside) 7-(6’’-p-Benzoylglucoside)* 5-(6’’-Malonylglucoside) 7-(6’’-Malonylglucoside) 7-[6’’-(2-Methylbutyryl)glucoside]* 7-[6’’-(3-Hydroxy-3-methylglutaryl)glucoside]* 3’-Acetylglucuronide 7-(6’’-Acetylglucoside) 3’-(3’’-Acetylglucuronide)* 3’-(4’’-Acetylglucuronide)*

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Flavone and Flavonol O-Glycosides

381. 7-Glucosyl(1 ! 6)(4’’’-caffeoylglucoside)* 382. 7-Glucoside-4’-(Z-2-methyl-2-butenoate)* 383. 7-Glucuronide-3’-feruloylglucoside 384. 7-Neohesperidoside-6’’-malonate 385. 7-(3’’-Acetylapiosyl)(1 ! 2)xyloside 386. 7-(6’’’-Acetylallosyl)(1 ! 2)glucoside 387. 7-(6’’’-Acetylsophoroside)* 388. 7-Apiosyl(1 ! 2)[glucosyl(1 ! 4)(6-malonylglucoside)]* 389. 7-(Acetylsophorotrioside)* 390. 7-(6’’’’-Acetylallosyl)(1 ! 3)glucosyl(1 ! 2)glucoside* 391. 7-(2’’-Feruloylglucuronosyl)(1 ! 2)glucuronide-4’-glucuronide* 392. 7,4’-Diglucuronide-3’-feruloylglucoside 393. 7-Lactate 394. 7-(2’’-Glucosyllactate) 395. 7-(2’’-Glucuronosyllactate) 396. 7-Sulfatoglucoside 397. 7-(2’’-Sulfatoglucoside)* 398. 7-Sulfatoglucuronide 399. 7-Sulfate-3’-glucoside 400. 7-Sulfatorutinoside 401. 7-Sulfate-3’-rutinoside 402. 7-Sulfate 403. 3’-Sulfate 404. 4’-Sulfate 405. 7-Disulfatoglucoside 406. 7,3’-Disulfate Luteolin 5-methyl ether 407. 7-Glucoside 408. 7-Xylosyl(1 ! 6)glucoside* Luteolin 7-methyl ether 409. 5-Glucoside 410. 3’-Glucoside* 411. 3’-Galactoside* 412. 4’-Rhamnoside 413. 5-Xylosylglucoside 414. 4’-Gentiobioside Luteolin 3’-methyl ether (chrysoeriol) 415. 5-Glucoside 416. 7-Xyloside 417. 7-Rhamnoside 418. 7-Glucoside 419. 7-Glucuronide 420. 4’-Glucoside 421. 5-Diglucoside 422. 7-Arabinofuranosyl(1 ! 2)glucoside 423. 7-a-L-Arabinofuranosyl(1 ! 6)galactoside* 424. 7-Apiosyl(1 ! 6)glucoside* 425. 7-Rutinoside 426. 7-Neohesperidoside* 427. 7-Rhamnosylgalactoside

817

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818

Flavonoids: Chemistry, Biochemistry, and Applications

428. 7-Rhamnosylglucuronide 429. 7-Digalactoside 430. 7-Mannosyl(1 ! 2)alloside 431. 7-Allosyl(1 ! 2)glucoside 432. 7-Glucuronosyl(1 ! 2)glucuronide 433. 5,4’-Diglucoside 434. 7,4’-Dixyloside 435. 7,4’-Diglucoside 436. 7-Glucuronide-4’-rhamnoside 437. 7,4’-Diglucuronide* 438. 7-Sophorotrioside 439. 7-(6’’-Crotonylglucoside) 440. 7-(Malonylglucoside) 441. 7-(3’’-Z-p-Coumaroylglucoside)* 442. 7-(3’’,6’’-Di-E-p-coumaroylglucoside)* 443. 7-p-Coumaroylglucosylglucuronide 444. 7-(2’’’-Feruloylglucuronosyl(1 ! 2)glucuronide)* 445. 7-(6’’’-Acetylglucosyl)(1 ! 2)mannoside 446. 7-[Glucuronosyl(1 ! 3)(2’’’-feruloylglucuronosyl)](1 ! 2)glucuronide* 447. 7-Sulfatoglucoside 448. 7-Disulfatoglucoside 449. 7-Sulfate Luteolin 4’-methyl ether (diosmetin) 450. 7-Glucoside 451. 7-Glucuronide 452. 3’-Glucoside* 453. 7-Arabinosyl(1 ! 6)glucoside* 454. 7-a-Glucosyl(1 ! 6)glucoside* 455. 7-b-Glucosyl(1 ! 6)arabinoside 456. 7-Xylosyl(1 ! 6)glucoside* 457. 7-Rutinoside (diosmin) 458. 7-Neohesperidoside (neodiosmin)* 459. 7-Diglucoside 460. 7-(2’’,6’’-Dirhamnosyl)glucoside* 461. 7-(6’’-Malonylglucoside) 462. 7-Apiosyl(1 ! 2)(6’’-Acetylglucoside)* 463. 7-Sulfate 464. 3’-Sulfate 465. 7,3’-Disulfate Luteolin 5,3’-dimethyl ether 466. 7-Glucoside* 467. 4’-Glucoside* Luteolin 5,4’-dimethyl ether 468. 7-Xylosyl(1 ! 6)glucoside* Luteolin 7,3’-dimethyl ether 469. 5-Rhamnoside 470. 5-Glucoside 471. 4’-Glucoside 472. 4’-Apiosyl(1 ! 2)glucoside*

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Flavone and Flavonol O-Glycosides

Luteolin 7,4’-dimethyl ether 473. 3’-Glucoside 474. 5-Xylosylglucoside Luteolin 3’,4’-dimethyl ether 475. 7-Rhamnoside 476. 7-Glucuronide Luteolin 5,3’,4’-trimethyl ether 477. 7-Xylosyl(1 ! 6)glucoside* 478. 7-Rutinoside* Luteolin 7,3’,4’-trimethyl ether 479. 5-Glucoside* 480. 5-Xylosyl(1 ! 6)glucoside* 6-Hydroxyluteolin 481. 5-Glucoside 482. 6-Xyloside 483. 6-Rhamnoside* 484. 6-Glucoside 485. 6-Glucuronide 486. 7-Arabinoside 487. 7-Xyloside 488. 7-Rhamnoside 489. 7-Apioside 490. 7-Glucoside 491. 7-Galactoside 492. 7-Glucuronide 493. 7-Xylosyl(1 ! 2)xyloside* 494. 7-Xylosyl(1 ! 6)glucoside* 495. 7-Rhamnosyl(1 ! 4)xyloside 496. 7-Sambubioside* 497. 6-Glucoside-3’-rhamnoside 498. 7-Rutinoside 499. 7-Sophoroside 500. 7-Gentiobioside 501. 7-Arabinoside-4’-rhamnoside 502. 7-(6’’-Malonylglucoside) 503. 7-[3’’-(3-Hydroxy-3-methylglutaryl)glucoside]* 504. 7-[4’’-(3-Hydroxy-3-methylglutaryl)glucoside]* 505. 7-[6’’-(3-Hydroxy-3-methylglutaryl)glucoside]* 506. 7-(6’’-E-Caffeoylglucoside)* 507. 7-(6’’’-p-Coumaroylsophoroside) 508. 7-(6’’’-Caffeoylsophoroside) 509. 6-Glucoside-7-[6’’’-(3-hydroxy-3-methylglutaryl)glucoside]* 510. 7-[6’’-(3-Hydroxy-3-methylglutaryl)glucoside]-3’-glucuronide* 511. 6-Sulfate 512. 7-Sulfate 513. 6,7-Disulfate 6-Methoxyluteolin 514. 7-Glucoside 515. 7-Glucuronide* 516. 7-Methylglucuronide* 517. 4’-Glucoside*

819

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820

Flavonoids: Chemistry, Biochemistry, and Applications

518. 7-Rutinoside 519. 7-Rhamnosyl-3’-xyloside* 520. 7-[6’’-(2-Methylbutyryl)glucoside]* 521. 7-Sulfate 522. 3’,4’-Disulfate 6-Hydroxyluteolin 7-methyl ether (pedalitin) 523. 6-Glucoside (pedaliin) 524. 6-Galactoside 525. 7-Glucuronide 526. 7-Methylglucuronide 527. 6-Galactosylglucoside 6-Hydroxyluteolin 3’-methyl ether (nodifloretin) 528. 7-Diglucoside 529. 7-[6’’-(3-Hydroxy-3-methylglutaryl)glucoside]* 530. 7-Sulfate 531. 6,7-Disulfate 6-Hydroxyluteolin 4’-methyl ether 532. 7-Allosyl(1 ! 2)glucoside 533. 7-Rhamnosyl(1 ! 2)(6’’-acetylglucoside)* 534. 7-[6’’’-Acetylallosyl(1 ! 2)6’’-acetylglucoside] 6-Hydroxyluteolin 6,7-dimethyl ether (cirsiliol) 535. 4’-Glucoside 6-Hydroxyluteolin 6,3’-dimethyl ether 536. 5-Rhamnoside* 537. 7-Rhamnoside 538. 7-Glucoside 539. 7-Rutinoside* 540. 7-Sulfate 541. 7,4-Disulfate 6-Hydroxyluteolin 6,4’-dimethyl ether 542. 7-Glucoside 543. 7-Rutinoside 6-Hydroxyluteolin 7,3’-dimethyl ether 544. 6-Glucoside 6-Hydroxyluteolin 6,7,3’-trimethyl ether (cirsilineol) 545. 4’-Glucoside 6-Hydroxyluteolin 5,6,3’,4’-tetramethyl ether 546. 7-Cellobioside* 8-Hydroxyluteolin (hypolaetin) 547. 7-Xyloside 548. 7-Glucoside 549. 8-Rhamnoside* 550. 8-Glucoside 551. 8-Glucuronide 552. 7-Sophoroside* 553. 7-Allosyl(1 ! 2)glucoside 554. 8-Gentiobioside 555. 8,4’-Diglucuronide 556. 8-Glucoside-3’-rutinoside* 557. 7-(6’’’-Acetylallosyl)(1 ! 2)glucoside

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Flavone and Flavonol O-Glycosides

558. 7-[6’’’-Acetylallosyl(1 ! 2)6’’-acetylglucoside] 559. 7-[6’’’-Acetylallosyl(1 ! 2)3’’-acetylglucoside] 560. 7-Sulfatoglucoside* 561. 7-Sulfatogalactoside* 562. 7-Sulfatoglucuronide* 563. 7-Sulfate-8-glucoside* 564. 8-Glucoside-3’-sulfate 565. 8-Sulfate Hypolaetin 7-methyl ether 566. 3’-Sulfatogalactoside* 567. 3’-Sulfatoglucuronide* Hypolaetin 3’-methyl ether 568. 7-Glucoside 569. 8-Glucuronide* 570. 7-Sophoroside* 571. 7-Allosyl(1 ! 2)glucoside 572. 7-Mannosyl(1 ! 2)glucoside Hypolaetin 4’-methyl ether 573. 8-Glucoside 574. 8-Glucuronide 575. 7-Allosyl(1 ! 2)glucoside 576. 7-(6’’’-Acetylallosyl)(1 ! 2)glucoside 577. 7-[6’’’-Acetylallosyl(1 ! 2)6’’-acetylglucoside]* 578. 8-Glucoside-3’-sulfate Hypolaetin 7,3’-dimethyl ether 579. 4’-Glucoside* Hypolaetin 8,3’-dimethyl ether 580. 7-Glucoside 5,6,4’-Trihydroxy-7,8-dimethoxyflavone (thymusin) 581. 6-Isobutyrate* 5,8,4’-Trihydroxy-6,7-dimethoxyflavone (isothymusin) 582. 8-Glucoside* 5,7,-Dihydroxy-6,8,4’-trimethoxyflavone (nevadensin) 583. 5-Glucoside* 584. 7-Glucoside* 585. 5-Gentiobioside* 586. 7-Rutinoside* 5,8-Dihydroxy-6,7,4’-trimethoxyflavone 587. 8-Glucoside* 5,6,7,8,3’,4’-Hexahydroxyflavone 588. 7-Glucoside* 5,6,7,3’,4’-Pentahydroxy-8-methoxyflavone (pleurostimin) 589. 7-Apioside 590. 7-Glucoside* 5,6,3’,4’-Tetrahydroxy-7,8-dimethoxyflavone (pleurostimin 7-methyl ether) 591. 6-Glucoside* 5,7,3’,4’-Tetrahydroxy-6,8-dimethoxyflavone 592. 7-Glucoside 5,8,3’,4’-Tetrahydroxy-6,7-dimethoxyflavone 593. 8-Glucoside

821

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Flavonoids: Chemistry, Biochemistry, and Applications

5,7,3’-Trihydroxy-6,8,4’-trimethoxyflavone (acerosin) 594. 5-(6’’-Acetylglucoside) 5,7,4’-Trihydroxy-6,8,3’-trimethoxyflavone (sudachitin) 595. 7-Glucoside 596. 4’-Glucoside 597. 7-(3-Hydroxy-3-methylglutarate)-4’-glucoside 598. 7-[6’’-(3-Hydroxy-3-methylglutaryl)glucoside] 599. 4’-[6’’-(3-Hydroxy-3-methylglutaryl)glucoside] 600. Sudachitin D 5,2’,3’-Trihydroxy-7,8-dimethoxyflavone 601. 3’-Glucoside 5,2’,6’-Trihydroxy-6,7-dimethoxyflavone 602. 2’-Glucoside* 5,2’,6’-Trihydroxy-7,8-dimethoxyflavone 603. 2’-Glucuronide* 5,2’-Dihydroxy-7,8,6’-trimethoxyflavone 604. 2’-Glucuronide* 5-Hydroxy-7,8,2’,3’-tetramethoxyflavone 605. 5-Glucoside 5,7,2’,4’,5’-Pentahydroxyflavone (isoetin) 606. 7-Glucoside 607. 7-Arabinoside 608. 2’-Xyloside 609. 4’-Glucuronide* 610. 5’-Glucoside 611. 7-Xylosylarabinosylglucoside 612. 7-Glucoside-2’-xyloside 613. 2’-(4’’-Acetylxyloside) 614. 7-Glucoside-2’-(4’’-acetylxyloside) 5,7,3’,4’,5’-Pentahydroxyflavone (tricetin) 615. 7-Glucoside 616. 3’-Xyloside 617. 3’-Glucoside 618. 3’-Rhamnosyl(1 ! 4)rhamnoside* 619. 7,3’-Diglucuronide 620. 3’-Glucoside-5’-rhamnoside* 621. 7-Glucoside-3’-[6’’-(3-hydroxy-3-methylglutaryl)glucoside]* 622. 7-Diglucoside 623. 3’,5’-Diglucoside 624. 3’-Sulfate 625. 3’-Disulfate Tricetin 7-methyl ether 626. 3’-Glucoside-5’-rhamnoside* Tricetin 3’-methyl ether 627. 7-Glucoside 628. 7-Glucuronide* 629. 7,5’-Diglucuronide Tricetin 4’-methyl ether 630. 7-Apiosyl(1 ! 2)(6’’-acetylglucoside)*

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Flavone and Flavonol O-Glycosides

Tricetin 3’,4’-dimethyl ether 631. 7-Glucuronide Tricetin 3’,5’-dimethyl ether (Tricin) 632. 5-Glucoside 633. 7-b-D-Arabinopyranoside* 634. 7-Xyloside 635. 7-Glucoside 636. 7-Glucuronide 637. 4’-Apioside* 638. 4’-Glucoside 639. 5-Diglucoside 640. 7-Rutinoside 641. 7-Neohesperidoside 642. 7-Diglucoside 643. 7-Fructosylglucoside 644. 7-Rhamnosylglucuronide 645. 7-Rhamnosyl(1 ! 2)galacturonide 646. 7-Diglucuronide 647. 5,7-Diglucoside 648. 7-Rutinoside-4’-glucoside 649. 7-(2’’-p-Coumaroylglucuronosyl)(1 ! 2)glucuronide* 650. 7-(2’’-Feruloylglucuronosyl)(1 ! 2)glucuronide* 651. 7-(2’’-Sinapoylglucuronosyl)(1 ! 2)glucuronide* 652. 7-[Glucuronosyl(1 ! 3)(2’’’-feruloylglucuronosyl)](1 ! 2)glucuronide* 653. 7-[X’-(3-Hydroxy-3-methylglutaryl)glucoside]* 654. 7-Sulfatoglucoside 655. 7-Sulfatoglucuronide 656. 7-Disulfatoglucuronide 3-(3-Methylbutyl)tricetin 657. 5-Neohesperidoside Tricetin 7,3’,4’-trimethyl ether 658. 5-Glucoside* Tricetin 7,3’,4’,5’-tetramethyl ether 659. 5-Glucoside* 660. 5-Xylosyl(1 ! 2)rhamnoside* 661. 5-Xylosyl(1 ! 6)glucoside* 6-Hydroxytricetin 6,3’,5’-trimethyl ether 662. 7-a-L-Arabinosyl(1 ! 6)glucoside* 6-Hydroxytricetin 6,4’,5’-trimethyl ether 663. 3’-Rhamnoside* 6-Hydroxytricetin 6,7,3’,5’-tetramethyl ether 664. 5-Robinobioside* 8-Hydroxytricetin 665. 5-Rhamnoside* 666. 5-Glucoside* 667. 7-Glucuronide 5,6,7,8,3’,4’-Hexahydroxyflavone 688. 7-Glucoside* 5,7,2’,5’-Tetrahydroxy-8,6’-dimethoxyflavone (viscidulin III) 669. 2’-Glucoside*

823

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Flavonoids: Chemistry, Biochemistry, and Applications

5,2’,6’-Trihydroxy-6,7,8-trimethoxyflavone 670. 2’-Glucoside* 5,4’-Dihydroxy-7,8,2’,3’-tetramethoxyflavone 671. 5-Glucoside C-Methylflavones 5,7-Dihydroxy-6-C-methylflavone 672. 7-Xylosyl(1 ! 3)xyloside* 3-C-Methylapigenin 673. 5-Rhamnoside 5,7,4’-Trihydroxy-3’-C-methylflavone 674. 4’-Rhamnoside 5,7-Dihydroxy-6,8-di-C-methylflavone (matteuorien) 675. 7-[6’’-(3-Hydroxy-3-methylglutaryl)glucoside]* 3-C-Methylluteolin 676. 5-Rhamnoside 677. Stachysetin (13.5)* Prenylated flavones 8-Prenylapigenin 678. 4’-Rutinoside* 3’-Prenylapigenin 679. 7-Rutinoside* 8-C-Prenyl-5,7,4’-trihydroxy-3’-methoxyflavone (8-C-Prenylchrysoeriol) 680. 7-Glucosyl(1 ! 3)-a-L-arabinopyranoside* *Flavone glycosides newly reported since 1992.

APPENDIX B CHECKLIST

OF

KNOWN FLAVONOL GLYCOSIDES 3⬘ 2⬘

4⬘

8 O

7

5⬘ 6⬘

3

6

OH

5 O 13.10

3,5,7-Trihydroxyflavone (galangin) 1. 3-Glucoside 2. 7-Glucoside 3. 3-Rutinoside 4. 3-Galactosyl(1 ! 4)rhamnoside 5. 8-Glucoside-8-sulfate* 6. 8-Sulfate* 3,7-Dihydroxy-8-methoxyflavone 7. 7-Rhamnoside* 8. 7-Rhamnosyl(1 ! 4)rhamnosyl(1 ! 6)glucoside* 3,7,4’-Trihydroxyflavone 9. 3-Glucoside

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Flavone and Flavonol O-Glycosides

10. 7-Glucoside 11. 4’-Glucoside 12. 7-Rutinoside 5,7-Dihydroxy-3,6-dimethoxyflavone 13. 5-a-L-Arabinosyl(1 ! 6)glucoside* 3,6,7-Trihydroxy-4’-methoxyflavone 14. 7-Rhamnoside* 8-Hydroxygalangin 3-methyl ether 15. 8-(Z-2-Methyl-2-butenoate) 16. 8-(2-Methylbutyrate) 8-Hydroxygalangin 7-methyl ether 17. 8-Acetate 18. 8-Butyrate 3,7,3’,4’-Tetrahydroxyflavone (fisetin) 19. 3-Glucoside 20. 7-Glucoside 21. 4’-Glucoside 22. 7-Rutinoside 3,7,4’-Trihydroxy-3’-methoxyflavone (geraldol) 23. 4’-Glucoside 3,5,7,4’-Tetrahydroxyflavone (kaempferol) 24. 3-a-D-Arabinopyranoside* 25. 3-Arabinofuranoside (juglanin) 26. 3-Xyloside 27. 3-Rhamnoside (afzelin) 28. 3-Glucoside (astragalin) 29. 3-a-D-Galactoside 30. 3-b-D-Galactoside (trifolin) 31. 3-Alloside (asiaticalin) 32. 3-Glucuronide 33. 3-(6’’-Ethylglucuronide) 34. 5-Rhamnoside 35. 5-Glucoside 36. 5-Glucuronide* 37. 7-Arabinoside 38. 7-Xyloside 39. 7-Rhamnoside 40. 7-Glucoside (populnin) 41. 7-Alloside* 42. 4’-Rhamnoside 43. 4’-Glucoside 44. 3-Rhamnosyl(1 ! 2)-a-L-arabinofuranoside (arapetaloside B)* 45. 3-Xylosyl(1 ! 2)rhamnoside 46. 3-Rhamnosylxyloside 47. 3-Arabinosyl(1 ! 6)galactoside 48. 3-Xylosyl(1 ! 2)glucoside* 49. 3-Xylosyl(1 ! 2)galactoside 50. 3-Rhamnosyl(1 ! 2)rhamnoside* 51. 3-Apiosyl(1 ! 2)glucoside 52. 3-Apiosyl(1 ! 2)galactoside 53. 3-Glucosyl(1 ! 2)rhamnoside*

825

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54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103.

Flavonoids: Chemistry, Biochemistry, and Applications

3-Glucosyl(1 ! 4)rhamnoside 3-Rutinoside 3-Neohesperidoside 3-Rhamnosyl(1 ! 3)glucoside (rungioside) 3-Robinobioside 3-Rhamnosyl(1 ! 2)galactoside 3-Sambubioside 3-Gentiobioside 3-Sophoroside 3-Glucosyl(1 ! 6)galactoside 3-Glucosyl(1 ! 2)galactoside 3-Galactosylglucoside 3-Digalactoside 7-Glucosyl(1 ! 4)xyloside* 7-Neohesperidoside* 7-Glucosyl(1 ! 3)rhamnoside* 7-Galactosyl(1 ! 4)rhamnoside 7-Sophoroside 3,5-Diglucoside 3,5-Digalactoside 3,7-Diarabinoside 3-Arabinoside-7-rhamnoside 3-a-L-Arabinofuranoside-7-a-L-rhamnopyranoside 3-Rhamnoside-7-arabinoside 3-Glucoside-7-arabinoside 3-Xyloside-7-rhamnoside 3-Rhamnoside-7-xyloside 3-Xyloside-7-glucoside 3-Glucoside-7-xyloside 3,7-Dirhamnoside 3-Rhamnoside-7-glucoside 3-a-D-Glucoside-7-a-L-rhamnoside 3-b-D-Glucoside-7-rhamnoside 3-Galactoside-7-rhamnoside 3-Glucoside-7-galactoside 3,7-Diglucoside 3-Rhamnoside-7-galacturonide 3-Glucoside-7-glucuronide 3-Glucuronide-7-glucoside 3,4’-Dixyloside 3,4’-Diglucoside* 3-Rhamnoside-4’-arabinoside 3-Rhamnoside-4’-xyloside 3-Galactoside-4’-glucoside 7,4’-Dirhamnoside 7-Rhamnoside-4’-glucoside* 7,4’-Diglucoside* 3-Glucosyl-b-(1 ! 4)arabinofuranosyl-a-(1 ! 2)arabinopyranoside (primflasine) 3-Xylosylrutinoside 3-Xylosyl(1 ! 3)rhamnosyl(1 ! 6)galactoside*

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Flavone and Flavonol O-Glycosides

104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153.

3-Xylosyl(1 ! 6)glucosyl(1 ! 2)rhamnoside* 3-Rhamnosyl(1 ! 2)rhamnosyl(1 ! 6)glucoside 3-Rhamnosyl(1 ! 3)rhamnosyl(1 ! 6)glucoside* 3-Rhamnosyl(1 ! 4)rhamnosyl(1 ! 6)glucoside 3-Rhamnosyl(1 ! 3)rhamnosyl(1 ! 6)galactoside (rhamninoside) 3-Rhamnosyl(1 ! 4)rhamnosyl(1 ! 6)galactoside (isorhamninoside) 3-Rhamnosyl(1 ! 2)glucosyl(1 ! 6)galactoside* 3-Rhamnosyl(1 ! 6)glucosyl(1 ! 6)galactoside* 3-Glucosyl(1 ! 4)rhamnosyl(1 ! 2)glucoside* 3-Glucosyl(1 ! 3)rhamnosyl(1 ! 6)galactoside 3-Glucosyl(1 ! 2)gentiobioside 3-Sophorotrioside 3-b-Maltosyl(1 ! 6)glucoside 3-Glucosyl(1 ! 2)galactosyl(1 ! 2)glucoside* 3-Xylosyl(1 ! 2)[rhamnosyl(1 ! 6)glucoside] 3-Rhamnosyl(1 ! 2)[rhamnosyl(1 ! 6)glucoside] (mauritianin) 3-Rhamnosyl(1 ! 2)[glucosyl(1 ! 3)glucoside]* 3-Rhamnosyl(1 ! 2)[glucosyl(1 ! 4)glucoside]* 3-Rhamnosyl(1 ! 6)[glucosyl(1 ! 2)glucoside] 3-Glucosyl(1 ! 2)[glucosyl(1 ! 3)rhamnoside]* 3-Glucosyl(1 ! 2)[rhamnosyl(1 ! 6)galactoside] 3-Galactosyl(1 ! 2)[rhamnosyl(1 ! 6)glucoside] 3-(2G-Rhamnosylrutinoside) 3-(2G-Rhamnosylgentiobioside) 3-(3R-Glucosylrutinoside) 3-(2G-Glucosylrutinoside) 3-(2’-Rhamnosyllaminaribioside) 3-(2G-Glucosylgentiobioside) 3-Apiosyl(1 ! 2)[rhamnosyl(1 ! 6)galactoside] 7-(3G-Glucosylgentiobioside)* 4’-Rhamnosyl(1 ! 2)[rhamnosyl(1 ! 6)galactoside] 3-Rhamnosylarabinoside-7-rhamnoside 3-Rhamnosyl(1 ! 2)galactoside-7-a-L-arabinofuranoside* 3-Robinobioside-7-a-L-arabinofuranoside* 3-Glucosylxyloside-7-xyloside 3-b-D-Apiofuranosyl(1 ! 2)-a-L-arabinofuranosyl-7-a-L-rhamnoside 3-Xylosyl(1 ! 2)rhamnoside-7-rhamnoside (sagittatin A) 3-Xylosyl(1 ! 4)rhamnoside-7-rhamnoside* 3-Rhamnoside-7-xylosyl(1 ! 2)rhamnoside* 3-Apiosyl(1 ! 4)rhamnoside-7-rhamnoside* 3-Rhamnosyl(1 ! 4)rhamnoside-7-rhamnoside 3-Rhamnosylxyloside-7-glucoside 3-Neohesperidoside-7-rhamnoside* 3-Glucosylrhamnoside-7-rhamnoside 3-Rutinoside-7-rhamnoside 3-Rhamnoside-7-rhamnosylglucoside 3-Rhamnoside-7-glucosyl(1 ! 2)rhamnoside* 3-Glucosyl(1 ! 3)rhamnoside-7-rhamnoside 3-Rhamnosyl(1 ! 2)galactoside-7-rhamnoside 3-Robinobioside-7-rhamnoside (robinin)

827

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154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169. 170. 171. 172. 173. 174. 175. 176. 177. 178. 179. 180. 181. 182. 183. 184. 185. 186. 187. 188. 189. 190. 191. 192. 193. 194. 195. 196. 197. 198. 199. 200. 201. 202. 203.

Flavonoids: Chemistry, Biochemistry, and Applications

3-Rhamnosyl(1 ! 2)galactoside-7-glucoside 3-Sophoroside-7-a-L-arabinoside 3-Glucosyl(1 ! 4)galactoside-7-a-L-arabinofuranoside* 3-Glucosyl(1 ! 6)galactoside-7-a-L-arabinofuranoside* 3-Apioside-7-rhamnosyl(1 ! 6)galactoside* 3-Robinobioside-7-glucoside 3-Lathyroside-7-rhamnoside 3-Sambubioside-7-glucoside 3-Rutinoside-7-glucoside 3-Neohesperidoside-7-glucoside 3-Glucosyl(1 ! 2)rhamnoside-7-glucoside* 3-Rutinoside-7-galactoside 3-Rutinoside-7-glucuronide 3-Sophoroside-7-rhamnoside 3-Laminaribioside-7-rhamnoside 3-Gentiobioside-7-rhamnoside* 3-Sophoroside-7-glucoside 3-Glucoside-7-sophoroside 3-Gentiobioside-7-glucoside 3-Glucoside-7-gentiobioside 3-Glucosyl(1 ! 2)galactoside-7-glucoside* 3-Sophoroside-7-glucuronide* 3-Gentiobioside-7-glucuronide 3-Rutinoside-4’-glucoside 3-Neohesperidoside-4’-glucoside* 3-Neohesperidoside-7,4’-diglucoside* 3-Sophoroside-4’-glucoside 3-Gentiobioside-4’-glucoside* 3-Glucoside-7,4’-dirhamnoside 3-Galactoside-3,4’-dirhamnoside* 3-Rhamnoside-7,4’-digalactoside* 4’-Rhamnosyl(1 ! 3)rhamnosyl(1 ! 6)galactoside* 3,7,4’-Triglucoside 3-Rhamnosyl(1 ! 2)[xylosyl(1 ! 3)rhamnosyl(1 ! 6)galactoside]* 3-Glucosyl(1 ! 3)rhamnosyl(1 ! 2)[rhamnosyl(1 ! 6)galactoside]* 3-Xylosylrutinoside-7-glucoside 3-Rhamnosyl(1 ! 4)rhamnosyl(1 ! 6)galactoside-7-rhamnoside* 3-Sophorotrioside-7-rhamnoside 3-Rutinoside-7-sophoroside* 3-(2G-Glucosylrutinoside)-7-rhamnoside* 3-(2G-Rhamnosylrutinoside)-7-glucoside* (mauritianin 7-glucoside) 3-Galactosyl(1 ! 6)glucoside-7-dirhamnoside (malvitin) 3-Sophorotrioside-7-glucoside 3-Sophoroside-7-cellobioside* 3-Rhamnosyl(1 ! 6)[glucosyl(1 ! 2)glucoside]-7-glucoside 3-(2G-Glucosylrutinoside)-7-glucoside 3-Rhamnosyl(1 ! 6)[rhamnosyl(1 ! 2)galactoside]-7-rhamnoside* (astrasikokioside) 3-Glucosyl(1 ! 2)[rhamnosyl(1 ! 6)galactoside]-7-rhamnoside* 3-Rutinoside-4’-diglucoside 3-Gentiobioside-7,4’-bisglucoside

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Flavone and Flavonol O-Glycosides

204. 3-Z/E-p-Coumarate 205. 3-[6’’-(3-Hydroxy-3-methylglutaryl)glucoside]* 206. 3-(p-Hydroxybenzoylglucoside) 207. 3-(6’’-p-Hydroxybenzoylgalactoside)* 208. 3-Benzoylglucoside 209. 3-(6’’-Succinylglucoside) 210. 3-(6’’-Malonylglucoside) 211. 3-(6’’-Malonylgalactoside) 212. 3-(2’’-Galloylarabinoside)* 213. 3-(2’’-Galloylglucoside) 214. 3-(6’’-Galloylglucoside) 215. 3-(6’’-Galloylgalactoside)* 216. 3-(2’’,6’’-Digalloylglucoside)* 217. 3-(6’’-Z-Cinnamoylglucoside) 218. 3-(2’’-E-p-Coumaroyl-a-L-arabinofuranoside)* 219. 3-(2’’-E-p-Coumaroylrhamnoside)* 220. 3-(2’’-Z-p-Coumaroylrhamnoside)* 221. 3-(X’’-p-Coumaroylglucoside) (tiliroside) 222. 3-(2’’-Z-p-Coumaroylglucoside) 223. 3-(3’’-p-Coumaroylglucoside) 224. 3-(4’’-p-Coumaroylglucoside)* 225. 3-(6’’-p-Coumaroylglucoside) (tribuloside) 226. 3-(6’’-p-Coumaroylgalactoside) 227. 3-(6’’-Caffeoylglucoside)* 228. 3-(5’’-Feruloylapioside)* 229. 3-(6’’-Feruloylglucoside)* 230. 3-(2’’-Acetylrhamnoside) 231. 3-(3’’-Acetylrhamnoside) 232. 3-(4’’-Acetylrhamnoside) 233. 3-(6’’-Acetylglucoside)* 234. 3-(3’’,4’’-Diacetylglucoside)* 235. 7-(6’’-Succinylglucoside) 236. 7-Galloylglucoside 237. 7-(6’’-p-Coumaroylglucoside)* 238. 3-(2’’,3’’-Di-E-p-coumaroylrhamnoside)* 239. 3-(2’’,4’’-Di-E-p-coumaroylrhamnoside)* 240. 3-(2’’,4’’-Di-Z-p-coumaroylrhamnoside)* 241. 3-(2’’,4’’-Di-p-coumaroylglucoside) 242. 3-(2’’,6’’-Di-E-p-coumaroylglucoside) 243. 3-(2’’,6’’-Di-Z-p-coumaroylglucoside)* 244. 3-(3’’,6’’-Di-Z-p-coumaroylglucoside) (stenopalustroside A)* 245. 3-(6’’-p-Coumaroylacetylglucoside) 246. 3-(3’’-Z-p-Coumaroyl-6’’-feruloylglucoside) (stenopalustroside B)* 247. 3-(4’’-Acetyl-6’’-p-coumaroylglucoside) 248. 3-(3’’-Z-p-Coumaroyl-6’’-E-p-coumaroylglucoside) (stenopalustroside C)* 249. 3-(3’’-E-p-Coumaroyl-6’’-Z-p-coumaroylglucoside) (stenopalustroside D)* 250. 3-(3’’-E-p-Coumaroyl-[6’’-(4-O-{4-hydroxy-3-methoxyphenyl)-1,3dihydroxyisopropyl-feruloyl}]glucoside (stenopalustroside E)* 251. 3-(2’’-E-p-Coumaroyl-6’’-acetylglucoside)* 252. 3-(3’’-Acetyl-6’’-p-coumaroylglucoside)*

829

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830

253. 254. 255. 256. 257. 258. 259. 260. 261. 262. 263. 264. 265. 266. 267. 268. 269. 270. 271. 272. 273. 274. 275. 276. 277. 278. 279. 280. 281. 282. 283. 284. 285. 286. 287. 288. 289. 290. 291. 292. 293. 294. 295. 296. 297. 298. 299. 300. 301. 302.

Flavonoids: Chemistry, Biochemistry, and Applications

3-(3’’,4’’-Diacetylglucoside)* 3-(2’’,3’’-Diacetyl-4’-p-coumaroylrhamnoside) 3-(2’’,3’’-Diacetyl-4’’-Z-p-coumaroyl)-6’’-(E-p-coumaroylglucoside) 3-(3’’,4’’-Diacetyl-2’’,6’’-di-E-p-coumaroylglucoside) 3-Apiosylmalonylglucoside 3-(6G-Malonylneohesperidoside)* 3-(2’’-E-Feruloylgalactosyl)(1 ! 4)glucoside* 3-(2’’-E-Feruloylgalactosyl)(1 ! 6)glucoside* 3-(2G-E-p-Coumaroylrutinoside)* 3-(4’’-E-p-Coumaroylrobinobioside) 3-(6’’’-p-Coumaroylglucosyl)(1 ! 2)rhamnoside 3-(4’’-Z-p-Coumaroylrobinobioside) 3-(6’’-Caffeylglucosyl)(1 ! 4)rhamnoside* 3-(Feruloylsophoroside) (petunoside) 3-(6’’-E-Feruloylglucosyl)(1 ! 2)galactoside* 3-(6’’’-Sinapoylglucosyl)(1 ! 2)galactoside* 3-(3’’’-Acetyl-a-L-arabinopyranosyl)(1 ! 6)glucoside* 3-(2’’’-Acetylarabinosyl)(1 ! 6)galactoside 3-(6’’’-Acetylglucosyl)(1 ! 3)galactoside* 3-[2’’’-Feruloylglucosyl(1 ! 2)6’’-malonylglucoside]* 3-Benzoylglucoside-7-glucoside 3-p-Hydroxybenzoylglucoside-7-glucoside 3-[6’’-(3-Hydroxy-3-methylglutaryl)glucoside]-7-glucoside* 3-(6’’-Malonylglucoside)-7-glucoside* 3-(2’’-E-p-Coumaroyl-a-L-arabinofuranoside)-7-rhamnoside* 3-(3’’-p-Coumaroylrhamnoside)-7-rhamnoside* 3-(6’’-E-p-Coumaroylglucoside)-7-glucoside* 3-Glucoside-7-(p-coumaroylglucoside) 3-Caffeoylsophoroside 3-(6’’’-Caffeoylglucosyl)(1 ! 2)galactoside 3-(2’’-Caffeoylglucoside)-7-rhamnoside 3-(Caffeoylglucoside)-7-glucoside 3-Feruloylglucoside-7-glucoside 3-(3’’-Acetylarabinofuranoside)-7-glucoside 3-(4’’-Acetylrhamnoside)-7-rhamnoside (sutchuenoside A) 3-(6’’-Acetylglucoside)-7-rhamnoside 3-(6’’-Acetylgalactoside)-7-rhamnoside 3-(6’’-Acetylglucoside)-7-glucoside 3-(2’’,3’’-Diacetylrhamnoside)-7-rhamnoside* 3-(2’’,4’’-Diacetylrhamnoside)-7-rhamnoside* 3-(3’’,4’’-Diacetylrhamnoside)-7-rhamnoside* 3-(4’’,6’’-Diacetylrhamnoside)-7-rhamnoside* 3-(2’’’,3’’’,4’’’-Triacetyl-a-L-arabinopyranosyl)(1 ! 6)glucoside* 3-(2’’’,3’’’,5’’’-Triacetylarabinofuranosyl)(1 ! 6)glucoside 3-[6’’’-(7’’’’-Glucosyl-p-coumaroyl)glucosyl](1 ! 2)rhamnoside* 3-(p-Coumaroylsophoroside) 3-(p-Coumarylglucoside)-4’-glucoside 3-(2-Hydroxypropionylglucoside)-4’-glucoside 3-[2Gal-(6’’-Feruloylglucosyl)robinobioside]* 3-(p-Coumaroylsophorotrioside)

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Flavone and Flavonol O-Glycosides

303. 304. 305. 306. 307. 308. 309. 310. 311. 312. 313. 314. 315. 316. 317. 318. 319. 320. 321. 322. 323. 324. 325. 326. 327. 328. 329. 330. 331. 332. 333. 334. 335. 336. 337. 338. 339. 340. 341. 342. 343. 344. 345. 346. 347. 348. 349. 350. 351. 352.

831

3-(Feruloylsophorotrioside) 3-Glucosyl(1 ! 4)[(6’’’-sinapoylglucosyl)(1 ! 2)galactoside]* 3-(2’’’-Sinapoylglucosyl)(1 ! 4)[(6’’’-sinapoylglucosyl)(1 ! 2)galactoside]* 3-Rhamnosyl(1 ! 4)(3’’’-acetylrhamnosyl)(1 ! 6)galactoside 3-Rhamnosyl(1 ! 3)(4’’’-acetylrhamnosyl)(1 ! 6)glucoside* 3-Rhamnosyl(1 ! 3)(2’’’-acetylrhamnosyl)(1 ! 6)galactoside* 3-Glucosyl(1 ! 3)(4’’’-acetylrhamnosyl)(1 ! 6)galactoside 3-[2-Gal-(6’’’-Feruloylglucosyl)robinobioside]* 3-[2Gal-(4’’-Acetylrhamnosyl)robinobioside]* 3-[2’’-(4’’’-Acetylrhamnosyl)sophoroside]* 3-Neohesperidoside-7-(6’’-malonylglucoside)* 3-(4’’-E-p-Coumaroylrobinobioside)-7-rhamnoside 3-(4’’-Z-p-Coumaroylrobinobioside)-7-rhamnoside (variabiloside D) 3-(p-Coumaroylrutinoside)-7-glucoside 3-Neohesperidoside-7-(2’’-E-p-coumaroylglucoside)* 3-(4’’-p-Coumaroylglucosyl)(1 ! 2)rhamnoside-7-glucoside* 3-(6’’-p-Coumaroylglucosyl)(1 ! 2)rhamnoside-7-glucoside* 3-Glucosyl(1 ! 2)rhamnoside-7-(6’’-E-p-coumaroylglucoside)* 3-(6’’’-E-p-Coumaroylglucosyl)(1 ! 2)glucoside-7-rhamnoside* 3-Glucoside-7-(6’’’-E-p-coumaroylglucosyl)(1 ! 3)rhamnoside* 3-(2’’’-E-p-Coumaroylsophoroside)-7-glucoside* 3-Apioside-7-rhamnosyl(1 ! 6)(2’’-E-caffeoylgalactoside)* 3-(Caffeoylrobinobioside)-7-rhamnoside 3-(6’’-E-Caffeoylglucosyl)(1 ! 2)glucoside-7-rhamnoside* 3-Glucoside-7-(6’’-E-caffeoylglucosyl)(1 ! 3)rhamnoside* 3-(2’’-Caffeoyllaminaribioside)-7-rhamnoside 3-(4’’-Caffeoyllaminaribioside)-7-rhamnoside 3-(2’’’-E-p-Coumaroylsophoroside)-7-glucoside* 3-(2’’’-E-Caffeoylsophoroside)-7-glucoside* 3-(Feruloylrobinobioside)-7-rhamnoside 3-Neohesperidoside-7-(2’’-E-feruloylglucoside)* 3-(2’’’-E-Feruloylsophoroside)-7-glucoside* 3-Sophoroside-7-(2’’-feruloylglucoside) 3-(Sinapoylsophoroside)-7-glucoside 3-Xylosyl(1 ! 3)(4’’-acetylrhamnoside)-7-rhamnoside 3-Xylosyl(1 ! 2)rhamnoside-7-(4’’’’-acetylrhamnoside)* 3-Neohesperidoside-7-(6’’-acetylglucoside)* 3-Glucosyl(1 ! 2)(6’’-acetylgalactoside)-7-glucoside* 3,4’-Diglucoside-7-(2’’-feruloylglucoside) 3-(p-Coumaroylglucoside)-7,4’-diglucoside 3-(2’’-Feruloylglucoside)-7,4’-diglucoside 3-(Sinapoylglucoside)-7-sophoroside 3-(p-Coumaroylferuloyldiglucoside)-7-rhamnoside 3-Rhamnosyl(1 ! 2)[glucosyl(1 ! 3)(4’’’-p-coumaroylrhamnosyl)(1 ! 6)galactoside]* 3-Rhamnosyl(1 ! 2)[xylosyl(1 ! 3)rhamnosyl(1 ! 6)(3’’-p-coumaroylgalactoside)]* 3-Rhamnosyl(1 ! 2)[xylosyl(1 ! 3)rhamnosyl(1 ! 6)(4’’-p-coumaroylgalactoside)]* 3-Rhamnosyl(1 ! 2)[xylosyl(1 ! 3)rhamnosyl(1 ! 6)(3’’-feruloylgalactoside)]* 3-Rhamnosyl(1 ! 2)[xylosyl(1 ! 3)rhamnosyl(1 ! 6)(4’’-feruloylgalactoside)]* 3-Gentiobioside-7-(caffeoylarabinosylrhamnoside) 3-Neohesperidoside-7-[2’’-E-p-coumaroyllaminaribioside]*

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832

Flavonoids: Chemistry, Biochemistry, and Applications

353. 3-(2’’’-E-Caffeoylglucosyl)(1 ! 2)glucoside-7-cellobioside* 354. 3-(2’’’-E-Feruloylglucosyl)(1 ! 2)glucoside-7-cellobioside* 355. 3-(2’’’-E-Sinapoylglucosyl)(1 ! 2)glucoside-7-cellobioside* 356. 3-Glucosyl(1 ! 6)[rhamnosyl(1 ! 3)(2’’-E-p-coumaroylglucoside)]-7rhamnosyl(1 ! 3)rhamnosyl(1 ! 3)(4’’-E-p-coumaroylrhamnoside)* 357. 3-Glucosyl(1 ! 6)[rhamnosyl(1 ! 3)(2’’-E-p-coumaroylglucoside)]-7rhamnosyl(1 ! 3)rhamnosyl(1 ! 3)(4’’-Z-p-coumaroylrhamnoside)* 358. 3-Rhamnosyl(1 ! 6)[rhamnosyl(1 ! 3)(2’’-E-p-coumaroylglucoside)]-7rhamnosyl(1 ! 3)rhamnosyl(1 ! 3)(4’’-E-p-coumaroylrhamnoside)* 359. 3-Sulfatorhamnoside 360. 3-a-(6’’-Sulfatoglucoside) 361. 3-b-(3’’-Sulfatoglucoside) 362. 3-b-(6’’-Sulfatoglucoside) 363. 3-Glucuronide-7-sulfate 364. 3-Sulfatorutinoside 365. 3-(6’’-Sulfatogentiobioside) 366. 3-Sulfate-7-a-arabinopyranoside* 367. 3-Sulfate 368. 7-Sulfate 369. 8-Sulfate* 370. 3,7-Disulfate 371. 3,7,4’-Trisulfate Kaempferol 3-methyl ether 372. 7-Rhamnoside 373. 7-Glucoside 374. 7-Glucuronide* 375. 7-Rutinoside Kaempferol 5-methyl ether 376. 3-Galactoside Kaempferol 7-methyl ether (rhamnocitrin) 377. 3-Rhamnoside 378. 3-Alloside 379. 3-Glucoside 380. 3-Galactoside 381. 3-Glucuronide 382. 5-Glucoside 383. 4’-Glucoside* 384. 3-Rutinoside 385. 3-Neohesperidoside 386. 3-Galactoside-4’-glucoside 387. 3-Rhamnosyl(1 ! 3)rhamnosyl(1 ! 6)galactoside (3-rhamninoside, alaternin, catharticin) 388. 3-Rhamnosyl(1 ! 4)rhamnosyl(1 ! 6)galactoside (3-isorhamninoside) 389. 3-Xylosyl(1 ! 2)[rhamnosyl(1 ! 6)glucoside]* 390. 3-Rhamnosyl(1 ! 3)[apiosyl(1 ! 6)glucoside]* 391. 3-Apiosyl(1 ! 5)apioside-4’-glucoside* 392. 3-Neohesperidoside-4’-glucoside* 393. 3-Apiosyl(1 ! 5)apiosyl(1 ! 2)[rhamnosyl(1 ! 6)glucoside]* 394. 3-[3-Hydroxy-3-methylglutaryl(1 ! 6)][apiosyl(1 ! 2)galactoside]* 395. 3-(5’’’-p-Coumaroylapiosyl)(1 ! 2)glucoside*

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Flavone and Flavonol O-Glycosides

396. 3-(5’’’-Feruloyllapiosyl)(1 ! 2)glucoside* 397. 3-(6’’-E-Sinapoylglucosyl)(1 ! 2)rutinoside* 398. 3-Glucoside-4’-(2’’-dihydrophaseoylglucoside) 399. 3-Glucoside-4’-(3’’’-dihydrophaseoylglucoside)* 400. 3-(6-E-3,5-Dimethoxy-4hydroxycinnamoylglucosyl)(1 ! 2)[rhamnosyl(1 ! 6)glucoside]* 401. 3-Sulfate Kaempferol 4’-methyl ether (kaempferide) 402. 3-Rhamnoside* 403. 3-Galactoside 404. 3-Glucuronide 405. 3-Neohesperidoside* 406. 3-Diglucoside 407. 3-Rhamnoside-7-xyloside* 408. 3,7-Dirhamnoside 409. 3-Rhamnoside-7-glucoside 410. 3-Glucoside-7-rhamnoside 411. 3,7-Diglucoside 412. 3-(4Rha-Rhamnosylrutinoside)* 413. 3-(2Glc-Glucosylrutinoside)* 414. 3-[6’’’-Acetyl(4’’-a-methylsinapoylneohesperidoside)]* 415. 3-Rhamnoside-7-(6’’-succinylglucoside) 416. 3-Sulfate Kaempferol 3,5-dimethyl ether 417. 7-Glucoside* Kaempferol 3,7-dimethyl ether 418. 4’-Glucoside* Kaempferol 3,4’-dimethyl ether 419. 7-Glucoside Kaempferol 7,4’-dimethyl ether 420. 3-Glucoside* 421. 3-Neohesperidoside* 422. 3-(6’’-p-Coumaroylglucoside) 423. 3-Sulfate 6-C-Methylkaempferol 424. 3-Glucoside 6-Hydroxykaempferol 425. 3-Glucoside* 426. 7-Glucoside 427. 7-Alloside* 428. 3-Rutinoside* 429. 7-Rutinoside 430. 3,6-Diglucoside* 431. 3-Rutinoside-6-glucoside* 432. 3,6,7-Triglucoside* 433. 7’-(6’’-Caffeoylglucoside)* 434. 7-Acetylglucoside 6-Hydroxykaempferol 3-methyl ether 435. 6-Glucoside 436. 7-Glucoside

833

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834

Flavonoids: Chemistry, Biochemistry, and Applications

437. 7-Sulfate 6-Hydroxykaempferol 5-methyl ether 438. 4’-Rhamnoside 439. 3-Arabinosylrhamnoside 6-Hydroxykaempferol 6-methyl ether (eupafolin) 440. 3-Rhamnoside 441. 3-Glucoside 442. 3-Galactoside 443. 3-Glucuronide 444. 7-Glucoside 445. 4’-Rhamnoside 446. 3-Rutinoside 447. 3-Robinobioside 448. 3,7-Dirhamnoside 449. 3-(6’’-p-Coumaroylglucoside)* 450. 3-Rhamnoside-7-(4’’’-acetylrhamnoside) 451. 3-(3’’-Acetylrhamnoside)-7-(3’’-acetylrhamnoside) 452. 3-(6’’-Acetylglucoside) 453. 3-Sulfate 6-Hydroxykaempferol 7-methyl ether 454. 6-Rhamnosyl(1 ! 4)xyloside 6-Hydroxykaempferol 4’-methyl ether 455. 7-Glucoside* 456. 7-Galactoside* 457. 3,7-Dirhamnoside 6-Hydroxykaempferol 3,6-dimethyl ether 458. 7-Glucoside 6-Hydroxykaempferol 6,7-dimethyl ether (eupalitin) 459. 3-Rhamnoside (eupalin) 460. 3-Galactoside 461. 5-Rhamnoside 462. 3-Galactosylrhamnoside 463. 3-Diglucoside 464. 3-Glucosylgalactoside 465. 3-Sulfate 6-Hydroxykaempferol 6,4’-dimethyl ether 466. 3-Glucoside* 467. 3-Galactoside 6-Hydroxykaempferol 7,4’-dimethyl ether 468. 3-Glucoside 469. 3-Sulfate 6-Hydroxykaempferol 3,6,7-trimethyl ether 470. 4’-Glucoside 6-Hydroxykaempferol 6,7,4’-trimethyl ether (mikanin) 471. 3-Glucoside 472. 3-Galactoside 6-Hydroxykaempferol 3,5,7,4’-tetramethyl ether 473. 6-Rhamnoside* 8-Hydroxykaempferol (herbacetin)

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Flavone and Flavonol O-Glycosides

474. 3-Glucoside 475. 3-b-D-Glucofuranoside* 476. 7-Arabinoside 477. 7-Rhamnoside 478. 7-Glucoside 479. 8-a-L-Arabinopyranoside 480. 8-Xyloside 481. 8-Rhamnoside 482. 8-Glucoside 483. 4’-Glucoside 484. 3-Rhamnoside-8-glucoside* 485. 3-Glucuronide-8-glucoside 486. 7-Glucosyl(1 ! 3)rhamnoside 487. 8-Rutinoside 488. 8-Gentiobioside 489. 3-Glucoside-8-xyloside 490. 7-Rhamnoside-8-glucoside 491. 8,4’-Dixyloside 492. 8-Arabinoside-4’-xyloside 493. 3-Sophoroside-8-glucoside 494. 7-(6’’-Quinylglucoside) 495. 8-(3’’-Acetyl-a-L-arabinopyranoside) 496. 8-(3’’-Acetylxyloside) 497. 8-(2’’,3’’-Diacetylxyloside) 498. 8-(Diacetylglucoside) 499. 8-(2’’,3’’,4’’-Triacetylxyloside) 500. 8-Acetate 501. 8-Butyrate Herbacetin 7-methyl ether 502. 8-Sophoroside* 503. 3-(2’’-E-Feruloylglucoside)* 504. 8-Acetate 505. 8-Butyrate Herbacetin 8-methyl ether (sexangularetin) 506. 3-Glucoside 507. 3-Galactoside 508. 3-Rutinoside 509. 3-Neohesperidoside* 510. 3-Sophoroside* 511. 3-Glucoside-7-rhamnoside 512. 3,7-Diglucoside 513. 3-Rhamnosylglucoside-7-rhamnoside 514. 3-Rutinoside-7-glucoside 515. 3-Glucoside-7-rutinoside Herbacetin 7,8-dimethyl ether 516. 3-Rhamnoside Herbacetin 7,4’-dimethyl ether 517. 8-Acetate 518. 8-Butyrate Herbacetin 7,8,4’-trimethyl ether (tambulin) 519. 3,5-Diacetate*

835

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836

Flavonoids: Chemistry, Biochemistry, and Applications

5,7,8-Trihydroxy-3-methoxyflavone 520. 8-(E-2-Methylbut-2-enoate)* 5,7,8-Trihydroxy-3,6-dimethoxyflavone 521. 8-(E-2-Methylbut-2-enoate)* 6,8-Dihydroxykaempferol 522. 3-Rutinoside* 3,5,7,3’,4’-Pentahydroxyflavone (quercetin) 523. 3-a-L-Arabinofuranoside (avicularin) 524. 3-a-L-Arabinopyranoside (guaijaverin, foeniculin) 525. 3-a-D-Arabinopyranoside* 526. 3-b-L-Arabinoside (polystachioside) 527. 3-Xyloside (reynoutrin) 528. 3-Rhamnoside (quercitrin) 529. 3-Glucoside (isoquercitrin) 530. 3-Galactoside (hyperin) 531. 3-Alloside 532. 3-Glucuronide (miquelianin) 533. 3-Galacturonide 534. 3-(6’’-Methylglucuronide) 535. 3-(6’’-Ethylglucuronide) 536. 5-Glucoside 537. 5-Glucuronide* 538. 7-Arabinoside 539. 7-Xyloside 540. 7-Rhamnoside 541. 7-Glucoside (quercimeritrin) 542. 7-a-Galactoside 543. 3’-Xyloside 544. 3’-Glucoside 545. 4’-Glucoside (spiraeoside) 546. 4’-Galactoside* 547. 4’-Glucuronide* 548. 3-Diarabinoside 549. 3-Arabinosylxyloside 550. 3-Rhamnosyl(1 ! 2)-a-L-arabinofuranoside (arapetaloside A)* 551. 3-Rhamnosyl(1 ! 2)arabinoside 552. 3-a-L-Arabinofuranosyl(1 ! 2)glucoside* 553. 3-Arabinosyl(1 ! 6)glucoside (vicianoside) 554. 3-Arabinosyl(1 ! 6)galactoside 555. 3-Galactosylarabinoside 556. 3-Dixyloside 557. 3-Xylosyl(1 ! 2)rhamnoside 558. 3-Xylosyl(1 ! 2)glucoside (3-sambubioside) 559. 3-Xylosyl(1 ! 6)glucoside* 560. 3-Glucosyl(1 ! 2)xyloside 561. 3-Xylosyl(1 ! 2)galactoside 562. 3-Apiofuranosyl(1 ! 2)arabinoside 563. 3-Apiofuranosyl(1 ! 2)xyloside 564. 3-Rhamnosylxyloside 565. 3-Rhamnosyl(1 ! 2)rhamnoside*

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 837 6.10.2005 10:36am

Flavone and Flavonol O-Glycosides

566. 567. 568. 569. 570. 571. 572. 573. 574. 575. 576. 577. 578. 579. 580. 581. 582. 583. 584. 585. 586. 587. 588. 589. 590. 591. 592. 593. 594. 595. 596. 597. 598. 599. 600. 601. 602. 603. 604. 605. 606. 607. 608. 609. 610. 611. 612. 613. 614. 615.

3-Rhamnosyl(1 ! 2)galactoside 3-Apiofuranosyl(1 ! 2)glucoside 3-Apiofuranosyl(1 ! 2)galactoside 3-Rutinoside (rutin) 3-Neohesperidoside 3-Glucosyl(1 ! 2)rhamnoside* 3-Glucosyl(1 ! 4)rhamnoside 3-Galactosyl(1 ! 2)rhamnoside* 3-Galactosyl(1 ! 4)rhamnoside 3-Rhamnosyl(1 ! 6)galactoside 3-Laminaribioside* 3-Sophoroside 3-Gentiobioside 3-Galactosylglucoside 3-Glucosyl(1 ! 2)galactoside 3-Glucosyl(1 ! 3)galactoside* 3-Glucosyl(1 ! 4)galactoside* 3-Glucosyl(1 ! 6)galactoside 3-Digalactoside 3-Glucosylmannoside 3-Glucosyl(1 ! 2)glucuronide* 3-Galactosylglucuronide 7-Rutinoside 7-Glucosylrhamnoside 3,5-Digalactoside 3-Arabinoside-7-glucoside 3-Glucoside-7-arabinoside 3-Xyloside-7-glucoside 3-Galactoside-7-xyloside 3,7-Dirhamnoside 3-Rhamnoside-7-glucoside 3-Glucoside-7-rhamnoside 3-Galactoside-7-rhamnoside 3,7-Diglucoside 3-Galactoside-7-glucoside 3-Glucoside-7-glucuronide 3-Glucuronide-7-glucoside 3,7-Diglucuronide 3,3’-Diglucoside 3-Rhamnoside-3’-glucoside* 3,4’-Diglucoside 7,4’-Diglucoside 3-Xylosyl(1 ! 2)rhamnosyl(1 ! 6)glucoside* 3-Xylosyl(1 ! 6)glucosyl(1 ! 2)rhamnoside* 3-Rhamnosyl(1 ! 2)rutinoside 3-Rhamnosyl(1 ! 4)rhamnosyl(1 ! 6)glucoside 3-Rhamnosyl(1 ! 4)rhamnosyl(1 ! 6)galactoside 3-Apiosyl(1 ! 2)rhamnosyl(1 ! 6)glucoside* 3-(6’’’-Rhamnosylgentiobioside)* 3-Rhamnosyl(1 ! 2)glucosyl(1 ! 6)galactoside*

837

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838

616. 617. 618. 619. 620. 621. 622. 623. 624. 625. 626. 627. 628. 629. 630. 631. 632. 633. 634. 635. 636. 637. 638. 639. 640. 641. 642. 643. 644. 645. 646. 647. 648. 649. 650. 651. 652. 653. 654. 655. 656. 657. 658. 659. 660. 661. 662. 663. 664. 665.

Flavonoids: Chemistry, Biochemistry, and Applications

3-Rhamnosyl(1 ! 6)glucosyl(1 ! 6)galactoside* 3-Glucosyl(1 ! 4)galactosylrhamnoside 3-Glucosyl(1 ! 3)rhamnosyl(1 ! 6)galactoside 3-Sophorotrioside 3-Glucosyl(1 ! 2)galactosyl(1 ! 2)glucoside* 3-(2G-Rhamnosylrutinoside) 3-(2G-Apiosylrutinoside) 3-Rhamnosyl(1 ! 2)[rhamnosyl(1 ! 6)galactoside] 3-Xylosyl(1 ! 2)[rhamnosyl(1 ! 6)glucoside] 3-(2G-Glucosylrutinoside) 3-(3R-Glucosylrutinoside) 3-(2G-Rhamnosylgentiobioside) 3-Rhamnosyl(1 ! 2)[glucosyl(1 ! 6)galactoside] 3-Glucosyl(1 ! 2)[rhamnosyl(1 ! 6)galactoside]* 3-(2G-Glucosylgentiobioside) 7-(2G-Xylosylrutinoside)* 3-Rhamnosyl(1 ! 2)-a-L-arabinopyranoside-7-glucoside* 3-Dixyloside-7-glucoside 3-Xylosyl(1 ! 2)glucoside-7-rhamnoside* 3-Xyloside-7-xylosylglucoside 3-Xylosyl(1 ! 2)glucoside-7-glucoside (3-sambubioside-7-glucoside) 3-Rutinoside-7-rhamnoside 3-Neohesperidoside-7-rhamnoside* 3-Glucosyl(1 ! 2)rhamnoside-7-rhamnoside 3-Rhamnosyl(1 ! 4)rhamnoside-7-galactoside* 3-Robinobioside-7-rhamnoside 3-Rutinoside-7-glucoside 3-Neohesperidoside-7-glucoside* 3-Glucosyl(1 ! 2)rhamnoside-7-glucoside* 3-Glucoside-7-rutinoside 3-Rhamnosyl(1 ! 2)galactoside-7-glucoside 3-Galactosyl-7-glucosyl(1 ! 4)rhamnoside* 3-Glucoside-7-neohesperidoside 3-Rutinoside-7-galactoside 3-Galactoside-7-neohesperidoside 3-Robinobioside-7-glucoside 3-Rutinoside-7-glucuronide 3-Gentiobioside-7-glucoside 3-Sophoroside-7-glucoside 3-Glucosyl(1 ! 2)galactoside-7-glucoside* 3-Sophoroside-7-glucuronide* 3-Gentiobioside-7-glucuronide 3-Sambubioside-3’-glucoside 3-Rutinoside-3’-apioside* 3-Xylosyl(1 ! 2)rhamnoside-4’-rhamnoside 3-Rutinoside-4’-glucoside 3,7,4’-Triglucoside 3,3’,4’-Triglucoside* 3-Xylosyl(1 ! 4)[xylosyl(1 ! 6)glucosyl(1 ! 2)rhamnoside]* 3-Xylosyl(1 ! 3)rhamnosyl(1 ! 6)[apiosyl(1 ! 2)galactoside]*

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Flavone and Flavonol O-Glycosides

666. 667. 668. 669. 670. 671. 672. 673. 674. 675. 676. 677. 678. 679. 680. 681. 682. 683. 684. 685. 686. 687. 688. 689. 690. 691. 692. 693. 694. 695. 696. 697. 698. 699. 700. 701. 702. 703. 704. 705. 706. 707. 708. 709. 710. 711. 712. 713. 714. 715.

3-Rhamnosylglucoside-7-xylosylglucoside 3-(2G-Rhamnosylrutinoside)-7-glucoside 3-Glucosyl(1 ! 4)rhamnoside-7-rutinoside* 3-Rhamnosyl(1 ! 6)[glucosyl(1 ! 2)glucoside]-7-rhamnoside* 3-Rhamnosyldiglucoside-7-glucoside 7-[Xylosyl(1 ! 2)rhamnosyl(1 ! 2)rhamnosyl](1 ! 6)glucoside* 3-Rutinoside-7,3’-bisglucoside 3-Rutinoside-4’-diglucoside 3-Isobutyrate 3’-Isobutyrate 4’-Isobutyrate 3-[6’’-(3-Hydroxy-3-methylglutaryl)galactoside] 3-(6’’-p-Hydroxybenzoylgalactoside) 3-(4’’-Malonylrhamnoside)* 3-(6’’-Malonylglucoside) 3-(6’’-Malonylgalactoside) 3-(2’’-Galloyl-a-arabinopyranoside) 3-(2’’-Galloylrhamnoside) 3-(2’’-Galloylglucoside) 3-(6’’-Galloylglucoside) 3-(2’’-Galloylgalactoside) 3-(6’’-Galloylgalactoside) 3-(2’’-p-Coumarylglucoside) 3-(3’’-p-Coumarylglucoside) 3-(6’’-p-Coumarylglucoside) (helichrysoside) 3-(6’’-Caffeoylgalactoside) 3-(2’’-Caffeoylglucuronide)* 3-(6’’-Feruloylgalactoside)* 3-Isoferuloylglucuronide 3-(2’’-Acetylrhamnoside)* 3-(3’’-Acetylrhamnoside) 3-(4’’-Acetylrhamnoside) 3-(6’’-Acetylglucoside) 3-(2’’-Acetylgalactoside)* 3-(3’’-Acetylgalactoside) 3-(6’’-Acetylgalactoside) 3-(6’’-n-Butylglucuronide) (parthenosin)* 7-(6’’-Galloylglucoside)* 7-(6’’-Acetylglucoside)* 4’-(6’’-Galloylglucoside)* 3-Diacetylglucoside 7-Acetyl-3’-glucoside 3-a-(2’’-p-Hydroxybenzoyl)-4’-p-coumarylrhamnoside 3-(2’’,6’’-Digalloylgalactoside)* 3-(3’’,6’’-Di-p-coumarylglucoside) 3-(3’’,6’’-Diacetylgalactoside)* 3-(2’’,3’’,4’’-Triacetylgalactoside)* 3-(2’’’-Galloylglucosyl)(1 ! 2)-a-L-arabinofuranoside* 3-(2’’-Galloylrutinoside)* 3-(6G-Malonylneohesperidoside)*

839

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840

716. 717. 718. 719. 720. 721. 722. 723. 724. 725. 726. 727. 728. 729. 730. 731. 732. 733. 734. 735. 736. 737. 738. 739. 740. 741. 742. 743. 744. 745. 746. 747. 748. 749. 750. 751. 752. 753. 754. 755. 756. 757. 758. 759. 760. 761. 762. 763. 764. 765.

Flavonoids: Chemistry, Biochemistry, and Applications

3-(X’’-Benzoyl-X’’-xylosylglucoside) 3-(X’’ or X’’’-Benzoyl-X’’-glucosylglucoside) 3-a-L-Arabinopyranosyl(1 ! 6)(2’’-E-p-coumaroylglucoside)* 3-a-L-Arabinopyranosyl(1 ! 6)(2’’-E-p-coumaroylgalactoside)* 3-(2G-E-p-Coumaroylrutinoside)* 3-(4’’-E-p-Coumaroylrobinobioside) 3-a-(6’’-p-Coumaroylglucosyl)(1 ! 4)rhamnoside 3-(2’’’-E-Caffeoyl-a-L-arabinopyranosyl)(1 ! 6)glucoside)* 3-(2’’-E-Caffeoyl-a-L-arabinopyranosyl)(1 ! 6)galactoside)* 3-(6’’-Caffeoylsophoroside)* 3-(6’’-Caffeoylgentiobioside)* 3-(Acetylrutinoside) 3-(2’’-Feruloylsophoroside)* 3-(6’’-Feruloylsophoroside)* 3-(6’’’-Sinapoylglucosyl)(1 ! 2)galactoside* 3-Rhamnosyl(1 ! 6)(2’’-acetylglucoside)* 3-(6’’-Acetylglucosyl)(1 ! 3)galactoside (euphorbianin) 3-(2’’’-Caffeoylglucoside)(1 ! 2)(6’’-malonylglucoside)* 3-(3,’’4’’-Diacetylrhamnosyl)(1 ! 6)glucoside* 3-[2’’’,3’’’,4’’’-Triacetyl-a-L-arabinopyranosyl(1 ! 6)glucoside]* 3-[2’’’,3’’’,4’’’-Triacetyl-a-L-arabinopyranosyl(1 ! 6)galactoside]* 3-[2’’’,3’’’,5’’’-Triacetyl-a-L-arabinopyranosyl(1 ! 6)glucoside]* 3-(6’’-Malonylglucoside)-7-glucoside* 3-(6’’-E-p-Coumaroylglucoside)-7-glucoside* 3-Feruloylglucoside-7-glucoside 3-(4’’-Acetylrhamnoside)-7-rhamnoside 3-(6’’-Acetylgalactoside)-7-rhamnoside 3-(2’’-Galloylglucoside)-4’-vinylpropionate* 3-Malonylglucoside-4’-glucoside 3-Feruloylglucoside-4’-glucoside 3-[2’’,6’’-{-p-(7’’’-Glucosyl)coumaroyl}glucosyl]rhamnoside* 3-(6’’’-p-Coumaroylsophorotrioside)* 3-(6’’’’-Caffeoylsophorotrioside)* 3-(6’’’’-Feruloylsophorotrioside)* 3-(6’’’’-Feruloylglucosyl)(1 ! 2)galactosyl(1 ! 2)glucoside* 3-(6’’’’-Sinapoylsophorotrioside)* 3-Glucosyl(1 ! 3)(4’’’-acetylrhamnosyl)(1 ! 6)-galactoside 3-(3’’’-Benzoylsophoroside)-7-rhamnoside 3-Rutinoside-7-(6’’-benzoylglucoside)* 3-(p-Coumaroylsambubioside)-7-glucoside* 3-(4’’-E-p-Coumaroylrobinobioside)-7-rhamnoside 3-(6’’’-p-Coumaroylglucosyl)(1 ! 2)rhamnoside-7-glucoside* 3-(4’’-E-p-Coumaroylrobinobioside)-7-glucoside (variabiloside A) 3-(4’’-Z-p-Coumaroylrobinobioside)-7-glucoside (variabiloside B) 3-(6’’-E-p-Coumaroylsophoroside)-7-rhamnoside* 3-(p-Coumaroylsophoroside)-7-glucoside* 3-(6’’-p-Coumaroylgentiobioside)-7-rhamnoside 3-(Caffeoylarabinosylglucoside)-7-glucoside* 3-(4’’’-Caffeoylrhamnosy)(1 ! 2)-a-L-arabinopyranoside-7-glucoside* 3-(2’’’-Caffeoylsambubioside)-7-glucoside*

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Flavone and Flavonol O-Glycosides

841

766. 3-Glucosyl-7-(6’’-E-caffeoylglucosyl)(1 ! 3)rhamnoside* 767. 3-(6’’-E-Caffeoylsophoroside)-7-rhamnoside* 768. 3-(2’’-E-Caffeoylsophoroside)-7-glucoside* 769. 3-Sophoroside-7-(6’’-E-caffeoylglucoside)* 770. 3-(6’’-Feruloylglucosyl)(1 ! 2)-b-arabinopyranoside-7-glucoside* 771. 3-(Feruloylsambubioside)-7-glucoside* 772. 3-(2’’-E-Feruloylsophoroside)-7-glucoside* 773. 3-(6’’-E-Sinapoylsophoroside)-7-rhamnoside* 774. 3-(Caffeoylsophoroside)-7-(caffeoylglucoside)* 775. 3-(Caffeoylsophoroside)-7-(feruloylglucoside)* 776. 3-Acetylsophoroside-7-rhamnoside 777. 3-Rhamnoside-7-glucoside-4’-(caffeoylgalactoside) 778. 3-Ferulylglucoside-7,4’-diglucoside 779. 3-(2’’-Sinapoylglucoside)-3’-(6’’-sinapoylglucoside)-4’-glucoside* 780. 3,4’-Diglucoside-3’-(6’’-sinapoylglucoside)* 781. 3-Rhamnosyl(1 ! 6)[rhamnosyl(1 ! 2)(3’’-E-p-coumaroylgalactoside)]-7-rhamnoside* 782. 3-Rhamnosyl(1 ! 6)[rhamnosyl(1 ! 2)(4’’-E-p-coumaroylgalactoside)]-7-rhamnoside* 783. 3-Rhamnosyl(1 ! 2)[glucosyl(1 ! 3)(4’’’-p-coumaroylrhamnosyl)(1 ! 6)galactoside]* 784. Diquercetin 3-galactoside ester of tetrahydroxy-m-truxinic acid (13.6)* 785. 3-Sulfatorhamnoside 786. 3-(3’’-Sulfatoglucoside) 787. 3-Sulfate-7-a-arabinopyranoside* 788. 3-Glucuronide-7-sulfate 789. 3-Rhamnoside-3’-sulfate* 790. 3-Glucoside-3’-sulfate* 791. 3-Acetyl-7,3’,4’-trisulfate 792. 3-Sulfate 793. 3’-Sulfate 794. 3,7-Disulfate 795. 3,3’-Disulfate 796. 7,4’-Disulfate* 797. 3’,4’-Disulfate 798. 3,7,3’-Trisulfate 799. 3,7,4’-Trisulfate 800. 3,7,3’,4’-Tetrasulfate 801. 3-Sulfatoglucoside 802. 3-Glucuronide-3’-sulfate Quercetin 3-methyl ether 803. 5-Glucoside* 804. 7-a-L-Arabinofuranosyl(1 ! 6)glucoside* 805. 7-Rhamnoside 806. 7-Glucoside 807. 3’-Xyloside 808. 4’-Glucoside 809. 7-Rutinoside* 810. 7-Gentiobioside* 811. 7-Galactosyl(1 ! 4)glucoside* 812. 7-Rhamnosyl-3’-xyloside 813. 7-Diglucoside-4’-glucoside 814. 5-Glucoside-3’-sulfate*

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842

Flavonoids: Chemistry, Biochemistry, and Applications

Quercetin 5-methyl ether (azaleatin) 815. 3-Arabinoside 816. 3-Rhamnoside (azalein) 817. 3-Galactoside 818. 3-Glucuronide 819. 3-Xylosylarabinoside 820. 3-Rhamnosylarabinoside 821. 3-Arabinosylgalactoside 822. 3-Rutinoside 823. 3-Diglucoside Quercetin 7-methyl ether (rhamnetin) 824. 3-a-L-Arabinofuranoside 825. 3-a-L-Arabinopyranoside 826. 3-Rhamnoside 827. 3-Glucoside 828. 3-Galactoside 829. 5-Glucoside 830. 3’-Glucuronide 831. 3-a-Diarabinoside 832. 3-b-Diarabinoside 833. 3-a-L-Arabinopyranosyl(1 ! 3)galactoside* 834. 3-Rhamnosyl(1 ! 4)rhamnoside 835. 3-Rutinoside 836. 3-Neohesperidoside 837. 3-Robinobioside* 838. 3-Laminaribioside* 839. 3-Gentiobioside* 840. 3-Galactosyl(1 ! 4)galactoside 841. 3-Galactosyl(1 ! 6)galactoside 842. 3-Mannosyl(1 ! 2)alloside 843. 3-Galactoside-3’-rhamnoside 844. 3-Rhamnosyl(1 ! 3)rhamnosyl(1 ! 6)galactoside (3-rhamninoside, xanthorhamnin A and B) 845. 3-a-L-Arabinopyranosyl(1 ! 3)[galactosyl(1 ! 6)galactoside]* 846. 3-Arabinoside-3’,4’-diglucoside 847. 3,3’,4’-Triglucoside 848. 3-Galactoside-3’,4’-diglucoside 849. 3-Rhamnosyl(1 ! 3)(4’’-acetylrhamnosyl)(1 ! 6)galactoside 850. 3-[3-Hydroxy-3-methylglutaryl(1 ! 6)][apiosyl(1 ! 2)galactoside]* 851. 3-(3’’’’-p-Coumaroylrhamninoside*) 852. 3-Sulfate 853. 3,3’-Disulfate* 854. 3,3’,4’-Trisulfate* 855. 3,5,4’-Trisulfate-3’-glucuronide Quercetin 3’-methyl ether (isorhamnetin) 856. 3-a-L-Arabinofuranoside 857. 3-a-L-Arabinopyranoside (distinchin) 858. 3-Xyloside 859. 3-Rhamnoside* 860. 3-Glucoside

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Flavone and Flavonol O-Glycosides

861. 862. 863. 864. 865. 866. 867. 868. 869. 870. 871. 872. 873. 874. 875. 876. 877. 878. 879. 880. 881. 882. 883. 884. 885. 886. 887. 888. 889. 890. 891. 892. 893. 894. 895. 896. 897. 898. 899. 900. 901. 902. 903. 904. 905. 906. 907. 908. 909. 910.

3-Galactoside 3-Glucuronide 5-Glucoside 5-Galactoside* 7-Rhamnoside 7-Glucoside 7-a-D-Glucosaminopyranoside* 3-Arabinosyl(1 ! 2)rhamnoside 3-Arabinosyl(1 ! 6)glucoside 3-a-Arabinopyranosyl(1 ! 6)galactoside* 3-Xylosyl(1 ! 2)glucoside* 3-Xylosyl(1 ! 6)glucoside* 3-Xylosyl(1 ! 2)galactoside* 3-Apiosyl(1 ! 2)glucoside* 3-Apiosyl(1 ! 2)galactoside* 3-Rhamnosyl(1 ! 2)rhamnoside 3-Rutinoside (narcissin) 3-Neohesperidoside 3-Rhamnosyl(1 ! 2)galactoside 3-Robinobioside 3-Laminaribioside* 3-Sophoroside 3-Gentiobioside 3-Lactoside 3-Glucosyl(1 ! 2)galactoside 3-Glucosyl(1 ! 3)galactoside* 4’-Rhamnosyl(1 ! 2)glucoside (crosatoside A)* 3-Arabinoside-7-rhamnoside 3-Arabinoside-7-glucoside 3-Glucoside-7-arabinoside 3-Glucoside-7-xyloside 3,7-Dirhamnoside 3-Rhamnoside-7-glucoside 3-Glucoside-7-rhamnoside 3-Galactoside-7-rhamnoside* 3,7-Diglucoside 3-Galactoside-7-glucoside 3-Glucoside-4’-rhamnoside 3,4’-Diglucoside (dactylin) 3-Galactoside-4’-glucoside 7-Sophoroside 3-Xylosyl(1 ! 3)rhamnosyl(1 ! 6)glucoside* 3-Xylosylrutinoside 3-Xylosylrobinobioside* 3-Rhamnosyl(1 ! 4)rhamnosyl(1 ! 6)glucoside 3-Apiosyl(1 ! 2)[rhamnosyl(1 ! 6)glucoside]* 3-Rutinosylglucoside 3-(2G-Rhamnosylrutinoside) (typhaneoside) 3-Rhamnosyl(1 ! 2)[rhamnosyl(1 ! 6)galactoside] 3-Rhamnosyl(1 ! 2)[glucosyl(1 ! 6)glucoside]*

843

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_c013 Revise Proof page 844 6.10.2005 10:36am

844

911. 912. 913. 914. 915. 916. 917. 918. 919. 920. 921. 922. 923. 924. 925. 926. 927. 928. 929. 930. 931. 932. 933. 934. 935. 936. 937. 938. 939. 940. 941. 942. 943. 944. 945. 946. 947. 948. 949. 950. 951. 952. 953. 954. 955. 956.

Flavonoids: Chemistry, Biochemistry, and Applications

3-Glucosyl(1 ! 2)[rhamnosyl(1 ! 6)galactoside] 3-Galactosyl(1 ! 2)[rhamnosyl(1 ! 6)glucoside]* 3-(4Rha-Galactosylrobinobioside)* 3-Xylosyl(1 ! 2)glucoside-7-rhamnoside* 3-Rutinoside-7-rhamnoside 3-Rhamnosyl(1 ! 2)galactoside-7-glucoside 3-Robinobioside-7-rhamnoside 3-Rutinoside-7-glucoside 3-Sophoroside-7-rhamnoside 3-Rhamnoside-7-sophoroside 3-Sophoroside-7-glucoside 3-Glucoside-7-gentiobioside 3-Gentiobioside-7-glucoside 3-Glucosyl(1 ! 6)galactoside-7-glucoside* 3-Rutinoside-4’-rhamnoside 3-Rutinoside-4’-glucoside 3-Gentiotrioside-7-glucoside 3-Rhamnosyl(1 ! 2)[gentiobiosyl(1 ! 6)glucoside]* 3-Rhamnosyl(1 ! 2)[glucosyl(1 ! 6)glucoside]-7-glucoside* 3-(2G-Rhamnosylrutinoside)-7-rhamnoside* 3-Rhamnosyl(1 ! 2)[rhamnosyl(1 ! 6)galactoside]-7-rhamnoside 3-(6’’-Malonylglucoside) 3-(6’’-Galloylglucoside) 3-(6’’-p-Coumaroylglucoside) 3-(2’’-Acetylglucoside) 3-(6’’-Acetylglucoside) 3-(6’’-Acetylgalactoside) 3-[6’’-(2-E-Butenoyl)glucoside]* 3-(2’’,3’’,4’’-Triacetylglucoside)* 7-(6’’-p-Coumaroylglucoside)* 3-(3-Methylbutyrylrutinoside) 3-(3’’,6’’-Di-p-Coumaroylglucoside) 3-(6’’-p-Coumaroylglucosyl)(1 ! 2)rhamnoside* 3-(4’’’-p-Coumaroylrobinobioside) 3-(3’’’-Feruloylrhamnosyl)(1 ! 6)galactoside* 3-(6’’-E-Sinapoylsophoroside)* 3-(2’’’-Acetyl-a-arabinopyranosyl)(1 ! 6)galactoside* 3-Rhamnosyl(1 ! 6)(2’’-acetylglucoside)* 3-(6’’-Acetylglucosyl)(1 ! 3)galactoside* 3-(4’’,6’’-Diacetylglucosyl)(1 ! 3)galactoside* 3-(6’’-E-p-Coumaroylglucoside)-7-glucoside* 3-Feruloyl-7-rhamnosylglucoside 3-Rhamnosyl(1 ! 6)[rhamnosyl(1 ! 2)(4’’-Z-p-coumaroylgalactoside)]* 3-[2’’-(4’’’-Acetylrhamnosyl)gentiobioside]* 3-(p-Coumaroylrhamnosylgalactoside)-7-rhamnoside 3-Rhamnosyl(1 ! 6)[rhamnosyl(1 ! 2)(3’’’-E-p-coumaroylgalactoside)]-7rhamnoside* 957. 3-Rhamnosyl(1 ! 6)[rhamnosyl(1 ! 2)(4’’-p-coumaroylgalactoside)]-7-rhamnoside* 958. 3-Rhamnosyl(1 ! 6)[rhamnosyl(1 ! 2)(4’’-E-feruloylgalactoside)]-7-rhamnoside* 959. 3-Sulfatorutinoside

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Flavone and Flavonol O-Glycosides

960. 3-Glucuronide-7-sulfate 961. 3-Sulfate 962. 7-Sulfate 963. 3,7-Disulfate 964. 3,4’-Disulfate 965. 3,7,4’-Trisulfate 966. 3-(4’’-Sulfatorutinoside)* Quercetin 4’-methyl ether (tamarixetin) 967. 3-Rhamnoside 968. 3-Glucoside 969. 3-Galactoside* 970. 3-Neohesperidoside* 971. 3-Robinobioside 972. 3-Glucosyl(1 ! 2)galactoside* 973. 3-Digalactoside 974. 3,7-Diglucoside* 975. 5-Glucoside-7-glucuronide 976. 3-Rutinoside-7-rhamnoside* 977. 3-Sulfate 978. 3-Glucoside-7-sulfate* Quercetin 3,5-dimethyl ether (caryatin) 979. 3’-(or 4’-)Glucoside 980. 7-Glucoside* Quercetin 3,7-dimethyl ether 981. 5-Glucoside 982. 3’-Neohesperidoside* 983. 3’-(6G-Rhamnosylneohesperidoside)* 984. 4’-Sulfate* Quercetin 3,3’-dimethyl ether 985. 7-Glucoside 986. 4’-Glucoside 987. 7-Rutinoside* Quercetin 3,4’-dimethyl ether 988. 7-Glucoside* 989. 7-a-L-Arabinofuranosyl(1 ! 6)glucoside* 990. 7-Rutinoside* 991. 7-(2G-Rhamnosylrutinoside)* 992. 7-(2G-Glucosylrutinoside)* Quercetin 5,3’-dimethyl ether 993. 3-Glucoside Quercetin 7,3’-dimethyl ether (rhamnazin) 994. 3-Glucoside 995. 3-Galactoside 996. 3-Rhamnoside 997. 4’-Glucoside 998. 3-Glucosyl(1 ! 5)-a-L-arabinofuranoside* 999. 3-Xylosyl(1 ! 2)glucoside* 1000. 3-Rutinoside 1001. 3-Neohesperidoside 1002. 3-Galactoside-4’-glucoside

845

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846

Flavonoids: Chemistry, Biochemistry, and Applications

1003. 3-Rhamnosyl(1 ! 3)rhamnosyl(1 ! 6)galactoside (xanthorhamnin C) 1004. 3-Rhamnosyl(1 ! 4)rhamnosyl(1 ! 6)galactoside (3-isorhamninoside) 1005. 3-Glucosyl(1 ! 5)[apiosyl(1 ! 2)-a-L-arabinofuranoside]* 1006. 3-Sulfate Quercetin 7,4’-dimethyl ether (ombuin) 1007. 3-Arabinofuranoside* 1008. 3-Glucoside* 1009. 3-Galactoside 1010. 3-Rutinoside (ombuoside) 1011. 3,5-Diglucoside 1012. 3-Rutinoside-5-glucoside 1013. 3-Sulfate Quercetin 3’,4’-dimethyl ether 1014. 3-Rutinoside 1015. 3-Neohesperidoside* 1016. 3,7-Diglucoside* 1017. 5-Glucoside-7-glucuronide Quercetin 3,7,4’-trimethyl ether 1018. 3-Sulfate* Quercetin 5,3’,4’-trimethyl ether 1019. 3-Galactosyl(1 ! 2)rhamnoside-7-rhamnoside* Quercetin 7,3’,4’-trimethyl ether 1020. 3-Arabinoside 1021. 3-Digalactoside Quercetin 5,7,3’,4’-tetramethyl ether 1022. 3-Arabinoside 1023. 3-Galactoside* 1024. 3-Rutinoside 3,5,7-Trihydroxy-3’,5’-dimethoxyflavone 1025. 7-Glucoside (lagotiside) 3,5,8,5’-Tetrahydroxy-7-methoxyflavone 1026. 8-Acetate* 6-Hydroxyquercetin (quercetagetin) 1027. 3-Rhamnoside 1028. 3-Glucoside (tagetiin) 1029. 6-Glucoside* 1030. 7-Glucoside 1031. 3,7-Diglucoside 1032. 7-(6’’-Isobutyrylglucoside)* 1033. 7-(6’’-Isovalerylglucoside)* 1034. 7-[6’’-(2-Methylbutyryl)glucoside]* 1035. 7-(6’’-E-Caffeoylglucoside)* 1036. 7-(6’’-Acetylglucoside)* Quercetagetin 3-methyl ether 1037. 7-Glucoside 1038. 7-Sulfate Quercetagetin 6-methyl ether (patuletin) 1039. 3-Xyloside 1040. 3-Rhamnoside 1041. 3-Glucoside

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Flavone and Flavonol O-Glycosides

1042. 3-Galactoside 1043. 3-Glucuronide 1044. 5-Glucoside 1045. 7-Glucoside 1046. 3-Rutinoside 1047. 3-Robinobioside 1048. 3-Galactosylrhamnoside 1049. 3-Gentiobioside 1050. 3-Digalactoside 1051. 3,7-Dirhamnoside 1052. 3,7-Diglucoside* 1053. 3-Digalactosylrhamnoside 1054. 3-Glucosyl(1 ! 6)[apiosyl(1 ! 2)glucoside] 1055. 3-(6’’-p-Coumaroylglucoside)* 1056. 3-(6’’-E-Feruloylglucoside)* 1057. 3-(6’’-Acetylglucoside) 1058. 7-(6’’-Isobutyrylglucoside)* 1059. 7-[6’’-(2-Methylbutyryl)glucoside]* 1060. 7-(6’’-Isovalerylglucoside)* 1061. 3-Rhamnoside-7-(2’’-acetylrhamnoside)* 1062. 3-Rhamnoside-7-(3’’’-acetylrhamnoside) 1063. 3-Rhamnoside-7-(4’’’-acetylrhamnoside) 1064. 3-(4’’-Acetylrhamnoside)-7-rhamnoside* 1065. 3-Rhamnoside-7-(3’’’,4’’’-diacetylrhamnoside) 1066. 3-(3’’-Acetylrhamnoside)-7-(3’’’-acetylrhamnoside) 1067. 3-(4’’-Acetylrhamnoside)-7-(2’’’-acetylrhamnoside)* 1068. 3-(4’’-Acetylrhamnoside)-7-(3’’’-acetylrhamnoside) 1069. 3-(4’’-Acetylrhamnoside)-7-(2’’’,4’’’-diacetylrhamnoside) 1070. 3-(4’’-Acetylrhamnoside)-7-(2’’’,4’’’-diacetylrhamnoside) 1071. 3-(2’’-Feruloylglucosyl)(1 ! 6)[apiosyl(1 ! 2)glucoside]* 1072. 3-Sulfate 1073. 7-Sulfate 1074. 3,3’-Disulfate 1075. 3-Glucoside-7-sulfate Quercetagetin 7-methyl ether 1076. 3-Glucoside 1077. 6-Glucoside* 1078. 4’-Glucoside* 1079. 3-Neohesperidoside* 1080. 3-Cellobioside* 1081. 3-(2’’’-Caffeoylglucosyl)(1 ! 2)glucuronide* Quercetagetin 3’-methyl ether 1082. 3-Glucoside 1083. 3-Galactoside 1084. 7-Glucoside Quercetagetin 4’-methyl ether 1085. 3-Arabinoside Quercetagetin 3,6-dimethyl ether (axillarin) 1086. 7-Glucoside (axillaroside) 1087. 4’-Glucuronide

847

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848

Flavonoids: Chemistry, Biochemistry, and Applications

1088. 5-a-L-Arabinosyl(1 ! 6)glucoside* 1089. 7-Sulfate* Quercetagetin 3,7-dimethyl ether 1090. 6-Glucoside 1091. 6-Galactoside 1092. 4’-Glucoside Quercetagetin 6,7-dimethyl ether 1093. 3-Rhamnoside (eupatolin) 1094. 3-Apioside 1095. 3-Glucoside 1096. 3-Galactoside 1097. 3-Glucosylgalactoside 1098. 3-Sulfate Quercetagetin 3,3’-dimethyl ether 1099. 7-Glucoside Quercetagetin 6,3’-dimethyl ether (spinacetin) 1100. 3-Glucoside 1101. 7-Glucoside 1102. 3-Rutinoside 1103. 3-Gentiobioside 1104. 3-(2’’-Apiosylgentiobioside)* 1105. 3-(2’’’-Feruloylgentiobioside)* 1106. 3-(2’’-p-Coumaroylglucosyl)(1 ! 6)[apiosyl(1 ! 2)glucoside]* 1107. 3-(2’’-Feruloylglucosyl)(1 ! 6)[apiosyl(1 ! 2)glucoside]* 1108. 3-Sulfate Quercetagetin 7,3’-dimethyl ether 1109. 6-Glucoside* Quercetagetin 3,6,7-trimethyl ether 1110. 4’-Glucoside Quercetagetin 3,6,3’-trimethyl ether (jaceidin) 1111. 5-Glucoside* 1112. 7-Glucoside (jacein) 1113. 7-Neohesperidoside 1114. 4’-Sulfate Quercetagetin 3,6,4’-trimethyl ether 1115. 7-Glucoside (centaurein) Quercetagetin 3,7,4’-trimethyl ether 1116. 6-Glucoside 1117. 3’-Glucoside Quercetagetin 6,7,3’-trimethyl ether (veronicafolin) 1118. 3-Rutinoside 1119. 3-Glucosyl(1 ! 3)galactoside* 1120. 3-Digalactoside 1121. 3-Sulfate Quercetagetin 6,7,4’-trimethyl ether (eupatin) 1122. 3-Sulfate Quercetagetin 6,3’,4’-trimethyl ether 1123. 3-Glucoside* 1124. 3-Sulfate Quercetagetin 7,3’,4’-trimethyl ether

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Flavone and Flavonol O-Glycosides

1125. 3-Rhamnoside Quercetagetin 3,6,7,3’-tetramethyl ether 1126. 4’-Glucoside (chrysosplenin) 1127. 4’-Galactoside (galactobuxin) Quercetagetin 3,6,7,3’,4’-pentamethyl ether (artemetin) 1128. 5-Glucosylrhamnoside 8-Hydroxyquercetin (gossypetin) 1129. 3-Glucoside 1130. 3-Galactoside 1131. 3-Glucuronide 1132. 7-Rhamnoside 1133. 7-Glucoside 1134. 8-a-D-Lyxopyranoside* 1135. 8-Rhamnoside 1136. 8-Glucoside 1137. 8-Glucuronide 1138. 3-Glucoside-8-glucuronide 1139. 3-Glucuronide-8-glucoside 1140. 7-Rhamnoside-8-glucoside 1141. 3-Gentiotrioside 1142. 3-Sophoroside-8-glucoside 1143. 8-Glucuronide-3-sulfate 1144. 3-Sulfate Gossypetin 7-methyl ether 1145. 3-Arabinoside 1146. 3-Rhamnoside 1147. 3-Galactoside 1148. 8-Glucoside 1149. 3-Rutinoside 1150. 3-Galactoside-8-glucoside Gossypetin 8-methyl ether (corniculatusin) 1151. 3-a-L-Arabinofuranoside 1152. 3-Glucoside 1153. 3-Galactoside 1154. 7-Glucoside 1155. 3-Xylosyl(1 ! 2)rhamnoside* 1156. 3-Robinobioside Gossypetin 3’-methyl ether 1157. 7-Glucoside 1158. 3-Rutinoside 1159. 7-Neohesperidoside (haploside F) 1160. 7-(6’’-Acetylglucoside) 1161. 7-(6’’-Acetylrhamnosyl)(1 ! 2)glucoside Gossypetin 3,8-dimethyl ether 1162. 5-Glucoside* Gossypetin 7,8-dimethyl ether 1163. 3-Glucoside* 1164. 4’-Glucoside* 1165. 3,3’-Disulfate* Gossypetin 7,4’-dimethyl ether

849

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Flavonoids: Chemistry, Biochemistry, and Applications

1166. 8-Glucoside 1167. 8-Acetate 1168. 8-Butyrate Gossypetin 8,3’-dimethyl ether (limocitrin) 1169. 3-Rhamnoside 1170. 3-Glucoside 1171. 3-Galactoside 1172. 3-Rutinoside 1173. 7-Glucoside 1174. 7-Neohesperidoside 1175. 3-Sophoroside 1176. 3,7-Diglucoside 1177. 3-Rutinoside-7-glucoside* 1178. 7-(6’’-Acetylglucoside) 1179. 7-(6’’-Acetylneohesperidoside) 3,5,7,3’,4’,5’-Hexahydroxyflavone (myricetin) 1180. 3-Arabinoside 1181. 3-a-Arabinofuranoside 1182. 3-Xyloside 1183. 3-Rhamnoside (myricitrin) 1184. 3-Glucoside 1185. 3-Galactoside 1186. 7-Arabinoside 1187. 7-Glucoside 1188. 3’-Arabinoside 1189. 3’-Xyloside 1190. 3’-Rhamnoside* 1191. 3’-Glucoside 1192. 3-Dixyloside 1193. 3-Dirhamnoside 1194. 3-Xylosyl(1 ! 2)rhamnoside 1195. 3-Xylosyl(1 ! 3)rhamnoside* 1196. 3-Xylosylglucoside 1197. 3-Rhamnosyl(1 ! 2)rhamnoside* 1198. 3-Rutinoside 1199. 3-Neohesperidoside* 1200. 3-Robinobioside* 1201. 3-Diglucoside 1202. 3-Galactosylglucoside 1203. 3-Digalactoside 1204. 3-Rhamnoside-7-glucoside 1205. 3-Rhamnoside-3’-glucoside* 1206. 3-Galactoside-3’-rhamnoside* 1207. 3,3’-Digalactoside 1208. 3,4’-Dirhamnoside* 1209. 3,4’-Diglucoside* 1210. 3-Rhamnosyl(1 ! 3)glucosyl(1 ! 6)glucoside* 1211. 3-(2G-Rhamnosylrutinoside)* 1212. 3-Glucosylrutinoside 1213. 3-Triglucoside

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Flavone and Flavonol O-Glycosides

1214. 1215. 1216. 1217. 1218. 1219. 1220. 1221. 1222. 1223. 1224. 1225. 1226. 1227. 1228. 1229. 1230. 1231. 1232. 1233. 1234. 1235. 1236. 1237. 1238. 1239.

3-Rutinoside-7-rhamnoside 3-Robinobioside-7-rhamnoside 3-Rutinoside-7-glucoside 3-Glucosyl(1 ! 2)rhamnoside-7-glucoside* 3-(2’’-p-Hydroxybenzoylrhamnoside)* 3-(4’’-Malonylrhamnoside)* 3-(2’’-Galloylrhamnoside) 3-(3’’-Galloylrhamnoside)* 3-(4’’-Galloylrhamnoside) 3-(2’’-Galloylglucoside)* 3-(6’’-Galloylglucoside) 3-(3’’-Galloylgalactoside)* 3-(6’’-Galloylgalactoside) 3-(6’’-p-Coumarylglucoside)* Nympholide A* (13.7) Nympholide B* (13.8) 3-(2’’-Acetylrhamnoside)* 3-(4’’-Acetylrhamnoside)* 7-(6’’-Galloylglucoside)* 3-(2’’,3’’-Digalloylrhamnoside)* 3-(3’’,4’’-Diacetylrhamnoside)* 3-(2’’,3’’,4’’-Triacetylxyloside)* 3-(4’’-Acetyl-2’’-galloylrhamnoside)* 3-[3’’’,6’’’-Diacetylglucosyl(1 ! 4)2’’,3’’-diacetylrhamnoside]* 3-(p-Coumarylrhamnosylgalactoside) 3-Glucosyl(1 ! 2)(6’’’-caffeylglucosyl)(1 ! 2)rhamnoside-4’rhamnosyl(1 ! 4)xyloside (montbretin A) 1240. 3-Glucosyl(1 ! 2)(6’’’-p-coumaroylglucosyl)(1 ! 2)rhamnoside-4’rhamnosyl(1 ! 4)xyloside (montbretin B) 1241. 3-Sulfatorhamnoside Myricetin 3-methyl ether 1242. 7-Rhamnoside 1243. 3’-Xyloside 1244. 3’-Glucoside 1245. 7-Rhamnoside-3’-xyloside Myricetin 5-methyl ether 1246. 3-Rhamnoside 1247. 3-Galactoside Myricetin 7-methyl ether (europetin) 1248. 3-Rhamnoside 1249. 3-(2’’-Galloylrhamnoside)* 1250. 3-(3’’-Galloylrhamnoside)* Myricetin 3’-methyl ether (larycitrin) 1251. 3-a-L-Arabinofuranoside* 1252. 3-Rhamnoside 1253. 3-Glucoside 1254. 3-Galactoside 1255. 7-Glucoside 1256. 5’-Glucoside 1257. 3-Rutinoside

851

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852

Flavonoids: Chemistry, Biochemistry, and Applications

1258. 3,5’-Diglucoside 1259. 3-Rhamnosylrutinoside 1260. 3-Rutinoside-7-glucoside 1261. 3,7,5’-Triglucoside 1262. 3-(4’’-Malonylrhamnoside)* 1263 3-p-Coumarylglucoside Myricetin 4’-methyl ether 1264. 3-Rhamnoside (mearnsitrin) 1265. 3-Galactoside* 1266. 3-Galactosyl(1 ! 4)galactoside 1267. 3,7-Dirhamnoside 1268. 3-(4’’-Acetylrhamnoside)* Myricetin 3,4’-dimethyl ether 1269. 3’-Xyloside 1270. 7-Rhamnoside-3’-xyloside Myricetin 7,4’-dimethyl ether 1271. 3-Galactoside Myricetin 3’,4’-dimethyl ether 1272. 3-Rhamnoside* 1273. 3-Glucoside* Myricetin 3’,5’-dimethyl ether (syringetin) 1274. 3-Arabinoside 1275. 3-Rhamnoside 1276. 3-Xyloside 1277. 3-Glucoside 1278. 3-Galactoside 1279. 3-Rhamnosyl(1 ! 5)-a-L-arabinofuranoside* 1280. 3-Rutinoside 1281. 3-Robinobioside* 1282. 3-Rhamnosylrutinoside 1283. 3-Rutinoside-7-glucoside 1284. 3-(p-Coumarylglucoside) 1285. 3-(2’’,3’’-Diacetylglucoside)* 1286. 3-(6’’-Acetylglucosyl)(1 ! 3)galactoside* 6-Hydroxymyricetin 6,3’,5’-trimethyl ether 1287. 3-Glucoside 6-Hydroxymyricetin 3,6,3’,5’-tetramethyl ether 1288. 7-Glucoside 8-Hydroxymyricetin (hibiscetin) 1289. 3-Glucoside 1290. 8-Glucosylxyloside 8-Hydroxymyricetin 8-methyl ether 1291. 3-Rhamnoside* 8-Hydroxymyricetin 8,5-dimethyl ether 1292. 3-Rhamnoside* 8-Hydroxymyricetin 8,3’,5’-trimethyl ether 1293. 3-Rhamnoside* 3,5,7,2’-Tetrahydroxyflavone (datiscetin) 1294. 3-Glucoside 1295. 3-Rutinoside

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Flavone and Flavonol O-Glycosides

3,7,2’,3’,4’-Pentahydroxyflavone 1296. 3-Neohesperidoside 3,7,3’,4’,5’-Pentahydroxyflavone (5-deoxymyricetin, robinetin) 1297. 7-Glucoside* 1298. 3-Rutinoside* 3,4’-Dihydroxy-7,3’,5’-trimethoxyflavone 1299. 3-Galactosyl(1 ! 4)xyloside* 3,5,7,2’,6’-Pentahydroxyflavone 1300. 2’-Glucoside* 5,7-Dihydroxy-3,6,8,4’-tetramethoxyflavone 1301. 7-Glucosyl(1 ! 3)galactoside* 7,4’-Dihydroxy-3,5,6,8-tetramethoxyflavone 1302. 4’-Glucosyl(1 ! 3)galactoside* 5,8-Dihydroxy-3,6,7,4’-tetramethoxyflavone 1303. 8-Neohesperidoside* 5,4’-Dihydroxy-6,7,8,3’-tetramethoxyflavone (africanutin) 1304. 4’-Galactoside* 3,5,7,2’,3’,4’-Hexahydroxyflavone 1305. 3-Glucoside* 5,7,2’-Trihydroxy-3,6,4’-trimethoxyflavone 1306. 7-Glucoside* 5,2’,5’-Trihydroxy-3,7,8-trimethoxyflavone 1307. 2’-Acetate 5,2’-Dihydroxy-3,7,4’-trimethoxyflavone 1308. 2’-Glucoside 5,2’,4’-Trihydroxy-3,7,5’-trimethoxyflavone 1309. 2’-Galactosyl(1 ! 4)glucoside* 5,2’-5’-Trihydroxy-3,7,4’-trimethoxyflavone 1310. 2’-Glucoside 5,6’,5’-Trihydroxy-3,7,4’-trimethoxyflavone 1311. 5’-Glucoside 5,2’-Dihydroxy-3,7,4’,5’-tetramethoxyflavone 1312. 2’-Glucoside 5,5’-Dihydroxy-3,6,7,4’-tetramethoxyflavone 1313. 5’-Glucoside 5,7,8-Trihydroxy-3,6,4’-trimethoxyflavone 1314. 8-Tiglate* 5,8,4’-Trihydroxyflavone-3,7,3’-trimethoxyflavone 1315. 8-Acetate 3,5,2’-Trihydroxy-7,8,4’-trimethoxyflavone 1316. 5-Glucosyl(1 ! 2)galactoside* 3,5,6,7,8,4’-Hexahydroxy-3’-methoxyflavone 1317. 3-Rhamnosyl(1 ! 4)rhamnosyl(1 ! 6)glucoside* 3,5,7,3’,4’-Pentahydroxy-6,8-dimethoxyflavone 1318. 3-Arabinoside 3,5,7,4’-Tetrahydroxy-6,8,3’-trimethoxyflavone 1319. 3-a-L-Arabinopyranosyl(1 ! 3)galactoside* 1320. 3-Rhamnosyl(1 ! 2)glucoside 1321. 3-a-L-Arabinopyranosyl(1 ! 3)[galactosyl(1 ! 6)galactoside]* 3,6,7,8,3’,4’-Hexahydroxy-5’-methoxyflavone

853

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Flavonoids: Chemistry, Biochemistry, and Applications

1322. 7-Neohesperidoside* 5,7,2’,3’,4’-Pentahydroxy-3,6-dimethoxyflavone 1323. 7-Glucoside* 5,2’,5’-Trihydroxy-3,6,7,4’-tetramethoxyflavone 1324. 5’-Glucoside 5,2’-Dihydroxy-3,6,7,4’,5’-pentamethoxyflavone (brickellin) 1325. 2’-Glucoside* 5,5’-Dihydroxy-3,6,7,2’,4’-pentamethoxyflavone 1326. 5’-Glucoside 5,8-Dihydroxy-3,7,2’,3’,4’-pentamethoxyflavone 1327. 8-Acetate 5,7,3’,5’-Tetrahydroxy-3,6,8,4’-tetramethoxyflavone 1328. 3’-Glucoside C-Methylated flavonol glycosides 5,7-Dihydroxy-6,8-di-C-methyl-3-methoxyflavone 1329. 7-Galactosyl(1 ! 2)rhamnoside* 3,5,7,4’-Tetrahydroxy-8-C-methyl flavone (8-C-Methylkaempferol) 1330. 7-Glucoside 3,5,7,3’,4’,5’-Hexahydroxy-2’-C-methyl flavone (2’-C-methylmyricetin) 1331. 3-Rhamnoside-5’-gallate* Prenylated, Pyrano and Methylenedioxy Flavonol Glycosides

OH HO

O

OH OH

O

13.11

8-Prenylkaempferol (noranhydroicaritin, 3,5,7,4’-tetrahydroxy-8-(3,’’3’’dimethylallyl)flavone) 1. 3-Rhamnoside (ikaroside A) 2. 3-Rhamnosyl(1 ! 2)rhamnoside 3. 3-Xylosyl(1 ! 2)rhamnoside (ikaroside D) 4. 3-Glucosyl(1 ! 2)rhamnoside (ikaroside B) 5. 3-Rhamnoside-7-glucoside (epimedoside A) 6. 3,7-Diglucoside* 7. 3-Rhamnosyl(1 ! 2)xyloside-7-glucoside (epimedoside E) 8. 3-Glucosyl(1 ! 2)rhamnoside-7-glucoside (Ikaroside C, diphylloside A) 9. 3-Rhamnosyl(1 ! 2)rhamnoside-7-glucoside (diphylloside B) 10. 3-Rhamnosyl(1 ! 2)glucoside-7-glucoside 11. 3-Glucosyl(1 ! 2)rhamnoside-7-glucosyl(1 ! 2)glucoside (diphylloside C) 12. 3-Xylosyl(1 ! 2)rhamnoside-7-glucosyl(1 ! 2)glucoside (hexandroside C) 13. 3-(4’’-Acetylrhamnoside) (ikaroside F) 8-Prenylkaempferol 7-methyl ether 14. 3-Rhamnosyl(1 ! 3)[apiosyl(1 ! 6)glucoside]*

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Flavone and Flavonol O-Glycosides

8-Prenylkaempferol 4’-methyl ether (anhydroicaritin) 15. 3-Rhamnoside 16. 3-Glucoside 17. 7-Glucoside (icariside I) 18. 3-Rhamnosyl(1 ! 2)rhamnoside* 19. 3-Xylosyl(1 ! 2)rhamnoside (sagittatoside B) 20. 3-Rutinoside 21. 3-Glucosyl(1 ! 2)rhamnoside (sagittatoside A) 22. 3-Rhamnoside-7-glucoside (icariin) 23. 7-Cellobioside (cuhuoside)* 24. 3-Xylosyl(1 ! 2)rhamnoside-7-glucoside (epimedin B) 25. 3-Xylosyl(1 ! 2)rhamnoside-7-glucoside 26. 3-Rhamnosyl(1 ! 2)rhamnoside-7-glucoside (epimedin C) 27. 3-Rhamnosyl(1 ! 3)rhamnoside-7-glucoside (hexandroside D) 28. 3-Glucosyl(1 ! 2)rhamnoside-7-glucoside (epimedin A) 29. 3-Glucosyl(1 ! 3)rhamnoside-7-glucoside* 30. 3-Galactosyl(1 ! 3)rhamnoside-7-glucoside 31. 3-Rhamnosyl(1 ! 6)galactoside-7-galactoside* 32. 3-Rhamnosyl(1 ! 2)rhamnoside-7-sophoroside* (acuminatoside) 33. 3-[3’’’-Acetylxylosyl(1 ! 3)4’’-acetylrhamnoside] (sempervirenoside) 34. 3-Glucosyl(1 ! 2)(3’’-acetylrhamnoside) (sagittatoside C) 35. 3-Glucosyl(1 ! 3)(4’’-acetylrhamnoside) (epimedokoreanoside II) 36. 3-[4’’’,6’’’-Diacetylglucosyl(1 ! 3)4’’-acetylrhamnoside]* 37. 3-[2’’’,6’’’-Diacetylglucosyl(1 ! 3)4’’-acetylrhamnoside]-7-glucoside (epimedin K) 38. 3-Xylosyl(1 ! 3)(4’’-acetylrhamnoside)-7-glucoside 39. 3-[6’’’-Acetylglucosyl(1 ! 3)4’’-acetylrhamnoside]-7-glucoside (epimedokoreanoside I) 40. 3-[4’’’,6’’’-Diacetylglucosyl(1 ! 3)4’’-acetylrhamnoside]-7-glucoside* 41. 3-(6’’’-Acetylgalactosyl)(1 ! 3)rhamnoside-7-glucoside 42. 3-[3’’’-Acetylxylosyl(1 ! 3)4’’-acetylrhamnoside]-7-glucoside 8-(3’’-Hydroxy-3’’-methylbutyl)kaempferol 4’-methyl ether (icaritin) 43. 3-Rhamnoside 44. 3-Rhamnosyl(1 ! 2)rhamnoside (wanepimedoside A)* 8-(g-Methoxy-gg-dimethyl)propylkaempferol 4’-methyl ether 45. 7-glucoside* (caohuoside D) 8-Prenylquercetin 4’-methyl ether 46. 3-Rhamnoside* (caohuoside C) 8-Prenylquercetin 7,4’-dimethyl ether 47. 3-Rhamnosyl(1 ! 4)rhamnoside* 6’’,6’’-Dimethylpyrano(2’’,3’’:7,8)kaempferol 48. 3-Rhamnoside 6’’,6’’-Dimethylpyrano(2’’,3’’:7,8)-4’-methoxykaempferol 49. 3-Rhamnoside* 3-Methoxy-5-hydroxy-6,7-methylenedioxyflavone 50. 4’-Glucuronide*

855

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Flavonoids: Chemistry, Biochemistry, and Applications

3,5,4’-Trihydroxy-6,7-methylenedioxyflavone 51. 3-Glucoside 3-Hydroxy-5,4’-dimethoxy-6,7-methylenedioxyflavone 52. 3-Xyloside (viviparum A)* 3,3’-Dihydroxy-5,4’-dimethoxy-6,7-methylenedioxyflavone 53. 3-Xyloside (viviparum B)* *Flavonol glycosides newly reported since 1992.

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14

C-Glycosylflavonoids Maurice Jay, Marie-Rose Viricel, and Jean-Franc¸ois Gonnet

CONTENTS 14.1

14.2

14.3

14.4

14.5 14.6

Natural Sources and Some Taxonomic Implications ............................................... 858 14.1.1 Plant Species Rich in C-Glycosylflavonoids................................................ 858 14.1.2 C-Glycosylflavonoids and Taxonomic Aspects ........................................... 858 14.1.2.1 Ferns............................................................................................ 858 14.1.2.2 Angiospermae Monocotyledonae ................................................ 863 14.1.2.3 Angiospermae Dicotyledonae ...................................................... 864 Naturally Occurring C-Glycosylflavonoids.............................................................. 867 14.2.1 Mono-C-Glycosylflavonoids ....................................................................... 867 14.2.2 Di- and Tri-C-Glycosylflavonoids............................................................... 867 14.2.3 O-Glycosyl-C-Glycosylflavonoids ............................................................... 874 14.2.4 O-Acyl-C-Glycosylflavonoids...................................................................... 886 Separation and Identification of C-Glycosylflavonoids ........................................... 886 14.3.1 Capillary Zone Electrophoresis Separation................................................. 886 14.3.1.1 Qualitative Aspects ...................................................................... 890 14.3.1.2 Quantitative Aspects.................................................................... 891 14.3.2 High-Speed Countercurrent Chromatography Separation.......................... 891 14.3.3 New Polymers for Column Chromatography ............................................. 892 14.3.4 Mass Spectrometry and Structural Identification ....................................... 892 14.3.4.1 Fast Atom Bombardment and Tandem Mass Spectrometry....... 892 14.3.4.2 Liquid Chromatography–Mass Spectrometry: Thermospray and Atmospheric Pressure Ionization ................... 893 14.3.4.3 LC–API-MS–MS......................................................................... 893 14.3.5 NMR Spectroscopy and Fine Structure Elucidation .................................. 893 14.3.5.1 Improved NMR Techniques........................................................ 893 14.3.5.2 NMR and Rotational Isomers .................................................... 894 Synthesis of C-Glycosylflavonoids ........................................................................... 896 14.4.1 O–C Glycoside Rearrangement ................................................................... 896 14.4.2 Fries-Type Rearrangement.......................................................................... 896 14.4.3 Via C-b-D-Glucopyranosyl 2,6-Dimethoxybenzene..................................... 897 C-Glycosylflavonoids and Vacuolar Storage ........................................................... 897 Biological Properties of C-Glycosylflavonoids......................................................... 898 14.6.1 Antioxidant Activity of C-Glycosylflavonoids ............................................ 898 14.6.2 C-Glycosylflavonoids and Plant–Insect Relationships ................................ 898 14.6.2.1 Zea mays and Helicoverpa zea..................................................... 898 14.6.2.2 Oryza sativa and Nilaparvata lugens ............................................ 899 14.6.3 C-Glycosylflavonoids and Antimolluscidal Activity ................................... 899 14.6.4 C-Glycosylflavonoids and Plant–Microorganism Relationships ................. 899

857

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14.6.4.1

Arbuscular Mycorrhiza: Cucumis melo and Glomus caledonium................................................................ 899 14.6.4.2 Disease: Cucumis sativus and Podosphaera xanthii ...................... 900 14.6.5 Antibacterial Role of C-Glycosylflavonoids ............................................... 900 14.6.6 C-Glycosylflavonoids and General Animal Physiology .............................. 900 14.6.6.1 Antinociceptive Activity .............................................................. 900 14.6.6.2 Antispasmodic Activity ............................................................... 900 14.6.6.3 Sedative Activity.......................................................................... 901 14.6.6.4 Antihepatotoxic Activity ............................................................. 901 14.6.6.5 Antiinflammatory Activity .......................................................... 901 14.6.6.6 Antidiabetic Activity.................................................................... 902 14.6.6.7 Antihypertensive Activity ............................................................ 902 14.7 Manufacture and Cultivation Process and C-Glycosylflavonoids ........................... 902 References .......................................................................................................................... 903

14.1 NATURAL SOURCES AND SOME TAXONOMIC IMPLICATIONS The natural sources of C-glycosylflavonoids reported for the last 10 years are listed in Table 14.1. The number of species possessing C-glycosylflavonoids is given in parentheses for each genus, except in the case where a unique species was under investigation.

14.1.1 PLANT SPECIES RICH

IN

C-GLYCOSYLFLAVONOIDS

In Bryophyta, the presence of C-glycosylflavones was reported for the first time in the genera Plagiochila and Plagiochasma. It is the same situation in Gymnospermae for the genera Cycas and Abies. In ferns, the confirmation of the presence of C-glycosylflavonoids was provided for three families: Aspleniaceae (Asplenium sp.), Athyriaceae, and Hymenophyllaceae (Trichomanes sp.). In monocots, several investigations have concerned two species, Zea mays and Hordeum vulgare, and two families, Restionaceae and Velloziaceae. In dicots, the first citations for C-glycosylflavones concern the families Araceae, Betulaceae, Brassicaceae, Capparaceae, Chenopodiaceae, Droseraceae, Geraniaceae, Illecebraceae, Mimosaceae, Oleaceae, Orchidaceae, Oxalidaceae, Pistaciaceae, Plumbaginaceae, Polygalaceae, Sapindaceae, Solanaceae, Sterculariaceae, Turneraceae, Urticaceae, and Violaceae; important additions to the occurrence of C-glycosylflavones were given for Cucurbitaceae, Rosaceae, and Theaceae.

14.1.2 C-GLYCOSYLFLAVONOIDS 14.1.2.1

AND

TAXONOMIC ASPECTS

Ferns

The Athyriaceae and Aspleniaceae are two large families of leptosporangiate ferns. However, until the second half of the 20th century, they were united in one family because of the superficial resemblance of their sori. This similarity having been analyzed as the result of convergence rather than of close phylogenetic relationship, the two subfamilies were raised to the family rank. The investigation of Umikalsom et al.362 provided additional chemical data for characterizing and separating the two taxa. A large collection of 15 species of Asplenium, four species of Athyrium, 12 species of Diplazium, and two species of Deparia were compared for their flavonoid contents based on proanthocyanidins, flavonol-O-glycosides, flavoneO-glycosides, and flavone-C-glycosides. Nearly all species representatives of these four genera showed their own specific flavonoid pattern. A large range of flavone C- and O-glycosides was found in Asplenium: the flavone C-glycosides were based on both apigenin and luteolin,

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C-Glycosylflavonoids

TABLE 14.1 Natural Sources of C-Glycosylflavonoids (Since 1991). The Number of Species Under Investigation Given in Parentheses BRYOPHYTA Frullania polysticha186 Frullania cesatiana187 Frullania tamatisci329 Plagiochila jamesonii318 Plagiochasma rupestre318 Plagiomnium sp.16,399 PTERIDOPHYTA Aspleniaceae Asplenium viviparum156 Asplenium (3)363 Asplenium (4 hybrids)249 Aspleniaceae (15)362 Athyriaceae Athyriaceae (18)362 Hymenophyllaceae Trichomanes (23)379 GYMNOSPERMAE Ephedraceae Ephedra aphylla153 Cycadaceae Cycas panzhihuaensis416 Pinaceae Abies (7)331 ANGIOSPERMAE MONOCOTYLEDONAE Eriocaulaceae Eriocaulaceae311 Syngonanthus (22)309 Gramineae Bambusa (13)351 Deschampsia antarctica383 Hordeum vulgare239,258,260,278,279 Hyparrhenia hirta37 Sasa borealis405 Triticum aestivum129,255 Zea mays333–336,345,346 Iridaceae Iris (2)14 Restionaceae Restionaceae (115)387 Velloziacieae Velloziaceae (4 genus)386 Vellozia (10)126,127 ANGIOSPERMAE DICOTYLEDONAE Acanthaceae Climacanthus nutans352 continued

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TABLE 14.1 Natural Sources of C-Glycosylflavonoids (Since 1991). The Number of Species Under Investigation Given in Parentheses — continued Amaranthaceae Alternanthera maritima316 Araceae Arum palaestinum8,9 Arum dracunculus300 Xanthosoma violaceum298 Betulaceae Betula platyphylla204 Bombacaceae Bombax ceiba99,100 Brassicaceae Barbarea vulgaris324 Capparaceae Cleome (4), Capparis (3)326 Caryophyllaceae Silene conoidea15 Stellaria media304 Chenopodiaceae Beta vulgaris109 Combretaceae Combretum quadrangulare24 Terminalia catappa213 Compositeae Achillea nobilis192,234 Achillea setacea235 Achillea sp.365 Atractylis carduus252 Centaurea (2)115–117 Felicia amelloides34 Otanthus maritimus92 Crucifereae Boreava orientalis312 Cucurbitaceae Bryonia (2)188,189 Citrullus colocynthis223 Cucumis sativus3,13,191,228 Lagenaria siceraria188,190 Droseraceae Drosophyllum lusitanicum43 Euphorbiaceae Aleurites moluccana253,254,268 Glochidion zeylanica288 Jatropha polhiana400 Gentianaceae Gentiana arisanensis198,211 Gentianella azurea414

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C-Glycosylflavonoids

TABLE 14.1 Natural Sources of C-Glycosylflavonoids (Since 1991). The Number of Species Under Investigation Given in Parentheses — continued Tripterospermum japonicum289 Geraniaceae Pelargonium reniform200 Pelargonium (58)392 Guttifereae Clusia sandiensis74 Illecebraceae Scleranthus uncinatus403,404 Labiateae Faradaya (4)120 Ocimum (9)121,122 Otostegia fruticosa2 Oxera (20)120 Salvia officinalis218 Schnabelia tetradonta76 Scutellaria albida330 Scutellaria amoena417 Scutellaria baicalensis412,413 Scutellaria pontica282 Leguminoseae Abrus precatorius222 Acacia saligna89,94 Acacia leucophloea366 Bocoa (2)180 Cassia nomame178 Cassia occidentalis130 Crotalaria thebaica154 Cyclopia intermedia168 Desmodium tortuosum207 Glycyrrhiza glabra210 Glycyrrhiza eurycarpa216 Herminiera elaphroxylon93 Lagonychium farcatum93 Lupinus hartwegii169 Lupinus luteus406 Mohgania macrophylla398 Phaseolus radiatus165 Phaseolineae393 Prosopis chilensis88 Rhynchosia (2)421 Vigna radiata199 Mimosaceae Mimosa pudica217 Myrtaceae Eucalyptus globulus232 continued

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TABLE 14.1 Natural Sources of C-Glycosylflavonoids (Since 1991). The Number of Species Under Investigation Given in Parentheses — continued Oleaceae Ligustrum vulgare353 Orchidaceae Ornithocephalinae (15)385 Tylostylis discolor231 Oxalidaceae Biophytum sensitivum42 Passifloraceae Passiflora incarnata56,208,305,373 Passiflora (3)295 Passiflora (2)294 Passiflora sp.1 Pistaciaceae Pistacia atlantica269 Plumbaginaceae Plumbago zeylanica212 Polygalaceae Polygala telephioides195 Polygonaceae Rumex (8)314 Polygonum perfoliatum418 Ranunculaceae Trollius lebedouri 420 Rhamnaceae Ziziphus jujuba54 Rhamnella inaequilatera350 Rosaceae Cotoneaster thymaefolia291 Cotoneaster wilsonii 49 Crataegus monogyna308 Crataegus pinnatifida175,411 Crataegus sinaica87 Cydonia oblonga102 Eriobotrya japonica159 Rutaceae Citrus (review)233 Citrus (2)124 Citrus sp.23,111,259–261,361 Feronia elephantum85 Raputia paraensis22 Sapindaceae Allophylus edulis143 Saxifragaceae Itea/Pterostemon35 Scrophulariaceae Gratiola officinalis123

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C-Glycosylflavonoids

TABLE 14.1 Natural Sources of C-Glycosylflavonoids (Since 1991). The Number of Species Under Investigation Given in Parentheses — continued Solanaceae Capsicum annuum246 Sterculariaceae Theobroma cacao317 Theaceae Thea sp.96,375 Thea (90 beverages)97 Thymeleaceae Daphne laureola359 Turneraceae Turnera diffusa297 Urticaceae Cecropia lyratifolia285 Verbenaceae Verbena pinnatifida85 Vitex polygama205 Violaceae Viola arvensis46 Viola yedoensis401 Vitidaceae Vitis (22)263 Tetrastigma hemsleyanum215

both mono-C- and di-C-glycosylated; some of them were further O-glycosylated. In Athyriaceae (the other three genera), it was only apigenin-based C-glycosides that were found; O-glycosyl-C-glycosylflavones and O-glycosylflavones were absent. Accordingly, the Athyriaceae were clearly distinguished and considered as more primitive than the Aspleniaceae. In the genus Asplenium, Matsumoto et al.249 studied the flavonoid composition of four natural hybrids in natural populations where the hybrids could be collected with individuals of parental genotypes: Asplenium normale
A. boreale, A. normale
A. shimurae, A. normale
A. oligophlebium, and A. boreale
A. oligophlebium. The phenolic patterns consisted of O-glycosylflavones and di-C-glycosylflavones. Interestingly, the flavonoid composition of the hybrids was shown to be total addition of the parental attributes. 14.1.2.2

Angiospermae Monocotyledonae

14.1.2.2.1 Family Eriocaulaceae A recent study by Salatino et al.311 concerned the distribution of flavonoids in four genera of Eriocaulaceae: Eriocaulon, Leiothrix, Paepalanthus, and Syngonanthus. The authors compared the flavonoid patterns with the results of cladistic analyses based on 49 predominantly morphological characters. This morphometric analysis suggests that Paepalanthus is polyphyletic, Eriocaulon is closely related to some small subgroups of Paepalanthus, while Leiothrix and Syngonanthus appear as more advanced sister groups. Moreover, at the sectional level within Syngonanthus, the Eulepis and Thysanocephalus sections seemed to constitute a more advanced monophyletic group than the Carpocephalus and Syngonanthus sections.

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The structural aspects of flavonoids seem to have paralleled the evolution of Eriocaulaceae. The 6-oxygenation has been superseded during evolution: in the primitive side, Paepalanthus and Eriocaulon accumulate 6-OH flavonols; in the more advanced groups, Leiothrix, Syngonanthus–Carpocephalus, Syngonanthus–Syngonanthus, 6-OH flavones are found; finally, in highly advanced sections, Syngonanthus–Eulepis and Syngonanthus–Thysanocephalus, 6-oxygenated derivatives are lacking while there is a prevalence of C-glycosylflavones. 14.1.2.2.2 Family Velloziaceae In another group of monocots, the Velloziaceae family, chemical studies127,386 clarified the delineation of subfamilies and genera, which had been the subject of much dispute. The flavonoid patterns were described for about 100 species representative of the subfamilies Vellozioideae (Vellozia, Nanuza, Barbaceniopsis, Xerophyta, Talbotia), Barbacenioideae (Aylthonia, Barbacenia, Burlemarxia, Pleurostigma). Flavone C-glycosides have been identified in both subfamilies; however, the Vellozioideae could be distinguished from the Barbacenioideae by the accumulation of flavone mono-C-glycosides rather than di-C-glycosides. It was apparent that Barbaceniopsis, Xerophyta (Madagascan species), and Talbotia differ from most other members of the subfamily in the absence of C-glycosylflavones, and predominance of flavonol glycosides. The species Nanuza plicata remains unique within Vellozioideae in the accumulation of biflavonoids. And finally the genus Pleurostigma was unique within the Barbacenioideae in accumulating 6-OH flavonoids instead of C-glycosylflavones. 14.1.2.3

Angiospermae Dicotyledonae

14.1.2.3.1 Tribe Phasaeolinae The C-glycosylflavones clarify the position of the genus Dysalobium within the tribe Phasaeolinae (Leguminosae Fam.).393 The Phasaeolinae is a taxonomically very complex group because of the limited number of useful morphological characters available to distinguish generic limits. The main taxa are Phaseolus, Dysolobium, Macroptilium, Strophostyles, and Vigna. The flavonoid profiles of 49 representative species of these five genera were compared and about 35 flavonoids were identified. A statistical procedure using binary presence– absence data for the leaf flavonoids, and based on Sneath’s simple matching coefficient, indicated four main groupings, one of them restricted to Dysalobium, which is clearly separated from all others while it alone produces only C-glycosylflavones. 14.1.2.3.2 Tribe Ornithocephalinae Ornithocephalinae,385 a small subtribe of the family Orchidaceae, is traditionally recognized as one of the most advanced in this family. The complexity and diversity of floral and vegetative morphologies of the species of this subtribe seem to have reached a level that is apparently only paralleled by some members of the Oncidiinae usually interpreted as a putative close relative. The results of the leaf flavonoid analyses of 15 species representative of the genera, Zygostates, Ornithocephalus, Chytroglossa, Phymatidium, and Rauhiella, showed the presence of 16 different C-glycosylflavones. These taxa could be distinguished from each other by occurrence of different isomers; these were all apigenin-based structures, with a large representation of different apigenin 7,4’-dimethylether 6-C-glycosyl X ’’-O-glycosides, and apigenin 7-methylether 6-C-glycosyl-X ’’-O-glycosides (O-glycosidic linkages were not precisely determined). All these flavonoids are unusual and quite rare in the Angiosperms. Methylated flavonoids, considered to be advanced chemical characters, suggested that Zygostates, Ornithocephalus, Chytroglossa, and Phymatidium might be highly evolved genera, while the presence of isovitexin and absence of methylated derivatives in Rauhiella clearly separated this genus from the other members.

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As already mentioned, subtribe Oncidiinae has been considered as a probable sister group of the Ornithocephalinae; Oncidium species so far surveyed lack flavone C-glycosides, and possess new and unusual 6-hydroxyflavone glycosides. Thus, different flavonoid patterns did not support a close association of these two subtribes. 14.1.2.3.3 Genus Pelargonium The first example concerns the chemical survey of 56 Pelargonium species (representative of 19 sections).392 Their flavonoid composition revealed a large chemical diversity: flavonols, flavones, C-glycosylflavones, proanthocyanidins, and ellagitannins. No individual phenolic compound or group of compounds provides taxonomic markers at the sectional level. However, the data indicated which sections are homogenous in their phenolic profiles and which not and in this way could support or refute the current classification. C-Glycosylflavones were well represented in the sections Subsucculentia, Chorisma, Perista, Reniformia, and Jenkinsonia, for example, while they were not found in the Pelargonium, Otidia, and Cortusina sections. Interestingly, most species possessing high levels of C-glycosylflavones showed a strong correlation between these compounds and the presence of ellagitannins. In other sections lacking C-glycosylflavones, a correlation exists between proanthocyanidins and the flavonol myricetin. Thanks to these correlations, it was possible to detect in each section well placed and misplaced species. Thus in Reniformia, three species, P. reniforme, P. exstipulatum, and P. album, have the basic flavone-C-glycoside or ellagitannin profile but P. odoratissimum has a very different myricetin or proanthocyanidin pattern, suggesting it may need to be moved. 14.1.2.3.4 Genus Itea and Pterostemon Itea and Pterostemon, sister taxa close to Ribes in the Saxifragaceae family, were studied35 for chemical data in comparison to gene sequence data. Recent phylogenetic analyses of rbcL, 18S rDNA, matK, and atpB sequences all concur in suggesting that Itea and Pterostemon are sister taxa, close to Ribes in the Saxifragaceae as a part of a larger Saxifragales clade that also includes Hamamelidaceae, Crassulaceae, Penthoraceae, etc. The flavonoid profile of Pterostemon comprises O-glycosides of quercetin and C-glucosylflavones (vitexin, isovitexin, orientin and their O-glycoside derivatives, especially X’’-O-xylosides). This C-glycosylflavone pattern resembles very closely that observed in Itea, and provides support for the closeness of their relationship recently demonstrated on the basis of gene sequence data. But this finding indicates that the flavonoid profiles of Itea and Pterostemon are dramatically different from the overall profile of a large number of species of Saxifragaceae, which is mainly based upon various O-glycosylflavonols but with no trace of C-glycosylflavones. If the DNA studies indicate that Itea and Pterostemon are sister taxa within the Saxifragaceae, the phenolic contents demonstrate that the two genera possess unusual and non-saxifragoid flavonoid chemistry. On the evolutionary sequence of flavonoid production, it appears that these genera represent a derived clade with a replacement of flavonols by C-glycosylflavones, and that Pterostemon, due to O-glycosylflavonols, possibly represents an intermediate form between Itea and the true Saxifragaceae. 14.1.2.3.5 Genus Centaurea Based on glycosylflavones within blue flowering alpine cornflowers, Centaurea montana L. and Centaurea triumfetti All. (Compositae), a major discussion concerned the influence of microscale environmental conditions and the role of reproductive modes on the distribution of C-glycosylflavones. Twenty-one out of the 48 flavonoid glycosides detected in plants from different origins are basic 6- and 8-C-monoglucosides of apigenin, luteolin, and chrysoeriol, 6,8-di-C-glucosyl apigenin, 2’’-O-glucosides and arabinosides of the 6-Cglucosides, and caffeoyl derivatives of 2’’-O-glucosides along with some other incompletely

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identified C-glycosides. The other 27 are O-glycosides, mono- and di-glycosides, most of which were based on the above three aglycones.115 In individual plants of Centaurea montana originating from different restricted areas in the French southern Alps, in addition to practically pure O-glycosidic patterns, these molecules are arranged in many diverse assemblages of simple or complex C-glycoside derivatives — along with O-glycosides in some. This results in an extraordinary diversity of flavonoid patterns of this species, which comprise from five to more than 20 compounds. This flavonoid variation is first correlated with the phytosociological origin of Centaurea montana plants: those displaying C-glycosidic patterns (all types) are largely predominant in meadows of Triseto-Polygonion while in tall grass prairies under Larix of Adenostylion, O-glycosidic types are the most frequent. In some meadows, the individuals with different types of C-glycosidic patterns are distributed according to microstational parameters as detected by aerial infrared remote sensing. The origin of the huge chemical diversity in Centaurea montana was shown to result from its reproductive mode combining vegetative reproduction and strictly allogamous pollination (completely preventing autogamy and strongly limiting fertility between genetically related partners), both confirmed by flavonoid analysis of wild and experimental plants from breeding experiences. Clonal ramets are readily identifiable by identical flavonoid profiles of closely collected individuals. Interindividual diversity is also consistently observed in the progeny of most of the experimental crosses, revealing a generalized heterozygosis of wild individuals, an expectable consequence of the obligate allogamy of this species. For instance, in a breeding experience involving two wild partners with O-glycosidic dominant profiles (more than 75% of the total flavonoids) and collected in a single meadow, one out the three descendants displayed a C-glycosidic pattern featuring 2’’-O-glycosides of mono-C-glucosides (35% of the total) and their caffeoyl derivatives (45% of the total) along with the three basic C-glycosides (10%). By contrast, in the lineage of combinations of other individuals featuring O-glycosidic patterns also, only O-glycosidic phenotypes were observed, in which the traces of C-glycosides present in the parental fingerprints (10 to 20% of the total) completely disappeared. Consequently, C-glycosidic phenotypes seemed to proceed from a hypostatic determinism. This was extensively confirmed by many experiments with individuals displaying the two extreme phenotypes detected in Centaurea montana. Thus, when crossing plants with O-glycosidic (but C-glycosides — all types — remaining present, each 2 to 5% of the total) and C-glycosidic (blend of ‘‘complex’’ [85%] and ‘‘simple’’ [5%] types; O-glycosides: 30 mg/ml).240 A compound isolated from leaves of Piper aduncum (Piperaceae) with identical physical and spectroscopic data to (þ)-methyllinderatin,252 but with the opposite sign of optical rotation, was characterized as (
)-methyllinderatin (277).241 Five 6’-O-linked p-menthenyl derivatives of 2’,6’-dihydroxy-4’-methoxydihydrochalcone, adunctins A–E (281–285), were also obtained from the same source.241 The p-menthenyl substituent is cyclized to the dihydrochalcone A-ring through an additional C–C bond at C-5’ in all but adunctin A (281). Adunctins B–D (282–284) and (
)-methyllinderatin (277) showed antibacterial activity toward Micrococcus luteus. Cytotoxicity toward a KB nasopharyngeal carcinoma cell line was shown by (
)-methyllinderatin (277), whereas adunctins A–E were inactive (281–285).241 Two isoprenylated derivatives of 2’,6’-dihydroxy-4’-methoxydihydrochalcone with additional methyl p-hydroxybenzoate substitution were obtained by bioassay-guided fractionation in a later

294

292 293

289 290 291

288

286 287

2’-OH, 4’-OMe, 6’-O-C10 2’-OH, 4’-OMe 2’-OH, 4’-OMe 2’-OH, 4’-OMe 2’-OH, 4’-OMe (2’,4’,4) 2’,4-diOH 2’-OH, 4-OMe Tetra O-substituted (2’,3’,4’,6’) 4’,6’-diOH, 3’-OMe, 2’-oxo (2’,4’,6’,4) 2’,4’,6’,4-tetraOH 2’,4’,6’,4-tetraOH 2’,4’,4-triOH, 6’-OMe (2’,4’,3,4) 2’,3,4-triOH 2’-OMe, 3,4-OCH2O(2’,4’,4,a) 2’,4’,4,a-tetraOH

Tri O-substituted (2’,4’,6’) 2’,4’,6’-triOH 2’,4’,6’-triOH 2’,6’-diOH, 4’-OMe 2’,6’-diOH, 4’-OMe 2’-OH, 4’-OMe 2’-OH, 4’-OMe

O-Substituents

Boronia inconspicua Boronia inconspicua Humulus lupulus Crotin

Kanzonol Y

C21H24O5 C25H30O5 C30H38O5 C21H24O5 C20H20O5 C19H16O5 C25H30O5

3’-Prenyl 3,5-Diprenyl 3-Geranyl, 5-prenyl 3’-Prenyl 6’’,6’’-Dimethylpyrano[2’’,3’’:4’,3’] Furano[2’’,3’’:4’,3’] 5’,3-Diprenyl

a,b-Dihydroxanthohumol

Helichrysum aphelexiodes

Crotaramosmin Crotaramin

C20H20O4 C21H22O4

Glycyrrhiza glabra

Crotalaria ramosissima Lonchocarpus subglaucescens

Crotalaria ramosissima Crotalaria ramosissima

aduncum aduncum aduncum aduncum aduncum

6’’,6’’-Dimethylpyrano[2’’,3’’:4’,3’] 6’’,6’’-Dimethylpyrano[2’’,3’’:4’,3’]

Piper Piper Piper Piper Piper

Adunctin A Adunctin B Adunctin C Adunctin D Adunctin E

C26H32O4 C26H30O4 C26H30O4 C26H30O4 C26H32O5

Mitrella kentii Mitrella kentii Piper aduncum Piper aduncum Piper longicaudatum Piper aduncum

Source

(
)-Linderatin (
)-Neolinderatin (
)-Methyllinderatin Piperaduncin A Longicaudatin Piperaduncin B

Trivial Name

C25H30O4 C35H46O4 C26H32O4 C29H30O7 C26H22O7 C29H30O8

Mol. Formula

3’-C10 3’,5’-diC10 3’-C10 5’-(1’’-Aryl)prenyl 5’’-Arylfurano[2’’,3’’:6’,5’] 4’’-Aryl-5’’-(2-hydroxyisopropyl) dihydrofurano[2’’,3’’:6’,5’] — [5’,6’]-C10 [5’,6’]-C10 [5’,6’]-C10 [5’,6’]-C10

Other Substituents

Leguminosae

Leguminosae Leguminosae

Rutaceae Rutaceae Cannabinaceae

Asteraceae

Leguminosae Leguminosae

Piperaceae Piperaceae Piperaceae Piperaceae Piperaceae

Annonaceae Annonaceae Piperaceae Piperaceae Piperaceae Piperaceae

Family

247

245 101

246 246 91

66

244 245

241 241 241 241 241

240 240 241 242 243 242

Ref.

1044

281 282 283 284 285

275 276 277 278 279 280

No.

TABLE 16.9 New Isoprenylated Dihydrochalcones Reported in the Literature from 1992 to 2003

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302

C26H32O6 C26H32O6

C24H26O7

299 300

C30H36O6

6’’,6’’-Dimethylpyrano[2’’,3’’:4’,3’]

2’,4’,6’,3-tetraOH, 4-OMe 2’,6’,3-triOH, 4-OMe

298

C30H38O6

C20H18O6

3’-Geranyl, 6’’,6’’dimethylpyrano[2’’,3’’:4,5] 3’,5-Diprenyl 5-Prenyl, 6’’,6’’-dimethyl-4’’,5’’dihydropyrano[2’’,3’’:4’,3’]

2’,4’,6’,3-tetraOH

297

C25H30O6

C25H30O5

Furano[2’’,3’’:4’,3’]

3’-Geranyl, 5-prenyl

2’,4’,6’,3,4-pentaOH

296

(2’,4’,3,4,b) 2’,b-diOMe, 3,4-OCH2OHexa O-substituted (2’,4’,5’,3,4,b) 2’,5’,b-triOMe, 3,4-OCH2O-

3’,5-Diprenyl

Penta O-substituted (2’,4’,6’,3,4) 2’,4’,6’,3,4-pentaOH

301

—

(2’,4’,4,a) continued 2’,4,a-triOH, 4’-geranyloxy

295

Ponganone VIII

Ponganone IX

Pongamia pinnata

Pongamia pinnata

Esenbeckia grandiflora ssp. grandiflora Esenbeckia grandiflora ssp. grandiflora Esenbeckia grandiflora ssp. grandiflora Metrodorea nigra Metrodorea nigra

Millettia usaramensis ssp. usaramensis

Leguminosae

Leguminosae

Rutaceae Rutaceae

Rutaceae

Rutaceae

Rutaceae

Leguminosae

53

53

250 250

249

249

249

248

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HO 4⬘ 2⬘

HO 4⬘

OH

2⬘

6⬘ OH O

6⬘ OH O

OH

MeO

OH 6⬘ 2⬘ OH O 278

276

275

MeO2C

MeO

OH

OH H

H

O 6⬘

MeO

2⬘ OH O

O 6⬘

MeO

O 6⬘ 2⬘ OH O

2⬘ OH O

281

280

OH

O 4⬘

282

HO 4⬘

OH

OH α

OH O

OH

O

286

294

OMe O 4⬘

OH

4 OMe

4 O

O 4⬘ β

OH OH O

OMe O 300

3 O

OMe

302

FIGURE 16.15 Isoprenylated dihydrochalcones (see Table 16.9).

study of P. aduncum constituents.242 The compounds piperaduncins A (278) and B (280) showed antibacterial activity toward both Bacillus subtilis and Micrococcus luteus and were cytotoxic toward a KB nasopharyngeal carcinoma cell line. Bioassay-guided fractionation of an extract of dried leaves and twigs of Piper longicaudatum (Piperaceae) gave piperaduncin B (280) and a new constituent, longicaudatin (279), a furanodihydrochalcone with the furan ring substituted by methyl p-hydroxybenzoate.243 Rao et al. revised the structure of crotaramosmin (286), formerly described as a prenylflavanone, to 2’,4-dihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]dihydrochalcone.244 Two derivatives of crotaramosmin, crotaramin (287) and crotin (292), were later isolated from the same source, Crotalaria ramosissima (cited incorrectly as Crotolaria ramosissima).245 Kanzonol Y (294) is an uncommon diprenylated a-hydroxydihydrochalcone found in cultivated licorice (Glycyrrhiza glabra)247 for which the absolute configuration was determined by

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Mosher’s method as a(R).253 All the new isoprenylated a- and b-hydroxydihydrochalcones reported in Table 16.9 are constituents of the Leguminosae, a general trend observed both in Table 16.8 and the earlier literature.10 Another apparent trend is the predominance of isoprenylated (2’,4’,6’,3,4)-penta-O-substituted dihydrochalcones in species of the Rutaceae (296–300).249,250 Only one other example of this type of compound has been recorded in the literature, a geranylated derivative from Helichrysum monticola (Asteraceae).254

16.3.3 DIHYDROCHALCONE GLYCOSIDES Relatively few dihydrochalcone glycosides have been reported in the literature, with only 11 O-glycosides and 3 C-glycosides published prior to 1992, according to the Handbook of Natural Flavonoids.9,10 The O-glycosides are mainly 2’- and 4’-O-glucosides of simple dihydrochalcones while only one higher glycoside, the incompletely characterized 2’-O-xylosylglucoside of phloretin (2’,4’,6’,4-tetrahydroxydihydrochalcone), has been described.255 Table 16.10 lists new dihydrochalcone glycosides published in the period 1992 to 2003, and some examples are shown in Figure 16.16. Among the new compounds are the first acylated dihydrochalcone glycosides, including two acetylated glucosides of phloretin (306, 307).258,259 Of particular interest are thonningianins A and B (303, 304), unusual galloylated glucosides of 2’,4’,6’-trihydroxydihydrochalcone isolated from the roots of the African medicinal herb Thonningia sanguinea (Balanophoraceae).256 Both structures feature a 4’-O-glucopyranosyl moiety acylated at 4-OH and 6-OH by a C–C linked digallic acid. The compounds are effective scavengers of the DPPH radical, according to analysis by EPR spectroscopy.256 In contrast, salicifolioside A, a 4’-O-gentobioside of 2’,4’-dihydroxy-3’,6’-dimethoxydihydroxychalcone isolated from aerial parts of Polygonum salicifolium (Polygonaceae), was not active in the DPPH assay.257 The b-Glc-(1 ! 6)-b-Glc interglycosidic linkage of this compound was confirmed from HMBC data. The first di-C-glycoside of a dihydrochalcone has been reported as a characteristic constituent of species of Fortunella (Rutaceae).260 The compound, phloretin 3’,5’-di-C-glucoside (308), accumulates in the fruits and leaves. Only two of 28 species of Citrus (C. halimii and C. madurensis) surveyed contain this glycoside and it was absent from Poncirus trifoliata. In contrast, large amounts were detected in many Fortunella–Citrus hybrids. The authors suggest that accumulation of phloretin 3’,5’-di-C-glucoside is a generic trait of Fortunella, and that inheritance of the trait among intergeneric hybrids is under the control of a dominant allele.260 A 3’-C-xyloside of 2’,4’,3,4,a(R)-pentahydroxydihydrochalcone (314), the corresponding aglycone (273), and a compound described as the 3’-O-xyloside of the same dihydrochalcone were obtained from Eysenhardtia polystachya (Leguminosae).234 However, the NMR data presented for the latter compound do not support its identification as an O-glycoside. Two 3’-C-glucosides of a-hydroxydihydrochalcones were isolated previously from E. polystachya (coatline A and B)239 and C-glucosides of both a-hydroxy- (coatline A)266 and b-hydroxydihydrochalcones have been reported from Pterocarpus marsupium (Leguminosae).267,268

16.3.4 DIHYDROCHALCONE DIMERS The only example of a dihydrochalcone dimer reported in the literature prior to 1992 is brackenin, a Ca–Ca linked dimer of davidigenin from Brackenridgea zanguebarica (Ochnaceae).269 Several new examples of this rare class of dihydrochalcones cited between 1992 and 2003 are shown in Table 16.11 and Figure 16.17 (note that the ‘‘mixed’’ chalcone–dihydrochalcone dimers 142 and 148–150 are described in Table 16.4 and Section 16.2.4). The leaves and inflorescences of Iryanthera sagotiana (Myristicaceae) yielded a dimer (317) comprising

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TABLE 16.10 New Dihydrochalcone Glycosides Reported from 1992 to 2003 No.

303

304

305

Compound 2’,4’,6’-Trihydroxydihydrochalcone 4’-O-(3’’-O-Galloyl-4’’,6’’-O,Ohexahydroxydiphenoylglucoside) (thonningianin A) 4’-O-(4’’,6’’-O,OHexahydroxydiphenoylglucoside) (thonningianin B)

Mol. Formula

Source

Family

Ref.

C42H34O21

Thonningia sanguinea

Balanophoraceae

256

C35H30O17

Thonningia sanguinea

Balanophoraceae

256

Polygonum salicifolium

Polygonaceae

257

2’,4’-Dihydroxy-3’,6’-dimethoxydihydrochalcone 4’-O-Glucosyl-(1’’’ ! 6’’)glucoside C29H38O15 (salicifolioside A)

306 307 308

2’,4’,6’,4-Tetrahydroxydihydrochalcone (phloretin) 2’-O-(6’’-O-Acetylglucoside) C23H26O11 4’-O-(2’’-O-Acetylglucoside) C23H26O11 3’,5’-Di-C-glucoside C27H34O15

Loiseleuria procumbens Lithocarpus pachyphyllus Fortunella spp.

Ericaceae Fagaceae Rutaceae

258 259 260

309

2’,4’,6’-Trihydroxy-4-methoxydihydrochalcone 2’-O-Glucoside C22H26O10

Iryanthera sagotiana

Myristicaceae

261

310

2’,4-Dihydroxy-4’,6’-diacetoxydihydrochalcone 2’-O-Glucoside (zosterin) C25H28O12

Zostera sp.

Zosteraceae

262

311

4-Hydroxy-2’,4’,6’-trimethoxydihydrochalcone 4-O-Glucoside (bidenoside B) C24H30O10

Bidens bipinnata

Asteraceae

263

312

2’,4’,4,a-Tetrahydroxydihydrochalcone a-O-Glucoside (licoagroside F) C21H24O10

Glycyrrhiza pallidiflora

Leguminosae

264

313

2’,4’,4,b-Tetrahydroxydihydrochalcone 2’-O-Glucoside (rocymosin B) C21H24O10

Rosa cymosa

Rosaceae

265

314

2’,4’,3,4,a-Pentahydroxydihydrochalcone 3’-C-Xyloside C20H22O10

Eysenhardtia polystachya

Leguminosae

234

two molecules of 2’,4’,6’-trihydroxy-4-methoxydihydrochalcone linked by a C–C bond between C-3’ of each A-ring.261 Cycloaltilisin 6 (319) is the only known example of an isoprenylated dihydrochalcone dimer and a constituent of the bud covers of Artocarpus altilis (Moraceae).272 This compound, which comprises two molecules of 2’,4’,3,4-tetrahydroxy-2’geranyldihydrochalcone linked by a C–C bond between the B-rings (Figure 16.17), is a potent inhibitor of cathepsin K, a novel cysteine protease implicated in osteoporosis. A novel feature of the structure of piperaduncin C (318) is a methylene bridge connecting C-3’ of the A-rings of two molecules of 2’,6’-dihydroxy-4’-methoxydihydrochalcone.242 Littorachalcone (315)270 and verbenachalcone (316)271 are the first examples of ether-linked dihydrochalcone dimers and were isolated from the aerial parts of Verbena littoralis (Verbenaceae). Both compounds enhanced the effect of neural growth factor on stimulating neurite outgrowth in PC12D cells, with littorachalcone (315) showing greater potency. A characteristic structural feature of both littorachalcone (315) and verbenachalcone (316) is an ether bridge between the

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HO

OH

HO HO 6⬙ O CH 2 O O O 4⬘ O 3⬙ OH O O

HO

O

HO

OH

OH HO HO

HO CH2OH

OH

O HO HO

303

OH

CH2OH

O HO

6⬙ O CH 2

HO HO

HO O

O 4⬘

OMe 6⬘

OH MeO

2⬘ OH

O

OH

5⬘

HO HOH2C HO HO

305

O

O OH

OH

3⬘ OH

OH

O

308

FIGURE 16.16 Dihydrochalcone glycosides (see Table 16.10).

B-rings of their constituent dihydrochalcone monomers. A concise synthesis of verbenachalcone (316) by catalytic copper-mediated coupling of phenol and aryl halides has been reported by Xing et al., who also prepared two further derivatives for preliminary structure–activity studies.277 One of the latter, the corresponding bichalcane (deoxo) derivative of verbenachalcone showed no activity in the neural outgrowth stimulation bioassay mentioned above. A resin from Dracaena cinnabari known as ‘‘dragon’s blood,’’ mentioned previously as the source of the dihydrochalcone 251 (Section 16.3.1), also yielded cinnabarone (321), a dihydrochalcone linked by a C–C bond from C-5 of its B-ring to the deoxo-carbon of a deoxotetrahydrochalcone.220 The closely related compound cochinchinenin (320) is characterized by the same linkage, and was isolated from ‘‘Chinese dragon’s blood,’’ the resin of D. cochinchinensis.273 It is interesting to note that both cochinchinenin and cinnabarone are dimers derived from retrodihydrochalcones, given the prevalence of this type of compound in species of Dracaena (Table 16.8). Trianguletin (322) is a novel dihydrochalcone–flavonol dimer in which the A-rings of the two flavonoids are linked by a methylene bridge similar to that of piperaduncin C (318).274 In the case of trianguletin, this bridge connects C-3’ of 2’,6’-dihydroxy-4’-methoxy-5’-methyldihydrochalcone with C-8 of 3,5,7-trihydroxy-4’-methoxyflavone (kaempferide). The structure of this compound, which is a constituent of the farinose exudate of the fronds of the fern, Pentagramma triangularis ssp. triangularis, was confirmed by x-ray crystallography.274 Four structurally related dimers also obtained from farinose exudates of P. triangularis comprise slightly different combinations of dihydrochalcones and flavonols; for example, trianguletin ‘‘B’’ (323) contains 5,7-dihydroxy-3-methoxyflavone (galangin 3-methyl ether) instead of kaempferide.275 Similarly, trianguletins ‘‘C’’ to ‘‘E’’ (324–326) comprise 2’,6’,4-trihydroxy4’-methoxy-5’-methyldihydrochalcone with kaempferide, ermanin (kaempferol 3,4’-dimethyl ether), and galangin 3-methyl ether, respectively.276

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TABLE 16.11 Dihydrochalcone Dimers and Heterodimers Reported from 1992 to 2003 No.

Compound

Mol. Formula

318 319

Dihydrochalcone–dihydrochalcone Littorachalcone Verbenachalcone 3’,3’-Bis(2’,4’,6’-trihydroxy-4methoxydihydrochalcone) Piperaduncin C Cycloaltilisin 6

320 321

Dihydrochalcone–deoxotetrahydrochalcone Cochinchinenin C31H30O7 Cinnabarone C32H32O7

322

Dihydrochalcone–flavonol Trianguletin

C34H30O10

323 324 325 326

Trianguletin ‘‘B’’ Trianguletin ‘‘C’’ Trianguletin ‘‘D’’ Trianguletin ‘‘E’’

C34H30O9 C34H30O11 C35H32O11 C34H30O10

315 316 317

Source

Family

Ref.

C30H26O8 C31H28O9 C32H30O10

Verbena littoralis Verbena littoralis Iryanthera sagotiana

Verbenaceae Verbenaceae Myristicaceae

270 271 261

C33H32O8 C50H58O10

Piper aduncum Artocarpus altilis

Piperaceae Moraceae

242 272

Dracaena cochinchinensis Dracaena cinnabari

Liliaceae Liliaceae

273 220

Pentagramma triangularis ssp. triangularis Pentagramma triangularis Pentagramma triangularis Pentagramma triangularis Pentagramma triangularis

Adiantaceae

274

Adiantaceae Adiantaceae Adiantaceae Adiantaceae

275 276 276 276

16.3.5 BENZYLATED DIHYDROCHALCONES New reports of C-benzylated dihydrochalcones are summarized in Table 16.12. Examples of this unique group of dihydrochalcones were known previously only from Xylopia africana and species of Uvaria (Annonaceae),10,278 and these taxa continue to be the only recorded sources of the compounds. Those listed in Table 16.12 were obtained from either the root bark of Uvaria leptocladon or the dried roots of Xylopia africana, and are based on uvangoletin (2’,4’-dihydroxy-6’-methoxydihydrochalcone), with the exception of 327, which is a derivative of 2’,6’-dihydroxy-4’-methoxydihydrochalcone.279 Some examples of this group of dihydrochalcones are shown in Figure 16.18. The 2-hydroxybenzyl substituents (2OHBn) can be at either C-3’ or C-5’ of the A-ring or at both positions. Many of the compounds have chains of 2-hydroxybenzyl unit linked successively from C-5n to C-1nþ1, which may also incorporate a C-3n to C-1nþ1 linkage. For example, compounds 332 and 333 feature chains of four 2-hydroxybenzyl groups as substituents to the dihydrochalcone Aring.283 Preliminary data on the antibacterial activity of some of the compounds (330–333) have been published.282,283

16.3.6 DIHYDROCHALCONE–LIGNAN CONJUGATES Iryantherins G–L (334–339) are flavonolignans thought to arise from the oxidative coupling of dihydrochalcones and lignans (Figure 16.18). They represent further examples of a series of compounds reported exclusively from species of Iryanthera (Myristicaceae). The diastereoisomeric pairs iryantherins G and H (334, 335) and I and J (336, 337) were isolated from the fruits of I. grandis, a known source of dihydrochalcones and lignans.284 The relative configurations of the lignan components of iryantherins G–J were deduced from NOE

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OH 4 O 4

HO

OH O

OH O

O

315

OH HO

OH O

OH

OH

3 4 O

HO

316 OMe HO HO

3'

3'

OH OH

OMe OMe

OH O OH

317

OH OH O

OH O

5

HO

OH

6 OH MeO MeO

OH 3' CH2 3' OH

OH O

OH O

O

HO

OH

318

319

OH O HO

HO

OR2

OR

Me

5 MeO

β' O

OR1 HO

OH 3' CH2 8 O

OH 320 R = H, R1 = Me, R2 = H 321 R = Me, R1 = H, R2 = Me

OMe

OH OH O

322

FIGURE 16.17 Dihydrochalcone dimers and heterodimers (see Table 16.11).

measurements and coupling constant data. The lignans are linked to C-3’ of the A-rings of either 2’,4’,6’-trihydroxy-4-methoxy- (G and H) or 2’,4’,6’-trihydroxy-3,4-methylenedioxydihydrochalcone (I and J). An additional pair of flavonolignan diastereoisomers (iryantherins K and L) was isolated subsequently by Silva et al. from the pericarps of I. lancifolia.229 Both compounds showed moderate antioxidant activity. Iryantherin L (339) appears to be synonymous with iryantherin B, a compound found previously in both I. laevis and I. ulei for which the relative stereochemistry was not defined.285 Iryantherins K (338) and L (339) are also known as constituents of the stem bark of I. megistophylla, and were assayed for antibacterial, antifungal, antiviral, and antiacetylcholinesterase activity.286 Iryantherin K (338) showed high levels of inhibition against potato virus, but only moderate inhibition of acetylcholinesterase.

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TABLE 16.12 Miscellaneous Dihydrochalcones Reported from 1992 to 2003 No.

327 328

Compound C-Benzylated Dihydrochalconesa 2’,6’-DiOH, 4’-OMe, 3’-(2-OHBn) 2’,4’-DiOH, 6’-OMe, 3’-(2-OHBn), 5’-(2  2-OHBn) (triuvaretin)

Mol. Formula

Source

Family

Ref.

C23H22O5 C37H34O7

Xylopia africana Uvaria leptocladon

Annonaceae Annonaceae

279 280

329

2’,4’-DiOH, 6’-OMe, 3’-(2  2-OHBn), 5’-(2-OHBn) (isotriuvaretin)

C37H34O7

Xylopia africana Uvaria leptocladon

Annonaceae Annonaceae

281 280

330 331 332 333

2’,4’-DiOH, 6’-OMe, 3’-(2-OHBn), 5’-(3  2-OHBn) 2’,4’-DiOH, 6’-OMe, 3’-(3  2-OHBn), 5’-(2-OHBn) 2’,4’-DiOH, 6’-OMe, 3’-(2-OHBn), 5’-(4  2-OHBn) 2’,4’-DiOH, 6’-OMe, 3’-(4  2-OHBn), 5’-(2-OHBn)

C44H40O8 C44H40O8 C51H46O9 C51H46O9

Xylopia africana Xylopia africana Xylopia africana Xylopia africana Xylopia africana

Annonaceae Annonaceae Annonaceae Annonaceae Annonaceae

281 282 282 283 283

334 335 336 337 338

Dihydrochalcone–lignans Iryantherin G Iryantherin H Iryantherin I Iryantherin J Iryantherin K

C34H36O7 C34H36O7 C34H34O8 C34H34O8 C35H38O7

Myristicaeae Myristicaeae Myristicaeae Myristicaeae Myristicaeae

284 284 284 284 229

339

Iryantherin L

C35H38O7

Iryanthera grandis Iryanthera grandis Iryanthera grandis Iryanthera grandis Iryanthera lancifolia (I. ulei) Iryanthera lancifolia (I. ulei)

Myristicaeae

229

a

Bn, benzyl.

16.4 AURONES 16.4.1 AURONES

AND

AURONOLS

The number of new aurone and auronol aglycones reported in the literature between 1992 and 2003 is relatively small, as Table 16.13 indicates. Some examples of these compounds are illustrated in Figure 16.19. Only six of the compounds listed in Table 16.13 represent new combinations of hydroxy and methoxy substituents. Among these are two examples from Asteraceae taxa, 5-hydroxy-4,6,4’-trimethoxyaurone (342) from the flowers of cultivated sunflowers (Helianthus annuus)288 and 4,6,7,4’-tetrahydroxyaurone (343) from Helminthia echioides ( ¼ Picris echioides).289,290 Hamiltrone (3’,4’-dihydroxy-4,5,6-trimethoxyaurone) (350) showed the highest DNA strand-scission activity of several constituents isolated from a combined leaf and stem extract of Uvaria hamiltonii (Annonaceae).48 The structural similarity of this aurone to combretastatin A-4, a tumor vascular targeting agent, prompted Lawrence et al. to develop a total synthesis for the compound.295 This was achieved in four steps and 37% overall yield from benzofuranone and benzaldehyde precursors and facilitated the preparation of a series of substituted aurone analogs. Synthetic hamiltrone showed only poor cell-growth inhibition against a K562 cell line (IC50 ¼ 12 mM), but the activity of 3’hydroxy-5,6,7,4’-tetramethoxyaurone was more than 200-fold greater (IC50 ¼ 50 nM).295 A general observation was that 5,6,7-trimethoxyaurones showed greater cell-growth inhibition

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OH

OH

OH

HO

OH

OH

OMe

OH

HO

OMe

6 2 OH O

OH

OH 332

328

HO

HO

OMe

OMe

HO

OH O

HO

OH O

338

HO

OMe

OMe

OH O

HO

339

FIGURE 16.18 C-Benzylated dihydrochalcones and dihydrochalcone–lignan conjugates (see Table 16.12).

than the corresponding 4,5,6-trimethoxyaurones. The two new auronols from the bark of Pseudolarix amabilis (Pinaceae), amaronols A (351) and B (352), were considered to be enantiomeric pairs because of the reversible hemiketal at C-2.293 These compounds were inactive in a series of antifungal and antibacterial assays against test organisms. The ground rhizomes and roots of Cyperus capitatus (Cyperaceae) are the only known source of aurone aglycones with C-methyl substituents (344–348),291,292 although two aurone glycosides with C-7 methyl groups were described in 1989 from Pterocarpus marsupium (Leguminosae).296,297 Two new examples of isoprenylated aurones based on sulfuretin (6,3’,4’-trihydroxyaurone) have been found in the cortex of Broussonetia papyrifera (Moraceae) and hairy root cultures of Glycyrrhiza glabra (Leguminosae), and assigned the trivial names of broussoaurone A (340)287 and licoagroaurone, respectively (341).88 Licoagroaurone is the first aurone to be isolated from species of Glycyrrhiza (licorice), from which more than 100 flavonoids have already been described.253 Perhaps the most unusual of the aurones in Table 16.13 are the chlorinated derivatives 353 and 354, obtained from the marine brown alga Spatoglossum variabile.294 These are the first halogenated aurones to be described from a natural source. The auronol 4’-chloro-2-hydroxyaurone (354) was found as a racemic mixture of (R)- and (S)-epimers at C-2.

16.4.2 AURONE GLYCOSIDES Nine aurone and auronol glycosides reported in the literature between 1992 and 2003 are listed in Table 16.14. Structures of some of these compounds are given in Figure 16.20. Dalmaisione D (355) from the roots of Polygala dalmaisiana (Polygalaceae) is an unusual example of an aurone glycoside for which the corresponding aglycone, 2’-hydroxyaurone, is unknown.298 Indeed, no other 2’-O-substituted aurones have been reported in the literature. Species from the genus Bidens (Asteraceae) are a well-documented source of glucosides and acylated glucosides of maritimetin (6,7,3’,4’-tetrahydroxyaurone)10 and two new di- and triacetylated 6-O-glucosides (358, 359) have now been described from the aerial parts of B. bipinnata and B. pilosa var. radiata, respectively.263,127 Caulesauroneside (356), an aurone

OH

(2,4,6,3’,4’,5’) 2,4,6,3’,4’,5’ 2,4,6,3’,5’

Halogenated 353 — 354 2

351 352

Auronols

Penta O-substituted (4,5,6,3’,4’) 350 3’,4’

(4,6,3’,4’) 4,6,3’,4’ 4,6,3’,4’ 6,3’,4’ 6,3’,4’ 6,3’ —

— —

— 4’

4,5,6

4’-Cl 4’-Cl

— —

—

5-Me 7-Me 5-Me 7-Me 5-Me —

—

—

— — 4 4 4,4’ 4,6,3’,4’

—

5-Pr 7-Pr

Other

4,6,4’

— —

OMe

C15H9ClO2 C15H11ClO3

C15H12O8 C16H14O8

C18H16O7

C16H12O6 C16H12O6 C17H14O6 C17H14O6 C18H16O6 C19H18O6

Amaronol A Amaronol B

Spatoglossum variabile Spatoglossum variabile

Pseudolarix amabilis Pseudolarix amabilis

Uvaria hamiltonii

Cyperus capitatus Cyperus capitatus Cyperus capitatus Cyperus capitatus Cyperus capitatus Cyperus capitatus

Helminthia echioides

C15H10O6

Broussonetia papyrifera Glycyrrhiza glabra

Source

Helianthus annuus

Hamiltrone

Broussoaurone A Licoagroaurone

Trivial Name

C18H16O6

C20H18O5 C20H18O5

Mol. Formula

Dictyotaceae Dictyotaceae

Pinaceae Pinaceae

Annonaceae

Cyperaceae Cyperaceae Cyperaceae Cyperaceae Cyperaceae Cyperaceae

Asteraceae

Asteraceae

Moraceae Leguminosae

Family

294 294

293 293

48

291 291 291 291 291 292

289, 290

288

287 88

Ref.

1054

344 345 346 347 348 349

Tetra O-substituted (4,5,6,4’) 342 5 (4,6,7,4’) 343 4,6,7,4’

Tri O-substituted (6,3’,4’) 340 6,3’,4’ 341 6,3’,4’

No.

TABLE 16.13 New Aurones and Auronols Reported in the Literature from 1992 to 2003

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HO 6

3⬘

O

4⬘

CH

5

OH

OH

MeO 6

OH

CH HO

O

4

CH

343

O OH 2 O

α

O

351 R = H 352 R = Me

O

OR1

4⬘

CH

344 R = R1 = H 346 R = Me, R1 = H 348 R = R1 = Me

OH 3⬘ 4⬘ OR 5⬘ OH

OH

MeO 6 MeO

4 OR

4 OH

4⬘

OH

O

OH

OH O

4⬘

CH

342

HO 6

HO 6

O

4

OMe O

340

Me

HO 6 4⬘ OMe

O

O CH O 353

4

OH

OMe O 350

4⬘

O OH Cl

2 O

4⬘ α

Cl

354

FIGURE 16.19 Aurones and auronols (see Table 16.13).

diglucoside from the roots and rhizomes of Asarum longirhizomatosum, is the first aurone to be found in the Aristolochiaceae.299 A C-methylated aurone rhamnoside (360)300 from the heartwood of Pterocarpus santalinus (Leguminosae) is an analog of similar structures described previously from P. marsupium.296,297 The characterization of the glycosidic component of a second aurone glycoside (357) from P. santalinus as neohesperidoside must be regarded as preliminary due to the incomplete nature of the supporting spectroscopic data.300 The first auronol glycosides to be described are all from genera of the Rhamnaceae and based on maesopsin (2,4,6,4’-tetrahydroxy-2-benzylcoumaranone). Hovetrichosides C (361) and D (363) were obtained from the bark of Hovenia trichocarea together with maesopsin and neolignan and phenylpropanoid glycosides.301 Similarly, maesopsin 6-O-glucoside (362) was obtained together with maesopsin from root bark of Ceanothus americanus.302 These compounds showed poor activity as inhibitors of the growth of both Gram-negative, anaerobic periodontal pathogens and Gram-positive carcinogenic bacteria.302

16.4.3 AURONE

AND

AURONOL DIMERS

The first biaurone to be reported in the literature has been isolated from the gametophytes of two species of moss, Aulacomnium androgynum and A. palustre, and named aulacomniumbiaureusidin (364).303 As the trivial name suggests, it is a dimer of the well-known compound aureusidin (4,6,3’,4’-tetrahydroxyaurone), and is characterized by a C–C bond from C-5’ of the B-ring of one aurone monomer to C-5 of the A-ring of the other (Figure 16.21). Two further biaurones have now been discovered as indicated in Table 16.15. One is a dimer of sulfuretin (6,3’,4’-trihydroxyaurone) based on a C–C linkage between Ca atoms (365)304 while licoagrone (366), the first isoprenylated biaurone, features a C–C bond from C-2’ of 7prenylsulfuretin to C-2 of a 5,3’-diprenylhispidol analog.305 Geiger and Markham have described the first aurone heterodimer, campylopusaurone (367), from the mosses Campylopus clavatus and C. holomitrium.306 In this unique compound, a C–C bond links C-5’ of the

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TABLE 16.14 New Aurone and Auronol Glycosides Reported from 1992 to 2003 No.

355

356 357 358 359

360

361 362 363

Mol. Formula

Compound 2’-Hydroxyaurone 2’-O-Glucosyl-(1’’’ ! 6’’)glucoside (dalmaisione D) 4,6,4’-Trihydroxyaurone 4,6-Di-O-glucoside (caulesauroneside) 4-O-Rhamnosyl-(1’’’ ! 2’’)-glucoside 6,7,3’,4’-Tetrahydroxyaurone (maritimetin) 6-O-(3’’,6’’-Di-O-acetylglucoside) (bidenoside A) 6-O-(3’’,4’’,6’’-Tri-O-acetylglucoside) 4,6-Dihydroxy,3’,4’,5’-Trimethoxy-7 -methylaurone 4-O-Rhamnoside 2,4,6,4’-Tetrahydroxy-2benzylcoumaranone (maesopsin) 4-O-Glucoside (hovetrichoside C) 6-O-Glucoside 4-O-Glucoside 4’-O-rhamnoside (hovetrichoside D)

Source

Family

C27H30O13 Polygala dalmaisiana

Ref.

Polygalaceae

298

C27H30O15 Asarum longirhizomatosum Aristolochiaceae 299 C27H30O14 Pterocarpus santalinus Leguminosae 300 C25H24O13 Bidens bipinnata

Asteraceae

263

C27H26O14 Bidens pilosa var. radiata

Asteraceae

127

C25H28O12 Pterocarpus santalinus

Leguminosae

300

C21H22O11 Hovenia trichocarea C21H22O11 Ceanothus americanus C27H32O15 Hovenia trichocarea

Rhamnaceae Rhamnaceae Rhamnaceae

301 302 301

B-ring of the aurone, aureusidin, to C-6 of the A-ring of the flavanone, eriodictyol (5,7,3’,4’tetrahydroxyflavanone). An extraordinary series of rare auronol dimers and heterodimers (368–377) has been described in several papers by Bekker and colleagues.307–310 Some examples of the structures of these compounds are shown in Figure 16.21. The source of the dimers is the heartwood of O CH

HOH2C HO HO

2⬘ O HO

O

OH

O HOH2C HO HO

O 6

O

O

4 O

RO AcO 3⬙

OH 7 O 6

CH

OH

358 R = H 359 R = Ac

3⬘

O

356

OH

O

O

OH 4⬘

OH 2

OH

HOH2C HO HO

FIGURE 16.20 Aurone and auronol glycosides (see Table 16.14).

OH

O

HO 6 6⬙ AcO CH 2 O

4⬘

CH

OH

HOH2C HO HO

OH 6⬙ CH2 O O OH

355

O

O

4 O

O

OH 361 R = H 363 R = α-Rha

4⬘

OR

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TABLE 16.15 Aurone and Auronol Dimers and Heterodimers Reported from 1992 to 2003 No.

Compound

364

Aurone–aurone Aulacomniumbiaureusidin

365 366 367

368 369 370 371

372 373 374 375

376 377

a

Disulfuretin Licoagrone Aurone–flavanone Campylopusaurone

Auronol–auronol (2S)-2-Deoxymaesopsin-(2 ! 7)-(2R)maesopsin (2R)-2-Deoxymaesopsin-(2 ! 7)-(2S)maesopsin (2R)-2-Deoxymaesopsin-(2 ! 7)-(2R)maesopsin (2S)-2-Deoxymaesopsin-(2 ! 7)-(2S)maesopsin Auronol–flavanone (2R,3S)-Naringenin-(3a ! 5)-(2R)maesopsin (2R,3S)-Naringenin-(3a ! 5)-(2S)maesopsin (2R,3S)-Naringenin-(3a ! 7)-(2R)maesopsin (zeyherin)a (2R,3S)-Naringenin-(3a ! 7)-(2S)maesopsina Auronol–isoflavanone (2S,3R)-Dihydrogenistein-(2a ! 7)-(2R)maesopsin (2S,3R)-Dihydrogenistein-(2a ! 7)-(2S)maesopsin

Mol. Formula

Source

Family

Ref.

Aulacomnium androgynum Aulacomnium palustre Cotinus coggygria Glycyrrhiza glabra

Aulacomniaceae

303

Anacardiaceae Leguminosae

304 305

C30H20O12

Campylopus clavatus Campylopus holomitrum

Dicranaceae

306

C30H22O11

Berchemia zeyheri

Rhamnaceae

307

C30H22O11

Berchemia zeyheri

Rhamnaceae

307

C30H22O11

Berchemia zeyheri

Rhamnaceae

307

C30H22O11

Berchemia zeyheri

Rhamnaceae

307

C30H22O11

Berchemia zeyheri

Rhamnaceae

308

C30H22O11

Berchemia zeyheri

Rhamnaceae

308

C30H22O11

Berchemia zeyheri

Rhamnaceae

309

C30H22O11

Berchemia zeyheri

Rhamnaceae

309

C30H22O11

Berchemia zeyheri

Rhamnaceae

308

C30H22O11

Berchemia zeyheri

Rhamnaceae

308

C30H18O12 C30H18O10 C45H42O10

Indicates revised structure

Berchemia zeyheri (Rhamnaceae), a tree native to southern Africa which is prized for its beautiful wood, known as ‘‘pink ivory’’ or ‘‘red ivory.’’ The complexity of the phenolic compounds present in heartwood extracts prompted their analysis as permethylated derivatives. Stereochemical features were determined by using both NMR and circular dichroism spectroscopy of the parent compounds and their degradation products. These methods were used successfully to obtain a full stereochemical description of the zeyherin epimers 374 and 375,309 which were first isolated in 1971 but not fully characterized at that time.311 Subsequent work has led to the discovery of further auronol dimers and novel heterodimers with flavanone or isoflavanone constituents as summarized in Table 16.15.307,308,310

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HO

HO 3'

HO HO 5' 5

HO

OH

OH

O

O

O

HO

4'

O

O

6 HO

365

OH

HO

4'

2'

O

6

O

364

HO

OH

HO

HO HO OH

5' 6 O

O

HO

2

OH HO O

O

5

O

O

O

HO 6

OH

α

O O

α

OH

HO OH

OH 4'

OH

O

366

367 OH OH

HO

O

OH

OH

2S OH

O 7

O

HO

HO 2R O

3S

2R OH

7

OH O

O

368

O 2R

HO

HO

OH

O OH

374

OH

HO

2R

O

O HO

O

2S

OH 7

OH 3R

OH O

OH

376

FIGURE 16.21 Aurone and auronol dimers and heterodimers (see Table 16.15).

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222. Malterud, K.E., C-Methylated dihydrochalcones from Myrica gale fruit extract, Acta Pharm. Nord., 4, 65, 1992. 223. Ramadan, M.A. et al., Minor phenolics from Crinum bulbispermum bulbs, Phytochemistry, 54, 891, 2000. 224. Gonza´lez, A.G. et al., Phenolic compounds of Dragon’s blood from Dracaena draco, J. Nat. Prod., 63, 1297, 2000. 225. Lu, W. et al., Studies on chemical constituents of chloroform extract of Dracaena cochinchinensis, Yaoxue Xuebao, 33, 755, 1998. 226. Sinz, A. et al., Phenolic compounds from Anomianthus dulcis, Phytochemistry, 50, 1069, 1999. 227. Lien, T.P. et al., Chalconoids from Fissistigma bracteolatum, Phytochemistry, 53, 991, 2000. 228. Majumder, P.L., Lahiri, S., and Mukhoti, N., Chalcone and dihydrochalcone derivatives from the orchid Lusia volucris, Phytochemistry, 40, 271, 1995. 229. Silva, D.H.S. et al., Dihydrochalcones and flavonolignans from Iryanthera lancifolia, J. Nat. Prod., 62, 1475, 1999. 230. Ichikawa, K. et al., Retrodihydrochalcones and homoisoflavones isolated from Thai medicinal plant Dracaena loureiri and their estrogen agonist activity, Planta Med., 63, 540, 1997. 231. Fleischer, T.C., Waigh, R.D., and Waterman, P.G., A novel retrodihydrochalcone from the stem bark of Uvaria mocoli, Phytochemistry, 47, 1387, 1998. 232. Leong, Y.-W. et al., A dihydrochalcone from Lindera lucida, Phytochemistry, 47, 891, 1998. 233. Iinuma, M., Tanaka, T., and Asai, F., Flavonoids in frond exudates of Pityrogramma tartarea, Phytochemistry, 36, 941, 1994. 234. Alvarez, L. and Delgado, G., C- and O-glycosyl-a-hydroxydihydrochalcones from Eysenhardtia polystachya, Phytochemistry, 50, 681, 1999. 235. Tanrisever, N. et al., Ceratiolin and other flavonoids from Ceratiola ericoides, Phytochemistry, 26, 175, 1987. 236. Krasnov, E.A. et al., Phenolic components of Empetrum nigrum extract and the crystal structure of one of them, Chem. Nat. Compd., 36, 493, 2000. 237. Miles, D.H. et al., 3’-Formyl-2’,4’,6’-trihydroxydihydrochalcone from Psidium acutangulum, Phytochemistry, 30, 1131, 1991. 238. Miles, D.H. et al., 3’-Formyl-2’,4’,6’-trihydroxy-5’-methyldihydrochalcone, a prospective new agrochemical from Psidium acutangulum, J. Nat. Prod., 53, 1548, 1990. 239. Beltrami, E. et al., Coatline A and B, two C-glucosyl-a-hydroxydihydrochalcones from Eysenhardtia polystachya, Phytochemistry, 21, 2931, 1982. 240. Benosman, A. et al., New terpenylated dihydrochalcone derivatives isolated from Mitrella kentii, J. Nat. Prod., 60, 921, 1997. 241. Orjala, J. et al., New monoterpene-substituted dihydrochalcones from Piper aduncum, Helv. Chim. Acta, 76, 1481, 1993. 242. Orjala, J. et al., Cytotoxic and antibacterial dihydrochalcones from Piper aduncum, J. Nat. Prod., 57, 18, 1994. 243. Joshi, A.S. et al., Dihydrochalcones from Piper longicaudatum, Planta Med., 67, 186, 2001. 244. Rao, M.S. et al., A revised structure for crotaramosmin from Crotolaria ramosissima, J. Nat. Prod., 61, 1148, 1998. 245. Kumar, J.K. et al., Further dihydrochalcones from Crotolaria ramosissima, J. Braz. Chem. Soc., 10, 278, 1999. 246. Ahsan, M., Armstrong, J.A., and Waterman, P.G., Dihydrochalcones from the aerial parts of Boronia inconspicua, Phytochemistry, 36, 799, 1994. 247. Fukai, T. et al., Isoprenylated flavonoids from underground parts of Glycyrrhiza glabra, Phytochemistry, 43, 1119, 1996. 248. Yenesew, A., Midiwo, J.O., and Waterman, P.G., Rotenoids, isoflavones and chalcones from the stem bark of Millettia usaramensis subspecies usaramensis, Phytochemistry, 47, 295, 1998. 249. Trani, M. et al., Dihydrochalcones and coumarins of Esembeckia grandiflora subsp. grandiflora, Gazz. Chim. Ital., 127, 415, 1997. 250. Mu¨ller, A.H. et al., Dihydrochalcones, coumarins and alkaloids from Metrodorea nigra, Phytochemistry, 40, 1797, 1995.

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251. Ichino, K., Tanaka, H., and Ito, K., Isolation and structure of 2 new flavonoids from Lindera umbellata, Chem. Lett., 363, 1989. 252. Ichino, K., Two flavonoids from two Lindera umbellata varieties, Phytochemistry, 28, 955, 1989. 253. Fukai, T. et al., An isoprenylated flavanone from Glycyrrhiza glabra and rec-assay of licorice phenols, Phytochemistry, 49, 2005, 1998. 254. Jakupovic, J. et al., Twenty-one acylphloroglucinol derivatives and further constituents from South African Helichrysum species, Phytochemistry, 28, 1119, 1989. 255. Williams, A.H., Dihydrochalcones, in Comparative Phytochemistry, Swain, T., Ed., Academic Press, London, 1966, chap. 17. 256. Ohtani, I.I. et al., Thonningianins A and B, new antioxidants from the African medicinal herb Thonningia sanguinea, J. Nat. Prod., 63, 676, 2000. 257. Calis, I. et al., Phenylvaleric acid and flavonoid glycosides from Polygonum salicifolium, J. Nat. Prod., 62, 1101, 1999. 258. Cuendet, M. et al., A stilbene and dihydrochalcones with radical scavenging activities from Loiseleuria procumbens, Phytochemistry, 54, 871, 2000. 259. Qin, X.-D. and Liu, J.-K., A new sweet dihydrochalcone-glucoside from leaves of Lithocarpus pachyphyllus (Kurz) Rehd. (Fagaceae), Z. Naturforsch. C, 58, 759, 2003. 260. Ogawa, K. et al., 3’,5’-Di-C-b-glucopyranosylphloretin, a flavonoid characteristic of the genus Fortunella, Phytochemistry, 57, 737, 2001. 261. Silva, D.H.S., Yoshida, M., and Kato, M.J., Flavonoids from Iryanthera sagotiana, Phytochemistry, 46, 579, 1997. 262. Yang, Z. et al., Chemical studies on the marine algae Zostera sp., Zhongguo Haiyang Yaowu, 11, 1, 1992 (Chem. Abstr. 118, 18925v, 1993). 263. Li, S. et al., A new aurone glucoside and a new chalcone glucoside from Bidens bipinnata Linne, Heterocycles, 61, 557, 2003. 264. Li, W. et al., Flavonoids from Glycyrrhiza pallidiflora hairy root cultures, Phytochemistry, 60, 351, 2002. 265. Yoshida, T., Feng, W.-S., and Okuda, T., Two polyphenol glycosides and tannins from Rosa cymosa, Phytochemistry, 32, 1033, 1993. 266. Bezuidenhoudt, B.C.B., Brandt, E.V., and Ferreira, D., Flavonoid analogues from Pterocarpus species, Phytochemistry, 26, 531, 1987. 267. Adinarayana, D. et al., Structure elucidation of pterosupin from Pterocarpus marsupium, the first naturally occurring C-glycosyl-b-hydroxy-dihydrochalcone, Z. Naturforsch. C, 37, 145, 1982. 268. Maurya, R. et al., Constituents of Pterocarpus marsupium, J. Nat. Prod., 47, 179, 1984. 269. Drewes, S.E. and Hudson, N.A., Brackenin, a dimeric dihydrochalcone from Brackenridgea zanguebarica, Phytochemistry, 22, 2823, 1983. 270. Li, Y. et al., Littorachalcone, a new enhancer of NGF-mediated neurite outgrowth, from Verbena littoralis, Chem. Pharm. Bull., 51, 872, 2003. 271. Li, Y.-S. et al., Verbenachalcone, a novel dimeric dihydrochalcone with potentiating activity on nerve growth factor-action from Verbena littoralis, J. Nat. Prod., 64, 806, 2001. 272. Patil, A.D. et al., A new dimeric dihydrochalcone and a new prenylated flavone from the bud covers of Artocarpus altilis: potent inhibitors of cathepsin K, J. Nat. Prod., 65, 624, 2002. 273. Zhou, Z., Wang, J., and Yang, C., Cochinchinenin-new chalcone dimer from Chinese dragon blood, Yaoxue Xuebao, 36, 200, 2001. 274. Roitman, J.N., Wong, R.Y., and Wollenweber, E., Methylene bisflavonoids from frond exudate of Pentagramma triangularis ssp triangularis, Phytochemistry, 34, 297, 1993. 275. Iinuma, M. et al., Two biflavonoids in the farinose exudate of Pentagramma triangularis, Phytochemistry, 35, 1043, 1994. 276. Iinuma, M. et al., Unusual biflavonoids in the farinose exudate of Pentagramma triangularis, Phytochemistry, 44, 705, 1997. 277. Xing, X. et al., Utilization of a copper-catalyzed diaryl ether synthesis for the preparation of verbenachalcone, Tetrahedron, 58, 7903, 2002. 278. Parmar, V.S. et al., Novel constituents of Uvaria species, Nat. Prod. Rep., 11, 219, 1994.

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279. Anam, E.M., 7-O-Methylbenzylflavanones and 4’-O-methylbenzyldihydrochalcone from Xylopia africana (Benth.) Oliver, Indian J. Chem., 33B, 870, 1994. 280. Nkunya, M.H.H. et al., Benzylated dihydrochalcones from Uvaria leptocladon, Phytochemistry, 32, 1297, 1993. 281. Anam, E.M., 6’’ ’’-Hydroxybenzyldiuvaretins and related compounds from Xylopia africana (Benth.) Oliver, Indian J. Chem., 32B, 1051, 1993. 282. Anam, E.M., 5’’,5’’ ’’-(2’’ ’’,2’’’ ’’-Dihydroxybenzyl) diuvaretin and 5’’’,3’’ ’’-(2’’ ’’,2’’’ ’’-dihydroxydibenzyl)iso-diuvaretin: two novel C-dibenzylated dihydrochalcones from the root extract of Xylopia africana (Benth.) Oliver (Annonaceae), Indian J. Chem., 36B, 57, 1997. 283. Anam, E.M., 2’’ ’’,2’’’ ’’,2’’ ’’ ’’-Trihydroxy-5’’,3’’ ’’,5’’’ ’’-tribenzyldiuvaretin & 2’’ ’’,2’’’ ’’,2’’ ’’ ’’-trihydroxy-5’’’,3’’ ’’,5’’’ ’’-tribenzyl isodiuvaretin: two novel tri-C-benzylated dihydrochalcones from the root extract of Xylopia africana (Benth.) Oliver (Annonaceae), Indian J. Chem., 33B, 204, 1994. 284. Silva, D.H.S. et al., Flavonolignoids from fruits of Iryanthera grandis, Phytochemistry, 38, 1013, 1995. 285. Conserva, L.M. et al., Iryantherins, lignoflavonoids of novel structural types from the Myristicaceae, Phytochemistry, 29, 3911, 1990. 286. Ming, D.S. et al., Bioactive constituents from Iryanthera megistophylla, J. Nat. Prod., 65, 1412, 2002. 287. Fang, S.-C., Shieh, B.-J., and Lin, C.-N., Phenolic constituents of Formosan Broussonetia papyrifera, Phytochemistry, 37, 851, 1994. 288. Alfatafta, A.A. and Mullin, C.A., Epicuticular terpenoids and an aurone from flowers of Helianthus annuus, Phytochemistry, 31, 4109, 1992. 289. Milovanovic´, M. and Djermanovic´, M., Constituents of Helminthia echoides, Fitoterapia, 65, 377, 1994. 290. Milovanovic´, M. et al., Antioxidant activities of the constituents of Picris echoides, J. Serbian Chem. Soc., 67, 7, 2002. 291. Seabra, R.M. et al., Methylaurones from Cyperus capitatus, Phytochemistry, 48, 1429, 1998. 292. Seabra, R.M. et al., Methoxylated aurones from Cyperus capitatus, Phytochemistry, 45, 839, 1997. 293. Li, X.-C. et al., Two auronols from Pseudolarix amabalis, J. Nat. Prod., 62, 767, 1999. 294. Atta-ur-Rahman et al., Two new aurones from marine brown alga Spatoglossum variabile, Chem. Pharm. Bull., 49, 105, 2001. 295. Lawrence, N.J. et al., The total synthesis of an aurone isolated from Uvaria hamiltonii: aurones and flavones as anticancer agents, Bioorg. Med. Chem. Lett., 13, 3759, 2003. 296. Mohan, P. and Joshi, T., Two aurone glycosides from the flowers of Pterocarpus marsupium, Phytochemistry, 28, 1287, 1989. 297. Mohan, P. and Joshi, T., Two anthochlor pigments from heartwood of Pterocarpus marsupium, Phytochemistry, 28, 2529, 1989. 298. Kobayashi, S., Miyase, T., and Noguchi, H., Polyphenolic glycosides and oligosaccharide multiesters from the roots of Polygala dalmaisiana, J. Nat. Prod., 65, 319, 2002. 299. Zhang, S.-X. et al., Glycosyl flavonoids from the roots and rhizomes of Asarum longerhizomatosum, J. Asian Nat. Prod. Res., 5, 25, 2003. 300. Singh, J., Aurone glycosides from Pterocarpus santalinus, J. Indian Chem. Soc., 80, 190, 2003. 301. Yoshikawa, K. et al., Hovetrichosides C–G, five new glycosides of two auronols, two neolignans, and a phenylpropanoid from the bark of Hovenia trichocarea, J. Nat. Prod., 61, 786, 1998. 302. Li, X.-C., Cai, L., and Wu, C.D., Antimicrobial compounds from Ceanothus americanus against oral pathogens, Phytochemistry, 46, 97, 1997. 303. Hahn, H. et al., The first biaurone, a triflavone and biflavonoids from two Aulacomnium species, Phytochemistry, 40, 573, 1995. 304. Westenburg, H.E. et al., Activity-guided isolation of antioxidative constituents of Cotinus coggygria, J. Nat. Prod., 63, 1696, 2000. 305. Asada, Y., Li, W., and Yoshikawa, T., The first prenylated biaurone, licoagrone from hairy root cultures of Glycyrrhiza glabra, Phytochemistry 50, 1015, 1999. 306. Geiger, H. and Markham, K.R., Campylopusaurone, an auronoflavanone biflavonoid from the mosses Campylopus clavatus and Campylopus holomitrum, Phytochemistry, 31, 4325, 1992.

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307. Bekker, R. et al., Biflavonoids. Part 5: Structure and stereochemistry of the first bibenzofuranoids, Tetrahedron, 56, 5297, 2000. 308. Bekker, R., Brandt, E.V., and Ferreira, D., Biflavonoids. Part 4. Structure and stereochemistry of novel flavanone- and the first isoflavanone–benzofuranone biflavonoids, Tetrahedron, 55, 10005, 1999. 309. Bekker, R., Brandt, E.V., and Ferreira, D., Absolute configuration of flavanone–benzofuranone-type biflavonoids and 2-benzyl-2-hydroxybenzofuranones, J. Chem. Soc., Perkins Trans. 1, 2535, 1996. 310. Bekker, R., Brandt, E.V., and Ferreira, D., Structure and stereochemistry of the first isoflavanone– benzofuranone biflavonoids, Tetrahedron Lett., 39, 6407, 1998. 311. du Volsteedt, F.R. and Roux, D.G., Zeyherin, a natural 3,8-coumaranonylflavanone from Phyllogeiton zeyheri Sond., Tetrahedron Lett., 12, 1647, 1971. 312. Nel, R.J.J. et al., Enantioselective synthesis of flavonoids. Part 5. Poly-oxygenated b-hydroxydihydrochalcones, Tetrahedron Lett., 39, 5623, 1998.

APPENDIX A

Index of Molecular Formulae

Chalcones, dihydrochalcones, and aurones described in the literature from 1992 to 2003

Formula

Compound Number

C15H9ClO2 C15H10O6 C15H11ClO3 C15H12O3 C15H12O4 C15H12O8 C15H14O4 C15H14O6 C16H12O6 C16H14O5 C16H14O6 C16H14O8 C16H16O3 C16H16O4 C16H16O5 C16H16O6 C17H12O6 C17H14O6 C17H16O4 C17H16O5 C17H16O6 C17H18O4 C17H18O5 C18H16O5 C18H16O6 C18H16O7 C18H17BrO5 C18H18O4 C18H18O5 C18H18O7 C18H20O5

353 343 354 1 3 351 256 273 344, 345 6, 11 18 352 249, 250, 251 252 263 274 24 346, 347 4 5, 8 15 253, 254, 255, 257 258, 260, 261, 265, 266 2, 12 342, 348 350 9 240 7, 10, 13, 14, 23, 264 20 259, 262, 267, 268

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Index of Molecular Formulae — continued

Formula

Compound Number

C18H20O6 C19H16O5 C19H18O6 C19H18O7 C19H20O4 C19H20O6 C19H20O7 C20H16O5 C20H16O7 C20H18O4 C20H18O5 C20H18O6 C20H20O4 C20H20O5 C20H20O6 C20H20O7 C20H22O7 C20H22O10 C21H20O4 C21H20O5 C21H22O4 C21H22O5 C21H22O6 C21H22O9 C21H22O11 C21H24O5 C21H24O7 C21H24O10 C22H22O5 C22H24O10 C22H26O10 C23H20O6 C23H22O5 C23H22O7 C23H24O5 C23H24O6 C23H26O11 C24H24O7 C24H26O7 C24H30O10 C25H24O4 C25H24O5 C25H24O13 C25H26O3

269, 270, 271 293 17, 349 25 241 16, 272 19 182 96 51, 66 104, 340, 341 301 49, 57, 286 33, 41, 58, 102, 292 95 26 21 314 34, 38, 67 30, 35, 74 65, 287 36, 39, 64, 68, 73, 90, 91, 98 70, 75, 76 109 361, 362 288, 291 22 312, 313 79, 80, 89 118, 121, 124 309 236 327 108 99 92, 93, 94 131, 306, 307 37 97, 302 311 60 77, 88, 107 358 28, 29

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APPENDIX A

Index of Molecular Formulae — continued

Formula

Compound Number

C25H26O4 C25H26O5 C25H26O13 C25H28O3 C25H28O4 C25H28O5 C25H28O6 C25H28O12 C25H30O4 C25H30O5 C25H30O6 C25H30O11 C26H22O7 C26H28O7 C26H30O4 C26H30O5 C26H30O9 C26H32O4 C26H32O5 C26H32O6 C27H26O14 C27H29O13N C27H30O13 C27H30O14 C27H30O15 C27H31O14N C27H32O4 C27H32O15 C27H32O16 C27H34O15 C28H22O7 C28H34O4 C28H34O6 C28H34O15 C29H26O7 C29H26O8 C29H30O7 C29H30O8 C29H36O15 C29H38O15 C30H18O10 C30H18O12 C30H20O9 C30H20O10

52, 54, 59 61, 72, 86, 103, 105 125 27 31, 45, 48, 62, 63, 191 32, 46, 47, 50, 69, 84, 100 53, 101, 106 310, 360 275 289, 294, 295 296 132 279 78 55, 187, 188, 192, 193, 194, 195, 196, 243, 282, 283, 284 40, 56, 71 113 277, 281 285 299, 300 359 245 355 357 356 248 185, 186 119, 130, 363 246 308 239 183, 184 189, 190 122 42, 43 81 278 280 133 305 365 364 135, 165 152

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APPENDIX A

Index of Molecular Formulae — continued

Formula

Compound Number

C30H20O12 C30H22O8 C30H22O9 C30H22O10 C30H22O11 C30H24O8 C30H24O9 C30H24O10 C30H26O6 C30H26O7 C30H26O8 C30H28O8 C30H28O9 C30H28O12 C30H34O5 C30H36O4 C30H36O6 C30H38O5 C30H38O6 C31H24O8 C31H26O8 C31H28O7 C31H28O8 C31H28O9 C31H30O7 C31H30O13 C32H26O8 C32H26O10 C32H30O7 C32H30O10 C32H30O12 C32H30O13 C32H30O15 C32H32O7 C32H40O18 C33H24O11 C33H32O8 C33H32O15 C33H42O20 C34H26O11 C34H28O8 C34H30O9 C34H30O10 C34H30O11

367 139, 143, 148 134, 150, 151, 163 136, 154, 155, 156 157, 158, 368–377 142, 149 153 137 199, 200 197, 198 315 44 82, 83 114, 115 87 242 298 290 297 140, 141, 171 147 201, 220 202, 203 316 320 128 138 146 238 317 116 117 126 321 110 166–169 318 129 120 170 159–162 323 322, 326 324

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Index of Molecular Formulae — continued

Formula

Compound Number

C34H34O8 C34H36O7 C35H30O17 C35H32O11 C35H34O7 C35H34O8 C35H34O9 C35H36O15 C35H38O7 C35H44O5 C35H46O4 C36H32O14 C36H38O16 C36H42O6 C37H34O7 C37H40O15 C39H34O16 C39H36O9 C40H34O12 C40H36O11 C40H36O12 C40H38O8 C40H38O9 C40H40O12 C42H34O21 C42H38O9 C42H40O8 C44H40O8 C44H44O24 C45H38O13 C45H42O10 C45H44O12 C45H46O11 C48H52O26 C50H58O10 C51H46O9 C51H48O12 C54H54O11 C60H48O15 C60H50O15 C66H46O21 C75H62O21 C90H70O22

336, 337 334, 335 304 325 228, 229 222–226, 232 221, 227 111 338, 339 85 276 164 112 237 328, 329 123 127 204 214 218, 219 210, 211, 213, 216, 217 206, 207 205 215 303 230, 231 144 330, 331 247 172, 173 366 208, 212 209 244 319 332, 333 145 233–235 175, 176, 177 178, 179 174 180 181

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Checklist of Known Chalcones, Dihydrochalcones, and Auronesa

CHALCONES Chalcone aglycones Mono-O-substituted (4’) 1. 4’-OMe (H2/454) Di-O-substituted (2’,4’) 2. 2’,4’-diOH (H2/457) 3. 2’,4’-diOH, 3’-prenyl (isocordoin, H2/582) 4. 2’,4’-diOH, 3’-(1,1-dimethylallyl) (c-isocordoin, H2/583) 5. 2’,4’-diOH, 3’,5’-diprenyl (spinochalcone A, 27) 6. 2’-OH, 4’-OMe, 3’-prenyl (derricin, H2/589) 7. 2’-OH, 4’-prenyloxy (derricidin, cordoin, H2/590) 8. 2’-OH, furano[2’’,3’’:4’,3’] (H2/556) 9. 2’-OH, 5’’-(2-hydroxyisopropyl)-4’’,5’’-dihydrofurano[2’’,3’’:4’,3’] (flemistrictin B, H2/ 586) 10. 2’-OH, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (lonchocarpin, H2/587) 11. 2’-OH, 6’’,6’’-dimethyl-5’’-hydroxy-4’’,5’’-dihydropyrano[2’’,3’’:4’,3’] (flemistrictin C, H2/588) 12. 2’-OH, 6’’-(4-methylpent-3-enyl),6’’-methylpyrano[2’’,3’’:4’,3’] (spinochalcone B, 28) 13. 2’-OH, 3’-prenyl, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’] (spinochalcone C, 29) 14. 2’-OH, complex substituent ((þ)-tephrosone, 30) 15. 4’-OH, 2’-OMe (H2/458) 16. 4’-OH, 5’’-(2-hydroxyisopropyl)-4’’,5’’-dihydrofurano[2’’,3’’:2’,3’] (flemistrictin E, H2/ 584) 17. 4’-OH, 6’’,6’’-dimethyl-5’’-hydroxy-4’’,5’’-dihydropyrano[2’’,3’’:2’,3’] (flemistrictin F, H2/585) 18. 2’-OMe, furano[2’’,3’’:4’,3’] (ovalitenin A, H2/557) 19. 2’-OMe, 4-Me, furano[2’’,3’’:4’,3’] (purpuritenin A, H2/559) 20. 2’-OMe, a-Me, furano[2’’,3’’:4’,3’] (purpuritenin B, H2/560) (2’,2) 21. 2’,2-diOH (H2/455) (2’,b) 22. 2’,b-diOH (H2/530) (3’,3) 23. 3’,3-diOH (1) (4’,4) 24. 4’,4-diOH (H2/456) Tri-O-substituted (2’,3’,4’)

a This checklist of chalcones, dihydrochalcones, and aurones contains compounds of these classes reported in the literature as natural products to the end of 2003. Compounds published before 1992 are cross-referenced to numbered entries in volumes 1 and 2 of the Handbook of Natural Flavonoids9,10 using the abbreviations H1 and H2, respectively. Compounds published from 1992 to 2003 are cross-referenced to Table 16.1– Table 16.15 using numbers in bold type. The compounds are listed according to the system outlined in Section 16.1.1, with the exception that isoprenylated derivatives are included under the heading of aglycones. Bn, benzyl.

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 25. 26. 27. 28. 29.

30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60.

2’,4’-diOH, 3’-OMe (larrein, H2/468) (2’,3’,2) 2’,3’,2-triOH, 4’-geranyl (flemiwallichin E, H2/661) (2’,4’,5’) 2’,4’-diOH, 5’-OMe (flemichapparin, H2/469) 2’,5’-diOH, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (flemichapparin A, H2/616) 2’,5’-diOH, (6’’-(4-hydroxy-4-methylpent-2-enyl),6’’-methyl)pyrano[2’’,3’’:4’,3’] (flemiwallichin F, H2/666) (2’,4’,6’) 2’,4’,6’-triOH (H2/470) 2’,4’,6’-triOH, 3’-prenyl (desmethylisoxanthohumol, H2/617) 2’,4’,6’-triOH, 3’-geranyl (H2/667) 2’,4’,6’-triOH, 3’-neryl (31) 2’,4’,6’-triOH, 3’-C10 (linderachalcone, H2/668) 2’,4’,6’-triOH, 3’,5’-diC10 (neolinderachalcone, H2/674) 2’,4’-diOH, 6’-OMe (cardamonin, H2/472) 2’,4’-diOH, 6’-OMe, 3’-Me (stercurensin, H2/579) 2’,4’-diOH, 6’-OMe, 3’,5’-diMe (H2/581) 2’,4’-diOH, 6’-OMe, 3’-prenyl (H2/622) 2’,4’-diOH, 3’-Me, 6’’,6’’-dimethylpyrano[2’’,3’’:6’,5’] (H2/659) 2’,4’-diOH, 3’-prenyl, 5’’-(2-hydroxyisopropyl)-4’’,5’’-dihydrofurano[2’’,3’’:6’,5’] (cedrediprenone, 32) 2’,4’-diOH, 6’’,6’’-dimethylpyrano[2’’,3’’:6’,5’], 3’-(3-acetyl-5-methyl-2,4,6trihydroxybenzyl) (rottlerin, H2/699) 2’,6’-diOH, 4’-OMe (H2/471) 2’,6’-diOH, 4’-OMe, 3’-CHO, 5’-Me (leridalchalcone, 2) 2’,6’-diOH, 4’-OMe, 3’-C10 (H2/669) 2’,6’-diOH, 4’-prenyloxy (H2/625) 2’,6’-diOH, 4’-OMe, 3’-Me (triangularin, H2/578) 2’,6’-diOH, 4’-OMe, 3’-prenyl (isoxanthohumol, H2/620) 2’,6’-diOH, 6’’,6’’-dimethyl-5’’-hydroxy-4’’,5’’-dihydropyrano[2’’,3’’:4’,3’] (helikrausichalcone, H2/618) 4’,6’-diOH, 2’-OMe, 3’-Me (aurentiacin A, H2/577) 4’,6’-diOH, 6’’,6’’-dimethyl-5’’-hydroxy-4’’,5’’-dihydropyrano[2’’,3’’:2’,3’] (33) 2’-OH, 4’,6’-diOMe (flavokawin B, H2/473) 2’-OH, 4’,6’-diOMe, 3’-Me (aurentiacin, H2/580) 2’-OH, 4’,6’-diOMe, 3’-prenyl (ovalichalcone, H2/624) 2’-OH, 6’-OMe, 4’-prenyloxy (H2/626) 2’-OH, 6’-OMe, 5’’-isopropenyl-4’’,5’’-dihydrofurano[2’’,3’’:4’,3’] (crassichalcone, 34) 2’-OH, 6’-OMe, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (pongachalcone I, oaxacacin (revised structure)69 H2/623) 2’-OH, 6’-OMe, 4’’,5’’-epoxy(6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:4’,3’]) (epoxyobovatachalcone, 35) 2’-OH, 6’-OMe, 6’’,6’’-dimethyl-5’’-hydroxy-4’’,5’’-dihydropyrano[2’’,3’’:4’,3’] (6’methoxyhelikrausichalcone, 36) 2’-OH, 6’-OMe, (6’’-(4-methylpent-3-enyl),6’’-methyl)pyrano[2’’,3’’:4’,3’] (boesenbergin B, H2/671)

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102.

2’-OH, 6’-OMe, complex substituent ((þ)-tephropurpurin, 37) 2’-OH, bis(6’’,6’’-dimethylpyrano)[2’’,3’’:4’,3’],[2’’,3’’:6’,5’] (flemiculosin, H2/627) 2’-OH, complex (4’,6’-di-O-,5’-C-) substituent, 3’-prenyl (3’-prenylrubranine, H2/697) 4’-OH, 2’-OMe, 6’’,6’’-dimethylpyrano[2’’,3’’:6’,5’] (cedreprenone, 38) 4’-OH, 6’-OMe, 6’’,6’’-dimethyl-5’’-hydroxy-4’’,5’’-dihydropyrano[2’’,3’’:2’,3’] (39) 6’-OH, 4’-OMe, 6’’,6’’-dimethyl-5’’-hydroxy-4’’,5’’-dihydropyrano[2’’,3’’:2’,3’] (helichromanochalcone, H2/621) 6’-OH, 4’-OMe, (6’’-(4-methylpent-3-enyl),6’’-methyl)pyrano[2’’,3’’:2’,3’] (boesenbergin A, H2/670) 6’-OH, 4’-OMe, complex substituent (linderol A, 40) 6’-OH, complex (2’,4’-di-O-,3’-C-) substituent (rubranine, H2/672) (2’,4’,4) 2’,4’,4-triOH (isoliquiritigenin, H2/462) 2’,4’,4-triOH, 3’-prenyl (isobavachalcone, H2/597) 2’,4’,4-triOH, 3’-(2-hydroxy-3-methylbut-3-enyl) (41) 2’,4’,4-triOH, 3’-geranyl (xanthoangelol, H2/663) 2’,4’,4-triOH, 3’-(3,7-dimethyl-6-hydroxy-2,7-octadienyl) (xanthoangelol B, H2/664structure drawing incorrect) 2’,4’,4-triOH, 3’-(3-methyl-6-oxo-2-hexenyl) (xanthoangelol C, H2/698) 2’,4’,4-triOH, 3’-(4-coumaroyloxy-3-methyl-but-2(E)-enyl) (isogemichalcone B, 42) 2’,4’,4-triOH, 3’-(4-coumaroyloxy-3-methyl-but-2(Z)-enyl) (gemichalcone B, 43) 2’,4’,4-triOH, 3’-(4-feruloyloxy-3-methyl-but-2(Z)-enyl) (gemichalcone A, 44) 2’,4’,4-triOH, 3’,5’-diprenyl (H2/612) 2’,4’,4-triOH, 3’,3-diprenyl (kanzonol C, 45) 2’,4’,4-triOH, 3’-prenyl, 3-(2-hydroxy-3-methylbut-3-enyl) (paratocarpin D, 46) 2’,4’,4-triOH, 3’-(2-hydroxy-3-methylbut-3-enyl), 3-prenyl (paratocarpin E, 47) 2’,4’,4-triOH, 3’,3,5-triprenyl (sophoradin, H2/613) 2’,4’,4-triOH, 5’-prenyl (broussochalcone B, H2/606) 2’,4’,4-triOH, 5’,3-diprenyl (stipulin, 48) 2’,4’,4-triOH, 3-prenyl (licoagrochalcone A, 49) 2’,4’,4-triOH, 3,5-diprenyl (abyssinone VI, H2/610) 2’,4’,4-triOH, 3-(2-hydroxy-3-methylbut-3-enyl), 5-prenyl (anthyllin, 50) 2’,4’-diOH, 4-OMe (H2/463) 2’,4’-diOH, 6’’,6’’-dimethylpyrano[2’’,3’’:4,3] (kanzonol B, 51) 2’,4’-diOH, 3’-prenyl, 6’’,6’’-dimethylpyrano[2’’,3’’:4,3] (paratocarpin C, 52) 2’,4’-diOH, 3’-prenyl, 5’’-(2-hydroxyisopropyl)-4’’-hydroxy-4’’,5’’dihydrofurano[2’’,3’’:4,3] (paratocarpin G, 53) 2’,4’-diOH,3’,5-diprenyl,6’’,6’’-dimethylpyrano[2’’,3’’:4,3](sophoradochromene,H2/614) 2’,4’-diOH, 5-prenyl, 6’’,6’’-dimethylpyrano[2’’,3’’:4,3] (anthyllisone, 54) 2’,4-diOH, 4’-OMe (H2/465) 2’,4-diOH, 4’-OMe, 5’-CHO (neobavachalcone, H2/576) 2’,4-diOH, 4’-OMe, 3’-prenyl (H2/602) 2’,4-diOH, 4’-OMe, 3’-(2-hydroxy-3-methylbut-3-enyl) (xanthoangelol D, H2/603) 2’,4-diOH, 4’-OMe, 3’-(2-hydroperoxy-3-methylbut-3-enyl) (xanthoangelol E, H2/604) 2’,4-diOH, 4’-OMe, 3’-geranyl (xanthoangelol F, 55) 2’,4-diOH, 4’-OMe, 3’-(3,7-dimethyl-6-hydroxy-2,7-octadienyl) (xanthoangelol G, 56) 2’,4-diOH, 4’-OMe, 5’-prenyl (bavachalcone, H2/608)

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 103. 2’,4-diOH, 4’-prenyloxy (H2/605) 104. 2’,4-diOH, 4’-geranyloxy (H2/662) 105. 2’,4-diOH, 5’’-(2-hydroxyisopropyl)-4’’,5’’-dihydrofurano[2’’,3’’,4’,3’] (bakuchalcone, H2/598) 106. 2’,4-diOH, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (isobavachromene, H2/599) 107. 2’,4-diOH, 6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:4’,3’] (dorsmanin A, 57) 108. 2’,4-diOH, 6’’,6’’-dimethyl-5’’-hydroxy-4’’,5’’-dihydropyrano[2’’,3’’:4’,3’] (58) 109. 2’,4-diOH, 3-prenyl, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (paratocarpin B, 59) 110. 2’,4-diOH, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’] (bavachromene, H2/607) 111. 2’,4-diOH, (6’’-(4-methylpent-3-enyl),6’’-methyl)pyrano[2’’,3’’:4’,3’] (lespeol, H2/665) 112. 4’,4-diOH, 2’-OMe (H2/464) 113. 4’,4-diOH, 2’-OMe, 5’-CHO (isoneobavachalcone, H2/575) 114. 4’,4-diOH, 6’’,6’’-dimethyl-5’’-hydroxy-4’’,5’’-dihydropyrano[2’’,3’’:2’,3’] (bavachromanol, H2/600) 115. 2’-OH, 4’,4-diOMe (H2/466) 116. 2’-OH, 4’,4-diOMe, 5’-prenyl (H2/609) 117. 2’-OH, 4-OMe, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (H2/601) 118. 2’-OH, bis(6’’,6’’-dimethylpyrano)[2’’,3’’:4’,3’],[2’’,3’’:4,3] (paratocarpin A, 60) 119. 2’-OH, 5’’-(2-hydroxyisopropyl)-4’’,5’’-dihydrofurano[2’’,3’’:4’,3’], 6’’,6’’dimethylpyrano[2’’,3’’:4,3] (paratocarpin F, 61) 120. 2’-OH, bis(6’’,6’’-dimethyl-4’’,5’’-dihydropyrano)[2’’,3’’:4’,3’],[2’’,3’’:4,3] (artoindonesianin J, 62) 121. 2’-OH, bis(6’’,6’’-dimethyl-4’’,5’’-dihydropyrano)[2’’,3’’:4’,5’],[2’’,3’’:4,3] (63) 122. 4-OH, 4’-OMe, 6’’,6’’-dimethyl-5’’-hydroxy-4’’,5’’-dihydropyrano[2’’,3’’:2’,3’] (xanthoangelol H, 64) (2’,4’,b) 123. b-OH, 2’,4’-diOMe, 5’-prenyl (pongagallone A, H2/540) 124. b-OH, 2’-OMe, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (H2/539) 125. b-OH, 2’-OMe, furano[2’’,3’’:4’,3’] (pongamol, H2/555) 126. 2’,b-diOMe, furano[2’’,3’’:4’,3’] (H2/558) (2’,5’,4) 127. 2’,5’,4-triOH (3) 128. 2’,5’-diOH, 4-OMe (H2/467) (2’,3,4) 129. 2’,3,4-triOH (H2/461) (3’,4’,4) 130. 4’,4-diOH, 6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:3’,2’] (crotmadine, H2/615) (4’,2,4) 131. 4’,4-diOH, 2-OMe (echinatin, H2/459) 132. 4’,4-diOH, 2-OMe, 3-prenyl (licochalcone C, 65) 133. 4’,4-diOH, 2-OMe, 5-(1,1-dimethylallyl) (licochalcone A, H2/594) 134. 2,4-diOH, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (munsericin, 66) 135. 4’-OH, 2-OMe, 6’’,6’’-dimethylpyrano[2’’,3’’:4,3] (licoagrochalcone B, 67) 136. 4’-OH, 2-OMe, 5’’-(2-hydroxyisopropyl)-4’’,5’’-dihydrofurano[2’’,3’’:4,3] (licoagrochalcone D, 68) 137. 4-OH, 4’,2-diOMe (glypallichalcone, 4) (2,4,6)

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 138. 4,6-diOH, 2-OMe, 3-CHO, 5-Me (H2/574) Tetra-O-substituted (2’,3’,4’,6’) 139. 2’,3’,6’-triOH, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’] (mallotus A, H2/647) 140. 2’,3’-diOH, 4’,6’-diOMe (H2/498) 141. 2’,4’-diOH, 3’,6’-diOMe (H2/497) 142. 2’,4’-diOH, 6’-OMe, 3’-angeloyloxy (H2/644) 143. 2’,4’-diOH, 6’-OMe, 3’-(2-methylbutyryloxy) (H2/645) 144. 2’,4’-diOH, 6’-OMe, 3’-isovaleryloxy (H2/646) 145. 2’,6’-diOH, 3’,4’-diOMe (pashanone, H2/496) 146. 2’-OH, 3’,4’,6’-triOMe (H2/500) 147. 6’-OH, 2’,3’,4’-triOMe (helilandin B, H2/499) 148. 2’,6’-diOMe, 3’,4’-OCH2O- (helilandin A, H2/563) 149. 2’,3’,4’,6’-tetraOMe (H2/501) (2’,3’,4’,4) 150. 2’,3’,4’,4-tetraOH (H2/485) 151. 2’,4’,4-triOH, 3’-OMe (kukulkanin B, H2/486) 152. 2’,4’-diOH, 3’,4-diOMe (kukulkanin A, H2/487) 153. 2’,4-diOH, 3’,4’-diOMe (heliannone A, 5) (2’,4’,5’,2) 154. 2’,4’,2-triOH, 5’-OMe, 3’-geranyl (H2/681) 155. 2’,5’,2-triOH, (6’’-(4-methylpent-3-enyl),6’’-methyl)pyrano[2’’,3’’:4’,3’] (flemingin A, H2/680) (2’,4’,5’,4) 156. 2’,5’,4-triOH, (6’’-(4-methylpent-3-enyl),6’’-methyl)pyrano[2’’,3’’:4’,3’] (flemingin D, H2/682) 157. 2’,5’,4-triOH, (6’’-(4-hydroxy-4-methylpent-2-enyl),6’’-methyl)pyrano[2’’,3’’:4’,3’] (flemingin E, H2/683) 158. 2’,5’,4-triOH, (6’’-(3-hydroxy-4-methylpent-4-enyl),6’’-methyl)pyrano[2’’,3’’:4’,3’] (flemingin F, H2/684) (2’,4’,6’,2) 159. 2’,4’,2-triOH, 6’-OMe (6) 160. 2’-OH, 4’,6’,2-triOMe (7) (2’,4’,6’,4) 161. 2’,4’,6’,4-tetraOH (chalconaringenin, H2/488) 162. 2’,4’,6’,4-tetraOH, 3’-geranyl (69) 163. 2’,4’,6’-triOH, 4-OMe (H2/489) 164. 2’,4’,4-triOH, 6’-OMe (helichrysetin, H2/491) 165. 2’,4’,4-triOH, 6’-OMe, 3’-prenyl (xanthohumol, H2/638) 166. 2’,4’,4-triOH, 6’-OMe, 3’-(2-hydroxy-3-methylbut-3-enyl) (xanthohumol D, 70) 167. 2’,4’,4-triOH, 6’-OMe, 3’,5’-diprenyl (5’-prenylxanthohumol, 71) 168. 2’,4’,4-triOH, 3’-prenyl, 6’’,6’’-dimethylpyrano[2’’,3’’:6’,5’] (xanthohumol E, 72) 169. 2’,4’,4-triOH, 3’-(3-acetyl-5-methyl-2,4,6-trihydroxybenzyl), 6’’,6’’dimethylpyrano[2’’,3’’:6’,5’] (4-hydroxyrottlerin, H2/701) 170. 2’,6’,4-triOH, 4’-OMe (neosakuranetin, H2/490) 171. 2’,6’,4-triOH, 4’-OMe, 3’-prenyl (xanthogalenol, 73) 172. 2’,6’,4-triOH, 4’-prenyloxy (H2/640)

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 173. 174. 175. 176. 177. 178. 179. 180. 181. 182. 183. 184. 185. 186. 187. 188. 189. 190. 191. 192. 193. 194. 195. 196. 197. 198. 199. 200. 201. 202. 203. 204. 205. 206. 207.

208. 209. 210.

2’,6’,4-triOH, 3’-prenyl, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’] (sericone, H2/641) 2’,4’-diOH, 6’,4-diOMe (8) 2’,6’-diOH, 4’,4-diOMe (gymnogrammene, H2/492) 2’,4-diOH, 4’,6’-diOMe (flavokawin C, H2/494) 2’,4-diOH, 4’,6’-diOMe, 3’-prenyl (H2/639) 2’,4-diOH, 6’-OMe, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (xanthohumol C, 74) 2’,4-diOH, 6’-OMe, 6’’,6’’-dimethyl-4’’-hydroxy-4’’,5’’-dihydropyrano[2’’,3’’:4’,3’] (isodehydrocycloxanthohumol hydrate, 75) 2’,4-diOH, 6’-OMe, 6’’,6’’-dimethyl-5’’-hydroxy-4’’,5’’-dihydropyrano[2’’,3’’:4’,3’] (xanthohumol B, 76) 2’,4-diOH, bis(6’’,6’’-dimethylpyrano)[2’’,3’’:4’,3’],[2’’,3’’:6’,5’] (laxichalcone, 77) 2’,4-diOH, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’], 6’’,6’’-dimethyl-4’’-hydroxy-5’’-methoxy4’’,5’’-dihydropyrano[2’’,3’’:6’,5’] (derrichalcone, 78) 4’,4-diOH, 2’,6’-diOMe (H2/493) 6’,4-diOH, 4’-OMe, 6’’,6’’-dimethylpyrano[2’’,3’’:2’,3’] (citrunobin, H2/637) 2’-OH, 4’,6’,4-triOMe (flavokawin A, H2/495) 2’-OH, 4’,6’,4-triOMe, 5’-Br (9) 2’-OH, 4’,4-diOMe, 6’’,6’’-dimethylpyrano[2’’,3’’:6’,5’] (79) 2’-OH, 6’,4-diOMe, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (glychalcone A, 80) 4’-OH, 2’,6’,4-triOMe (10) (2’,4’,6’,b) 2’,4’,6’,b-tetraOH, 3’-CHO, 5’-Me (H2/537) 2’,4’,b-triOH, 6’-OMe (H2/534) 2’,6’,b-triOH, 4’-OMe (H2/533) 2’,6’,b-triOH, 4’-OMe, 3’-CHO, 5’-Me (H2/536) 2’,6’,b-triOH, 4’-OMe, 3’-prenyl (98) 2’,b-diOH, 4’,6’-diOMe, 3’-Me (23) 2’,b-diOH, 6’-OMe, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (demethylpraecansone B, H2/538) b-OH, 2’,6’-diOMe, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (praecansone B, H2/549) 2’,6’,b-triOMe, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (99) (2’,4’,2,4) 2’,4’,2,4-tetraOH (H2/477) 2’,4’,2,4-tetraOH, 3’-prenyl (morachalcone A, H2/630) 2’,4’,2,4-tetraOH, 3’-lavandulyl (ammothamnidin, H2/677) 2’,4’,2,4-tetraOH, 3’-(4-coumaroyloxy-3-methyl-but-2(E)-enyl) (demethoxyisogemichalcone C, 81) 2’,4’,2,4-tetraOH, 3’-(4-feruloyloxy-3-methyl-but-2(E )-enyl) (isogemichalcone C, 82) 2’,4’,2,4-tetraOH, 3’-(4-feruloyloxy-3-methyl-but-2(Z )-enyl) (gemichalcone C, 83) 2’,4’,2,4-tetraOH, 5-geranyl (kuwanol D, H2/676) 2’,2,4-triOH, 3’-prenyl, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’] (H2/631) (2’,4’,2,5) 2’,2,5-triOH (6’’-(4-methylpent-3-enyl),6’’-methyl)pyrano[2’’,3’’:4’,3’] (flemiwallichin D, H2/679) (2’,4’,3,4) 2’,4’,3,4-tetraOH (butein, H2/478) 2’,4’,3,4-tetraOH, 3’-geranyl (84) 2’,4’,3,4-tetraOH, 3’,5-digeranyl (85)

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 211. 212. 213. 214. 215.

2’,4’,3,4-tetraOH, 5’-prenyl (broussochalcone A, H2/634) 2’,4’,3-triOH, 4-OMe (H2/480) 2’,4’,3-triOH, 3’-prenyl 6’’,6’’-dimethylpyrano[2’’,3’’:4,5] (86) 2’,4’,4-triOH, 3-OMe (homobutein, H2/479) 2’,4’,4-triOH, 3’-prenyl, (6’’-(4-methylpent-3-enyl),6’’-methyl)pyrano[2’’,3’’:3,2] (poinsettifolin B, 87) 216. 2’,3,4-triOH, 4’-OMe (calythropsin, 11) 217. 2’,3,4-triOH, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (H2/632) 218. 4’,3,4-triOH, 2’-OMe (sappanchalcone, H2/481) 219. 2’,4’-diOH, 3,4-diOMe (H2/483) 220. 2’,3-diOH, bis(6’’,6’’-dimethylpyrano)[2’’,3’’:4’,3’],[2’’,3’’:4,5] (glyinflanin G, 88) 221. 2’,4-diOH, 3’-OMe, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (pongachalcone II, H2/633) 222. 2’-OH, 3,4-diOMe, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (3,4-dimethoxylonchocarpin, 89) 223. 2’-OH, 3,4-OCH2O-, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (glabrachromene II, H2/571) 224. 2’-OMe, 3,4-OCH2O-, furano[2’’,3’’:4’,3’] (ovalitenin C, H2/561) 225. 2’,4’-diOMe, 3,4-OCH2O- (12) (2’,4’,3,5) 226. 2’,4’,3,5-tetraOH (pseudosindorin, H2/484) (2’,4’,4,b) 227. 2’,4’,4,b-tetraOH (licodione, H2/531) 228. 2’,4’,4,b-tetraOH, 5’-prenyl (H2/541) 229. 2’,4’,4,b-tetraOH, 5’,3-diprenyl (glycyrdione A, 100) 230. 2’,4’,4,b-tetraOH, 5’-prenyl, 3-(2-hydroxy-3-methylbut-3-enyl) (glyinflanin E, 101) 231. 2’,4’,4,b-tetraOH, 3-prenyl (kanzonol A, 102) 232. 2’,4’,b-triOH, 5’-prenyl, 6’’,6’’-dimethylpyrano[2’’,3’’:4,3] (glycyrdione B, 103) 233. 2’,4,b-triOH, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’] (glyinflanin B, 104) 234. 2’,4,b-triOH, 3-prenyl, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’] (glyinflanin C, 105) 235. 2’,4,b-triOH, 3-prenyl, 5’’-(2-hydroxyisopropyl)-4’’,5’’-dihydrofurano[2’’,3’’:4’,5’] (glyinflanin F, 106) 236. 4’,4,b-triOH, 2’-OMe (H2/532) 237. 2’,b-diOH, bis(6’’,6’’-dimethylpyrano)[2’’,3’’:4’,5’],[2’’,3’’:4,3] (glyinflanin D, 107) (2’,3,4,5) 238. 2’-OH, 3,4,5-triOMe (crotaoprostrin, 13) (3’,4’,2,4) 239. 3’,4’,4-triOH, 2-OMe, 3-prenyl (licoagrochalcone C, 90) (4’,2,3,4) 240. 4’,3,4-triOH, 2-OMe (licochalcone B, H2/475) 241. 4’,3,4-triOH, 2-OMe, 3’-prenyl (licochalcone D, 91) (4’,2,4,6) 242. 2,4-diOH, 4’,6-diOMe (H2/476) (2,3,4,6) 243. 2-OH, 3,4,6-triOMe (tepanone, 14) (2,4,6,b) 244. 2,6,b-triOMe, 6’’,6’’-dimethylpyrano[2’’,3’’:4,3] (praecansone A, H2/629) Penta-O-substituted (2’,3’,4’,5’,6’) 245. 2’,4’-diOH, 3’,5’,6’-triOMe (isodidymocarpin, H2/520)

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 246. 247. 248. 249. 250. 251. 252. 253. 254. 255. 256. 257. 258. 259. 260. 261. 262. 263.

264.

265. 266. 267. 268. 269. 270. 271. 272. 273. 274. 275. 276.

277.

2’,5’-diOH, 3’,4’,6’-triOMe (pedicin, H2/519) 4’,6’-diOH, 2’,5’-diOMe, 3’-angeloyloxy (H2/656) 4’,6’-diOH, 2’,5’-diOMe, 3’-(2-methylbutyryloxy) (melafolone, H2/657) 4’,6’-diOH, 2’,5’-diOMe, 3’-isovaleryloxy (valafolone, H2/658) 2’-OH, 3’,4’,5’,6’-tetraOMe (kanakugiol, H2/522) 3’-OH, 2’,4’,5’,6’-tetraOMe (H2/521) 2’,3’,4’,5’,6’-pentaOMe (pedicellin, H2/523) (2’,3’,4’,6’,2) 2’,4’-diOH, 3’,6’,2-triOMe (H2/504) (2’,3’,4’,6’,4) 2’,4-diOH, 3’,4’,6’-triOMe (H2/517) 2’,4-diOH, 6’-OMe, 3’,4’-OCH2O- (H2/564) 6’,4-diOH, 2’,3’,4’-triOMe (H2/516) 6’-OH, 2’,3’,4’,4-tetraOMe (H2/518) (2’,3’,4’,3,4) 2’,3’,4’,3,4-pentaOH (okanin, H2/506) 2’,4’,3,4-tetraOH, 3’-OMe (lanceoletin, H2/507) 2’,4’,4-triOH, 3’,3-diOMe (15) 2’-OH, 3’,4’,3,4-tetraOMe (H2/508) (2’,4’,5’,2,5) 2’,4’,2,5-tetraOH, 5’-OMe, 3’-geranyl (homoflemingin, H2/694) 2’,5’,2,5-tetraOH (6’’-(4-methylpent-3-enyl),6’’-methyl)pyrano[2’’,3’’:4’,3’] (flemingin C, H2/691) (2’,4’,5’,2,6) 2’,5’,2,6-tetraOH (6’’-(4-methylpent-3-enyl),6’’-methyl)pyrano[2’’,3’’:4’,3’] (flemingin B, H2/692) (2’,4’,5’,3,4) 2’,4’,5’,3,4-pentaOH (neoplathymenin, H2/509) 2’,4’-diOH, 5’-OMe, 3,4-OCH2O- (prosogerin B, H2/565) 2’-OH, 5’,3,4-triOMe, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (ponganone VI, 92) 5’-OH, 2’-OMe, 3,4-OCH2O-, furano[2’’,3’’:4’,3’] (H2/562) (2’,4’,6’,2,3) 2’-OH, 4’,6’,2,3-tetraOMe (16) (2’,4’,6’,2,4) 2’,4’,2,4-tetraOH, 6’-OMe, 3’-lavandulyl (kuraridin, H2/687) 2’,4’,2,4-tetraOH, 6’-OMe, 3’-(5-hydroxy-2-isopropenyl-5-methylhexyl) (kuraridinol, H2/688) 2’,4’,4-triOH, 6’,2-diOMe 3’-lavandulyl (kushenol D, H2/678) 2’,4’-diOH, 6’,2,4-triOMe (cerasin, H2/502) 2’-OH, 4’,6’,2,4-tetraOMe (cerasidin, H2/503) (2’,4’,6’,2,5) 2’,4’,2,5-tetraOH, 6’-OMe, 3’-geranyl (flemiwallichin C, H2/690) 2’,6’,2,5-tetraOH (6’’-(4-methylpent-3-enyl),6’’-methyl)pyrano[2’’,3’’:4’,3’] (flemiwallichin B, H2/689) (2’,4’,6’,2,6) 2’,6’,2,6-tetraOH (6’’-(4-methylpent-3-enyl),6’’-methyl)pyrano[2’’,3’’:4’,3’] (flemiwallichin A, H2/693)

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 278. 2’,2,6-triOH, 6’-OMe, 3’-prenyl, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’] (orotinichalcone, H2/649) (2’,4’,6’,3,4) 279. 2’,4’,6’,3,4-pentaOH (H2/510) 280. 2’,4’,6’,3-tetraOH, 4-OMe, 3’,2-diprenyl (antiarone C, H2/655) 281. 2’,4’,6’,3-tetraOH, 4-OMe, 2,5-diprenyl (antiarone E, H2/652) 282. 2’,4’,6’,3-tetraOH, 4-OMe, (2,b)-C5 (antiarone J, H2/653) 283. 2’,4’,6’,4-tetraOH, 3-OMe (H2/511) 284. 2’,4’,6’,4-tetraOH, 3-OMe, 3’,2-diprenyl (antiarone D, H2/654) 285. 2’,4’,3,4-tetraOH, 6’’,6’’-dimethylpyrano[2’’,3’’:6’,5’], 3’-(3-acetyl-5-methyl-2,4,6trihydroxybenzyl) (3,4-dihydroxyrottlerin, H2/700) 286. 2’,6’,3,4-tetraOH, 3’,4’-dihydrooxepino (H2/651) 287. 2’,4’,6’-triOH, 3,4-diOMe, (2,b)-C5 (antiarone K, H2/650) 288. 2’,6’,4-triOH, 4’,3-diOMe (H2/512) 289. 2’,3-diOH, 4’,6’,4-triOMe (H2/513) 290. 2’-OH, 4’,6’,3,4-tetraOMe (H2/514) 291. 2’-OH, 4’,3,4-triOMe, 6’’,6’’-dimethylpyrano[2’’,3’’:6’,5’] (93) 292. 2’-OH, 6’,3,4-triOMe, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (glychalcone B, 94) 293. 2’-OH, 4’,6’-diOMe, 3,4-OCH2O- (tephrone, H2/566) 294. 2’-OH, 4’,6’-diOMe, 3,4-OCH2O-, 3’-prenyl (ovalichalcone A, H2/572) 295. 2’-OH, 6’-OMe, 3,4-OCH2O-, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (glabrachromene I, H2/ 573) 296. 2’,4’,6’-triOMe, 3,4-OCH2O- (17) (2’,4’,2,4,5) 297. 2’,4’,2,4,5-pentaOH, 3’-prenyl (ramosismin, 95) 298. 2’-OH, 2,4,5-triOMe, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (glabrachalcone, H2/648) (2’,4’,3,4,5) 299. 2’,4’,3,4,5-pentaOH (robtein, H2/505) (2’,4’,3,4,a) 300. 2’,4’,3,4,a-pentaOH (H2/515) 301. 2’,4’,3,4-tetraOH, cyclo[a-OCH2-2] (mopachalcone, H2/720) (2’,4’,3,4,b) 302. b-OH, 2’,4’-diOMe, 3,4-OCH2O- (milletenone, H2/552) 303. b-OH, 2’,4’-diOMe, 3,4-OCH2O-, 5’-prenyl (pongagallone B, H2/550) 304. b-OH, 2’,4’-diOMe, 3,4-OCH2O-, a-Me (tinosporinone, H2/553) 305. b-OH, 2’-OMe, 3,4-OCH2O-, furano[2’’,3’’:4’,3’] (ovalitenone, H2/554) (2’,4’,4,5,a) 306. 2’,4’,4,5-tetraOH, cyclo[a-OCH2-2] (peltochalcone, H2/719) (3’,4’,2,3,4) 307. 3’,4’,3,4-tetraOH, 2-OMe (18) (3’,4’,3,4,b) 308. b-OH, 3’,4’:3,4-bis(-OCH2O-) (galiposin, 24) Hexa-O-substituted (2’,3’,4’,5’,6’,4) 309. 2’,5’-diOH, 3’,4’,6’,4-tetraOMe (H2/527) 310. 3’,4-diOH, 2’,4’,5’,6’-tetraOMe (19) (2’,3’,4’,6’,3,4)

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 311. 312. 313. 314. 315.

6’,3,4-triOH, 2’,3’,4’-triOMe (hamilcone, 20) 3’,6’-diOH, 2’,4’-diOMe, 3,4-OCH2O- (agestricin, H2/567) 2’-OH, 3’,4’,6’,3,4-pentaOMe (21) 2’-OH, 3’,6’-diOMe, 3,4-OCH2O-, furano[2’’,3’’:4’,5’] (96) 6’-OH, 2’,3’,4’,3,4-pentaOMe (H2/526) (2’,4’,6’,2,3,4) 316. 2’,4’,6’,2,3,4-hexaOMe (22) (2’,4’,6’,2,4,5) 317. 2’-OH, 4’,6’,2,4,5-pentaOMe (rubone, H2/524) (2’,4’,6’,3,4,5) 318. 2’-OH, 4’,6’,3,4,5-pentaOMe (H2/525) 319. 6’-OH, 4’,3,4,5-tetraOMe, 6’’,6’’-dimethylpyrano[2’’,3’’:2’,3’] (97) (2’,4’,6’,3,4,b) 320. b-OH, 2’,4’,6’-triOMe, 3,4-OCH2O- (ponganone X, 25) 321. b-OH,2’,6’-diOMe,3,4-OCH2O-,6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’](pongapinoneA,108) (3’,4’,2,4,6,b) 322. 2,4,6,b-tetraOMe, 3’,4’-OCH2O- (26) Octa-O-substituted (2’,3’,4’,6’,2,3,4,5) 323. 2’,2-diOH, 6’,3,4,5-tetraOMe, 3’,4’-OCH2O- (H2/568) 324. 6’-OH, 2’,3’,4’,2,3,4,5-heptaOMe (H2/528) 325. 6’-OH, 2’,2,3,4,5-pentaOMe, 3’,4’-OCH2O- (H2/569) 326. 2’,3’,4’,6’,2,3,4,5-octaOMe (H2/529) 327. 2’,6’,2,3,4,5-hexaOMe, 3’,4’-OCH2O- (H2/570) (2’,4’,5’,2,3,4,5,b) 328. b-OH, 2’,4’,5’,2,3,4,5-heptaOMe (H2/535) Chalcone glycosides 4’-Hydroxychalcone 329. 4’-O-Glucoside (H2/721) 2’,4-Dihydroxychalcone 330. 4-O-Glucoside (H2/723) 3,4-Dihydroxychalcone 331. 4-O-b-Arabinosyl-(1’’’ ! 4’’)-galactoside (H2/722) 2’,3’,4-Trihydroxychalcone 332. 4-O-Glucoside (109) 2’,4’,4-Trihydroxychalcone (isoliquiritigenin) 333. 2’-O-Glucosyl-(1’’’ ! 4’’)-rhamnoside (H2/729) 334. 4’-O-Glucoside (neoisoliquiritin, H2/725) 335. 4’-O-Glucosylglucoside (H2/730) 336. 4’,4-Di-O-glucoside (H2/728) 337. 4’-O-Glucoside 4-O-apiofuranosyl-(1’’’ ! 2’’)-glucoside (110) 338. 4’-O-Glucosylglucoside 4-O-glucoside (H2/731) 339. 4-O-Glucoside (isoliquiritin, H2/724) 340. 4-O-Apiofuranosyl-(1’’’ ! 2’’)-glucoside (licuroside, H2/726) 341. 4-O-(5’’’-O-p-Coumaroyl)apiofuranosyl-(1’’’ ! 2’’)-glucoside (111) 342. 4-O-(5’’’-O-Feruloyl)apiofuranosyl-(1’’’ ! 2’’)-glucoside (112) 343. 4-O-Rhamnosylglucoside (H2/727)

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 344. 3’-C-Glucoside (H1/2597) 2’,4’,4-Trihydroxy-3’-prenylchalcone (3’-prenylisoliquiritigenin) 345. 4’-O-Glucoside (113) 2’,3’,4’,4-Tetrahydroxychalcone 346. 4’-O-(2’’-O-p-Coumaroyl)glucoside (114) 347. 4’-O-(6’’-O-p-Coumaroyl)glucoside (115) 348. 4’-O-(2’’-O-Acetyl-6’’-O-cinnamoyl)glucoside (116) 349. 4’-O-(2’’-O-p-Coumaroyl-6’’-O-acetyl)glucoside (117) 2’,6’,2-Trihydroxy-4’-methoxychalcone 350. 2’-O-Glucoside (androechin, 118) 2’,4’,6’,4-Tetrahydroxychalcone (chalconaringenin) 351. 2’-O-Glucoside (isosalipurposide, H2/744) 352. 2’-O-(6’’-O-p-Coumaroyl)glucoside (H2/742) 353. 2’-O-Xyloside (H2/743) 354. 2’-O-Rhamnosyl-(1’’’ ! 4’’)-glucoside (H2/747) 355. 2’-O-Rhamnosyl-(1’’’ ! 4’’)-xyloside (H2/746) 356. 2’,4’-Di-O-glucoside (119) 357. 2’-O-Glucoside 4’-O-gentobioside (120) 358. 4’-O-Glucoside (H2/745) 359. 4-O-Glucoside (H2/741) 2’,4’,4-Trihydroxy-6’-methoxychalcone (helichrysetin) 360. 4’-O-Glucoside (helichrysin, H2/749) 361. 4-O-Glucoside (121) 362. 4’,4-Di-O-a-glucoside (122) 2’,6’,4-Trihydroxy-4’-methoxychalcone (neosakuranetin) 363. 2’-O-Glucoside (neosakuranin, H2/748) 2’,4-Dihydroxy-4’,6’-dimethoxychalcone (flavokawin C) 364. 4-O-Glucoside (H2/751) 365. 4-O-Apiosyl-(1’’’ ! 2’’)-glucoside (H2/752) 366. 4-O-(5’’’-O-p-Cinnamoyl)apiofuranosyl-(1’’’ ! 2’’)-glucoside (123) 2’,4’,6’,b-Tetrahydroxychalcone 367. 2’-O-Glucoside (H2/753) 368. 4’-O-Glucoside (H2/754) 2’,4’,3,4-Tetrahydroxychalcone (butein) 369. 2’,3-Di-O-glucoside (H2/735) 370. 4’-O-Glucoside (coreopsin, H2/733) 371. 4’-O-Malonylglucoside (H2/734) 372. 4’-O-Arabinosyl-(1’’’ ! 4’’)-galactoside (H2/737) 373. 4’-O-Glucosylglucoside (H2/738) 374. 4’-O-Malonylsophoroside (H2/739) 375. 4’,3-Di-O-glucoside (isobutrin, H2/736) 376. 3-O-Glucoside (monospermoside, H2/732) 2’,4’,4-Trihydroxy-3-methoxychalcone (homobutein) 377. 4’-O-Glucoside (124) 378. 4-O-Glucoside (H2/740) 2’,4-Dihydroxy-4’,6’,3-trimethoxychalcone

1085

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 379. 4-O-Glucoside (H2/780) 2’,3’,4’,3,4-Pentahydroxychalcone (okanin) 380. 3’-O-Glucoside (H2/755) 381. 3’,4’-Di-O-glucoside (H2/764) 382. 4’-O-Glucoside (marein, H2/756) 383. 4’-O-(6’’-O-Acetyl)glucoside (H2/757) 384. 4’-O-(6’’-O-p-Coumaroyl)glucoside (H2/758) 385. 4’-O-(4’’,6’’-Di-O-acetylglucoside) (125) 386. 4’-O-(4’’-O-Acetyl-6’’-O-p-coumaroyl)glucoside (H2/759) 387. 4’-O-(2’’-O-Caffeoyl-6’’-O-acetylglucoside) (126) 388. 4’-O-(2’’-O-Caffeoyl-6’’-O-p-coumaroylglucoside) (127) 389. 4’-O-(2’’,4’’,6’’-Tri-O-acetyl)glucoside (H2/760) 390. 4’-O-(2’’,4’’-Di-O-acetyl-6’’-O-p-coumaroyl)glucoside (H2/762) 391. 4’-O-(3’’,4’’,6’’-Tri-O-acetyl)glucoside (H2/761) 392. 4’-O-(3’’,4’’-Di-O-acetyl-6’’-O-p-coumaroyl)glucoside (H2/763) 393. 4’-O-a-Arabinofuranosyl-(1’’’ ! 4’’)-glucoside (H2/765) 394. 4’-O-Glucosyl-(1’’’ ! 6’’)-glucoside (H2/766) 2’,3’,4’,3-Tetrahydroxy-4-methoxychalcone (okanin 4-methyl ether) 395. 3’-O-Glucoside (H2/767) 396. 3’-O-(6’’-O-Acetyl)glucoside (H2/768) 397. 4’-O-Glucoside (H2/769) 398. 4’-O-(6’’-O-Acetyl)glucoside (H2/770) 399. 4’-O-(6’’-O-p-Coumaroylglucoside) (128) 400. 4’-O-(2’’-O-Caffeoyl-6’’-O-acetylglucoside) (129) 401. 4’-O-Primveroside (130) 2’,4’,3,4-Tetrahydroxy-3’-methoxychalcone (lanceoletin) 402. 4’-O-Glucoside (lanceolin, H2/772) 2’,3’,4’-Trihydroxy-3,4-dimethoxychalcone (okanin 3,4-dimethyl ether) 403. 4’-O-Glucoside (H2/773) 2’,4’,4-Trihydroxy-3’,3-dimethoxychalcone (okanin 3’,3-dimethyl ether) 404. 4’-O-Glucoside (131) 2’,4’-Dihydroxy-3’,3,4-trimethoxychalcone (okanin 3’,3,4-trimethyl ether) 405. 4’-O-Glucoside (H2/774) 2’,4’,5’,3,4-Pentahydroxychalcone 406. 4’-O-Glucoside (stillopsin, H2/776) 2’-Hydroxy-4’,6’,2,4-tetramethoxychalcone 407. 2’-O-Glucoside (132) 2’,4’,6’,3,4-Pentahydroxychalcone 408. 2’-O-Glucoside (H2/777) 409. 4’-O-Glucoside (H2/778) 2’,4’,6’,4-Tetrahydroxy-3-methoxychalcone 410. 2’-O-Glucoside (H2/779) 4’,6’,3-Trihydroxy-2’,4-dimethoxychalcone 411. 4’-O-Rutinoside (133) 2’,4’,6’,3,4,5-Hexahydroxychalcone 412. 2’-O-Glucoside (H2/781) 2’,4’,6’,3,4,b-Hexahydroxychalcone

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 413. 2’-O-Glucoside (H2/782) 2’,3’,4’,6’,3,4,a-Heptahydroxychalcone 414. 2’-O-Glucoside (H2/783) Chalcone dimers and oligomers Dimers (chalcone) 415. Azobechalcone A (147) 416. Brackenridgea orange pigment (H1/3090) 417. Calodenin A (150) 418. Calodenin B (H1/3089) 419. a-Diceroptene (H1/3145) 420. Dihydrolophirone C (149) 421. a-Diohobanin (H1/3144) 422. Flavumone A (152) 423. Isolophirone C (148) 424. Isombamichalcone (H1/3097) 425. Kamalachalcone A (144) 426. Kamalachalcone B (145) 427. Licobichalcone (146) 428. Lophirone C (H1/3092) 429. Lophirone F (H1/3098) 430. Lophirone G (H1/3099) 431. Lophirone K (151) 432. Matosine (137) 433. Mbamichalcone (H1/3096) 434. Rhuschalcone I (138) 435. Rhuschalcone II (139) 436. Rhuschalcone III (140) 437. Rhuschalcone IV (141) 438. Rhuschalcone V (142) 439. Rhuschalcone VI (143) 440. Urundeuvine A (134) 441. Urundeuvine B (135) 442. Urundeuvine C (136) Dimers (chalcone–flavan) 443. Daphnodorin A (H2/1727) 444. Daphnodorin C (H2/1728) 445. Daphnodorin J (153) 446. Daphnodorin M (154) 447. Daphnodorin N (155) Dimers (chalcone–flavan-3-ol) 448. Daphnodorin B (H2/1895) 449. Daphnodorin I (156) 450. Dihydrodaphnodorin B (H2/1896) 451. Genkwanol A145 452. Genkwanol B (157) 453. Genkwanol C (158) 454. Larixinol (H2/1897)

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued Dimers (chalcone–flavanone) 455. Chalcocaryanone A (159) 456. Chalcocaryanone B (160) 457. Chalcocaryanone C (161) 458. Chalcocaryanone D (162) 459. Flavumone B (165) 460. 6’’’-Hydroxylophirone B (163) 461. 6’’’-Hydroxylophirone B 4’’’-O-glucoside (164) 462. Lophirone B (H1/3086) 463. Lophirone H (H1/3087) 464. Occidentoside (H1/2946) Dimers (chalcone–flavene) 465. Bongosin (H1/3085) Dimers (chalcone–flavone) 466. Aristolochia dimer ‘‘A’’ (166) 467. Aristolochia dimer ‘‘B’’ (167) 468. Aristolochia dimer ‘‘C’’ (168) 469. Aristolochia dimer ‘‘D’’ (169) 470. Calodenone (171) 471. Chamaechromone (H1/3127) 472. Cissampeloflavone (170) 473. Lophirone A (H1/3125) Trimers 474. Caloflavan A (172) 475. Caloflavan B (173) Tetramers 476. Alatachalcone (175) 477. Aristolochia tetraflavonoid (174) 478. Isolophirachalcone (176) 479. Lophirochalcone (H1/3133) 480. Lophiroflavan A (177) 481. Lophiroflavan B (178) 482. Lophiroflavan C (179) Pentamer 483. Ochnachalcone (180) Hexamer 484. Azobechalcone (181) Chalcone Diels–Alder adducts Chalcone–isoprene 485. Sanggenon R (182) Chalcone–monoterpene 486. Boesenbergia adduct (191) 487. Crinatusin A1 (183) 488. Crinatusin A2 (184) 489. Crinatusin B1 (185) 490. Crinatusin B2 (186) 491. Crinatusin C1 (187)

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 492. Crinatusin C2 (188) 493. Fissistin (189) 494. Isofissistin (190) 495. Isoschefflerin (H2/685) 496. Kaempferia adduct ‘‘A’’ (192) 497. Kaempferia adduct ‘‘B’’ (193) 498. (+)-Nicolaioidesin A (194) 499. (+)-Nicolaioidesin B (195) 500. (+)-Nicolaioidesin C (196) 501. Panduratin A (H2/673) 502. Panduratin B (H2/675) 503. Schefflerin (H2/686) Chalcone–coumarin 504. Palodesangren A (197) 505. Palodesangren B (198) 506. Palodesangren C (199) 507. Palodesangren D (200) 508. Palodesangren E (201) 509. Palodesangretin A (202) 510. Palodesangretin B (203) Chalcone–arylbenzofuran 511. Albafuran C (H2/954) 512. Albanol A (mulberrofuran G) (H2/957) 513. Albanol B (H2/958, possible artifact) 514. Chalcomoracin (H2/966) 515. Mulberrofuran C (H2/983) 516. Mulberrofuran E (H2/984) 517. Mulberrofuran J (H2/985) 518. Mulberrofuran O (H2/986) 519. Mulberrofuran T (H2/987) 520. Mulberrofuran U (204) Chalcone–chalcone 521. Artonin C (H2/959) 522. Artonin D (H2/960) 523. Artonin X (205) 524. Brosimone A (H2/963) 525. Brosimone D (H2/964) 526. Dorstenia chalcone dimer (207) 527. Dorstenone (206) 528. Kuwanon I (H2/968) 529. Kuwanon J (H2/969) 530. Kuwanon Q (H2/974) 531. Kuwanon R (H2/975) 532. Kuwanon V (H2/976) 533. Sorocein B (H2/995) Chalcone–flavanone 534. Kuwanon K (H2/970)

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 535. Kuwanon N (H2/971) 536. Kuwanon O (H2/972) 537. Sanggenol J (208) 538. Sanggenol M (209) 539. Sanggenon C (210) 540. Sanggenon D (211) 541. Sanggenon E (212) 542. Sanggenon O (213) 543. Sanggenon P (H2/993) 544. Sanggenon Q (H2/994) 545. Sanggenon S (214) 546. Sanggenon T (215) 547. Cathayanon A (216) 548. Cathayanon B (217) Chalcone–flavone 549. Albanin F (kuwanon G, moracenin B) (H2/955) 550. Albanin G (kuwanon H, moracenin A) (H2/956) 551. Artonin I (218) 552. Brosimone B (H2/965) 553. Kuwanon W (H2/977) 554. Moracenin C (H2/981) 555. Moracenin D (H2/982) 556. Multicaulisin (219) Chalcone–stilbene 557. Kuwanol E (H2/967) 558. Kuwanon P (H2/973) 559. Kuwanon X (H2/978) 560. Kuwanon Y (H2/979) 561. Kuwanon Z (H2/980) Miscellaneous 562. Sorocenol B (220) Chalcone conjugates Chalcone–diarylheptanoid 563. Calyxin A (221) 564. Calyxin B (223) 565. Calyxin F (225) 566. Calyxin H (228) 567. Calyxin I (230) 568. Calyxin L (232) 569. Deoxycalyxin A (222) 570. Epicalyxin B (224) 571. Epicalyxin F (226) 572. Epicalyxin H (229) 573. Epicalyxin I (231) 574. 6-Hydroxycalyxin F (227) Chalcone–bis(diarylheptanoid) 575. Blepharocalyxin A (233)

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 576. Blepharocalyxin B (234) 577. Blepharocalyxin E (235) Miscellaneous 578. 8-Caffeoyl-3,4-dihydro-5,7-dihydroxy-4-phenylcoumarin (H2/704) 579. 8-Cinnamoyl-3,4-dihydro-5,7-dihydroxy-4-phenylcoumarin (H2/702) 580. 8-p-Coumaroyl-3,4-dihydro-5,7-dihydroxy-4-phenylcoumarin (H2/703) 581. Cryptocaryone (H2/716) 582. Didymocalyxin B (239) 583. 2’,4’-Dihydroxy-3’-C-(2,6-dihydroxybenzyl)-6’-methoxychalcone (236) 584. 2’,4’-Dihydroxy-6’-methoxy-3’-(8,17-epoxy-16-oxo-12,14-labdadien-15-yl)chalcone (237) 585. Lophirone D (H2/705) 586. Lophirone E (H2/706) 587. Infectocaryone (240) 588. Kurzichalcolactone (238) Quinochalcones Aglycones 589. Ceroptene (H2/713) 590. Desmosdumotin C (241) 591. 2-Hydroxy-7,8-dehydrograndiflorone (H2/712) 592. Methylpedicinin (H2/715) 593. Munchiwarin (242) 594. Pedicinin (H2/714) 595. Ohobanin (H2/711) 596. Tunicatachalcone (243) C-Glycosides 597. Anhydrosafflor yellow B (244) 598. Carthamin (H1/2845) 599. Cartormin (245) 600. Hydroxysafflor yellow A (246) 601. Precarthamin (247) 602. Safflomin A (H1/2944) 603. Safflomin C (H1/2945) 604. Safflor yellow A (H1/2734) 605. Safflor yellow B (H1/2846) 606. Tinctormine (248) DIHYDROCHALCONES Dihydrochalcone aglycones 607. Dihydrochalcone (H2/784) Di-O-substituted (2’,4’) 608. 2’,4’-diOH (H2/785) 609. 2’-OH, 4’-OMe (249) 610. 2’-OH, 4’-prenyloxy (dihydrocordoin, H2/875) 611. 4’-OH, 2’-OMe (250) (2,4)

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 612. 4-OH, 2-OMe (251) Tri-O-substituted (2’,4’,6’) 613. 2’,4’,6’-triOH (H2/791) 614. 2’,4’,6’-triOH, 3’-Me (252) 615. 2’,4’,6’-triOH, 3’-formyl (H2/868) 616. 2’,4’,6’-triOH, 3’-prenyl (H2/877) 617. 2’,4’,6’-triOH, 3’-C10 ((þ)-linderatin, H2/889) 618. 2’,4’,6’-triOH, 3’-C10 ((
)-linderatin, 275) 619. 2’,4’,6’-triOH, 3’,5’-diprenyl (H2/882) 620. 2’,4’,6’-triOH, 3’,5’-diC10 ((þ)-neolinderatin, H2/891) 621. 2’,4’,6’-triOH, 3’,5’-diC10 ((
)-neolinderatin, 276) 622. 2’,4’-diOH, 6’-OMe (uvangoletin, H2/793) 623. 2’,4’-diOH, 6’-OMe, 3’-Me (myrigalone H, 253) 624. 2’,4’-diOH, 6’-OMe, 3’,5’-diMe (angoletin, H2/872) 625. 2’,4’-diOH, 3’-Me, 6’’,6’’-dimethyl-4’’-hydroxy-4’’,5’’-dihydropyrano[2’’,3’’:6’,5’] (H2/886) 626. 2’,4’-diOH, 3’-Me, 6’’,6’’-dimethyl-5’’-hydroxy-4’’,5’’-dihydropyrano [2’’,3’’:6’,5’] (H2/887) 627. 2’,6’-diOH, 4’-OMe (H2/792) 628. 2’,6’-diOH, 4’-prenyloxy (H2/880) 629. 2’,6’-diOH, 3’,4’-dihydrooxepino (H2/878) 630. 2’,6’-diOH, 4’-OMe, 3’-Me (myrigalone G, 254) 631. 2’,6’-diOH, 4’-OMe, 3’,5’-diMe (myrigalon B, H2/871) 632. 2’,6’-diOH, 4’-OMe, 3’-prenyl (H2/879) 633. 2’,6’-diOH, 4’-OMe, 3’-C10 ((þ)-methyllinderatin, H2/890) 634. 2’,6’-diOH, 4’-OMe, 3’-C10 ((
)-methyllinderatin, 277) 635. 2’,6’-diOH, 4’-OMe, 5’-(1’’-aryl)prenyl (piperaduncin A, 278) 636. 2’-OH, 4’,6’-diOMe (dihydroflavokawin B, H2/794) 637. 2’-OH, 4’,6’-diOMe, 3’-Me (H2/869) 638. 2’-OH, 4’,6’-diOMe, 3’-formyl, 5’-Me (H2/870) 639. 2’-OH, 4’-OMe, 5’’-arylfurano[2’’,3’’:6’,5’] (longicaudatin, 279) 640. 2’-OH, 4’-OMe, 4’’-aryl-5’’-(2-hydroxy isopropyl)dihydrofurano[2’’,3’’:6’,5’] (piperaduncin B, 280) 641. 2’-OH, 4’-OMe, 6’-O-C10 (adunctin A, 281) 642. 2’-OH, 4’-OMe, [5’,6’]-C10 (adunctin B, 282) 643. 2’-OH, 4’-OMe, [5’,6’]-C10 (adunctin C, 283) 644. 2’-OH, 4’-OMe, [5’,6’]-C10 (adunctin D, 284) 645. 2’-OH, 4’-OMe, [5’,6’]-C10 (adunctin E, 285) 646. 2’-OH, 6’-OMe, 4’-prenyloxy (H2/881) (2’,4’,4) 647. 2’,4’,4-triOH (davidigenin, H2/789) 648. 2’,4’,4-triOH, 3’,5’-diprenyl (gancaonin J, H2/876) 649. 2’,4’,4-triOH, 3-geranyl (H2/888) 650. 2’,4-diOH, 4’-OMe (H2/790) 651. 2’,4-diOH, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (crotaramosmin, 286) 652. 2’-OH, 4-OMe, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (crotaramin, 287)

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 653. 4-OH, 2’,4’-diOMe (255) (2’,4’,a) 654. 2’,a-diOH, furano[2’’,3’’:4’,3’] (castillene E, H2/826) (2’,4’,b) 655. 2’,b-diOMe, furano[2’’,3’’:4’,3’] (ovalitenin B, H2/827) (4’,2,4) 656. 4’,2,4-triOH (256) 657. 4’,2-diOH, 4-OMe (H2/787) 658. 4’,4-diOH, 2-OMe (loureirin C, H2/786) 659. 4’-OH, 2,4-diOMe (loureirin A, H2/788) (4’,2,6) 660. 4’-OH, 2,6-diOMe (257) Tetra-O-substituted (2’,3’,4’,6’) 661. 2’,4’,6’-triOH, 3’-OMe, 5’-prenyl (H2/885) 662. 2’,3’-diOH, 4’,6’-diOMe (258) 663. 2’,6’-diOH, 3’,4’-diOMe (dihydropashanone, H2/805) 664. 2’,6’-diOMe, 3’,4’-OCH2O- (H2/820) 665. 3’,6’-diOMe, 2’-OMe, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’] (flemistrictin D, H2/884) 666. 2’-OH, 3’,4’,6’-triOMe (259) (2’,3’,4’,4) 667. 2’,4’-diOH, 3’,4-diOMe (lusianin, 260) (2’,4’,6’,4) 668. 2’,4’,6’,4-tetraOH (phloretin, H2/799) 669. 2’,4’,6’,4-tetraOH, 3,5-diprenyl (289) 670. 2’,4’,6’,4-tetraOH, 3-geranyl, 5-prenyl (290) 671. 2’,4’,6’-triOH, 4-OMe (H2/800) 672. 2’,4’,4-triOH, 6’-OMe (H2/802) 673. 2’,4’,4-triOH, 6’-OMe, 3’-prenyl (a,b-dihydroxanthohumol, 291) 674. 2’,6’,4-triOH, 4’-OMe (asebogenin, H2/801) 675. 2’,6’,4-triOH, 4’-OMe, 3’-Me (H2/873) 676. 2’,6’,4-triOH, 4’-OMe, 3’,5’-diMe (H2/874) 677. 2’,4’-diOH, 6’,4-diOMe (H2/804) 678. 2’,6’-diOH, 4’,4-diOMe (calomelanone, H2/803) 679. 2’,4-diOH, 4’,6’-diOMe (261) 680. 2’-OH, 4’,6’,4-triOMe (262) (2’,4’,3,4) 681. 2’,4’,3,4-tetraOH, 2-geranyl (H2/892) 682. 2’,3,4-triOH, 4’-OMe (dihydrocalythropsin, 263) 683. 2’,4’,4-triOH, 3-OMe (H2/797) 684. 2’,4’,4-triOH, (6’’-(4-methylpent-3-enyl),6’’-methyl)pyrano[2’’,3’’:3,2] (H2/893) 685. 2’,3,4-triOH, 6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’] (crotin, 292) 686. 2’,4’-diOH, 3,4-OCH2O- (H2/819) 687. 2’-OMe, 3,4-OCH2O-, furano[2’’,3’’:4’,3’] (293) 688. 2’,4’-diOMe, 3,4-OCH2O- (ponganone VII, 264) (2’,4’,4,a)

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 689. 690. 691. 692. 693. 694. 695.

2’,4’,4,a-tetraOH (H2/811) 2’,4’,4,a-tetraOH, 5’,3-diprenyl (kanzonol Y, 294) 2’,4’,a-triOH, 4-OMe (H2/812) 2’,4,a-triOH, 4’-geranyloxy (295) 4’,4,a-triOH, 2’-OMe (H2/813) 2’,a-diOH, 4’,4-diOMe (odoratol, H2/814) a-OH, 2’,4’,4-triOMe (H2/815) (4’,2,4,6) 696. 4’,2,4-triOH, 6-OMe (loureirin D, H2/795) 697. 4’,2-diOH, 4,6-diOMe (265) 698. 4’,4-diOH, 2,6-diOMe (266) 699. 4’-OH, 2,4,6-triOMe (loureirin B, H2/796) (2,3,4,6) 700. 2-OH, 3,4,6-triOMe (267) 701. 6-OH, 2,3,4-triOMe (268) Penta-O-substituted (2’,3’,4’,5’,6’) 702. 2’,5’-diOH, 3’,4’,6’-triOMe (dihydropedicin, 269) 703. 3’,5’-diOH, 2’,4’,6’-triOMe (270) 704. 2’-OH, 3’,4’,5’,6’-tetraOMe (dihydrokanakugiol, H2/810) (2’,3’,4’,6’,4) 705. 2’,3’,4’,6’,4-pentaOH, 5’-geranyl (H2/896) 706. 2’,3’,4’,6’,4-pentaOH, 5’-neryl (H2/897) (2’,3’,4’,6’,b) 707. b-OH, 2’,6’-diOMe, 3’,4’-OCH2O- (H2/825) (2’,4’,6’,3,4) 708. 2’,4’,6’,3,4-pentaOH (H2/806) 709. 2’,4’,6’,3,4-pentaOH, 3’,5-diprenyl (296) 710. 2’,4’,6’,3,4-pentaOH, 3’-geranyl, 5-prenyl (297) 711. 2’,4’,6’,3-tetraOH, 3’-geranyl, 6’’,6’’-dimethylpyrano[2’’,3’’:4,5] (298) 712. 2’,4’,6’,3-tetraOH, 4-OMe, 3’,5-diprenyl (299) 713. 2’,4’,3,4-tetraOH, 6’-OMe, 3’-geranyl (H2/895) 714. 2’,6’,3-triOH, 4-OMe, 5-prenyl, 6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:4’,5’] (300) 715. 2’,4’-diOH, 6’,3,4-triOMe (H2/808) 716. 2’,4’-diOH, 6’-OMe, 3,4-OCH2O- (H2/821) 717. 2’,6’-diOH, 4’,3,4-triOMe (271) 718. 2’,4’,6’-triOMe, 3,4-OCH2O- (272) (2’,4’,6’,4,a) 719. 2’,4’,6’,4,a-pentaOH (nubigenol, H2/817) (2’,4’,6’,4,b) 720. 2’,4’,4,b-tetraOH, 6’-OMe (274) (2’,4’,3,4,a) 721. 2’,4’,3,4,a-pentaOH (273) 722. 4’,3,4,a-tetraOH, 2’-OMe (H2/816) (2’,4’,3,4,b) 723. 2’,4’,b-triOMe, 3,4-OCH2O- (dihydromilletenone methyl ether, H2/824)

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 724. 2’,b-diOMe, 3,4-OCH2O-, furano[2’’,3’’:4’,3’] (ponganone IX, 301) (3’,4’,2,4,b) 725. 2,4,b-triOMe, 3’,4’-OCH2O- (dihydroisomilletenone methyl ether, H2/823) Hexa-O-substituted (2’,3’,4’,5’,6’,4) 726. 2’,6’-diOH, 3’,4-diOMe, 4’,5’-OCH2O- (H2/822) (2’,3’,4’,6’,3,4) 727. 6’-OH, 2’,3’-diOMe, 3,4-OCH2O-, furano[2’’,3’’:4’,5’] (H2/828) (2’,4’,5’,3,4,b) 728. 2’,5’,b-triOMe, 3,4-OCH2O-, 6’’,6’’-dimethylpyrano[2’’,3’’,4’,3’] (ponganone VIII, 302) (2’,4’,3,4,5,b) 729. 2’,4’,3,5,b-pentaOH, 4-OMe (gliricidol, H2/818) Dihydrochalcone glycosides 2’,4’,6’-Trihydroxydihydrochalcone 730. 4’-O-(3’’-O-Galloyl-4’’,6’’-O,O-hexahydroxydiphenoylglucoside) (thonningianin A, 303) 731. 4’-O-(4’’,6’’-O,O-Hexahydroxydiphenoylglucoside) (thonningianin B, 304) 2’,4’,2-Trihydroxydihydrochalcone (davidigenin) 732. 2’-O-Glucoside (davidioside, H2/857) 733. 4’-O-Glucoside (confusoside, H2/858) 2’,4-Dihydroxy-4’-methoxydihydrochalcone 734. 2’-O-Glucoside (H2/859) 2’,4’-Dihydroxy-3’,6’-dimethoxydihydrochalcone 735. 4’-O-Glucosyl-(1’’’ ! 6’’)-glucoside (salicifolioside A, 305) 2’,4’,6’,4-Tetrahydroxydihydrochalcone (phloretin) 736. 2’-O-Glucoside (phloridzin, H2/860) 737. 2’-O-(6’’-O-Acetyl)glucoside (306) 738. 2’-O-Rhamnoside (glycyphyllin, H2/861) 739. 2’-O-Xylosylglucoside (H2/863) 740. 4’-O-Glucoside (trilobatin, H2/862) 741. 4’-O-(2’’-O-Acetyl)glucoside (307) 742. 3’,5’-Di-C-glucoside (308) 2’,4’,6’-Trihydroxy-4-methoxydihydrochalcone 743. 2’-O-Glucoside (309) 2’,6’,4-Trihydroxy-4’-methoxydihydrochalcone (asebogenin) 744. 2’-O-Glucoside (asebotin, H2/864) 2’,4’-Dihydroxy-4’,6’-diacetoxydihydrochalcone 745. 2’-O-Glucoside (zosterin, 310) 4-Hydroxy-2’,4’,6’-trimethoxydihydrochalcone 746. 4-O-Glucoside (bidenoside B, 311) 2’,4’,4,a-Tetrahydroxydihydrochalcone 747. a-O-Glucoside (licoagroside F, 312) 748. 3’-C-Glucoside (coatline A, H1/2598) 2’,4’,4,b-Tetrahydroxydihydrochalcone 749. 2’-O-Glucoside (rocymosin B, 313) 750. 3’-C-Glucoside (pterosupin, H1/2600) 2’,4’,6’,3,4-Pentahydroxydihydrochalcone

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 751. 2’-O-Galactoside (H2/865) 752. 2’-O-Glucoside (H2/866) 753. 4’-O-Glucoside (sieboldin, H2/867) 754. 3’-C-Glucoside (aspalathin, H1/2579) 2’,4’,3,4,a-Pentahydroxydihydrochalcone 755. 3’-C-Glucoside (coatline B, H1/2599) 756. 3’-C-Xyloside (314) Dihydrochalcone dimers Dihydrochalcone–dihydrochalcone 757. Brackenin (H1/3095) 758. Cycloaltilisin 6 (319) 759. Iryantherin F (H2/846) 760. Littorachalcone (315) 761. Piperaduncin C (318) 762. 3’,3’-bis(2’,4’,6’-Trihydroxy-4-methoxydihydrochalcone) (317) 763. Verbenachalcone (316) Dihydrochalcone–deoxotetrahydrochalcone 764. Cinnabarone (321) 765. Cochinchinenin (320) Dihydrochalcone–flavonol 766. Trianguletin (322) 767. Trianguletin ‘B’ (323) 768. Trianguletin ‘C’ (324) 769. Trianguletin ‘D’ (325) 770. Trianguletin ‘E’ (326) Dihydrochalcone conjugates C-Benzyl derivatives 771. 2’,4’-diOH, 6’-OMe, 3’-(2-OHBn) (uvaretin, H2/830) 772. 2’,4’-diOH, 6’-OMe, 3’-(2  2-OHBn) (angoluvarin, H2/832) 773. 2’,4’-diOH, 6’-OMe, 3’-(2-OHBn), 5’-Me (anguvetin, H2/831) 774. 2’,4’-diOH, 6’-OMe, 3’,5’-di(2-OHBn) (diuvaretin, H2/833) 775. 2’,4’-DiOH, 6’-OMe, 3’-(2-OHBn), 5’-(2  2-OHBn) (triuvaretin, 328) 776. 2’,4’-DiOH, 6’-OMe, 3’-(2-OHBn), 5’-(3  2-OHBn) (330) 777. 2’,4’-DiOH, 6’-OMe, 3’-(2-OHBn), 5’-(4  2-OHBn) (332) 778. 2’,4’-DiOH, 6’-OMe, 3’-(2  2-OHBn), 5’-(2-OHBn) (isotriuvaretin, 329) 779. 2’,4’-DiOH, 6’-OMe, 3’-(3  2-OHBn), 5’-(2-OHBn) (331) 780. 2’,4’-DiOH, 6’-OMe, 3’-(4  2-OHBn), 5’-(2-OHBn) (333) 781. 2’,6’-diOH, 4’-OMe, 3’-(2-OHBn) (327) 782. 4’,6’-diOH, 2’-OMe, 3’-(2-OHBn) (isouvaretin, H2/829) 783. Chamuvaretin (H2/834) Dihydrochalcone–lignans 784. Iryantherin A (H2/841) 785. Iryantherin B (H2/842) 786. Iryantherin C (H2/843) 787. Iryantherin D (H2/844) 788. Iryantherin E (H2/845) 789. Iryantherin G (334)

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 790. Iryantherin H (335) 791. Iryantherin I (336) 792. Iryantherin J (337) 793. Iryantherin K (338) 794. Iryantherin L (339) Miscellaneous 795. Calomelanol A (H2/836) 796. Calomelanol B (H2/837) 797. Calomelanol C (H2/838) 798. Calomelanol D-1 (H2/835) Quinodihydrochalcones 799. Ceratiolin (H2/850) 800. Grandiflorone (H2/849) 801. Grenoblone (H2/854) 802. Helichrysum aphelexiodes quinodihydrochalcone (288) 803. Helichrysum forskahlii quinodihydrochalcone (H2/852) 804. Helihumulone (H2/853) 805. Helilupolone (H2/856) 806. 4-Hydroxygrenoblone (H2/855) 807. Myrica gale quinodihydrochalcone (H2/848) 808. Syzygiol (H2/851) AURONES Aurone aglycones Mono-O-substituted (6) 809. Furano[2’’,3’’:6,7] (H2/910) Di-O-substituted (4,6) 810. 4-OH, Furano[2’’,3’’:6,7] (H2/911) 811. 4-OMe, Furano[2’’,3’’:6,7] (H2/912) (6,4’) 812. 6,4’-diOH (hispidol, H2/898) Tri-O-substituted (4,5,6) 813. 6-OH, 4,5-OCH2O- (H2/909) (4,6,4’) 814. 4,6,4’-triOH (H2/899) (6,3’,4’) 815. 6,3’,4’-triOH (sulfuretin, H2/900) 816. 6,3’,4’-triOH, 5-prenyl (broussoaurone A, 340) 817. 6,3’,4’-triOH, 7-prenyl (licoagroaurone, 341) 818. 3’,4’-OCH2O-, furano[2’’,3’’:6,7] (H2/913) Tetra-O-substituted (4,5,6,4’) 819. 5-OH, 4,6,4’-triOMe (342) (4,6,7,4’)

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 820. 4,6,7,4’-tetraOH (343) (4,6,3’,4’) 821. 4,6,3’,4’-tetraOH (aureusidin, H2/901) 822. 4,6,3’,4’-tetraOH, 5-Me (344) 823. 4,6,3’,4’-tetraOH, 7-Me (345) 824. 4,6,3’,4’-tetraOH, 5,2’-diprenyl (antiarone A, H2/907) 825. 4,6,3’,4’-tetraOH, 2’,5’-diprenyl (antiarone B, H2/908) 826. 6,3’,4’-triOH, 4-OMe (rengasin, H2/902) 827. 6,3’,4’-triOH, 4-OMe, 5-Me (346) 828. 6,3’,4’-triOH, 4-OMe, 7-Me (347) 829. 6,3’-diOH, 4,4’-diOMe, 5-Me (348) 830. 4,6,3’,4’-tetraOMe (349) (6,7,3’,4’) 831. 6,7,3’,4’-tetraOH (maritimetin, H2/903) 832. 6,3’,4’-triOH, 7-OMe (leptosidin, H2/904) Penta-O-substituted (4,5,6,3’,4’) 833. 3’,4’-diOH, 4,5,6-triOMe (hamiltrone, 350) (4,6,3’,4’,5’) 834. 4,6,3’,4’,5’-pentaOH (bracteatin, H2/905) Halogenated 835. 4’-Cl (353) Miscellaneous 836. Derriobtusone A (H2/914) 837. Derriobtusone B (H2/915) Auronol aglycones Di-O-substituted (2,6) 838. 2-OMe, furano[2’’,3’’:6,7] (castillene A, H2/949) Tetra-O-substituted (2,4,6,4’) 839. 2,4,6,4’-tetraOH (maesopsin, H2/943) 840. 2,6,4’-triOH, 4-OMe (carpusin, H2/944) (2,6,3’,4’) 841. 2,6,3’,4’-tetraOH (H2/945) 842. 2,6,3’-triOH, 4’-OMe (H2/946) 843. 2-OMe, 3’,4’-OCH2O-, furano[2’’,3’’:6,7] (castillene D, H2/952) Penta-O-substituted (2,4,6,3’,4’) 844. 2,4,6,3’,4’-pentaOH (alphitonin, H2/947) (2,6,7,3’,4’) 845. 2,6,7,3’,4’-pentaOH (nigrescin, H2/948) Hexa-O-substituted (2,4,6,3’,4’,5’) 846. 2,4,6,3’,4’,5’-hexaOH (amaronol A, 351) 847. 2,4,6,3’,5’-pentaOH, 4’-OMe (amaronol B, 352) Halogenated

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 848. 2-OH, 4’-Cl (354) Miscellaneous 849. Castillene B (H2/950) 850. Castillene C (H2/951) 851. Crombenin (H2/953) Aurone and auronol glycosides 2’-Hydroxyaurone 852. 2’-O-Glucosyl-(1’’’ ! 6’’)-glucoside (dalmaisione D, 355) 6,4’-Dihydroxyaurone (hispidol) 853. 6-O-Glucoside (H2/916) 6,4’-Dihydroxy-7-methylaurone 854. 6-O-Rhamnoside (H2/941) 4,6,4’-Trihydroxyaurone 855. 4-O-Rhamnosyl-(1’’’ ! 2’’)-glucoside (357) 856. 4,6-di-O-Glucoside (caulesauroneside, 356) 857. 6-O-Rhamnoside (H2/917) 4,6,4’-Trihydroxy-7-methylaurone 858. 4-O-Rhamnoside (H2/942) 6,3’,4’-Trihydroxyaurone (sulfuretin) 859. 6-O-Glucoside (sulfurein, H2/918) 860. 6-O-Glucosylglucoside (H2/919) 861. 6,3’-Di-O-glucoside (palasitrin, H2/920) 4,6,3’,4’-Tetrahydroxyaurone (aureusidin) 862. 4-O-Glucoside (cernuoside, H2/921) 863. 4,6-Di-O-glucoside (H2/925) 864. 6-O-Glucoside (aureusin, H2/922) 865. 6-O-Glucuronide (H2/924) 866. 6-O-Rhamnoside (H2/923) 6,7,3’,4’-Tetrahydroxyaurone (maritimetin) 867. 6-O-Glucoside (maritimein, H2/926) 868. 6-O-(6’’-O-Acetyl)glucoside (H2/927) 869. 6-O-(6’’-O-p-Coumaroyl)glucoside (H2/928) 870. 6-O-(3’’,6’’-Di-O-acetyl)glucoside (bidenoside A, 358) 871. 6-O-(4’’,6’’-Di-O-acetyl)glucoside (H2/929) 872. 6-O-(2’’,4’’,6’’-Tri-O-acetyl)glucoside (H2/930) 873. 6-O-(3’’,4’’,6’’-Tri-O-acetyl)glucoside (359) 874. 6-O-Glucosylglucoside (H2/932) 875. 7-O-Glucoside (H2/931) 6,3’,4’-Trihydroxy-7-methoxyaurone (leptosidin) 876. 6-O-Glucoside (leptosin, H2/933) 877. 6-O-Glucosyl-(1’’’ ! 4’’)-rhamnoside (H2/935) 878. 6-O-Xylosyl-(1’’’ ! 4’’)-arabinoside (H2/934) 4,6,3’,4’,5’-Pentahydroxyaurone (bracteatin) 879. 4-O-Glucoside (bractein, H2/936) 880. 6-O-Glucoside (H2/937) 4,6-Dihydroxy-3’,4’,5’-trimethoxy-7-methylaurone

1099

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APPENDIX B Checklist of Known Chalcones, Dihydrochalcones, and Aurones — continued 881. 4-O-Rhamnoside (360) 6,3’,4’,5’-Tetrahydroxy-4-methoxyaurone (bracteatin 4-methyl ether) 882. 6-O-Rhamnosyl-(1’’’ ! 4’’)-glucoside (subulin, H2/938) 2,4,6,4’-Tetrahydroxy-2-benzylcoumaranone (maesopsin) 883. 4-O-Glucoside (hovetrichoside C, 361) 884. 6-O-Glucoside (362) 885. 4-O-Glucoside 4’-O-rhamnoside (hovetrichoside D, 363) Miscellaneous 886. Neoraufuracin (H2/939) 887. Ambofuracin (H2/940) Aurone and auronol dimers Aurone–aurone 888. Aulacomniumbiaureusidin (364) 889. Disulfuretin (365) 890. Licoagrone (366) Aurone–flavanone 891. Campylopusaurone (367) Auronol–auronol 892. (2S)-2-Deoxymaesopsin-(2 ! 7)-(2R)-maesopsin (368) 893. (2R)-2-Deoxymaesopsin-(2 ! 7)-(2S)-maesopsin (369) 894. (2R)-2-Deoxymaesopsin-(2 ! 7)-(2R)-maesopsin (370) 895. (2S)-2-Deoxymaesopsin-(2 ! 7)-(2S)-maesopsin (371) Auronol–flavanone 896. (2R,3S)-Naringenin-(3a ! 5)-(2R)-maesopsin (372) 897. (2R,3S)-Naringenin-(3a ! 5)-(2S)-maesopsin (373) 898. (2R,3S)-Naringenin-(3a ! 7)-(2R)-maesopsin (zeyherin epimer, 374) 899. (2R,3S)-Naringenin-(3a ! 7)-(2S)-maesopsin (zeyherin epimer, 375) Auronol–isoflavanone 900. (2S,3R)-Dihydrogenistein-(2a ! 7)-(2R)-maesopsin (376) 901. (2S,3R)-Dihydrogenistein-(2a ! 7)-(2S)-maesopsin (377)

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Bi-, Tri-, Tetra-, Penta-, and Hexaflavonoids Daneel Ferreira, Desmond Slade, and Jannie P.J. Marais

CONTENTS 17.1 17.2 17.3

Introduction ........................................................................................................... 1102 Nomenclature......................................................................................................... 1102 Structure and Distribution ..................................................................................... 1103 17.3.1 Biflavonoids............................................................................................... 1103 17.3.1.1 Agathisflavones [(I-6,II-8)-Coupling]....................................... 1103 17.3.1.2 Amentoflavones [(I-3’,II-8)-Coupling] ..................................... 1104 17.3.1.3 Bi-4-aryldihydrocoumarins (Bineoflavones) ............................ 1105 17.3.1.4 Biauronols and Biaurones........................................................ 1105 17.3.1.5 Bichalcones .............................................................................. 1106 17.3.1.6 (I-6,O,II-8)-Biflavones ............................................................. 1107 17.3.1.7 (I-2’,II-8)-Biflavones ................................................................ 1108 17.3.1.8 (I-2’,II-6)-Biflavones and Aurone–Flavones ............................ 1108 17.3.1.9 (I-3,II-6)-Biflavones ................................................................. 1109 17.3.1.10 (I-4’,O,II-8)-Biflavones............................................................. 1109 17.3.1.11 (I-3,O,II-4’)-Biflavones............................................................. 1109 17.3.1.12 (I-3’,II-3)-Biflavones ................................................................ 1110 17.3.1.13 (I-2’,II-2’)-Biflavonols .............................................................. 1110 17.3.1.14 (I-3’,II-3’)-Biflavones................................................................ 1110 17.3.1.15 Bi-Isoflavonoids....................................................................... 1110 17.3.1.16 Chamaejasmins [(I-3,II-3)-Coupling] ....................................... 1111 17.3.1.17 Cupressuflavones [(I-8,II-8)-Coupling] .................................... 1112 17.3.1.18 Flavanone–Auronols ............................................................... 1112 17.3.1.19 Flavanone– and Flavone–Chalcones ....................................... 1112 17.3.1.20 Flavanone–Isoflavans .............................................................. 1113 17.3.1.21 GB-flavones [(I-3,II-8)-Coupling] ............................................ 1114 17.3.1.22 Hinokiflavones [(I-4’,O,II-6)-Coupling] ................................... 1114 17.3.1.23 Isoflavanone–Auronols [(I-2,II-7)-Coupling] ........................... 1115 17.3.1.24 Ochnaflavones [(I-3’,O,II-4’)-Coupling] ................................... 1115 17.3.1.25 Robustaflavones [(I-3’,II-6)-Coupling]..................................... 1116 17.3.1.26 Succedaneaflavones [(I-6,II-6)-Coupling]................................. 1117 17.3.1.27 ‘‘Unusual’’ Biflavonoids .......................................................... 1117 17.3.1.28 Miscellaneous Biflavonoids...................................................... 1119 17.3.2 Triflavonoids ............................................................................................. 1120 17.3.3 Tetraflavonoids ......................................................................................... 1122 17.3.4 Pentaflavonoids ......................................................................................... 1124 17.3.5 Hexaflavonoids.......................................................................................... 1124 References ........................................................................................................................ 1124 1101

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17.1 INTRODUCTION Several comprehensive reviews dealing with bi- and triflavonoids have been published.1–7 This chapter focuses on compounds that have been reported since the last review by Geiger was published in 1994.7 Since that time tetra-, penta-, and hexaflavonoids have also been identified, hence necessitating a change in the title of this chapter compared to the previous review.7 Together with the proanthocyanidins, the bi- and triflavonoids constitute the two major classes of complex C6–C3–C6 secondary metabolites. These compounds represent products of phenol oxidative coupling of flavones, flavonols, dihydroflavonols, flavanones, isoflavones, aurones, auronols, and chalcones, and thus predominantly possess a carbonyl group at C-4 or its equivalent in every constituent unit. However, there are now several examples where the presence of a C-4 carbonyl group is not evident, e.g., the flavanone–isoflavan, licoagrodin (91),88 where the carbonyl group was subject to secondary modifications, e.g., the calycopterones (127–129),102,104 or where the carbon framework is obscured by, e.g., a dienone–phenol rearrangement as in licobichalcone (35).68 It should also be emphasized that the terms bi- and triflavonoids are used loosely. A multitude of compounds that ‘‘do not arise’’ via phenol oxidative coupling of the aforementioned classes of monomeric flavonoids possessing C-4 carbonyl functional groups are also being reported as ‘‘bi- or triflavonoids.’’ This is exemplified by bichalcone (139), a ‘‘biflavonoid’’ generated via an intermolecular Diels–Alder process.105 Several additional examples can be found in Chapter 11 or by simply entering ‘‘biflavonoid’’ in one of the several powerful electronic search engines that cover the primary literature. Essentially all the biflavonoid classes covered in the Geiger review7 were supplemented since 1992. In addition, several new classes have been reported, e.g., the bi-4-aryldihydrocoumarins (neoflavones) (16 and 17),29 the biauronols (19–22),38 the isoflavanone–auronols (100 and 101),35,36 a number of O-linked bichalcones (see Section 17.3.1.5), and the first (I-6,O,II8)- (42),89 (I-2’,II-8)- (43),87 and (I-3,II-6)- (49–52)45,84 biflavones. Such a rapid growth not only in the number of new compounds but also in the extended diversity in the location of the interflavonoid bond is discernable in terms of their genesis via phenol oxidative coupling reactions.8 Notable in these radical couplings is the exclusive formation of carbon–carbon and carbon–oxygen bonds but the conspicuous absence of the generation of oxygen–oxygen bonds.

17.2 NOMENCLATURE There is no commonly accepted trivial nomenclature for the bi- and triflavonoids and higher oligomeric forms. Their full systematic names, not to mention their often complex common names, are extremely cumbersome. Geiger and Quinn have proposed a system3–5,7 that requires frequent reference for understanding and has become increasingly difficult to implement as the number of new compounds has grown. No doubt, the nomenclature of this class of compounds is in disarray and it depends on active researchers in the field to select a simple but logical system and then to use it consistently. Locksley2 has proposed a system in which the position of substitution of the upper (I) and lower (II) units in biflavonoids is defined from the usual numbering of the parent flavonoid, and each unit is also described from the parent monomer, e.g., apigenin, luteolin, naringenin, genistein, etc. Thus, the well-known biflavones, amentoflavone is named apigeninyl-(I-3’, II-8)-apigenin, the tri-O-methyl derivative (11) 7,4’-di-O-methylnaringeninyl-(I-3’,II-8)-4’O-methylnaringenin, and the flavanone–auronol (74) (2S)-naringeninyl-(I-3a,II-5)-(2R)-mae-

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sopsin. The consistent implementation of this method for naming the many straightforward examples should be strongly encouraged.

17.3 STRUCTURE AND DISTRIBUTION The naturally occurring bi- and triflavonoids, together with their plant sources are listed in the following sections. The entries listed are confined to new compounds reported in the post1992 period or those that have not been dealt with in Geiger’s 1994 review.7 In order to be comprehensive, the listed compounds must be considered in conjunction with the tables in the Geiger and Quinn3–5,7 and Hemingway6 reviews. Since many of the analogs have been reported under trivial names these will be retained to facilitate future electronic literature searches. The first compounds belonging to the tetra-, penta-, and hexaflavonoid classes have also been reported. These complex structures are covered in Sections 17.3.3–17.3.5. As with all published complex structures the reader must avail himself or herself of the correctness of the proposed structure based upon the supporting experimental data. With a few exceptions the issue of absolute configuration of optically active analogs is often completely ignored. In a large number of cases absolute configuration is readily accessible from chiroptical data. The utility of the circular dichroism method in this regard has been amply demonstrated in several reports. Useful information may be extracted from papers dealing with the chiroptical properties of monomeric constituent units like flavanones and 3-hydroxyflavanones (dihydroflavonols),110 auronols,114 a summary of the various classes of stereogenic monomers (Ref. 113 and references cited therein), dimeric compounds like the flavanone– and isoflavanone–auronol- and bis-auronol-type biflavonoids,35–38 and several other classes of biflavonoids.23,74,111,112 In addition to the multitude of biological activities reported in the references listed with the compound or natural source, supplementary information can also be found in Refs. 90 and 97. Representative contributions regarding synthesis of the biflavonoids are available in Refs. 91–93, 96, and 99, while useful NMR and x-ray data may be retrieved from Refs. 94 and 98, respectively. A comprehensive listing of chalcone dimers and oligomers, dihydrochalcone dimers, and aurone and auronal dimers may also be found in Chapter 16.

17.3.1 BIFLAVONOIDS 17.3.1.1

Agathisflavones [(I-6,II-8)-Coupling] OH

OMe MeO OMe

R1O OMe

O

O I

I 8

6

OH

8

6 OH

OMe O MeO

HO

O

O

O II

II OMe O

O OH OMe (1) Ouratea multiflora, relative configuration, Ref. 25

OH (2) R1 = Me ---- Ouratea spectabilis, Ref. 28 (3) R1 = H ---- Ouratea hexasperma, Ref. 33

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17.3.1.2

Amentoflavones [(I-3’,II-8)-Coupling] O O

OR3

OMe OMe O MeO

3'

O

II 8

OR2 O

O

I

R1O MeO

OH

3'

O

OH

II 8

O

I

O

O

(4) Anacarduflavanone — Semecarpus anacardium Linn., rel. config., Ref. 18 R1 R1 R1 R1 R1

(5) (6) (7) (8) (9)

= = = = =

OH

OH

O

R2 = R3 = H — Pyranoamentoflavone — Calophyllum inophylloide, Ref. 19 Me, R2 = R3 = H R3 = H, R2 = Me — Calophyllum venulosum, Refs. 20,21 R3 = Me, R2 = H 2 3 R = Me, R = H OR1 OH

OMe O OH

MeO

O MeO

3'

O

II O

O

HO

I

OH

II 8

I

8

MeO

3'

O

OH

OH

O

(12) (I-2S,II-2S)-I-7,II-7-Di-O-methyltetrahydroamentoflavone — Rhus retinorrhoea, abs. config., Ref. 23

OH

O

(10) R1 = H — Taxus baccata, Ref. 22 (11) R1 = Me Amentoflavone is the free phenolic form of compound (11)

OH

OH

OH

OH O

HO

O

3'

O II MeO

8

O

O

HO

(13)

O

O

OH

MeO

R1

OH

OH

O

(15) Amentotaxus yunnanensis, rel. config., Ref. 44

R1 =

— Calophyllum venulosum, Ref. 21 (14) R1 =

II 8

I

I

OH

3'

HO

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17.3.1.3

Bi-4-aryldihydrocoumarins (Bineoflavones) OH

HO

O

O

I

3

H

H

3 O

II O

OH

OH (16) — Pistacia chinensis Bunge, rel. config., Ref. 29

(17)

17.3.1.4

Biauronols and Biaurones OH

OH OH

OH OH HO

O I

HO

HO

O

OH

5

5'

II O O

2

O I

II

2 OH

OH

OH

O

O

7

O HO

OH

OH

(18) Aulacomniumbiaureusidin — Aulacomnium palustre and A. androgynum, Ref. 24

(19)

(I-2),

(II-2)

(20)

(I-2),

(II-2)

(21)

(I-2),

(II-2)

(22)

(I-2),

(II-2)

— Berchemia zeyheri, abs. config., Ref. 38

OH OH HO

O I

2'

O

OH OH

2

O O

II

OH

HO

O I

O

OH O O II

HO

O

OH

HO (23) Licoagrone — Glycyrrhiza glabra, Ref. 56

(24) Disulfuretin — Cotinus coggygria, Ref. 57

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17.3.1.5

Bichalcones

HO

OH

OH

HO

O

OH

4 O β I

α

I

HO

O

O

α

α

3

OH

II O

OH

II

OH

O HO

HO

(25) Cordigone — Cordia goetzei, no config. indicated, Ref. 31

OH (26) Cordigol — Cordia goetzei, no config. indicated, Ref. 31 OH

HO

OH

OH

4 O β I

OH 3

O

O

α

II

OH

OH

O

HO

2⬘ O β

HO

I

(27) Lophirone K — Ochna calodendron, rel. config., Ref. 32

α

3⬘ OH

II

OH

O

HO (28) Calodenin A — Ochna calodendron, Ref. 32 O R1 O

O 5⬘ 4

I

II

2

OH

R O OH

OH

O

(29) R1 = R2 = Me — Rhuschalcone I Ref. 58 (30) R1 = R2 = H — Rhuschalcone II — Rhus pyroides Burch. 1 2 Ref. 67 (31) R = Me, R = H — Rhuschalcone III

OH OH

O

O I

I MeO

HO OH

5⬘ O 4⬘

HO

OH

5⬘ 3

OH

OH II

II β

α O

OH

O

(32) Rhuschalcone IV — Rhus pyroides Burch., Ref. 67

(33) Rhuschalcone V (34) α,β-Double bond, rhuschalcone VI

OH — Rhus pyroides Burch., Ref. 67

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1107

Bi-, Tri-, Tetra-, Penta-, and Hexaflavonoids OH HO O

HO OH O

HO

2⬘ O

OMe O

β

I α

HO

OMe OMe

OH

II

OH

OH

O HO

OH

(36) Flavumone A — Ouratea flava, Ref. 64

OH (35) Licobichalcone — Glycyrrhiza uralensis, rel. config., Ref. 68

HO HO

4 O I

β β

OH

O

4 O I

, Mbamichalcone — Lophira alata, rel. config., Ref. 61

(40)

, Isombamichalcone — Lophira lanceolata, rel. config., Ref. 62

β

OH

3 α OH

O

II

OH

MeO

HO (41) Azobechalcone — Lophira alata, rel. config., Ref. 50

17.3.1.6

(I-6,O,II-8)-Biflavones OH O

HO

I HO

O O

8

6 OH HO

O

II

O

OH

(39)

— Ochna afzelii, Ref. 66

HO

β

OH

HO

(37) Isolophirone C (38) Dihydrolophirone C, α,β-dihydro analog of isolophirone C

α

O

OH

O

H H

α

I

HO II

OH II

O

H

3 α OH

HO

OH (42) Viburnum cotinifolium, Ref. 89

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17.3.1.7

(I-2’,II-8)-Biflavones OH HO

O

OH

I

2⬘

HO O

8

OH

OMe

O OH II

OH O (43) Philonotisflavone-II-4⬘-methyl ether — Mnium hornum, Ref. 87

17.3.1.8

(I-2’,II-6)-Biflavones and Aurone–Flavones HO OH OH

HO

O

O HO HO OH

OH

2'

I

I

6

O

OH

OH

2' 6

HO

OH

O O

O II

II O

O

OH

OH OH

OH (44) Tetrahydrodicranolomin — Pilotrichella flexilis, abs. config., Ref. 71

(45) Pilotrichellaaurone — Pilotrichella flexilis, abs. config., Ref. 71 O

OH HO

O

O I

OH

HO O

2'

OH

6

OH

O I

OH

O O

2'

OH

6

OH

O O

II O

II O OH O OH

(46) 3⵮-Desoxydicranolomin — Plagiomnium undulatum, Ref. 85 (47) I-2,3-Dihydro derivative

OH

(48) Leucaediflavone — Leucaena diversifolia, Ref. 107

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1109

Bi-, Tri-, Tetra-, Penta-, and Hexaflavonoids

17.3.1.9

(I-3,II-6)-Biflavones OMe R2O

O I OR1

OH

3

O

6

O

II OMe

HO

O

OH (49) R1 = H, R2 = Me — Aristolochia ridicula, Ref. 45 (50) R1 = Me, R2 = H OR1 MeO

O I

OH

OH

3

O

6

O

II

MeO

O

OMe (51) R1 = H, Stephaflavone A — Stephania tetrandra, Ref. 84 (52) R1 = Me, Stephaflavone B

17.3.1.10

(I-4’,O,II-8)-Biflavones OR1

O II 4' O 8 MeO

O

O HO

I

OH

OH O (53) R1 = H — Ouratea semiserrata, Ref. 26 (54) R1 = Me

17.3.1.11

(I-3,O,II-4’)-Biflavones OH HO

O I

3 O 4'

OH

O

O II OH O HO (55) Delicaflavone — Selaginella delicatula, Ref. 10

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17.3.1.12

(I-3’,II-3)-Biflavones OH O HO

OH

3' H

O I

3

II O

OH

OH

H

O

HO (56) Lanceolatin A — Lophira lanceolatum, rel. config., Ref. 83

17.3.1.13

(I-2’,II-2’)-Biflavonols OH O HO

OH

O 2⬘

II

I

2⬘

O OH

OH

O HO

(57) Garcinia nervosa, Ref. 108

17.3.1.14

(I-3’,II-3’)-Biflavones O

OH

OH HO HO

II

3'

O

3'

I OH HO OH

O

O

OH HO

II

3'

O

O

OH

OH

O

3'

I

(58) Hypnogenol B1 — Hypnum cupressiforme, rel. config., Ref. 34

OH

HO OH

O

(59) 2,3-Dihydroapigeninyl-(I-3',II-3')-apigenin — Homalothecium lutescens, rel. config., Ref. 40

17.3.1.15

Bi-Isoflavonoids

HO

H

O

HO

H

O

O

O I

I 3 OH

3

O

OH 5'

OH

OH

HO

O 8

O OH II

O II OH O

OH

O OH

(61) Lupinus albus L., rel. config., Ref. 12 HO

OH

(60) Lupinus albus L., rel. config., Ref. 12

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1111

Bi-, Tri-, Tetra-, Penta-, and Hexaflavonoids

HO O OR

O

1

H MeO MeO

OH

H

R3O

O

I

H 2 2 H

II

O II

O

H2 2 H

I O

OMe

OMe H O

OR1

OMe (65) Dehydroxyhexaspermone C — Ochna macrocalyx, rel. config., Ref. 13

H O

OMe (62) R1 = R2 = H, R3 = Me, Hexaspermone A (63) R1 = R3 = H, R2 = Me, Hexaspermone B (64) R1 = R2 = R3= H, Hexaspermone C HO

— Ouratea hexasperma, rel. config., Ref. 30

O O

OH

H

O

OR2 H OR1

HO

(66) R1 = R2 = Me, Afzelone D — Ochna afzelii, rel. config., Ref. 16 (67) R1 = H, R2 = Me, Calodenone — Ochna calodendron, rel. config., Ref. 42 (68) R1 = R2 = H, Lophirone A — Lophira lanceolata, rel. config., Ref. 65

17.3.1.16

Chamaejasmins [(I-3,II-3)-Coupling] OMe

OH H MeO

HO

O O

I

I

OH

H 3

3 H

OH

O

H OH

II

O

3

O

O

O 3

II O

OH MeO

(69) Stellera chamaejasme L., rel. config., Ref. 27

(70) Ruixianglangdusu A — Stellera chamaejasme, rel. config., Ref. 81 OMe

OMe H

H

HO

O I

3 H

OH

O

O

OH

I

H 3

O

3 H

II O

OH

O

O

OH

H 3

II O

OH

OMe

H

H MeO

OMe

H

HO

MeO

OH

H

HO

(72) Sikokianin — Wikstroemia sikokiana, rel. config., Ref. 82 (71) Ruixianglangdusu B — Stellera chamaejasme, Also named Sikokianin C — Wikstroemia indica, Ref. 109 rel. config., Ref. 81

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17.3.1.17

Cupressuflavones [(I-8,II-8)-Coupling] OH

O

I OH HO

O

8

OH OH HO

8

O II

OH

O

(73) Mogathin (I-3⬘-hydroxycupressuflavone) — Glossostemon bruguieri (Desf.), Ref. 9

17.3.1.18

Flavanone–Auronols OH

HO

OH

O I

HO OH

3

O

HO

I

O

3

OH 2

II O OH

5

O

OH HO

7

O

II O

HO

OH

OH O (74) Diastereoisomer shown (75) (II-2)-S-epimer

17.3.1.19

2

(76) Diastereoisomer shown (77) (II-2)-S-epimer

OH

—Berchemia zeyheri, abs. config., Ref. 37

— Berchemia zeyheri, abs. config., Refs. 35, 36

Flavanone and Flavone–Chalcones HO O 4' O

R 1O

α

O 3' I

β

II

1

OR

7 O OMe

I 6 II

O O

OH

HO (80) —Afzelone A — C-β-epimers, Ochna afzelii, — rel. config., Ref. (81) Afzelone B (78) R1 = H, Lophirone I — “Cleaved” chalcones — Lophira 1 (79) R = Me, Lophirone J — lanceolata, rel. config., Ref. 48 O

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1113

Bi-, Tri-, Tetra-, Penta-, and Hexaflavonoids

OH R2O

HO

O O I

R1

O OH

I

3 3

OR1

OH

O

OH

6

O

OH

α β

5 O

II

O HO

II OH

R2

(83) = =H, 6'''-Hydroxylophirone B — Ochna integerrima, — abs. config., Ref. 52 (84) R1 = H, R2 = β-D-Glc

OH (82) Flavumone B — Ouratea flava, rel. config., Ref. 64

OH MeO

OH HO

OH

O I

β

HO OH

3

O

O 7

O OMe I

α 6

3' O OH

HO

II

O HO

OMe

O

II

OH

(85) Flavanone-α-hydroxychalcone — Berchemia zeyheri, abs. config., Ref. 37

OMe (86) Cissampeloflavone — Cissampelos pareira, Ref. 53

OH O

OH

6 O I MeO OMe

α

I O

7

β

OH

II

HO 6 O

R2

O

II

(87) R1 = Me, R2 = R4 = H, R3 = OMe (88) R1 = R3 = H, R2 = OMe, R4 = Me (89) R1 = R4 = Me, R2 = H, R3 = OH Note the odd I-A hydroxylation pattern.

17.3.1.20

O

HO

R1O R3

OMe

HO (90) Aristolochia ridicula, Ref. 45 Note the odd I-A hydroxylation pattern. — Aristolochia ridicula, Ref. 45

OR4

Flavanone–Isoflavans OH OH

HO

OMe

7 α

O HO

O

β

O

O

I II O

O H O

HH

OH (91) Licoagrodin — Glycyrrhiza glabra, rel. config., Ref. 88

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Flavonoids: Chemistry, Biochemistry, and Applications

17.3.1.21

GB-flavones [(I-3,II-8)-Coupling] OH

HO

OH

OH HO

O I

O I

3

OH 3 O

O 8 OH

8 II

O HO

OH

II

O HO

O

O

OH (93) GB-2a-II-4'-OMe — Rheedia gardneriana, rel. config., Ref. 70

OH (92) Garcinianin atropisomers — Garcinia kola, rel. config., Ref. 69

OH HO

OH

OH HO

O I

I

3 O

O OH

8

II

O HO

OH

OH HO HO

O HO

II

O OH (95) Pancibiflavonol — Callophyllum panciflorum, rel. config., Ref. 73

O OH (94) (+)-GB-lb — Garcinia kola, abs. config., Ref. 72

OH

O I

OH

OH 3 8

O

O II

OH

HO O OH (96) GB-4, (I-2R,3S; II-2R,3R) — Gnidia involucrata, abs. config., Ref. 74 (97) GB-4a, (I-2S,3R; II-2R,3R)

17.3.1.22

OH

O

3 8

OMe

Hinokiflavones [(I-4’,O,II-6)-Coupling] OMe 4' O 6 MeO

O HO

O II

I O OH

O

OH (98) I-7,II-7-Di-O-methyltetrahydrohinokiflavone — Cycas beddomei, abs. config., Ref. 80

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1115

Bi-, Tri-, Tetra-, Penta-, and Hexaflavonoids

OMe 4⬘ O 6 HO

O

HO

O II

I O OH

O

OH (99) 2,3-Dihydroisocryptomerin — Selaginella delicatula, rel. config., Ref. 10

17.3.1.23

Isoflavanone–Auronols [(I-2,II-7)-Coupling] OH

HO

O

2 O II

HO

OH

O 2 7 I OH OH

O

(100) Diastereoisomer shown (101) (II-2)-S-epimer

17.3.1.24

OH — Berchemia zeyheri, abs. config., Refs. 35, 36

Ochnaflavones [(I-3’,O,II-4’)-Coupling] OH HO

3⬘

O

O 4⬘

I

OR1

O OH

II

O

O OH (102) R1 = H — Luxemburgia nobilis (EICHL), rel. config., Refs. 14, 77 (103) R1 = Me — Ochna integerrima, rel. config., Ref. 77 OR3 R2O

3⬘

O

O 4⬘

I

OR4

O 1

OR

II

O

O R1

R2

R3

R4

OR1

(104) = = = =H — Ochna obtusata, rel. config., Ref. 75 (105) R1 = R3 = R4= H, R2 = Me 1 2 3 4 (106) R = H, R = R = R = Me — Ochna beddomei, rel. config., Ref. 78

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Flavonoids: Chemistry, Biochemistry, and Applications

OH MeO

3'

O

O 4'

I

OR1

O OH

II

O

O OH (107) R1 = H — Ochna beddomei, abs. config., Ref. 76 (108) R1 = Me — Quntinia acutifolia, rel. config., Ref. 79

17.3.1.25

Robustaflavones [(I-3’,II-6)-Coupling] OMe OH R1O

O

OMe OMe MeO

O 3'

3' HO

6 O

O HO

O II

O

(109) Selaginella delicatula, rel. config., Ref. 10

3'

OH OMe OMe

OMe 1 OR O

OH — Selaginella delicatula, Ref. 11

(110) R1 = H (111) R1 = Me

O

MeO

O II

OH

I

OH

6

I

HO

O 3'

6

6

I

I

O

HO HO

O II

OH

II OH

O O

O O

OH OH (112) R1 = H (113) R1 = Me

(114) Dysoxylum lenticellare, Ref. 15

— Selaginella delicatula, rel. config., Ref. 11 OH OH OH HO

O 3'

6

I HO

O II

OH

O

OH O OH

(115) Plagiomnium undulatum, rel. config., Ref. 85

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1117

Bi-, Tri-, Tetra-, Penta-, and Hexaflavonoids

17.3.1.26

Succedaneaflavones [(I-6,II-6)-Coupling] OH MeO OMe 6

O II 6 OH

O

O

OH

O

OH I

OH O O

HO

OH HO

II

(116) 6,6''-Bigenkwanin — Ouratea spectabilis, Ref. 28

6

6

OH OH

O

O

OH I

O

O OH HO OH

17.3.1.27

(117) Albiproflavone — Albizia procera, Ref. 107 Note the naphthopyrano functionalities.

‘‘Unusual’’ Biflavonoids

OH OH

O 2 I

H

HO

O O

OH O

H

OH O

O

O O 2

O

II

H O

OH OH

O (119) (120) (121) (122)

OH

Bicaryone Bicaryone Bicaryone Bicaryone

HO OH

O O

OH

HO O

OH OH

O

O

OR

O

H

O

(118) VC-15B (vahlia biflavone) — Vahlia capensis, Ref. 100

A (I-2S, II-2S) B (I-2S, II-2R) C (I-2R, II-2S) D (I-2R, II-2R)

— Cryptocarya infectoria, Ref. 101

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Flavonoids: Chemistry, Biochemistry, and Applications

O 2 I

H

O O H

H

O O

O

O O

H

II

H

OH

O O 2

O

H

II

H O

O A

H

O

O (125) Chalcocaryanone C (I-2S) (126) Chalcocaryone D (I-2R)

(123) Chalcocaryanone A (I-2R) (124) Chalcocaryone B (I-2S) Cryptocarya infectoria, Ref. 101

Cryptocarya infectoria, Ref. 101

O

O OR3

R1O

OR2 OMe OMe

O O

OMe

R1

OMe OMe OMe

O O

OMe

OMe O (127) R1 = R3 = Me, R2 = H, Calycopterone (128) R1 = R2 = Me, R3 = H, Isocalycopterone (129) R1 = R2 = H, R3 = Me, 4-Demethylcalycopterone

O (130) R1 = OH, Neocalycopterone (131) R1 = OMe, Neocalycopterone-4-Me Calycopteris floribunda, Ref. 102

Calycopteris floribunda Lamk., Ref. 102

MeO

O O

MeO MeO O

R1

OMe HO

O OMe OMe

OMe O (132) R1 = OMe, Calyflorenone A (133) R1 = OH, Calyflorenone B Calycopteris floribunda, Ref. 103

O O

OMe OMe OMe

O (134) 6''-Demethoxyneocalycopterone Calycopteris floribunda, abs. config., Ref. 104

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1119

Bi-, Tri-, Tetra-, Penta-, and Hexaflavonoids

O

MeO

O

MeO

MeO

MeO

OH

MeO O

OR1

MeO O

O

O 6⬘⬘OMe OMe H

OMe

OH O (135) Calyflorenone D — Calycopteris floribunda, abs. config., Ref. 104

OR2 R1

O

R2

(136) = = H, 6''β-OMe, Calyflorenone C (137) R1 = H, R2 = Me, 6''α-OMe, 6-epi-Calyflorenone B (138) R1 = R2 = H, 6''α-OMe, 6-epi-Calyflorenone C Calycopteris floribunda, abs. config., Ref. 104

HO HO

O

O H

OH

H

O

O OH Me (139) Dorstenia zenkeri, rel. config., Ref. 105

17.3.1.28 17.3.1.28.1

Miscellaneous Biflavonoids Methylene-Bridged Analogs Me R

3

HO

MeO

OMe I

OH

3' R2

O O

I O

OH

OH HO

8

O II

8 HO

8

OH

OH O

O

(141) R1 = R3 = H, R2 = OMe, Trianguletin — Pentagramma triangularis spp.triangularis, Ref. 41

II OH OH

OR1

OMe

O

(140) Pentagrametin — Pentagramma triangularis spp. triangularis, Ref. 41

(142) R1 = Me, R2 = R3 = H — Pentagramma triangularis, Ref. 43 (143) R1 = H, R2 = OMe, R3 = OH (144) R1 = Me, R2 = OMe, R3 = OH (145) R1 = Me, R2 = H, R3 = OH

— Pentagramma triangularis, Ref.

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Flavonoids: Chemistry, Biochemistry, and Applications

17.3.1.28.2

Hypnumbiflavonoid A HO

O HO O

I OH OH

O 2' O 7

1' 8

O II OH

OH

O

(146) Hypnumbiflavonoid A — Hypnum cupressiforme, rel. config., Ref. 34 See also the structures of two phenylacetic acid-substituted aromadendrin analogs from the same source.

17.3.1.28.3

Bongosin OH HO

O O I

OH

3 3 II HO

OH

(147) Bongosin — Lophira alata, Ref. 59

17.3.2 TRIFLAVONOIDS OH O HO OH

OH

O OH II II

HO 3'

6 OH

O

2'

OH HO

O OH

8

OH

8

OH O HO

O

3'

II

2' OH III

8

O

I

HO HO

OH

OH O

HO

OH

OH

HO

OH O (149) Aulacomniumtriluteolin — Aulacomnium palustre, Ref. 24

O 2' 8

O I

OH O (148) Cyclobartramiatriluteolin — Bartramia stricta, Ref. 17

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1121

Bi-, Tri-, Tetra-, Penta-, and Hexaflavonoids

OH O

HO OH HO

O 2'

I

OH

2'

I

OH

OH

OHO

OH

8

OH 8

OHO

O II

2'

OHO

8

OH

OH

OH

O 2'

OH

II OHO

6

OH

OH O

OH

O

III

OH

O

III

OH

O OH

(150) Epibartamiatriluteolin atropisomers Bartramia pomiformis and B. stricta, Ref. 55

OH (151) Strictatriluteolin atropisomers — Bartramia pomiformis and B. stricta, Ref. 55

OH

OH HO

HO

O

OH

6

O HO

O

OH

2'

I

OH

OH

OH

2'

I

6

O HO

OH

O

O II

OH

O HO

II O HO

O

OH

OH III

2' 6

2'

8

O III

OH

O

O OH

OH OH (152) Distichumtriluteolin — Rhizogonium distichum, Ref. 86

OH

HO (153) Rhizogoniumtriluteolin — Rhizogonium OH disticum, Ref. 86

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Flavonoids: Chemistry, Biochemistry, and Applications

17.3.3 TETRAFLAVONOIDS OMe HO O

OH

OMe 3' O

6 O IV O

II

4

β α

7

HO

O 3 I O

O

OH O

MeO III

OMe

OMe

HO

O

6

MeO

OH

(154) Aristolochia ridicula, Ref. 45 Note the odd hydroxylation pattern of the IV-A-ring.

OH

HO H O

O

OH

O

OH O

H

H OH OH O HO

OH

OH

OH (155) Lophiroflavan A — Lophira alata, rel. config., Ref. 49

HO

OH H

OH O

OH

OH

H O

O

OH HO

O HO

OH OH (156)

, Lophiroflavan B

(157)

, Lophiroflavan C

OH

— Lophira alata, rel. config., Ref. 47

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Bi-, Tri-, Tetra-, Penta-, and Hexaflavonoids

OH OH HO

O

OH

OH

O β α

H OH

O

α⬘ β⬘

HO

OH O HO

OH (158) Isolophirachalcone (159) (C-α,α⬘,β-enantiomer) Lophirachalcone

OH

— Lophira alata, rel. config., Refs. 50, 51

HO O

OH

HO α

β

OH HO

OH

OH

O O OH OH

(160) Alatachalcone — Lophira alata, rel. config., Ref. 57 Note the odd chalcone hydroxylation pattern.

O HO

OH OH

OMe O

MeO

I

39 39

MeO S OH

O

O

OH II O

HO 6 6

HO HO

HO

OH

OH

OH

O

OH

H

H O H

O

OH III OH

O

HO

Me

HO OH

IV OMe

OH O

3 39

O OMe OH

(162) Taiwanhomoflavone C — Cephalotaxus wilsoniana, Ref. 60

OH (161) Lophirochalcone — Lophira lanceolata, rel. config., Ref. 62

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17.3.4 PENTAFLAVONOIDS OH

HO

OH H O

HO

H OH

OH

O

OH

H HO

HO

(163) Ochnachalcone — Ochna calodendron, rel. config., Ref. 106

O

OH

H OH

OH

HO O

H

O

HO

H

OH

H HO

17.3.5 HEXAFLAVONOIDS HO OH

OH HO

O

O

O OH

OH HO

O

OH

H

O OH

O

OH

H HO

HO

OH

OH

HO

OH

(164) Azobechalcone — Lophira alata, rel. config., Ref. 46

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

ISOFLAVANES 7,4’-Dihydroxyisoflavan 7,2’,4’-Trihydroxyisoflavan 2’,4’-Dihydroxy-7-methoxyisoflavan 7,2’-Dihydroxy-4’-methoxyisoflavan 7,4’-Dihydroxy-2’-methoxyisoflavan 7,4’-Dihydroxy-3’-methoxyisoflavan 2’,5’-Diketo-7-hydroxy-4’-methoxyisoflavan 2’-Hydroxy-7,4’-dimethoxyisoflavan 4’-Hydroxy-7,2’-dimethoxyisoflavan 7-Hydroxy-2’,4’-dimethoxyisoflavan 3,7,2’-Trihydroxy-4’-methoxyisoflavan (3R)-7,2’,3-Trihydroxy-4’-methoxyisoflavan 7,2’,4’-Trihydroxy-5’-methoxyisoflavan 7-Hydroxy-2’-methoxy-4’,5’-methylenedioxyisoflavan 2’,4’-Dihydroxy-5,7-dimethoxyisoflavan (3R)-7,2’-Dihydroxy-4’,5’-dimethoxyisoflavan (3R)-8,2’-Dihydroxy-7,4’-dimethoxyisoflavan (3S)-7,2’-Dihydroxy-3’,4’-dimethoxyisoflavan (3S)-7,2’-Dihydroxy-8,4’-dimethoxyisoflavan 7,2’-Dihydroxy-5,4’-dimethoxyisoflavan 7,3’-Dihydroxy-2’,4’-dimethoxyisoflavan 7,4’-Dihydroxy-2’,3’-dimethoxyisoflavan (3R)-7,8,2’,3’-Tetrahydroxy-4’-methoxyisoflavan (3R)-2’,5’-Diketo-3-hydroxy-7,8-dimethoxyisoflavan 2’,5’-Diketo-7-hydroxy-3’,4’-dimethoxyisoflavan (3R)-2’,5’-Diketo-7-hydroxy-8,4’-dimethoxyisoflavan (3S)-2’,5’-Diketo-7-hydroxy-8,4’-dimethoxyisoflavan (3R)-2’-Hydroxy-7,3’,4’-trimethoxyisoflavan

Name

242.28 258.28 272.30 272.30 272.30 272.30 286.29 286.33 286.33 286.33 288.30 288.30 288.30 300.31 302.33 302.33 302.33 302.33 302.33 302.33 302.33 302.33 304.30 316.31 316.31 316.31 316.31 316.35

Mass

C15H14O3 C15H14O4 C16H16O4 C16H16O4 C16H16O4 C16H16O4 C16H14O5 C17H18O4 C17H18O4 C17H18O4 C16H16O5 C16H16O5 C16H16O5 C17H16O5 C17H18O5 C17H18O5 C17H18O5 C17H18O5 C17H18O5 C17H18O5 C17H18O5 C17H18O5 C16H16O6 C17H16O6 C17H16O6 C17H16O6 C17H16O6 C18H20O5

Formula

continued

2719 2720 2723 2721 2722 F90 2758 2725 2726 2724 F28 F255 F171 2727 2732 3059 F255 2728 F63 2731 2729 2730 3062 F63 2759 2760a 2760b F261

Ref.

Appendix

Isomucronulatol 8-Methoxyvestitol 5-Methoxyvestitol Mucronulatol Sphaerosin (3R)-8,3’-Dihydroxyvestitol Astragaluquinone Pendulone Mucroquinone Mucroquinone 7-O-Methylisomucronulatol

Arizonicanol A Lespedezol G1 Astraciceran Lotisoflavan Methoxyvestitol

Claussequinone Isosativan Arvensan Sativan

Equol Demethylvestitol Neovestitol Vestitol Isovestitol

Trivial Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004

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(3R)-7-Hydroxy-2’,3’,4’-trimethoxyisoflavan (3R,4S)-4,2’3’,4’-Tetrahydroxy-6,7-methylenedioxyisoflavan 6,7,3’-Trihydroxy-2’,4’-dimethoxyisoflavan 7,8,3’-Trihydroxy-2’,4’-dimethoxyisoflavan 2’,4’-Dihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavan (3R)-2’,4’-Dihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavan (3R)-7,4’-Dihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:2’,3’]isoflavan 7,2’-Dihydroxy-5’’-(1-methylethenyl)-4’’,5’’-dihydrofurano[2’’,3’’:4’,5’]isoflavan 7,2’-Dihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflavan 3’-Hydroxy-2’,4’-dimethoxyfurano[2’’,3’’:8,7]isoflavan (3R)-2’,4’-Dihydroxy-5’’,4’’,4’’-trimethyl-4’’,5’’-dihydrofurano[2’’,3’’:7,6]isoflavan (3R)-7,2’,4’-Trihydroxy-5’-(1,1-dimethyl-2-propenyl)isoflavan (3R)-7,2’,4’-Trihydroxy-6-prenylisoflavan 7,2’,4’-Trihydroxy-6-(1,2-dimethyl-2-propenyl)isoflavan (3R)-2’,5’-Diketo-7,3’,4’-trimethoxyisoflavan (3R)-2’,5’-Diketo-7,4’,6’-trimethoxyisoflavan 8-Carboxyaldehyde-7,3’-dihydroxy-2’,4’-dimethoxyisoflavan (3R)-2’,5’-Dihydroxy-7,3’,4’-trimethoxyisoflavan (3R)-3’,5’-Dihydroxy-7,2’,4’-trimethoxyisoflavan (3R)-7,2’-Dihydroxy-8,3’,4’-trimethoxyisoflavan (3R)-7,5’-Dihydroxy-2’,3’,4’-trimethoxyisoflavan 7,3’-Dihydroxy-8,2’,4’-trimethoxyisoflavan 7,4’-Dihydroxy-2’,3’,6’-trimethoxyisoflavan 2’-Hydroxy-4’-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavan 2’-Hydroxy-4’-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavan (6aR,11aR)-9-Hydroxy-3-methoxy-10-prenylpterocarpan 7-Hydroxy-2’-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflavan 7-Hydroxy-4’-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:2’,3’]isoflavan (3R)-7,2-Dihydroxy-4’-methoxy-3’-prenylisoflavan (3R)-7,2’-Dihydroxy-4’-methoxy-6-(1,1-dimethyl-2-propenyl)isoflavan 2’-O-Methylphaseollinisoflavan Gancaonin Y Gancaonin Z (R)-Isomillinol B

Duartin Lonchocarpan Gancaonin X 4’-O-Methylglabridin

Bolusanthol A Bryaflavan 8-Demetylduartin Glabridin Eryvarin C Erythbidin A Crotmarine Phaseollinisoflavan Smiranicin Cyclomillinol Manuifolin K Manuifolin H Neomillinol Colutequinone Colutequinone B Sphaerosin s3 Colutehydroquinone Coluteol Isoduartin

Trivial Name 316.35 318.28 318.33 318.33 324.37 324.37 324.37 324.37 324.37 326.34 326.39 326.39 326.39 326.39 330.34 330.34 330.34 332.36 332.36 332.36 332.36 332.36 332.36 338.40 338.40 338.40 338.40 338.40 340.42 340.42

Mass C18H20O5 C16H14O7 C17H18O6 C17H18O6 C20H20O4 C20H20O4 C20H20O4 C20H20O4 C20H20O4 C19H18O5 C20H22O4 C20H22O4 C20H22O4 C20H22O4 C18H18O6 C18H18O6 C18H18O6 C18H20O6 C18H20O6 C18H20O6 C18H20O6 C18H20O6 C18H20O6 C21H22O4 C21H22O4 C21H22O4 C21H22O4 C21H22O4 C21H24O4 C21H24O4

Formula

F257 F30 2733 2734 2740 F282 F273 3061 2739 F220 3064 F347 F347 F204 F82 F83 2729 F82 F83 3060 F257 2736 2735 F77 2742 F168 2741 F77 F77 F212

Ref.

1130

29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58

Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92

(3R)-7,4’-Dihydroxy-2’-methoxy-6-(1,1-dimethyl-2-propenyl)isoflavan (3S)-7,2’-Dihydroxy-4’-methoxy-8-prenylisoflavan 7,4’-Dihydroxy-2’-methoxy-3’-prenylisoflavan 7,2’,4’-Trihydroxy-6-(1-hydroxymethyl-1-methyl-2-propenyl)isoflavan 2’,5’-Diketo-7-hydroxy-8,3’,4’-trimethoxyisoflavan 3’,6’-Diketo-7-hydroxy-8,2’,4’-trimethoxyisoflavan 6,8,2’-Trihydroxy-7,3’,4’-trimethoxyisoflavan 2’-Hydroxy-4’,5’-methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavan 2’,3’-Dihydroxy-4’-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavan 2’,3’-Dihydroxy-4’-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavan 2’,4’-Dihydroxy-3’-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavan 2’,4’-Dihydroxy-5-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavan 7,4’-Dihydroxy-5-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:2’,3’]isoflavan (3R)-7,2’,4’-Trihydroxy-5-methoxy-6-prenylisoflavan 7,2’,3’-Trihydroxy-4’-methoxy-5’-(1,1-dimethyl-2-propenyl)isoflavan 7,3’,4’-Trihydroxy-2’-methoxy-5’-(1,1-dimethyl-2-propenyl)isoflavan 2’,5’-Diketo-6,7,3’,4’-tetramethoxyisoflavan (3S)-7,3’-Dihydroxy-8,2’,4’,5’-tetramethoxyisoflavan 6,2’-Dihydroxy-7,8,3’,4’-tetramethoxyisoflavan 6,2’-Dihydroxy-4’,5’-methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavan (3R)-3’-Hydroxy-2’,4’-dimethoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavan 4’-Hydroxy-2’,3’-dimethoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavan (3R)-2’,4’-Dihydroxy-5,7-dimethoxy-6-prenylisoflavan (3R)-7,2’-Dihydroxy-5,4’-dimethoxy-3’-prenylisoflavan 7,3’-Dihydroxy-2’,4’-dimethoxy-5’-(1,1-dimethyl-2-propenyl)isoflavan 7,3’-Dihydroxy-2’,4’-dimethoxy-8-prenylisoflavan (3S)-7-Hydroxy-8,2’,3’,4’,5’-pentamethoxyisoflavan 2’,5’-Diketo-6-hydroxy-7,8,3’,4’-tetramethoxyisoflavan (3S)-2’,5’-Diketo-7-hydroxy-6,8,3’,4’-tetramethoxyisoflavan (3S)-2’,5’-Diketo-8-hydroxy-6,7,3’,4’-tetramethoxyisoflavan (6aR,11aR)-9-Acetoxy-3-methoxy-2-prenylpterocarpan (3R)-8-Carboxyaldehyde-7,4’-dihydroxy-5-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:2’,3’]isoflavan (3R)-8-Carboxyaldehyde-7,2’,4’-trihydroxy-5-methoxy-3’-prenylisoflavan 2’,5’-Diketo-6,7,8,3’,4’-pentamethoxyisoflavan Kanzonol O Kanzonol N Abruquinone B

Abruquinone C Abruquinone D Abruquinone F

Machaerol B Leiocinol Glyasperin H Sphaerosinin Glyasperin D Kanzonol R Unanisoflavan Sphaerosin s1

Millinol B 4’-O-Methylpreglabridin 2’-O-Methylphaseollidinisoflavan Millinolol Amorphaquinone Laurentiquinone Machaerol C Leiocin Arizonicanol B 3’-Hydroxy-4’-O-methylglabridin 3’-Methoxyglabridin Neorauflavane Gancaonol C Glyasperin C Secundiflorol G a,a-Dimethylallylcyclolobin Abruquinone A

340.42 340.42 340.42 342.39 346.34 346.34 348.35 352.38 354.40 354.40 354.40 354.40 354.40 356.41 356.41 356.41 360.37 362.38 362.38 368.39 368.43 368.43 370.45 370.45 370.45 370.45 376.40 376.37 376.37 376.37 380.43 382.41 384.42 390.39

3063 3065 2743 F204 2761 F117 2737 2744 F289 F121 2746 2747 F70 F350 F289 2748 2762 F10 2738 2745 F151 2749 F350 F76 2750 F151 F10 2763 F133 F133 F168 F76 F76 2764

Appendix

continued

C21H24O4 C21H24O4 C21H24O4 C20H22O5 C18H18O7 C18H18O7 C18H20O7 C21H20O5 C21H22O5 C21H22O5 C21H22O5 C21H22O5 C21H22O5 C21H24O5 C21H24O5 C21H24O5 C19H20O7 C29H22O7 C19H22O7 C21H20O6 C22H24O5 C22H24O5 C22H26O5 C22H26O5 C22H26O5 C22H26O5 C20H24O7 C19H20O8 C19H20O8 C19H20O8 C23H24O5 C22H22O6 C22H24O6 C20H22O8

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1131

119

2’-Hydroxy-(2’’,3’’:7,8),(2’’’,3’’’:4’,3’)-bis(6,6-dimethylpyrano)isoflavan 4’-Hydroxy-(2’’,3’’:7,6),(2’’’,3’’’:2’,3’)-bis(6,6-dimethylpyrano)isoflavan 4’-Hydroxy-(2’’,3’’:7,8),(2’’’,3’’’:2’,3’)-bis(6,6-dimethylpyrano)isoflavan 2’,4’-Dihydroxy-3’-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavan 2’,4’-Dihydroxy-8-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavan (3R)-7,4’-Dihydroxy-6-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:2’,3’]isoflavan 7,2’-Dihydroxy-8-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflavan (3R)-7,2’-Dihydroxy-5’-(1,1-dimethyl-2-propenyl)-4’-prenyloxyisoflavan (3R)-7,2’,4’-Trihydroxy-5’-(1-isopropylethenyl)-8-prenylisoflavan (3R)-7,2’,4’-Trihydroxy-6,5’-bis(1,1-dimethyl-2-propenyl)isoflavan (3R)-7,2’,4’-Trihydroxy-8,3’-diprenyloxyisoflavan (3R)-8-Carboxyaldehyde-7,2’-dihydroxy-5,4’-dimethoxy-3’-prenylisoflavan 2’-Hydroxy-4’-methoxy-6’’-methyl-6’’-(4-methyl-3-pentenyl)pyrano[2’’,3’’:7,8]isoflavan (3R)-7,2’,4’-Trihydroxy-6,8-diprenylisoflavan (3R)-7,4’-Dihydroxy-2’-methoxy-5’-(1,1-dimethyl-2-propenyl)-8-prenyloxyisoflavan (3R)-7,2’,4’-Trihydroxy-5’-(1,1-dimethyl-2-propenyl)-8-(3-hydroxy-3-methylbutyl)isoflavan (3S)-2’,5’-Diketo-6,7,8,3’,4’,6’-hexamethoxyisoflavan 2’-Hydroxy-5’,6’-methylenedioxy-6’’-methyl-6’’-(4-methyl-3-pentenyl)pyrano[2’’,3’’:7,8]isoflavan 2’,3’-Dihydroxy-4’-methoxy-6’’-methyl-6’’-(4-methyl-3-pentenyl)pyrano[2’’,3’’:7,8]isoflavan (3R)-4’-Hydroxy-5-methoxy-6’’,6’’,6’’’,6’’’-tetramethylpyrano[2’’,3’’:2’,3’]-4’’’,5’’’dihydropyrano[2’’’,3’’’:7,6]isoflavan (3R)-2’,4’-Dihydroxy-5-methoxy-6’’,6’’-dimethyl-3’-prenyl-4’’,5’’-dihydropyrano[2’’,3’’:7,6]isoflavan 5,2’,4’-Trihydroxy-7-methoxy-6,3’-diprenylisoflavan 7,2’,4’-Trihydroxy-5-methoxy-6,3’-diprenylisoflavan (3R)-4’-Hydroxy-5,7-dimethoxy-6-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:2’,3’]isoflavan (þ)-2’,4’-Dihydroxy-5,7-dimethoxy-6,3-diprenylisoflavan (3R,4R)-7,2’-Dihydroxy-4’-methoxy-4-(2,4-dihydroxy-5’(1,1-dimethyl-2-propenyl)phenyl)isoflavan 2’-Hydroxy-4’-methoxy-4’’-phenylpyrano[2’’,3’’:7,6]-6’’-ylidene-5’’’-hydroxy-2’’’ -methoxy-2’’’,5’’’-cyclohexadien-1’’’-one-isoflavan Neocandenaton

Kanzonol I 7-O-Methyllicoricidin Manuifolin Q

Kanzonol H Licoricidin

Manuifolin D Manuifolin F Manuifolin E Kanzonol X Kanzonol M Heminitidulan Eryzerin C Tenuifolin A Manuifolin G Abruquinone E Nitidulan Nitidulin Kanzonol J

Hispaglabridin B Glyinflanin J Glyinflanin K Hispaglabridin A Eryzerin D Glyinflanin I

Trivial Name

522.54

424.54 424.54 424.54 436.54 438.57 448.51

390.48 390.48 390.48 392.50 392.50 392.50 392.50 394.50 394.50 394.50 394.50 398.46 406.51 406.51 408.53 412.52 420.41 420.50 422.51 422.51

Mass

C32H26O7

C26H32O5 C26H32O5 C26H32O5 C27H32O5 C27H34O5 C27H28O6

C25H26O4 C25H26O4 C25H26O4 C25H28O4 C25H28O4 C25H28O4 C25H28O4 C25H30O4 C25H30O4 C25H30O4 C25H30O4 C23H26O6 C26H30O4 C26H30O4 C26H32O4 C25H32O5 C21H24O9 C26H28O5 C26H30O5 C26H30O5

Formula

F21

F74 2756 F168 F74 3066 F349

2751 F75 F75 2752 F277 F75 F121 F346 F346 F346 F73 F76 2753 F277 F348 F347 F133 2754 2755 F74

Ref.

1132

113 114 115 116 117 118

93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112

Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

Glabrene 2-Methoxyjudaicin Eryvarin I Erypoegin B Bidwillol A Burttinol A Erypoegin A Neorauflavene Dehydroglyasperin C

Judaicin 7-O-glucoside Judaicin 7-O-(6’’-malonylglucoside)

Isoflavene glycosides 7-Hydroxy-2’-methoxy-4’,5’-methylenedioxyisoflav-3-ene 7-O-glucoside 7-Hydroxy-2’-methoxy-4’,5’-methylenedioxyisoflav-3-ene 7-O-(6’’-malonylglucoside)

146 147

2’-O-Methylsepiol Hagenin A Eryvarin H

Lespedezol F1 Haginin E Hagenin D Bolusanthin III Hagenin B Sepiol Hagenin C Judaicin Odoriflavene

ISOFLAVENES 7,2’,4’-Trihydroxyisoflav-2-ene 7,4’-Dihydroxyisoflav-3-ene 7,2’,4’-Trihydroxyisoflav-3-ene 7,2’-Dihydroxy-4’-methoxyisoflav-3-ene 7,4’-Dihydroxy-2’-methoxyisoflav-3-ene 7,2’,3’-Trihydroxy-4’-methoxyisoflav-3-ene 7,2’,4’-Trihydroxy-3’-methoxyisoflav-3-ene 7-Hydroxy-2’-methoxy-4’,5’-methylenedioxyisoflav-3-ene 7,2’-Dihydroxy-3’,4’-dimethoxyisoflav-3-ene 7,2’-Dihydroxy-8,4’-dimethoxyisoflav-3-ene 7,3’-Dihydroxy-2’,4’-dimethoxyisoflav-3-ene 7,4’-Dihydroxy-2’,3’-dimethoxyisoflav-3-ene 7,4’-Dihydroxy-2’,5’-dimethoxyisoflav-3-ene 6,7,3’-Trihydroxy-2’,4’-dimethoxyisoflav-3-ene 7,4’-Dihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:2’.3’]isoflav-3-ene 7-Hydroxy-2,2’-dimethoxy-4’,5’-methylenedioxyisoflav-3-ene 3-Hydroxy-2’-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflav-3-ene 4’-Hydroxy-2’-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflav-3-ene 7,4’-Dihydroxy-2’-methoxy-3’-prenylisoflav-3-ene 7,4’-Dihydroxy-2’-methoxy-6-(1,1-dimethyl-2-propenyl)isoflav-3-ene 7,4’-Dihydroxy-2’-methoxy-8-prenylisoflav-3-ene 2’,4’-Dihydroxy-5-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavene 7,2’,4’-Trihydroxy-5-methoxy-6-prenylisoflav-3-ene

123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145

Isomucronulatol 7-O-glucoside Isomucronulatol 7,2’-di-O-glucoside 5’-Hydroxyisomucronulatol 2’,5’-di-O-glucoside

Isoflavan glycosides 7,2’-Dihydroxy-3’,4’-dimethoxyisoflavan 7-O-glucoside (3R)-7,2’-Dihydroxy-3’,4’-dimethoxyisoflavan 7,2’-O-diglucoside (3R)-7,2’,5’-Trihydroxy-3’,4’-dimethoxyisoflavan 2’,5’-O-diglucoside

120 121 122

460.44 546.48

256.25 240.26 256.26 270.29 270.29 286.29 286.29 298.30 300.31 300.31 300.31 300.31 300.31 316.31 322.36 328.32 336.40 336.40 338.40 338.40 338.40 352.38 354.40

464.47 626.60 642.60

C23H24O10 C26H26O13

C15H12O4 C15H12O3 C15H12O4 C16H14O4 C16H14O4 C16H14O5 C16H14O5 C17H14O5 C17H16O5 C17H16O5 C17H16O5 C17H16O5 C17H16O5 C17H16O6 C20H18O4 C18H16O6 C21H20O4 C21H20O4 C21H22O4 C21H22O4 C21H22O4 C21H20O5 C21H22O5

C23H28O10 C29H3815 C29H3816

F260 F260

F171 F170 2765 F116 2766 2767 2768 F260 3067 3068 2769 2770 F276 2771 F73 F300 F276 F278 F104 F337 F278 2773 F124

3236 F261 F261

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Appendix 1133

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Appendix — Checklist for Isoflavonoids Øyvind M. Andersen The following checklist of isoflavonoids contains compounds reported in the literature as natural products to the end of 2004. Compounds published before 1991 are referenced to numbered entries in Volume 2 of the Handbook of Natural Flavonoids (J.B. Harborne and H. Baxter), John Wiley & Sons, Chichester, 1999, using a number consisting of four digits. Compounds published in the period 1991–2004 are referenced with numbers having F as prefix before the number of the publication found in the reference list. The various isoflavonoid classes are shown in Figure A1.

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Appendix

FIGURE A1 Isoflavonoid classes.

1135

ISOFLAVAN-4-OLS 5-Hydroxy-8-methoxy-6,7-methylenedioxyisoflavan-4-ol 2’-Methoxy-4’,5’-methylenedioxyfurano[2’’,3’’:7,6]isoflavan-4-ol

ISOFLAVANONES 7,4’-Dihydroxyisoflavanone 7-Hydroxy-4’-methoxyisoflavanone 7,2’,4’-Trihydroxyisoflavanone 5,7-Dihydroxy-4’-methoxyisoflavanone 7,2’-Dihydroxy-4’-methoxyisoflavanone 7,3’-Dihydroxy-4’-methoxyisoflavanone 5,7,2’,4’-Tetrahydroxy-4’-isoflavanone 7,2’-Dihydroxy-4’,5’-methylenedioxyisoflavanone 2’-Hydroxy-7,4’-dimethoxyisoflavanone 7-Hydroxy-2’,4’-dimethoxyisoflavanone 7-Hydroxy-3’,4’-dimethoxyisoflavanone 3,7,2’-Trihydroxy-4’-methoxyisoflavanone (3R)-4’-Methoxy-3,7,2’-trihydroxyisoflavanone (3R)-7,2’,3’-Trihydroxy-4’-methoxyisoflavanone 5,2’,4’-Trihydroxy-7-methoxyisoflavanone 5,7,2’-Trihydroxy-4’-methoxyisoflavanone 5,7,3’-Trihydroxy-4’-methoxyisoflavanone 5,7,4’-Trihydroxy-2’-methoxyisoflavanone 7,2’,4’-Trihydroxy-5’-methoxyisoflavanone 7-Hydroxy-2’-methoxy-4’,5’-methylenedioxyisoflavanone 5,2’,4’-Trihydroxy-7-methoxy-6-methylisoflavanone 5,4’-Dihydroxy-5,2’-dimethoxyisoflavanone 5,4’-Dihydroxy-7,2’-dimethoxyisoflavanone 5,7-Dihydroxy-2’,4’-dimethoxyisoflavanone 7,3’-Dihydroxy-2’,4’-dimethoxyisoflavanone

148 149

150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174

Name

Cajanol Homoferreirin Violanone

Dihydrocajanin Ferreirin Kenusanone G Isoferreirin Lespedol D Onogenin Ougenin

256.26 270.29 272.26 286.29 286.29 286.29 288.26 300.27 300.31 300.31 300.31 302.29 302.29 302.29 302.29 302.29 302.29 302.29 302.29 314.29 316.31 316.31 316.31 316.31 316.31

316.31 340.33

Mass

C15H12O4 C16H14O4 C15H12O5 C16H14O5 C16H14O5 C16H14O5 C15H12O6 C16H12O6 C17H16O5 C17H16O5 C17H16O5 C16H14O6 C16H14O6 C16H14O6 C16H14O6 C16H14O6 C16H14O6 C16H14O6 C16H14O6 C17H14O6 C17H16O6 C17H16O6 C17H16O6 C17H16O6 C17H16O6

C17H16O6 C19H16O6

Formula

2514 2515 2516 2536 2517 2518 2537 2521 2522 2519 2520 F132 F35 2986 F192 2538 F100 2539 F171 2523 2543 2980 2541 2540 2524

3069 2757

Ref.

1136

Dihydrodaidzein Dihydroformononetin 2’-Hydroxydihydrodaidzein Dihydrobiochanin A Vestitone 3’-Hydroxydihydroformononetin Dalbergioidin Sophorol Isosativanone Sativanone 3’-Methoxydihydroformononetin

Laphatinol Ambanol

Trivial Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208

7,4’-Dihydroxy-2’,3’-dimethoxyisoflavanone 7,4’-Dihydroxy-2’,5’-dimethoxyisoflavanone 7,4’-Dihydroxy-3’,5’-dimethoxyisoflavanone 3,5,3,2’-Tetrahydroxy-4’-methoxyisoflavanone 3,5,7,3’-Tetrahydroxy-4’-methoxyisoflavanone 7-Hydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflavanone 2’,3’-Dimethoxyfurano[2’’,3’’:7,6]isoflavanone 6,7-Dimethoxy-3’,4’-methylenedioxyisoflavanone 2’-Hydroxy-7,3’,4’-trimethoxyisoflavanone 7-Hydroxy-2’,3’,4’-trimethoxyisoflavanone 5,7,2’,4’-Tetrahydroxy-5’-methoxy-6-methylisoflavanone 5,7,3’-Trihydroxy-2’,4’-dimethoxyisoflavanone 5,7,4’-Trihydroxy-2’,3’-dimethoxyisoflavanone 2’-Methoxy-4’,5’-methylenedioxyfurano[2’’,3’’:7,6]isoflavanone 7,4’-Dihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:2’,3’]isoflavanone (þ)-5,7,4’-Trihydroxy-6-prenylisoflavanone 7,2’,4’-Trihydroxy-3’-prenylisoflavanone 7,2’,4’-Trihydroxy-8-prenylisoflavanone 2’,4’-Dihydroxy-7-methoxy-6-prenylisoflavanone 5,7-Dihydroxy-2’,4’,5’-trimethoxyisoflavanone 7-Hydroxy-2’-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’]isoflavanone 2’-Hydroxy-6’-methoxy-4’,5’-methylenedioxyfurano[2’’,3’’:7,6]isoflavanone 2’,3’,4’-Trimethoxyfurano[2’’,3’’:7,6]isoflavanone 2’,4’,5’-Trimethoxyfurano[2’’,3’’:7,6]isoflavanone 5,2’,4’-Trihydroxy-5’’-(1-methylethenyl)-4’’,5’’-dihydrofurano(2’’,3’’;7,6)isoflavanone 5,2’,4’-Trihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavanone 5,7,2’-Trihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflavanone 5,7,4’-Trihydroxy-6’’,6’’-dimethylpyrano(2’’,3’’;2’,3’]isoflavanone 7,2’-Dihydroxy-4’-methoxy-5’-prenylisoflavanone 7,3’-Dihydroxy-4’-methoxy-2’-prenylisoflavanone 7,4’-Dihydroxy-2’-methoxy-5’-prenylisoflavanone 5,7,2’,4’-Tetrahydroxy-6-prenylisoflavanone 5,7,2’,4’-Tetrahydroxy-8-prenylisoflavanone 5,7,3’,4’-Tetrahydroxy-5-prenylisoflavanone Eryvellutinone Sigmoidin H Erosenone Nepseudin Ambonone Uncinanone B Cyclokievitone 1’’,2’’-dehydrocyclokievitone Licoisoflavanone Glyasperin F Prostratol C Secundiflorol F Sigmoidin I Diphysolone Kievitone Bolusanthol B

3’-Methoxyisosativanone 3’-O-Methylviolanone Lespedol E Secundiflorol H Parvisflavanone Neotenone 5-Deoxyglyasperin F (þ)-Dihydrowighteone 2,3-Dihydro-2’-hydroxyneobavaisoflavanone 4-Deoxykievitone

Ferreirino Bolusanthin 5-Deoxylicoisoflavanone Neoraunone

Lespedeol C Eryvarin M

316.31 316.31 316.31 318.28 318.28 322.36 324.34 328.32 330.34 330.34 332.30 332.30 332.30 338.32 338.36 340.38 340.38 340.38 346.34 346.34 352.38 354.32 354.36 354.36 354.36 354.36 354.36 354.36 354.40 354.40 354.40 356.37 356.37 356.37

2525 F280 2987 F60 2981 F168 2529 2526 2528 2527 F171 F289 2542 2530 F168 2992 F168 2531 F317 F48 F182 2534 2532 2533 F297 2545 2544 F168 F106 F242 F187 F297 2546 F28

Appendix

continued

C17H16O6 C17H16O6 C17H16O6 C16H14O7 C16H14O7 C20H18O4 C19H16O5 C18H16O6 C18H18O6 C18H18O6 C17H16O7 C17H16O7 C17H16O7 C19H14O6 C20H18O5 C20H20O5 C20H20O5 C20H20O5 C18H18O7 C18H18O7 C21H20O5 C19H14O7 C20H18O6 C20H18O6 C20H18O6 C20H18O6 C20H18O6 C20H18O6 C21H22O5 C21H22O5 C21H22O5 C20H20O6 C20H20O6 C20H20O6

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209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239

7,2’,4’-Trihydroxy-8-(4-hydroxy-3-dimethyl-2-butenyl)isoflavanone (S)-5,7,2’,4’-Tetrahydroxy-3’-prenylisoflavanone 7,2’,4’-Trihydroxy-8-(3-hydroxy-3-methylbutyl)isoflavanone 5,7,3’-Trihydroxy-6,4’,5’-trimethoxyisoflavanone 5,4’-Dihydroxy-2’-methoxy-5’’-(1-methylethenyl)-4’’,5’’-dihydrofurano-(2’’,3’’;7,6)-isoflavanone 5,7-Dihydroxy-2’-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflavanone 7,2’-Dihydroxy-5-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflavanone 7,3’-Dihydroxy-5-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’]isoflavanone (3R)-7,2’,3’-Trihydroxy-4’-methoxy-5’-(1,1-dimethyl-2-propenyl)isoflavanone (3R)-7,2’,3’-Trihydroxy-4’-methoxy-5’-prenylisoflavanone (3S)-5,7,3’-Trihydroxy-4’-methoxy-5’-prenylisoflavanone 5,2’,4’-Trihydroxy-7-methoxy-6-prenylisoflavanone 5,7,2’-Trihydroxy-4’-methoxy-5’-prenylisoflavanone 5,7,2’-Trihydroxy-4’-methoxy-6-prenylisoflavanone 5,7,2’-Trihydroxy-4’-methoxy-8-prenylisoflavanone 5,7,3’-Trihydroxy-4’-methoxy-2’-prenylisoflavanone 5,7,4’-Trihydroxy-2’-methoxy-3’-prenylisoflavanone 5,7,4’-Trihydroxy-2’-methoxy-5’-(1,1-dimethyl-2-propenyl)isoflavanone 5,7,4’-Trihydroxy-2’-methoxy-5’-prenylisoflavanone 5,7,2’,4’-Tetrahydroxy-8-(4-hydroxy-3-dimethyl-2-butenyl)isoflavanone 5,7,3’,4’-Tetrahydroxy-5’-(2-epoxy-3-methylbutyl)isoflavanone 5-Hydroxy-7,2’-dimethoxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’]isoflavanone 3,5,7-Trihydroxy-2’-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflavanone (3R)-7,2’-Dihydroxy-3’,4’-dimethoxy-5’-(1,1-dimethyl-2-propenyl)isoflavanone 5,4’-Dihydroxy-7,2’-dimethoxy-5’-(1,1-dimethyl-2-propenyl)isoflavanone 5,4’-Dihydroxy-7,2’-dimethoxy-5’-prenylisoflavanone 7,4’-Dihydroxy-2’,5’-dimethoxy-6-prenylisoflavanone 7,4’-Dihydroxy-2’,5’-dimethoxy-8-prenylisoflavanone (R)-5,2’,4’-Trihydroxy-7-methoxy-6-methyl-8-prenylisoflavanone (S)-5,2’-Dihydroxy-7,4’-dimethoxy-6-prenylisoflavanone 3,5,7,4’-Tetrahydroxy-2’-methoxy-3’-prenylisoflavanone

Name

Erypoegin G Sophoronol Pervilleanone Echinoisosophoranone Erypoegin D Sigmoidin J Eryvarin N Desmodianone B Glyasperin K Kenusanone F

356.37 356.37 358.39 362.33 368.39 368.39 368.39 368.39 370.40 370.40 370.40 370.40 370.40 370.40 370.40 370.40 370.40 370.40 370.40 372.37 372.37 382.41 384.39 384.42 384.42 384.42 384.42 384.42 384.42 384.42 386.40

Mass C20H20O6 C20H20O6 C20H22O6 C18H18O8 C21H20O6 C21H20O6 C21H20O6 C21H20O6 C21H22O6 C21H22O6 C21H22O6 C21H22O6 C21H22O6 C21H22O6 C21H22O6 C21H22O6 C21H22O6 C21H22O6 C21H22O6 C20H20O7 C20H20O7 C22H22O6 C21H20O7 C22H24O6 C22H24O6 C22H24O6 C22H24O6 C22H24O6 C22H24O6 C22H24O6 C21H22O7

Formula

2991 F59 2982 F112 F297 2547 F72 2990 F80 F303 2989 F350 F14 2984 2985 F289 2548 F102 F278 2993 F28 F272 2999 F80 2988 F278 F181 F280 F51 F72 F100

Ref.

1138

Glyasperin B Vogelin A Diphysolidone 4-O-Methylkievitone Arizonicanol D Sophoraisoflavanone A Fraserinone A Erypoegin C Kievitol

5-Deoxykievitol Dihydrolicoisoflavone 5-Deoxykievitone hydrate 2,3-Dihydroirigenin Uncinanone C Isosophoronol Glyasperin M Glycyrrhisoflavanone 3’-O-Demethylpervilleanone

Trivial Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273

3,7,2’,3’-Tetrahydroxy-4’-methoxy-5’-(1,1-dimethyl-2-propenyl)isoflavanone (3R)-5,7,2’,3’-Tetrahydroxy-4’-methoxy-5’-prenylisoflavanone (3S)-3,7,2’,3’-Tetrahydroxy-4’-methoxy-5’-prenylisoflavanone 7,4’-Dihydroxy-3’-( (2E)-3,7-dimethyl-2,6-octadienyl)isoflavanone 7,4’-Dihydroxy-4’-methoxy-6,3’-diprenylisoflavanone (þ)-3,5,7-Trihydroxy-2’,4’-dimethoxy-3’-prenylisoflavanone 5,7,3’-Trihydroxy-2’,4’-dimethoxy-5’-(1,1-dimethyl-2-propenyl)isoflavanone 5,7,3’-Trihydroxy-2’,4’-dimethoxy-6-prenylisoflavanone 3,5,7,2’,3’-Tetrahydroxy-4’-methoxy-3’-(1,1-dimethyl-2-propenyl)isoflavanone 2’,4’-Dihydroxy-6-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavanone 2’,4’-Dihydroxy-6’’-(4-methyl-3-pentenyl)-6’’-methylpyrano[2’’,3’’:7,6]isoflavanone 2’,4’-Dihydroxy-8-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavanone 5,7,4’-Trihydroxy-3’-((2E)-3,7-dimethyl-2,6-octadienyl)isoflavanone 5,7,4’-Trihydroxy-6,3’-diprenylisoflavanone 7,2’,4’-Trihydroxy-5’-((2E)-3,7-dimethyl-2,6-octadienyl)isoflavanone 7,2’,4’-Trihydroxy-6,3’-diprenylisoflavanone 7,2’,4’-Trihydroxy-6,8-diprenylisoflavanone 7,2’,4’-Trihydroxy-6,8-diprenylisoflavanone (+)-7,2’,4’-Trihydroxy-8,3’-diprenylisoflavanone (3R)-5-Hydroxy-2’,4’,5’-trimethoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavanone 5,7,2’-Trihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’](1’’’-methylphenyl)[3’’’,4’’’:4’’,5’’]isoflavanone 5,2’,4’-Trihydroxy-3’-prenyl-6’’-methyl-6’’-(4-methyl-3-pentenyl)pyrano[2’’,3’’:7,6]isoflavanone 5,2’,4’-Trihydroxy-3’-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavanone 5,2’,4’-Trihydroxy-8-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavanone (3R)-5,7-Dihydroxy-4’-methoxy-6,3’-diprenylisoflavanone (3R)-7,4’-Dihydroxy-2’-methoxy-6,8-diprenylisoflavanone 7,4’-Dihydroxy-2’-methoxy-6-((2E)-3,7-dimethyl-2,6-octadienyl)isoflavanone 3,7,2’,4’-Tetrahydroxy-6,8-diprenylisoflavanone 5,7,2’,4’-Tetrahydroxy-5’-[(2E)-3,7-dimethyl-2,6-octadienyl]isoflavanone 5,7,2’,4’-Tetrahydroxy-6-geranylisoflavanone 5,7,2’,4’-Tetrahydroxy-6,3’-diprenylisoflavanone 5,7,2’,4’-Tetrahydroxy-6,5’-diprenylisoflavanone 5,7,2’,4’-Tetrahydroxy-6,8-diprenylisoflavanone 5,7,2’,4’-Tetrahydroxy-8-[(2E)-3,7-dimethyl-2,6-octadienyl]isoflavanone Orientanol D Kenusanone A Lespedeol B Glisoflavanone Tetrapterol G Orientanol E Kenusanone H

Eriotrichin B Bidwillon A Eryzerin A Saclenone Tetrapterol A Lespedeol A Cajanone 2,3-Dihydroauriculatin Vogelin D Eryzerin B

Bidwillon B Tetrapterol D Bolusanthol C Prostratol A

Tetrapterol E Tetrapterol I (þ)-Echinoisoflavanone Secundiflorol E Arizonicanol C Secundiflorol A Orientanol F

Secundifloran

386.40 386.40 386.40 392.50 392.50 400.43 400.43 400.43 402.39 406.47 406.47 406.47 408.50 408.50 408.50 408.50 408.50 408.50 408.50 412.44 418.45 422.48 422.48 422.48 422.51 422.51 422.51 424.50 424.50 424.50 424.50 424.50 424.50 424.50

C21H22O7 C21H22O7 C21H22O7 C25H28O4 C25H28O4 C22H24O7 C22H24O7 C22H24O7 C21H22O8 C25H26O5 C25H26O5 C25H26O5 C25H28O5 C25H28O5 C25H28O5 C25H28O5 C25H28O5 C25H28O5 C25H28O5 C23H24O7 C25H22O6 C25H26O6 C25H26O6 C25H26O6 C26H30O5 C26H30O5 C26H30O5 C25H28O6 C25H28O6 C25H28O6 C25H28O6 C25H28O6 C25H28O6 C25H28O6

Appendix

continued

2535 F303 F303 F101 F241 2998 F242 F289 F103 F281 F167 F97 F101 F28 F106 F168 F186 F97 F277 F338 F101 2550 2549 2997 F209 F277 F167 F281 F98 2551 F88 F241 F281 F100

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294 295 296 297 298

436.50 436.50 438.51 438.51 438.51 438.51 438.51 438.51 438.51 440.49 440.49 452.50 452.50 476.62 492.62

Desmodianone A Kanzonol G Sophoraisoflavanone B Tetrapterol H Isosophoranone Tetrapterol C Phyllanone B Desmodianone C Bolusanthin II Erysengalensein B Phyllanone A Erysengalensein B Sophoraisoflavanone C Sophoraisoflavanone D

Dihydrodaidzin Dihydroformononetin 7-O-glucoside Dihydrogenistin Dalbergioidin 4’-O-glucoside Onogenin 7-O-glucoside

Isoflavanon glycosides 7,4’-Dihydroxyisoflavanone 7-O-glucoside 7-Hydroxy-4’-methoxyisoflavanone 7-O-glucoside 5,7,4’-Trihydroxyisoflavanone 7-O-glucoside 5,7,2’,4’-Tetrahydroxyisoflavanone 4’-O-glucoside 7-Hydroxy-2’-methoxy-4’,5’-methylenedioxyisoflavanone 7-O-glucoside

418.39 432.43 434.39 450.39 476.44

436.50 436.50

424.50 424.50 432.47

Desmodianone E

2’-O-Methylcajanone Desmodianone D

Dalversinol A 3’-Dimethylallylkievitone Methyltetrapterol A

Mass

5,7,2’,4’-Tetrahydroxy-8-prenyl-3’-(1,1-dimethyl-2-propenyl)isoflavanone 5,7,2’,4’-Tetrahydroxy-8,3’-diprenylisoflavanone 5,7,2’-Trihydroxy-6-methyl-6’’,6’’-dimethyl-4’’-5’’dihydropyrano[2’’,3’’:4’,5’]-3’’’-methylbenzo[1’’’,6’’’:5’’,4’’]isoflavanone 5,4’-Dihydroxy-2’-methoxy-3’-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavanone 5,7-Dihydroxy-6-methyl-3-(1a,2,3,3a,8b,8c-hexahydro-6-hydroxy-1,1,3a-trimethyl1H-4-oxabenzo[f]cyclobut[cd]inden-7-yl)-2,3-dihydro 4H-1-benzopyran-4-one 5,7,2’-Trihydroxy-6-methyl-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:4’,5’]-2’’’methylcyclohexene[5’’’,6’’’:5’’,4’’]isoflavanone (R)-5,7,2’-Trihydroxy-6,6’’-dimethyl-6’’-(4-methylpent-3-enyl)pyrano(2’’,3’’:4’,5’)isoflavanone (3S)-5,2’,4’-Trihydroxy-7-methoxy-6,3’-diprenylisoflavanone 5,7,2’-Trihydroxy-4’-methoxy-6,3’-diprenylisoflavanone 5,7,2’-Trihydroxy-4’-methoxy-8,5’-diprenylisoflavanone 5,7,4’-Trihydroxy-2’-methoxy-6,3’-diprenyisoflavanone 5,7,4’-Trihydroxy-2’-methoxy-8-((2E,6E)-3,7-dimethyl-2,6-octadienyl)isoflavanone 5,7,4’-Trihydroxy-2’-methoxy-8,3’-diprenylisoflavanone (R)-5,7,2’,4’-Tetrahydroxy-6-methyl-5’-(3,7-dimethylocta-2(E),6-dienyl)isoflavanone 3,5,7,2’,4’-Pentahydroxy-8,3’-diprenylisoflavanone 5,7,2’,4’,5’-Pentahydroxy-6,8-diprenylisoflavanone 3,5,7-Trihydroxy-2’-methoxy-8-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflavanone 5,2’,4’-Trihydroxy-5’-methoxy-8-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavanone 5,7,4’-Trihydroxy-3’-geranyl-6-prenylisoflavanone 5,7,2’,4’-Tetrahydroxy-5’-geranyl-6-prenylisoflavanone

Trivial Name

C21H22O9 C22H24O9 C21H22O10 C21H22O11 C23H24O11

C26H28O6 C26H30O6 C26H30O6 C26H30O6 C26H30O6 C26H30O6 C26H30O6 C26H30O6 C25H28O7 C25H28O7 C26H28O7 C26H28O7 C30H36O5 C30H36O5

C26H28O6

C26H28O6 C26H28O6

C25H28O6 C25H28O6 C26H24O6

Formula

F92 3219 F92 F99 3220

F51 F74 2554 F241 2553 F101 F219 F51 F29 F306 F219 F306 2994 2995

F31

2552 F31

F26 2996 F31

Ref.

1140

280 281 282 283 284 285 286 287 288 289 290 291 292 293

279

277 278

274 275 276

Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331

ISOFLAVONES 5,8-Dihydroxy-7-methoxyisoflavone 7-Hydroxy-2-methylisoflavone 5,7-Dihydroxyisoflavone 7,4’-Dihydroxyisoflavone 8,4’-Dihydroxyisoflavone 7-Methoxy-2-methylisoflavone 4’-Hydroxy-7-methoxyisoflavone 5-Hydroxy-4’-methoxyisoflavone 5-Hydroxy-7-methoxyisoflavone 7-Hydroxy-4’-methoxyisoflavone 5,7,3’-Trihydroxyisoflavone 5,7,4’-Trihydroxyisoflavone 6,7,4’-Trihydroxyisoflavone 7,2’,4’-Trihydroxyisoflavone 7,3’,4’-Trihydroxyisoflavone 7,8,4’-Trihydroxyisoflavone 3’-Carboxyaldehyde-7,4’-dihydroxyisoflavone 7-Hydroxy-3’,4’-methylenedioxyisoflavone 5,7-Dimethoxyisoflavone 7,4’-Dimethoxyisoflavone 2’,4’-Dihydroxy-7-methoxyisoflavone 5,4’-Dihydroxy-7-methoxyisoflavone 5,7-Dihydroxy-3’-methoxyisoflavone 5,7-Dihydroxy-4’-methoxyisoflavone 5,7,2’-Trihydroxy-6-methylisoflavone 6,4’-Dihydroxy-7-methoxyisoflavone 6,7-Dihydroxy-4’-methoxyisoflavone 6’,7-Dihydroxy 3’-methoxyisoflavone 7,2’-Dihydroxy-4’-methoxyisoflavone 7,2’-Dihydroxy-5’-methoxyisoflavone 7,2’-Dihydroxy-6-methoxyisoflavone 7,3’-Dihydroxy-4’-methoxyisoflavone 7,3’,4’,5’-Tetrahydroxyisoflavone 3’-Hydroxyformononetin Baptigenin

2’-Hydroxyformononetin

7,4’-Di-O-methyldaidzein 2’-Methoxyformononetin Prunetin Mutabilein Biochanin A Abronisoflavone Kakkatin Texasin

Genistein Demethyltexasin 2’-Hydroxydaidzein 3’-Hydroxydaidzein 8-Hydroxydaidzein Corylinal Pseudobaptigenin

Formononetin

Isoformononetin Pallidiflorin

Daidzein

238.24 252.27 254.24 254.24 254.24 266.30 268.27 268.27 268.27 268.27 270.24 270.24 270.24 270.24 270.24 270.24 282.25 282.25 282.30 282.30 284.27 284.27 284.27 284.27 284.27 284.27 284.27 284.27 284.27 284.27 284.27 284.27 284.27

C15H10O3 C16H12O3 C15H10O4 C15H10O4 C15H10O4 C17H14O3 C16H12O4 C16H12O4 C16H12O4 C16H12O4 C15H10O5 C15H10O5 C15H10O5 C15H10O5 C15H10O5 C15H10O5 C16H10O5 C16H10O5 C17H14O4 C17H14O4 C16H12O5 C16H12O5 C16H12O5 C16H12O5 C16H12O5 C16H12O5 C16H12O5 C16H12O5 C16H12O5 C16H12O5 C16H12O5 C16H12O5 C15H10O6

Appendix

continued

F243 2339 2839 2340 2870 2341 2343 2867 2416 2342 2840 2417 2346 2344 2345 2877 2347 2348 2418 2349 F113 2420 F55 2419 F321 2355 2354 F344 2350 F343 2843 2352 2358

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1141

332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362

7,4’-Dihydroxy-2’-methoxyisoflavone 7,4’-Dihydroxy-3’-methoxyisoflavone 7,4’-Dihydroxy-5-methoxyisoflavone 7,4’-Dihydroxy-6-methoxyisoflavone 7,8-Dihydroxy-4’-methoxyisoflavone 8,4’-Dihydroxy-7-methoxyisoflavone 5,6,7,4’-Tetrahydroxyisoflavone 5,7,2’,4’-Tetrahydroxyisoflavone 5,7,3’,4’-Tetrahydroxyisoflavone 7,8,2’,4’-Tetrahydroxyisoflavone 7-Acetoxy-2-methylisoflavone 8-Acetyl-7-hydroxy-2-methylisoflavone 4’-Methoxy-7,8-methylenedioxyisoflavone 7-Methoxy-3’,4’-methylenedioxyisoflavone (4’’S,5’’R)-5,7,4’’,5’’-Tetrahydroxy-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:4’,3’]isoflavone 7,2’-Dimethoxy-8-methylisoflavone 5,2’-Dihydroxy-6,7-methylenedioxyisoflavone 5,4’-Dihydroxy-6,7-methylenedioxyisoflavone 5,7-Dihydroxy-3’,4’-methylenedioxyisoflavone 7,2’-Dihydroxy-3’,4’-methylenedioxyisoflavone 2’,5’-Diketo-7-hydroxy-4’-methoxyisoflavone 2’-Hydroxy-7,4’-dimethoxyisoflavone 4’-Hydroxy-6,7-methoxyisoflavone 4’-Hydroxy-7,3’-dimethoxyisoflavone 5-Hydroxy-7,4’-dimethoxyisoflavone 5,7,4’-Trihydroxy-6,8-dimethylisoflavone 6-Hydroxy-7,4’-dimethoxyisoflavone 7-Hydroxy-2’,4’-dimethoxyisoflavone 7-Hydroxy-3’,4’-dimethoxyisoflavone 7-Hydroxy-3’,5’-dimethoxyisoflavone 7-Hydroxy-5,4’-dimethoxyisoflavone

Name

5-O-Methylbiochanin A

Alfalone 2’-Methoxyformononetin Cladrin

Sayanedine

Irisone B Irilone 5-Hydroxypseudobaptigenin Glyzaglabrin Bowdichione

284.27 284.27 284.27 284.27 284.27 284.27 286.24 286.24 286.24 286.24 294.31 294.31 296.28 296.28 296.32 296.32 298.25 298.25 298.25 298.25 298.25 298.30 298.30 298.30 298.30 298.30 298.30 298.30 298.30 298.30 298.30

Mass C16H12O5 C16H12O5 C16H12O5 C16H12O5 C16H12O5 C16H12O5 C15H10O6 C15H10O6 C15H10O6 C15H10O6 C18H14O4 C18H14O4 C17H12O5 C17H12O5 C20H18O7 C18H16O4 C16H10O6 C16H10O6 C16H10O6 C16H10O6 C16H10O6 C17H14O5 C17H14O5 C17H14O5 C17H14O5 C17H14O5 C17H14O5 C17H14O5 C17H14O5 C17H14O5 C17H14O5

Formula

2351 2353 2421 2356 2357 F95 2424 2422 2423 2878 2359 2360 2845 2361 F201 F27 2881 2427 2425 2363 2511 F191 F159 2364 F352 F33 2875 F113 2362 F1 2426

Ref.

1142

Glyzarin Maximaisoflavone H Pseudobaptigenin methyl ether Dihydroisoderrondiol

6-Hydroxygenistein 2’-Hydroxygenistein Orobol

Theralin 3-Methoxydaidzein 5-O-Methylgenistein Glycitein Retusin

Trivial Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396

7-Hydroxy-6,4’-dimethoxyisoflavone 7-Hydroxy-8,4’-dimethoxyisoflavone 5,2’,4’-Trihydroxy-7-methoxyisoflavone 5,3’,4’-Trihydroxy-7-methoxyisoflavone 5,6,4’-Trihydroxy-7-methoxyisoflavone 5,7,2’-Trihydroxy-4’-methoxyisoflavone 5,7,3’-Trihydroxy-4’-methoxyisoflavone 5,7,4’-Trihydroxy-2’-methoxyisoflavone 5,7,4’-Trihydroxy-3’-methoxyisoflavone 5,7,4’-Trihydroxy-6-methoxyisoflavone 5,7,4’-Trihydroxy-8-methoxyisoflavone 7,2’,3’-Trihydroxy-4’-methoxyisoflavone 7,2’,4’-Trihydroxy-3’-methoxyisoflavone 7,3’,5’-Trihydroxy-4’-methoxyisoflavone 7,4’,5’-Trihydroxy-2’-methoxyisoflavone 7,8,3’-Trihydroxy-4’-methoxyisoflavone 7,8,4’-Trihydroxy-6-methoxyisoflavone 5,7,8,2’,4’-Tetrahydroxyisoflavone (7,8:3’,4’)-Bis(methylenedioxy)isoflavone 2’-Hydroxy-5-methoxy-6,7-methylenedioxyisoflavone 4’-Hydroxy-5-methoxy-6,7-methylenedioxyisoflavone 5-Hydroxy-2’-methoxy-6,7-methylenedioxyisoflavone 5-Hydroxy-7-methoxy-3’,4’-methylenedioxyisoflavone 6-Hydroxy-7-methoxy-3’,4’-methylenedioxyisoflavone 7-Hydroxy-2’-methoxy-4’,5’-methylenedioxyisoflavone 7-Hydroxy-6-methoxy-3’,4’-methylenedioxyisoflavone 7-Hydroxy-8-methoxy-3’,4’-methylenedioxyisoflavone 7,3’,4’-Trimethoxyisoflavone 2’,5’-Diketo-5,7-dihydroxy-4’-methoxyisoflavone 2’,4’-Dihydroxy-5,7-dimethoxyisoflavone 5,2’-Dihydroxy-6,7-dimethoxyisoflavone 5,2’-Dihydroxy-7,8-dimethoxyisoflavone 5,3’-Dihydroxy-7,4’-dimethoxyisoflavone 5,4’-Dihydroxy-6,7-dimethoxyisoflavone 7-O-Methyltectorigenin

Irilin A

Acicerone Cuneatin Fujikinetin Maximaisoflavone E Cabreuvin 5-Hydroxybowdichione

Maximaisoflavone A Betavulgarin Irisolone Irisone A

Gliricidin

3’-O-Methylorobol Tectorigenin Isotectorigenin Koparin

2’-Hydroxybiochanin A Pratensein

Afrormosin 8-O-Methylretusin Cajanin Santal

298.30 298.30 300.27 300.27 300.27 300.27 300.27 300.27 300.27 300.27 300.27 300.27 300.27 300.27 300.27 300.27 300.27 302.24 310.26 312.28 312.28 312.28 312.28 312.28 312.28 312.28 312.28 312.32 314.25 314.29 314.29 314.29 314.29 314.29

C17H14O5 C17H14O5 C16H12O6 C16H12O6 C16H12O6 C16H12O6 C16H12O6 C16H12O6 C16H12O6 C16H12O6 C16H12O6 C16H12O6 C16H12O6 C16H12O6 C16H12O6 C16H12O5 C16H12O6 C15H10O5 C17H10O6 C17H12O6 C17H12O6 C17H12O6 C17H12O6 C17H12O6 C17H12O6 C17H12O6 C17H12O6 C18H16O5 C16H10O7 C17H14O6 C17H14O6 C17H14O6 C17H14O6 C17H14O6

Appendix

continued

2365 2366 2431 2432 F91 2428 2429 F125 2430 2433 2434 2367 2838 2368 F25 2879 2893 2892 2369 2435 2436 2882 F352 F139 2370 2372 2846 2371 2979 2871 F18 2890 2842 2439

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1143

397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427

5,4’-Dihydroxy-7,3’-dimethoxyisoflavone 5,7-Dihydroxy-2’,4’-dimethoxyisoflavone 5,7-Dihydroxy-3’,4’-dimethoxyisoflavone 5,7-Dihydroxy-6,2’-dimethoxyisoflavone 5,7-Dihydroxy-6,4’-dimethoxyisoflavone 5,7-Dihydroxy-8,4’-dimethoxyisoflavone 6,4’-Dihydroxy-5,7-dimethoxyisoflavone 7,2’-Dihydroxy-4’,5’-dimethoxyisoflavone 7,2’-Dihydroxy-6,4’-dimethoxyisoflavone 7,3’-Dihydroxy-6,4’-dimethoxyisoflavone 7,3’-Dihydroxy-8,4’-dimethoxyisoflavone 7,4’-Dihydroxy-3’,5’-dimethoxyisoflavone 7,4’-Dihydroxy-5,3’-dimethoxyisoflavone 7,8-Dihydroxy-6,4’-dimethoxyisoflavone 5,6,7,2’-Tetrahydroxy-3’-methoxyisoflavone 5,6,7,3’-Tetrahydroxy-4’-methoxyisoflavone 5,6,7,4’-Tetrahydroxy-8-methoxyisoflavone 5,7,2’,4’-Tetrahydroxy-5’-methoxyisoflavone 5,7,3’,4’-Tetrahydroxy-6-methoxyisoflavone 5,7,3’,5’-Tetrahydroxy-4’-methoxyisoflavone 4’-Hydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 4’-Hydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 6-Hydroxy-6’’,6’’-dimethylpyrano[2’’,3’’: 4’,3’]isoflavone 7-Hydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’.3’]isoflavone 7-Hydroxy-4’-prenyloxyisoflavone 7,4’-Dihydroxy-3’-prenylisoflavone 7,4’-Dihydroxy-8-prenylisoflavone 7-Acetoxy-2’-methoxy-8-methylisoflavone 3’,4’-Dimethoxy-6,7-methylenedioxyisoflavone 3’,4’-Dimethoxy-7,8-methylenedioxyisoflavone 5,2’-Dimethoxy-6,7-methylenedioxyisoflavone

Name

Maximaisoflavone D Tlatlancuayin

Corylin Nordurlettone Neobavaisoflavone 8-Prenyldaidzein

Piscerygenin Irilin D Junipegenin A Erythrinin A Bidwillon C

314.29 314.29 314.29 314.29 314.29 314.29 314.29 314.29 314.29 314.29 314.29 314.29 314.29 314.29 316.27 316.27 316.27 316.27 316.27 316.27 320.34 320.34 320.34 320.34 322.36 322.36 322.36 324.34 326.31 326.31 326.31

Mass C17H14O6 C17H14O6 C17H14O6 C17H14O6 C17H14O6 C17H14O6 C17H14O6 C17H14O6 C17H14O6 C17H14O6 C17H14O6 C17H14O6 C17H14O6 C17H14O6 C16H12O7 C16H12O7 C16H12O7 C16H12O7 C16H12O7 C16H12O7 C20H16O4 C20H16O4 C20H16O4 C20H16O4 C20H18O4 C20H18O4 C20H18O4 C19H16O5 C18H14O6 C18H14O6 C18H14O6

Formula

2872 2437 2841 2850 2438 F23 2440 F35 2876 2373 2374 F37 F36 2375 2852 F112 2855 F176 F42 2441 2397 F104 F4 2396 2868 2398 F85 F27 2378 2848 2443

Ref.

1144

Gerontoisoflavone A Dipteryxin

Odoratin 3’-Hydroxy-8-O-methylretusin

Muningin

Irisolidone

7,3’-Dimethylorobol 2’-Methoxybiochanin A Pratensein 3’-O-methyl ether

Trivial Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461

5,4’-Dimethoxy-6,7-methylenedioxyisoflavone 5,7-Dimethoxy-3’,4’-methylenedioxyisoflavone 6,7-Dimethoxy-3’,4’-methylenedioxyisoflavone 7,2’-Dimethoxy-4’,5’-methylenedioxyisoflavone 7,3’-Dimethoxy-4’,5’-methylenedioxyisoflavone 7,8-Dimethoxy-3’,4’-methylenedioxyisoflavone 5-Carboxyaldehyde-5,7,3’-trihydroxy-4’-methoxyisoflavone 5,3’-Dihydroxy-2’-methoxy-6,7-methylenedioxyisoflavone 5,3’-Dihydroxy-4’-methoxy-6,7-methylenedioxyisoflavone 5,7-Dihydroxy-6-methoxy-3’,4’-methylenedioxyisoflavone 6,3’-Dihydroxy-7-methoxy-4’,5’-methylenedioxyisoflavone 6,7-Dihydroxy-3’-methoxy-4’,5’-methylenedioxyisoflavone 2’-Hydroxy-7,3’,4’-trimethoxyisoflavone 3’-Hydroxy-6,7,4’-trimethoxyisoflavone 5-Hydroxy-6,7,4’-trimethoxyisoflavone 5-Hydroxy-7,3’,4’-trimethoxyisoflavone 6-Hydroxy-7,2’,4’-trimethoxyisoflavone 7-Hydroxy-2’,4’,5’-trimethoxyisoflavone 7-Hydroxy-5,6,4’-trimethoxyisoflavone 7-Hydroxy-5,8,4’-trimethoxyisoflavone 7-Hydroxy-6,3’,4’-trimethoxyisoflavone 7-Hydroxy-8,3’,4’-trimethoxyisoflavone 5,3’,4’-Trihydroxy-6,7-dimethoxyisoflavone 5,6,3’-Trihydroxy-7,2’-dimethoxyisoflavone 5,6,4’-Trihydroxy-7,3’-dimethoxyisoflavone 5,7,2’-Trihydroxy-4’,5’-dimethoxyisoflavone 5,7,2’-Trihydroxy-6,5’-dimethoxyisoflavone 5,7,3’-Trihydroxy-6,4’-dimethoxyisoflavone 5,7,3’-Trihydroxy-8,4’-dimethoxyisoflavone 5,7,4’-Trihydroxy-2’,5’-dimethoxyisoflavone 5,7,4’-Trihydroxy-6,3’-dimethoxyisoflavone 5,7,4’-Trihydroxy-6,8-dimethoxyisoflavone 5,8,3’-Trihydroxy-7,2’-dimethoxyisoflavone 6,7,3’-Trihydroxy-5,2’-dimethoxyisoflavone Olibergin A Iristectorigenin B

2’-Hydroxy-5’-methoxybiochanin A Podospicatin Iristectorigenin A

5-Methoxyafrormosin Iso-5-methoxyafrormosin Cladrastin

Isocladrastin 7,4’-Di-O-methyltectorigenin

Soforanarin A Dalspinin

5’-Formylpratensein

Irisolone methyl ether Derrustone Fujikinetin methyl ether Cuneatin methyl ether

326.31 326.31 326.31 326.31 326.31 326.31 328.28 328.28 328.28 328.28 328.28 328.28 328.32 328.32 328.32 328.32 328.32 328.32 328.32 328.32 328.32 328.32 330.29 330.29 330.29 330.29 330.29 330.29 330.29 330.29 330.29 330.29 330.29 330.29

C18H14O6 C18H14O6 C18H14O6 C18H14O6 C18H14O6 C18H14O6 C17H12O7 C17H12O7 C17H12O7 C17H12O7 C17H12O7 C17H12O7 C18H16O6 C18H16O6 C18H16O6 C18H16O6 C18H16O6 C18H16O6 C18H16O6 C18H16O6 C18H16O6 C18H16O6 C17H14O7 C17H14O7 C17H14O7 C17H14O7 C17H14O7 C17H14O7 C17H14O7 C17H14O7 C17H14O7 C17H14O7 C17H14O7 C17H14O7

Appendix

continued

2444 2442 2377 2376 F53 2880 F336 2883 F15 2853 F356 F312 2380 F217 2445 F299 F313 2379 2446 2447 2381 2382 2884 F3 F91 2873 2448 2449 2451 F111 2450 F23 F3 F3

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1145

7,8,3’-Trihydroxy-6,4’-dimethoxyisoflavone 4’-Methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 2’-Methoxy-4’,5’-methylenedioxyfurano[2’’,3’’:7,6]isoflavone 3’,4’-Methyleneoxyfurano[2’’,3’’:7,8]isoflavone 5,4’-Dihydroxy-5’’-(1-methylethenyl)-4’’,5’’-dihydrofurano[2’’,3’’:7,6]isoflavone 5,4’-Dihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5,4’-Dihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 5,7-Dihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflavone 7,2’-Dihydroxy-6’’,6’’-dimethylpyrano(2’’,3’’:4’,3’)isoflavone 7,2’-Dihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’]isoflavone 7,2’-Dihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflavone 7,4’-Methoxy-4’-prenyloxyisoflavone 4’-Methoxy-7-prenyloxyisoflavone 5,4’-Dihydroxy-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:7,6]isoflavone 5,4’-Dihydroxy-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:7,8]isoflavone 5,7,4’-Trihydroxy-3’-prenylisoflavone 5,7,4’-Trihydroxy-6-(1,1-dimethyl-2-propenyl)isoflavone 5,7,4’-Trihydroxy-6-prenylisoflavone 5,7,4’-Trihydroxy-8-(1,1-dimethylprop-2-enyl)isoflavone 5,7,4’-Trihydroxy-8-prenylisoflavone 7,2’,4’-Trihydroxy-3’-prenylisoflavone 7,5’’-Dihydroxy-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:4’,3’]isoflavone 3’-Methoxy-6,7:4’,5’-bis(methylenedioxy)isoflavone 5-Methoxy-6,7:3’,4’-bis(methylenedioxy)isoflavone 5,7,8-Trimethoxy-3’,4’-methylenedioxyisoflavone 3’-Hydroxy-5,4’-dimethoxy-6,7-methylenedioxyisoflavone 3’-Hydroxy-5,5’-dimethoxy-6,7-methylenedioxyisoflavone 4’-Hydroxy-3’,5’-dimethoxy-6,7-methylenedioxyisoflavone 4’-Hydroxy-5,3’-dimethoxy-6,7-methylenedioxyisoflavone 5-Hydroxy-3’,4’-dimethoxy-6,7-methylenedioxyisoflavone 5-Hydroxy-7,3’-dimethoxy-4,5-methylenedioxyisoflavone Iriskumaonin Isoiriskashmirianin Kashmigenin Iriskashmirianin Squarrosin Sanchemarroquin

Lupiwighteone Eurycarpin A Psoralenol

Calopogoniumisoflavone A Dehydroneotenone Garhwalin Licoagroisoflavone Alpinumisoflavone 5 Derrone Isoderrone Eurycarpin B Puerarone Glabron Durlettone Maximaisoflavone J Erythrivarone A Crotalarin Isowighteone 6-(1,1-Dimethylallyl)genistein Wighteone

Trivial Name 330.29 334.37 336.30 336.30 336.34 336.34 336.34 336.34 336.34 336.34 336.34 336.38 336.39 338.36 338.36 338.36 338.36 338.36 338.36 338.36 338.36 338.36 340.28 340.28 340.33 342.30 342.30 342.30 342.30 342.30 342.30

Mass C17H14O7 C21H18O4 C19H12O6 C19H12O6 C20H16O5 C20H16O5 C20H16O5 C20H16O5 C20H16O5 C20H16O5 C20H16O5 C21H20O4 C21H20O4 C20H18O5 C20H18O5 C20H18O5 C20H18O5 C20H18O5 C20H18O5 C20H18O5 C20H18O5 C20H18O5 C18H12O7 C18H12O7 C19H16O6 C18H14O7 C18H14O7 C18H14O7 C18H14O7 C18H14O7 C18H14O7

Formula

F253 2399 2402 2934 F141 2468 2469 2898 F353 2896 2400 2401 2835 F94 2933 2856 2470 2471 F210 2921 F354 2403 F299 F299 F180 2453 2888 F217 2887 2886 F56

Ref.

1146

462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492

Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525

6-Hydroxy-7,2’-dimethoxy-4’,5’-methylenedioxyisoflavone 7-Hydroxy-5,6-dimethoxy-3’,4’-methylenedioxyisoflavone 7-Hydroxy-5,8-dimethoxy-3’,4’-methylenedioxyisoflavone 7-Hydroxy-6,2’-dimethoxy-4’,5’-methylenedioxyisoflavone 7-Hydroxy-8,2’-dimethoxy-4’,5’-methylenedioxyisoflavone 6,7,3’,4’-Tetramethoxyisoflavone 7,2’,4’,5’-Tetramethoxyisoflavone 5,3’-Dihydroxy-6,7,2’-trimethoxyisoflavone 5,3’-Dihydroxy-7,4’,5’-trimethoxyisoflavone 5,3’-Dihydroxy-7,8,2’-trimethoxyisoflavone 5,4’-Dihydroxy-7,2’,5’-trimethoxyisoflavone 5,7-Dihydroxy-2’,4’,5’-trimethoxyisoflavone 5,7-Dihydroxy-3’,4’,5’-trimethoxyisoflavone 5,7-Dihydroxy-6,3’,4’-trimethoxyisoflavone 5,7-Dihydroxy-6,8,4’-trimethoxyisoflavone 5,7-Dihydroxy-8,3’,4’-trimethoxyisoflavone 6,3’-Dihydroxy-5,7,2’-trimethoxyisoflavone 7,3’-Dihydroxy-5,6,2’-trimethoxyisoflavone 8,3’-Dihydroxy-5,7,2’-trimethoxyisoflavone 3’,4’-Methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 3’,4’-Methylenedioxy-7-prenyloxyisoflavone 4’-Hydroxy-5-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 5-Hydroxy-4’-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5-Hydroxy-4’-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 5-Methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 7-Hydroxy-3’-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’]isoflavone 7,8-Methylenedioxy-4’-prenyloxyisoflavone 5,2’,4’-Trihydroxy-5’’-(1-methylethenyl)-4’’,5’’-dihydrofurano[2’’,3’’:7,6]isoflavone 5,2’,4’-Trihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5,2’,4’-Trihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 5,4’-Dihydroxy-4’’,5’’-epoxy-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:7,6]isoflavone 5,4’-Dihydroxy-5’’-(1-hydroxy-1-methylethyl)furano[2’’,3’’:7,6]isoflavone 5,4’-Dihydroxy-6’’-hydroxymethyl-6’’-methylpyrano[2’’,3’’:6,7]isoflavone Calopogoniumisoflavone B Maximaisoflavone B Lanceolone 4’-O-Methylalpinumisoflavone 4’-O-Methylderrone Indicanine C Piscisoflavone C Auricularin Lupinisoflavone A Parvisoflavone B Parvisoflavone A Anagyroidisoflavone B Erysubin A Hydroxyalpinumisoflavone

Derrugenin 7-Demethylrobustigenin Panchovillin Junipegenin B

Vavain

Dipteryxine Platycarpanetin Dalpatein Maximaisoflavone F

342.30 342.30 342.30 342.30 342.30 342.35 342.35 344.32 344.32 344.32 344.32 344.32 344.32 344.32 344.32 344.32 344.32 344.32 344.32 348.36 350.37 350.37 350.37 350.37 350.37 350.37 350.37 352.34 352.34 352.34 352.34 352.34 352.34

C18H14O7 C18H14O7 C18H14O7 C18H14O7 C18H14O7 C19H18O6 C19H18O6 C18H16O7 C18H16O7 C18H16O7 C18H16O7 C18H16O7 C18H16O7 C18H16O7 C18H16O7 C18H16O7 C18H16O7 C18H16O7 C18H16O7 C21H16O5 C21H18O5 C21H18O5 C21H18O5 C21H18O5 C21H18O5 C21H18O5 C21H18O5 C20H16O6 C20H16O6 C20H16O6 C20H16O6 C20H16O6 C20H16O6

Appendix

continued

2384 2452 2454 2385 2849 2386 2383 F3 F189 2891 2455 F336 2874 2456 F23 2457 F3 F3 F3 2404 2405 F199 2472 2473 F305 F176 F213 2862 2475 2476 F222 F283 F202

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1147

526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556

5,4’-Dihydroxy-6’’-hydroxymethyl-6’’-methylpyrano[2’’,3’’:7,6]isoflavone 5,7,2’-Trihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’.3’]isoflavone 5,7,3’-Trihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’]isoflavone 5,7,4’-Trihydroxy-5’’-(1-methylethenyl)-4’’,5’’-dihydrofurano[2’’,3’’:2’,3’]isoflavone 5,7,4’-Trihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:2’,3’]isoflavone 3’-Hydroxy-4’-methoxy-7-prenyloxyisoflavone 5,4’-Dihydroxy-7’-methoxy-6-prenylisoflavone 5,7-Dihydroxy-4’-methoxy-3’-prenylisoflavone 5,7-Dihydroxy-4’-methoxy-6-prenylisoflavone 5,7-Dihydroxy-4’-methoxy-8-prenylisoflavone 7,4’-Dihydroxy-5-methoxy-8-prenylisoflavone (2E)-5,7,4’-Trihydroxy-3’-(4-hydroxy-3-methyl-2-butenyl)isoflavone (2E)-5,7,4’-Trihydroxy-6-(4-hydroxy-3-methyl-2-butenyl)isoflavone 5,2’,4’-Trihydroxy-4’’,4’’,5’’-trimethyl-4’’,5’’-dihydrofurano(2’’,3’’:7,6)isoflavone 5,2’,4’-Trihydroxy-7-prenyloxyisoflavone 5,4’-Dihydroxy-5’’-(1-hydroxy-1-methylethyl)-4’’,5’’-dihydrofurano[2’’,3’’:7,6]isoflavanone 5,7-Dihydroxy-5’’-(1-hydroxy-1-methylethyl)-4’’,5’’-dihydrofurano[2’’,3’’:4’,3’]isoflavone 5,7,2’,4’-Tetrahydroxy-3’-prenylisoflavone 5,7,2’,4’-Tetrahydroxy-5’-(1,1-dimethyl-2-propenyl)isoflavone 5,7,2’,4’-Tetrahydroxy-5’-prenylisoflavone 5,7,2’,4’-Tetrahydroxy-6-prenylisoflavone 5,7,2’,4’-Tetrahydroxy-8-(1,1-dimethylprop-2-enyl)isoflavone 5,7,2’,4’-Tetrahydroxy-8-prenylisoflavone 5,7,3’,4’-Tetrahydroxy-6-prenylisoflavone 5,7,3’,4’-Tetrahydroxy-8-prenylisoflavone 5,7,4’-Trihydroxy-6-(2-hydroxy-3-methyl-3-butenyl)isoflavone 5,7,4’-Trihydroxy-6-(4-hydroxy-3-methyl-2-butenyl)isoflavone 5,7,4’-Trihydroxy-8-(4-hydroxy-3-methyl-2-butenyl)isoflavone 5,7,5’’(S)-Trihydroxy-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’;4’,3’]isoflavone 5,2’,5’-Trimethoxy-6,7-methylenedioxyisoflavone 5,3’,4’-Trimethoxy-6,7-methylenedioxyisoflavone

Name

Gancaonin L Laburnetin Hydroxywighteone Gancaonin C Ficuisoflavone Hemerocallone Iriskumaonin methyl ether

2,3-Dehydrokievitone

Erythrinin C Lupinisoflavone C Licoisoflavone A Fremontin Allolicoisoflavone A Luteone

352.34 352.34 352.34 352.34 352.34 352.38 352.38 352.38 352.38 352.38 352.38 354.36 354.36 354.36 354.36 354.36 354.36 354.36 354.36 354.36 354.36 354.36 354.36 354.36 354.36 354.36 354.36 354.36 354.36 356.33 356.33

Mass

C20H16O6 C20H16O6 C20H16O6 C20H16O6 C20H16O6 C21H20O5 C21H20O5 C21H20O5 C21H20O5 C21H20O5 C21H20O5 C20H18O6 C20H18O6 C20H18O6 C20H18O6 C20H18O6 C20H18O6 C20H18O6 C20H18O6 C20H18O6 C20H18O6 C20H18O6 C20H18O6 C20H18O6 C20H18O6 C20H18O6 C20H18O6 C20H18O6 C20H18O6 C19H16O7 C19H16O7

Formula

F283 2474 2905 2900 2899 2836 2913 F336 2912 2922 2923 F209 F345 F210 F210 2479 2857 2477 2901 F176 2478 F210 2480 2915 2925 F222 2917 2927 F142 2844 2459

Ref.

1148

Gancaonin A Gancaonin M 5-Methyllupiwighteone Vogelin E Glabrisoflavone

Gancaonin G

Erysubin B Licoisoflavone B Semilicoisoflavone B Crotarin Sophoraisoflavone A

Trivial Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589

5,6,7-Trimethoxy-3’,4’-methylenedioxyisoflavone 6,7,2’-Trimethoxy-4’,5’-methylenedioxyisoflavone 6,7,3’-Trimethoxy-4’,5’-methylenedioxyisoflavone 6,7,8-Trimethoxy-3’,4’-methylenedioxyisoflavone 7,8,2’-Trimethoxy-3’,4’-methylenedioxyisoflavone 7,8,2’-Trimethoxy-4’,5’-methylenedioxyisoflavone 8,3’,4’-Trimethoxy-6,7-methylenedioxyisoflavone 5,3’-Dihydroxy-4’,5’-dimethoxy-6,7-methylenedioxyisoflavone 5,7-Dihydroxy-6,2’-dimethoxy-4’,5’-methylenedioxyisoflavone 3’-Hydroxy-5,6,7,2’-tetramethoxyisoflavone 5-Hydroxy-6,7,3’,4’-tetramethoxyisoflavone 5-Hydroxy-7,2’,4’,5’-tetramethoxyisoflavone 6-Hydroxy-2’,4’,5’,7-tetramethoxyisoflavone 7-Hydroxy-6,2’,4’,5’-trimethoxyisoflavone 7,4’-Dihydroxy-5,3’,5’-trimethoxy-6-methylisoflavone 5,7-Dihydroxy-4’-(p-methylbenzyl)isoflavone 5,7,3’-Trihydroxy-6,4’,5’-trimethoxyisoflavone 5,7,4’-Trihydroxy-2’,3’,6’-trimethoxyisoflavone 6,4’,5’-Trihydroxy-5,7,3’-trimethoxyisoflavone 7,8,5’-Trihydroxy-6,3’,4’-trimethoxyisoflavone 3-Hydroxy-4’,5’-methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 3’-Carboxyaldehyde-5,4’-dihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 3’-Hydroxy-4,5-methylenedioxy-6’’,6’’-dimethylpyrano(2’’,3’’:7,8)isoflavone 5-Hydroxy-3’,4’-methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5-Hydroxy-3’,4’-methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 5,4’-Dimethoxy-5’’-(1-methylethenyl)-4’’,5’’-dihydrofurano[2’’,3’’:7,6]isoflavone 5,4’-Dimethoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 6,4’-Dimethoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 2’-Hydroxy-3’,4’-methylenedioxy-7-prenyloxyisoflavone 2’,4’-Dihydroxy-5-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 5,3’-Dihydroxy-4’-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5,7-Dihydroxy-3’,4’-methylenedioxy-6-prenylisoflavone 7,2’-Dihydroxy-5-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’]isoflavone Thonninginisoflavone Alpinumisoflavone dimethyl ether 6-Methoxycalopogonium Maximaisoflavone K Barpisoflavone C 3’-Hydroxyalpinumisoflavone 4’-methyl ether Derrubone Glycyrrhiza isoflavone B

Norisojamicin Scandenal Norisojamicin Robustone

Irigenin Nervosin Soforanarin B

Brachyrachisin

Belamcandin Robustigenin

Dalpalatin

Petalostetin Maximaisoflavone L

Odoratine

356.33 356.33 356.33 356.33 356.33 356.33 356.33 358.30 358.30 358.35 358.35 358.35 358.35 358.35 358.35 358.39 360.32 360.32 360.32 360.32 364.35 364.35 364.35 364.35 364.35 364.40 364.40 364.40 366.36 366.36 366.36 366.36 366.36

2458 2387 2388 2390 F205 2389 2391 2854 2889 F3 2885 2460 F130 2392 F221 F178 2461 F107 F15 F208 F333 F43 F342 2481 2932 F13 2482 F340 F205 2931 2484 2483 F89

Appendix

continued

C19H16O7 C19H16O7 C19H16O7 C19H16O7 C19H16O7 C19H16O7 C19H16O7 C18H14O8 C18H14O8 C19H18O7 C19H18O7 C19H18O7 C19H18O7 C19H18O7 C19H18O7 C23H18O4 C18H16O8 C18H16O8 C18H16O8 C18H16O8 C21H16O6 C21H16O6 C21H16O6 C21H16O6 C21H16O6 C22H20O5 C22H20O5 C22H20O5 C21H18O6 C21H18O6 C21H18O6 C21H18O6 C21H18O6

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_app Revise Proof page 1149 6.10.2005 2:36pm

1149

590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620

7,2’-Dihydroxy-5’-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflavone 7,4’-Dihydroxy-5’-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:3’,2’]isoflavone 3’,4’-Dihydroxy-7-prenyloxyisoflavone 5,2’,4’-Trihydroxy-7-methoxy-6-prenylisoflavone 5,7-Dihydroxy-6-methoxy-4’-prenyloxyisoflavone 5,7-Dihydroxy-8-methoxy-4’-prenyloxyisoflavone 5,7,2’-Trihydroxy-4’-methoxy-5’-prenylisoflavone 5,7,2’-Trihydroxy-4’-methoxy-6-prenylisoflavone 5,7,3’-Trihydroxy-4’-methoxy-5’-prenylisoflavone 5,7,3’-Trihydroxy-4’-methoxy-6-prenylisoflavone 5,7,4’-Trihydroxy-2-methoxy-5’-prenylisoflavone 5,7,4’-Trihydroxy-3’-methoxy-5’-prenylisoflavone 5,7,4’-Trihydroxy-3’-methoxy-8-prenylisoflavone 5,7,4’-Trihydroxy-5’-methoxy-3’-prenylisoflavone 7,2’-Dihydroxy-6’-methoxy-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:4’,5’]isoflavone 7,2’,3’-Trihydroxy-4’-methoxy-3’-(1,1-dimethyl-2-propenyl)isoflavone 7,2’,4’-Trihydroxy-5-methoxy-8-prenylisoflavone 7,2’,4’-Trihydroxy-5’-methoxy-3’-prenylisoflavone 7,3’,4’-Trihydroxy-5-methoxy-5’-prenylisoflavone 7,4’,6’-Trihydroxy-3’-methoxy-2’-prenylisoflavone 5,2’-Dimethoxy-6,7:4’,5’-bis(methylenedioxy)isoflavone 5,3’-Dimethoxy-6,7:4’,5’-bis(methylenedioxy)isoflavone 5,2’,4’-Trihydroxy-5’’-(1-hydroxy-1-methylethyl)-4’’,5’’-dihydrofurano[2’’,3’’:7,6]isoflavone 5,2’,4’-Trihydroxy-5’’-(1-hydroxy-1-methylethyl)-4’’,5’’-dihydrofurano[2’’,3’’:7,8]isoflavone 5,7,2’-Trihydroxy-5’’-(1-hydroxy-1-methylethyl)-4’’,5’’-dihydrofurano[2’’,3’’:4’,3’]isoflavone 5,7,2’,4’-Tetrahydroxy-8-(4-hydroxy-3-methyl-2-butenyl)isoflavone 5-Hydroxy-3’,4’,5’-trimethoxy-6,7-methylenedioxyisoflavone 5,6,7,3’,4’-Pentamethoxyisoflavone 5,7,2’,4’-Tetrahydroxy-8-(3-hydroxy-3-methyl-2-butyl)isoflavone 5,7,2’,4’,5’-Pentamethoxyisoflavone 6,7,2’,3’,4’-Tetramethoxyisoflavone

Name

2,3-Dehydrokievitol hydrate Robustigenin methyl ether

Lupinisoflavone B Lunatone Lupinisoflavone D 2,3-Dehydrokievitol

Secundiflorol C Barpisoflavone B Piscisoflavone A Glisoflavone Kwakhurin

2’-Deoxypiscerythrone

366.36 366.36 366.41 368.39 368.39 368.39 368.39 368.39 368.39 368.39 368.39 368.39 368.39 368.39 368.39 368.39 368.39 368.39 368.39 368.39 370.32 370.32 370.36 370.36 370.36 370.36 372.33 372.37 372.37 372.37 372.37

Mass C21H18O6 C21H18O6 C22H22O5 C21H20O6 C21H20O6 C21H20O6 C21H20O6 C21H20O6 C21H20O6 C21H20O6 C21H20O6 C21H20O6 C21H20O6 C21H20O6 C21H20O6 C21H20O6 C21H20O6 C21H20O6 C21H20O6 C21H20O6 C19H14O8 C19H14O8 C20H18O7 C20H18O7 C20H18O7 C20H18O7 C19H16O8 C20H20O7 C20H20O7 C20H20O7 C20H20O7

Formula

F176 F264 2837 F339 2851 2485 F62 2914 F336 2916 F209 2859 2926 F264 F89 F103 2924 F176 2902 2897 F299 F299 2863 2935 2858 2928 F322 F299 2930 2462 2393

Ref.

1150

Gancaonin B Vogelin F 2’-Deoxypiscerythrone

7-O-Methylluteone Isoaurmillone Aurmillone Lysisteisoflavanone Gancaonin N

Piscisoflavone B Piscisoflavone D

Trivial Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653

6,7,2’,4’,5’-Tetramethoxyisoflavone 6,7,3’,4’,5’-Tetramethoxyisoflavone 7,8,3’,4’,5’-Pentamethoxyisoflavone 5,3’-Dihydroxy-6,7,8,2’-tetramethoxyisoflavone 5,7-Dihydroxy-6,2’,3’,4’-tetramethoxyisoflavone 5,7-Dihydroxy-6,2’,4’,5’-tetramethoxyisoflavone 5,7-Dihydroxy-6,3’,4’,5’-tetramethoxyisoflavone 5,7-Dihydroxy-8,2’,4’,5’-tetramethoxyisoflavone 5-Hydroxy-5’-methoxy-2’-prenyloxazol[2’’,3’’:4’,3’]isoflavone 7-Hydroxy-5’-methoxy-2’-prenyloxazol[2’’,3’’:4’,3’]isoflavone 2’-Methoxy-4’,5’-methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 3’-Methoxy-4’,5’-methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 5-Methoxy-3’,4’-methylenedioxy-5’’-(1-methylethenyl)-4’’,5’’-dihydrofurano[2’’,3’’:7,6]isoflavone 5-Methoxy-3’,4’-methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 6-Methoxy-3’,4’-methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 2’-Hydroxy-5,4’-dimethoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 2’-Methoxy-4’,5’-methylenedioxy-7-prenyloxyisoflavone 6-Hydroxy-3’,4’-dimethoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 7-Hydroxy-6-methoxy-3’,4’-methylenedioxy-8-prenylisoflavone 8-Methoxy-3’,4’-methylenedioxy-7-prenyloxyisoflavone 5,5’’-Dihydroxy-3’,4’-dimethylenedioxy-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:7,6]isoflavone 5,7,3’,5’’-Tetrahydroxy-5-methoxy-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:4’,5’]isoflavone 5,7-Dihydroxy-3’,4’-dimethoxy-5’-prenylisoflavone 7,3’-Dihydroxy-5,4’-dimethoxy-5’-prenylisoflavone 7,6’-Dihydroxy-2’,4’-dimethoxy-3’-prenylisoflavone 5,4’-Dihydroxy-5’’-(1-hydroxy-1-methylethyl)-4’’-methoxyfurano[2’’,3’’:7,6]isoflavone 5,4’,5’’-Trihydroxy-4’’-methoxy-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:7,6]isoflavone 5,7-Dihydroxy-3’-methoxy-5’’-(1-hydroxy-1-methylethyl)-4’’,5’’-dihydrofurano[2’’,3’’:4’,5’]isoflavone 5,7,2’-Trihydroxy-4’-methoxy-8-(4-hydroxy-3-methyl-2-butenyl)isoflavone 5,7,2’,3’-Tetrahydroxy-4’-methoxy-3’-(1,1-dimethyl-2-propenyl)isoflavone 5,7,2’,4’-Tetrahydroxy-5’-methoxy-3’-prenylisoflavone 5,7,2’,4’-Tetrahydroxy-5’-methoxy-6-prenylisoflavone 5,7,3’,4’-Tetrahydroxy-5’-methoxy-2’-prenylisoflavone Anagyroidisoflavone A Piscerynetol Gancaonin D Secundiflorol B Piscerythrone Isopiscerythrone Piscidone

Licoricone

Harpalycin Glycyrrhiza isoflavone A Piscerythrinetin

Predurmillone

Irisjaponin B Caviunin Junipegenin C Isocaviunin Piscerythoxazole Piscerythoxazole Jamaicin Isojamaicin Glabrescione A Robustone methyl ether Durmillone Indicanin E Maximaisoflavone C

372.37 372.37 372.37 374.35 374.35 374.35 374.35 374.35 377.39 377.39 378.38 378.38 378.38 378.38 378.38 380.40 380.40 380.40 380.40 380.40 382.27 382.37 382.41 382.41 382.41 384.39 384.39 384.39 384.39 384.39 384.39 384.39 384.39

2394 2395 F40 2894 F169 2463 2464 2465 F177 F264 2406 2911 2487 2486 2407 F184 2408 F341 2936 2847 F47 F89 2903 2904 2409 F138 F222 F264 2929 F103 2488 F176 F268

Appendix

continued

C20H20O7 C20H20O7 C20H20O7 C19H18O8 C19H18O8 C19H18O8 C19H18O8 C19H18O8 C22H19O5N1 C22H19O5N1 C22H18O6 C22H18O6 C22H18O6 C22H18O6 C22H18O6 C22H20O6 C22H20O6 C22H20O6 C22H20O6 C22H20O6 C21H18O7 C20H18O7 C22H22O6 C22H22O6 C22H22O6 C21H20O7 C21H20O7 C21H20O7 C21H20O7 C21H20O7 C21H20O7 C21H20O7 C21H20O7

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_app Revise Proof page 1151 6.10.2005 2:36pm

1151

654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684

5,7,4’-Trihydroxy-3’-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:5’,6’]isoflavone 5,2’,3’,6’-Tetrahydroxy-6,7-methylenedioxyisoflavone 5,3’,4’,5’-Tetramethoxy-6,7-methylenedioxyisoflavone 5,6,7,8-Tetramethoxy-3’,4’-methylenedioxyisoflavone 7,4’,6’-Trihydroxy-3’-methoxy-2’-(3-hydroxy-3-methylbutyl)isoflavone 6,8,3’-Trichloro-5,4’-dihydroxy-7-methoxyisoflavone 4’-Prenyloxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 7,3’-Dihydroxy-8,2’-diprenylisoflavone 5-Hydroxy-8-methoxy-3’,4’-methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 6-Hydroxy-5-methoxy-3’,4’-methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 2’,4’,5’-Trimethoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 2’,4’,5’-Trimethoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 6,3’,4’-Trimethoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 4’-Hydroxy-2’,5’-dimethoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5,4’-Dihydroxy-2’,5’-dimethoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 5,4’-Dihydroxy-3’,5’-dimethoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 7-Hydroxy-6,3’,4’-trimethoxy-8-prenylisoflavone 5,7,4’-Trihydroxy-5’-methoxy-5’’-(1-hydroxy-1-methylethyl)-4’’,5’’-dihydrofurano[2’’,3’’:2’,3’]isoflavone 5,7-Dihydroxy-4’,5’-dimethoxy-3’-((1E)-3-hydroxy-3-methyl-1-butenyl)isoflavone 5,7,2’-Trihydroxy-4’,5’-dimethoxy-3’-prenylisoflavone 5,7,4’-Trihydroxy-2’,5’-dimethoxy-6-prenylisoflavone 5,7,2’-Trihydroxy-5’-methoxy-5’’-(1-hydroxy-1-methylethyl)-4’’,5’’-dihydrofurano[2’’,3’’:4’,3’]isoflavone 5,7,2’,4’-Tetrahydroxy-5’-methoxy-3’-((2E)-4-hydroxy-3-methyl-2-butenyl)isoflavone 5,7,2’,5’’-Tetrahydroxy-5’-methoxy-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:4’,3’]isoflavone 5,7,4’-Trihydroxy-5’-methoxy-5’’-(1-hydroxy-1-methylethyl)-4’’,5’’-dihydrofurano[2’’,3’’:2’,3’]isoflavone 5,7,4’,5’’-Tetrahydroxy-5’-methoxy-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:2’,3’]isoflavone 5,7,4’,5’’-Tetrahydroxy-5’-methoxy-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:3’,2’]isoflavone 6,7,8,3’,4’,5’-Hexamethoxyisoflavone 5-Hydroxy-(2’’,3’’:7,6),(2’’’,3’’’:4’,3’)-bis(6,6-dimethylpyrano)isoflavone 5-Hydroxy-(2’’,3’’:7,8),(2’’’,3’’’:4’,3’)-bis(6,6-dimethylpyrano)isoflavone 4’-(6’’-Methyl)salicylate-5,7-dihydroxyisoflavone

Name

Mass

384.39 386.36 386.36 386.36 Kwakhurin hydrate 386.40 387.60 388.46 Erysubin F 390.48 394.38 Griffonianone B 394.38 394.42 Barbigerone 394.42 Durallone 394.42 Elongatin 396.40 4’-Demethyltoxicarol 396.40 Pumilaisoflavone D 396.40 Predurallone 396.44 Piscerisoflavone E 398.36 Piscerynetin 398.41 2’-Hydroxypiscerythrinetin 398.41 Viridiflorin 398.41 Piscerisoflavone B 400.38 400.38 Piscerisoflavone D 400.38 Piscerisoflavone A 400.38 Piscerisoflavone C 400.38 Piscidanol 400.38 402.39 Ulexin B 402.45 Ulexone B 402.45 Genistein-4’-(6’’-methyl)salicylate 404.37

Piscidanone Madhushazone Irisflorentin

Trivial Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

C21H20O7 C20H18O8 C20H18O8 C20H18O8 C21H22O7 C16H9O5Cl3 C25H24O4 C25H26O4 C22H18O7 C22H18O7 C23H22O6 C23H22O6 C23H22O6 C22H20O7 C22H20O7 C22H20O7 C23H24O6 C21H18O8 C22H22O7 C22H22O7 C22H22O7 C21H20O8 C21H20O8 C21H20O8 C21H20O8 C21H20O8 C21H20O8 C21H22O8 C25H22O5 C25H22O5 C23H16O7

Formula

F176 F245 2466 2467 2895 F301 F341 F275 F156 F331 F118 2410 F341 2490 F49 2918 F341 F264 F264 2906 2860 F264 F264 F264 F264 F264 F264 F40 F165 2962 F159

Ref.

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_app Revise Proof page 1152 6.10.2005 2:36pm

1152 Flavonoids: Chemistry, Biochemistry, and Applications

685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717

5,7-Dihydroxy-6,2’,3’,4’,5’-pentamethoxyisoflavone 5-Hydroxy-4’-prenyloxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5,4’-Dihydroxy-3’-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5,4’-Dihydroxy-3’-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 5,4’-Dihydroxy-6-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5,4’-Dihydroxy-8-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5,7-Dihydroxy-6-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflavone 5,7-Dihydroxy-8-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflavone 5,7,4’-Trihydroxy-8-((1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl)isoflavone 4’-Methoxy-7-geranyloxyisoflavone 3’,4’-Dihydroxy-7-(3,7-dimethyl-2(E),6-octadienyloxy)isoflavone 4’-Hydroxy-(2’’,3’’:5,6),(2’’’,3’’’:7,8)-bis(4,5-dihydro-6,6-dimethylpyrano)isoflavone 5,7,2’,4’-Tetrahydroxy-3’-prenyl-5’-(1,1-dimethyl-2-propenyl)isoflavone 5,7,4’-Trihydroxy-3’,5’-diprenylisoflavone 5,7,4’-Trihydroxy-6,3’-diprenylisoflavone 5,7,4’-Trihydroxy-6,8-diprenylisoflavone 5,7,4’-Trihydroxy-8-(3,7-dimethyl-2,6-octadienyl)isoflavone 5,7,4’-Trihydroxy-8,3’-diprenylisoflavone 7-Hydroxy-4’-geranyloxyisoflavone 2’,6’-Dimethoxy-3’,4’-methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 5,6-Dimethoxy-3’,4’-methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 6,2’-Dimethoxy-4’,5’-methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 5-Hydroxy-2’,4’,5’-trimethoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 7-Hydroxy-2’,5’-dimethoxy-3’,4’-methylenedioxy-8-prenylisoflavone 7-Hydroxy-5,6-dimethoxy-3’,4’-methylenedioxy-8-prenylisoflavone 7,2’,4’,5’-Tetramethoxy-8-prenylisoflavone 5,7-Dihydroxy-4’,5’-dimethoxy-5’’-(1-hydroxy-1-methylethyl)-4’’,5’’-dihydrofurano[2’’,3’’:2’,3’]isoflavone 5,7,5’’-Trihydroxy-4’,5’-dimethoxy-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:2’,3’]isoflavone 5,7,2’-Trihydroxy-4’,5’-dimethoxy-3’-(3-hydroxy-3-methyl-butyl)isoflavone 2’-Methoxy-(2’’,3’’:7,6),(2’’’,3’’’:4’,3’)-bis(6,6-dimethylpyrano)isoflavone 5-Hydroxy-5’’’-(1-hydroxy-1-methylethyl)furano[2’’’,3’’’:7,6]-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflavone 5,2’-Dihydroxy-(2’’,3’’:7,6),(2’’’,3’’’:4’,3’)-bis(6,6-dimethylpyrano)isoflavone 5,7-Dihydroxy-6’’-hydroxymethyl-6’’,6’’’,6’’’-trimethyl-(2’’,3’’:7,8),(2’’’,3’’’:4’,3’)-bis(pyrano)isoflavone Munetone Ulexin C Kraussianone 1 Ulexone D

Erythrivarone B Fremontone 3’,5’-Diprenylgenistein Lupalbigenin 6,8-Diprenylgenistein Lespedezol E1 Isolupalbigenin Conrauinone D Ferrugone 5-Methoxydurmillone Ichthynone Toxicarolisoflavone Preferrugone Pre-5-methoxydurmillone Prebarbigerone Piscerisoflavone F Piscerisoflavone G

Irisjaponin A 4’-O-prenylalpinumisoflavone Chandalone Scanderone Osajin Warangalone Isochandalone Ulexone A Ficusin A 7-Geranylformononetin

404.37 404.46 404.46 404.46 404.46 404.46 404.46 404.46 404.46 404.51 406.47 406.47 406.47 406.47 406.47 406.47 406.47 406.47 406.47 408.41 408.41 408.41 410.42 410.42 410.42 410.47 414.41 414.41 416.42 416.48 418.45 418.45 418.45

F169 2861 2491 F157 2492 2493 2940 2960 F5 2869 F332 F94 2908 2907 2494 2495 F171 F267 F69 2411 2938 2412 2496 2910 2937 2909 F264 F264 F264 2413 F164 F58 2963

Appendix

continued

C20H20O9 C25H24O5 C25H24O5 C25H24O5 C25H24O5 C25H24O5 C25H24O5 C25H24O5 C25H24O5 C26H28O4 C25H26O5 C25H26O5 C25H26O5 C25H26O5 C25H26O5 C25H26O5 C25H26O5 C25H26O5 C25H26O5 C23H20O7 C23H20O7 C23H20O7 C23H22O7 C23H22O7 C23H22O7 C24H26O6 C22H22O8 C22H22O8 C22H24O8 C26H24O5 C25H22O6 C25H22O6 C25H22O6

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_app Revise Proof page 1153 6.10.2005 2:36pm

1153

734 735 736 737 737b 738 739 740 741 742 743 744

3’,4’-Methylenedioxy-7-((2E)-3,7-dimethyl-2,6-octadienyloxy)isoflavone 4’-Hydroxy-5-methoxy-6-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 5-Methoxy-4’-prenyloxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5-Hydroxy-5’’-(1-hydroxy-1-methylethyl)-4’’,5’’-dihydrofurano[2’’,3’’:7,8]-6’’’,6’’’dimethylpyrano[2’’’,3’’’:4’,3’]isoflavone 5-Hydroxy-5’’’-(1-hydroxy-1-methylethyl)-4’’’,5’’’-dihydrofurano[2’’’,3’’’:7,6]-6’’,6’’dimethylpyrano[2’’,3’’:4’,3’]isoflavone 5,2’-Dihydroxy-4’-prenyloxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5,2’,4’-Trihydroxy-3’-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5,2’,4’-Trihydroxy-8-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5,3’-Dihydroxy-4’-prenyloxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5,3’,4’-Trihydroxy-6-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 5,3’,4’-Trihydroxy-8-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5,4’-Dihydroxy-6-(2-hydroxy-3-methyl-3-butenyl)-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 5,4’-Dihydroxy-8-(2-hydroxy-3-methyl-3-butenyl)-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5,4’-Dihydroxy-8-(2-hydroxy-3-methyl-3-butenyl)-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5,4’-Dihydroxy-8-(2,3-epoxy-3-methylbutyl)-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5,4’,7’’-Trihydroxy-7’’-methyl-4’’-(1-methylethenyl)-3’’a,4’’,5’’,6’’,7’’,7’’ahexahydrobenzofurano[2’’,3’’:7,8]isoflavone 5,7-Dihydroxy-6-(2-hydroxy-3-methyl-3-butenyl)-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflavone 5,7,2’-Trihydroxy-6-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflavone 5,7,2’-Trihydroxy-6-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’]isoflavone 5,7,3’-Trihydroxy-6-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’]isoflavone 5,7,3’-Trihydroxy-2’-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’]isoflavone 5,7,4’-Trihydroxy-8-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:2’,3’]isoflavone 4’-Methoxy-7-(8-hydroxy-3,7-dimethyl-2(E),6(Z)-octadienyloxy)isoflavone 5,4’-Dihydroxy-7-methoxy-8,3’-diprenylisoflavone 5,7-Dihydroxy-4’-methoxy-8-geranylisoflavone 7-Hydroxy-5-methoxy-4’-geranyloxyisoflavone 7,4’-Dihydroxy-5-methoxy-6,8-diprenylisoflavone 3,5,7,4’-Tetrahydroxy-6,3’-diprenylisoflavone 7-O-Methylisolupalbigenin Olibergin A Conrauinone C Derrisisoflavone A Glyasperin A

Glyasperin N

Ulexin A Angustone B Kraussianone 2 Gancaonin H

Isoauriculatin Angustone C Auriculatin Isoauriculasin Pomiferin Auriculasin Euchrenone b9 Erysenegalensein M Euchrenone b8 Erysenegalensein G Ficusin B

Ulexin D

Ulexone C

7-O-Geranylpseudobaptigenin Scandinone

Trivial Name

420.46 420.46 420.46 420.46 420.46 420.46 420.50 420.50 420.50 420.50 420.50 422.48

420.46 420.46 420.46 420.46 420.46 420.46 420.46 420.46 420.46 420.46 420.46

420.46

418.49 418.49 418.49 420.46

Mass

C25H24O6 C25H24O6 C25H24O6 C25H24O6 C25H24O6 C25H24O6 C26H28O5 C26H28O5 C26H28O5 C26H28O5 C26H28O5 C25H26O6

C25H24O6 C25H24O6 C25H24O6 C25H24O6 C25H24O6 C25H24O6 C25H24O6 C25H24O6 C25H24O6 C25H24O6 C25H24O6

C25H24O6

C26H26O5 C26H26O5 C26H26O5 C25H24O6

Formula

F165 2944 F58 2948 F4b F72 F332 F164 F111 F69 F232 F350

2498 2954 2501 2499 2500 2502 2973 F309 2968 F310 F5

F164

F333 2497 F13 2964

Ref.

1154

723 724 725 726 727 728 729 730 731 732 733

722

718 719 720 721

Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_app Revise Proof page 1154 6.10.2005 2:36pm

Flavonoids: Chemistry, Biochemistry, and Applications

772 773

771

770

765 766 767 768 769

745 746 747 748 749 750 751 752 753 754 755 756 757 757b 758 759 760 761 762 763 764

4’’,5’’-Dihydro-5,7-dihydroxy-3’-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:4’,5’]isoflavone 5,4’-Dihydroxy-5’’-(1-hydroxy-1-methylethyl)-3’-prenyl-4’’,5’’-dihydrofurano[2’’,3’’:7,6]isoflavone 5,4’-Dihydroxy-5’’-(1-hydroxy-1-methylethyl)-6-prenyl-4’’,5’’-dihydrofurano[2’’,3’’:7,8]isoflavone 5,4’-Dihydroxy-5’’-(1-hydroxy-1-methylethyl)-8-prenyl-4’’,5’’-dihydrofurano[2’’,3’’:7,6]isoflavone 5,4’-Dihydroxy-6-(3-hydroxy-3-methylbutyl)-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 5,4’-Dihydroxy-8-(3-hydroxy-3-methylbutyl)-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5,4’,5’’-Trihydroxy-3’-prenyl-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:7,6]isoflavone 5,7,2’,4’-Tetrahydroxy-6,3’-diprenylisoflavone 5,7,2’,4’-Tetrahydroxy-6,8-diprenylisoflavone 5,7,2’,4’-Tetrahydroxy-8,3’-diprenylisoflavone 5,7,2’,4’-Tetrahydroxy-8,5’-diprenylisoflavanone 5,7,3’,4’-Tetrahydroxy-6,5’-diprenylisoflavone 5,7,3’,4’-Tetrahydroxy-6,8-diprenylisoflavone 5,7,3’,4’-Tetrahydroxy-2’,5’-diprenylisoflavone 5,7,4’-Trihydroxy-3’-(2-hydroxy-3-methyl-3-butenyl)-6-prenylisoflavone 5,7,4’-Trihydroxy-6-(2-hydroxy-3-methyl-3-butenyl)-3’-prenylisoflavone 5,7,4’-Trihydroxy-6-(2-hydroxy-3-methyl-3-butenyl)-8-prenylisoflavone 5,7,4’-Trihydroxy-8-(2-hydroxy-3-methyl-3-butenyl)-6-prenylisoflavone 5,7,5’’-Trihydroxy-6-prenyl-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:4’,3’]isoflavone 7,2’,4’,5’-Tetrahydroxy-3’-(3,7-dimethyl-2,6-octadienyl)isoflavone 7,4’-Dihydroxy-5’’-(1-hydroxy-1-methylethyl)-8’-prenyl-6’’,6’’-dimethyl-4’’,5’’dihydropyrano[2’’,3’’:5,6]isoflavone 6,8,3’,5’-Tetrachloro-5,4’-dihydroxy-7-methoxyisoflavone 5-Hydroxy-2’-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]-4’-prenyloxyisoflavone 5,2’-Dihydroxy-4’-methoxy-8-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5’’-Hydroxy-2’-methoxy-4’’,5’’-dihydro-(2’’,3’’:7,6),(2’’’,3’’’:4’,3’)-bis(6,6-dimethylpyrano)isoflavone 5-Hydroxy-5’’’-(1-hydroxy-1-methylethyl)-4’’’,5’’’-dihydrofurano[2’’’,3’’’:4’,3’]-6’’,6’’dimethylpyrano[2’’,3’’:7,6]isoflavone 5,2’-Dihydroxy-5’’-(1-hydroxy-1-methylethyl)-4’’,5’’-dihydrofurano[2’’,3’’:7,6]-6’’’,6’’’dimethylpyrano[2’’’,3’’’:4’,3’]isoflavone 5,2’-Dihydroxy-5’’’-(1-hydroxy-1-methylethyl)-4’’’,5’’’-dihydrofurano[2’’’,3’’’:4’,3’]-6’’,6’’dimethylpyrano[2’’,3’’:7,6]isoflavone 5,2’,4’-Trihydroxy-8-(2-hydroxy-3-methyl-3-butenyl)-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5,2’,4’-Trihydroxy-8-(2,3-epoxy-3-methylbutyl)-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone Erysenegalensein L Erysenegalensein F

Lupinisoflavone L

Lupinisoflavone K

Auriculin Mundulone

Derrisisoflavone B Lupinisol A Isoerysenegalensein E Erysenegalensein E Derrisisoflavone F Lespedezol E2 Eryvarin B

Vogelin G Lupinisoflavone G Isosenegalensin Euchrenone b10 Euchrenone b7 Euchrenone b6 Lupinisolone A Angustone A 8-Prenylluteone 2’-Hydroxyisolupalbigenin Vogelin C Isoangustone A 6,8-Diprenylorobol

436.46 436.46

436.46

436.46

423.05 434.49 434.49 434.49 436.46

422.48 422.48 422.48 422.48 422.48 422.48 422.48 422.48 422.48 422.48 422.48 422.48 422.48 422.48 422.48 422.48 422.48 422.48 422.48 422.48 422.48

C25H24O7 C25H24O7

C25H24O7

C25H24O7

F309 F310

2955

2959

F301 F213 2505 2415 F43

F209 2957 F62 F279 2974 2969 2956 2503 2965 2961 F14 2947 2504 F4b F232 2950 F62 F307 F232 F171 F284

Appendix

continued

C16H9O5Cl3 C26H26O6 C26H26O6 C26H26O6 C25H24O7

C25H26O6 C25H26O6 C25H26O6 C25H26O6 C25H26O6 C25H26O6 C25H26O6 C25H26O6 C25H26O6 C25H26O6 C25H26O6 C25H26O6 C25H26O6 C25H26O6 C25H26O6 C25H26O6 C25H26O6 C25H26O6 C25H26O6 C25H26O6 C25H26O6

Andersen and Markham / Flavonoids: Chemistry, Biochemistry, and Applications #2021_app Revise Proof page 1155 6.10.2005 2:36pm

1155

Kraussianone 6 Kraussianone 7 1’’,2’’-Dihydro-2’hydroxycycloosajin 4’-Hydroxy-3’-methoxy-(2’’,3’’:5,6),(2’’’,3’’’:7,8)-bis(4,5-dihydro-6,6-dimethylpyrano)isoflavone 1’’,2’’-Dihydro-Omethylcyclopomiferin 4’-Hydroxy-5-methoxy-5’’-(1-hydroxy-1-methylethyl)-6-prenyl-4’’,5’’-dihydrofurano[2’’,3’’:7,8]isoflavone Derrisisoflavone C Eturunagarone 5,4’-Dihydroxy-8-(3-methoxy-3-methylbutyl)-6’’,6’’-dimethylpyrano(2’’,3’’:7,6)isoflavone 5,7,3’-Trihydroxy-4’-methoxy-6,8-diprenylisoflavone 6,8-Diprenylpratensein 5,7,4’-Trihydroxy-2’-methoxy-6,3’-diprenylisoflavone 2’-Methoxylupalbigenin 5,7,4’-Trihydroxy-2’-methoxy-6,8-diprenylisoflavone Euchrenone b15 5,7,4’-Trihydroxy-3’-methoxy-2’,5’-diprenylisoflavone Millewanin A 7,4’-Dihydroxy-5-methoxy-6-(2-hydroxy-3-methyl-3-butenyl)-8-prenylisoflavone Derrisisoflavone D 7,4’-Dihydroxy-5-methoxy-8-(2-hydroxy-3-methyl-3-butenyl)-6-prenylisoflavone Derrisisoflavone E 4’-Amino-5,7,3’-trihydroxy-5’-methoxy-2’,6’-diprenylisoflavone Piscerythramine 5,6,2’-Trimethoxy-4’,5’-methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone Conrauinone A 5-Hydroxy-(2’’,3’’:7,6),(2’’’,3’’’:4’,3’)-bis(5-(1-hydroxy-1-methylethyl)-4,5-dihydrofurano)isoflavone Isolupinisoflavone E 5,2’,4’-Trihydroxy-5’’-(1-hydroxy-1-methylethyl)-3’-prenyl-4’’,5’’-dihydrofurano[2’’,3’’:7,6]isoflavone Lupinisoflavone H Erysenegalensein H 5,2’,4’-Trihydroxy-5’’-(1-hydroxy-1-methylethyl)-8-prenyl-4’’,5’’-dihydrofurano[2’’,3’’:7,6]isoflavone 5,2’,4’-Trihydroxy-8-prenyl-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:7,6]isoflavone Erysenegalensein I 5,2’,4’,5’’-Tetrahydroxy-6-prenyl-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:7,8]isoflavone Erysenegalensein O 5,4’-Dihydroxy-8-(2-hydroperoxy-3-methyl-3-butenyl)-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:7,6]isoflavone Millewanin E 5,7,2’-Trihydroxy-5’’-(1-hydroxy-1-methylethyl)-6-prenyl-4’’,5’’-dihydrofurano[2’’,3’’:4’,3’]isoflavone Lupinisoflavone I 5,7,2’-Trihydroxy-6-(3-hydroxy-3-methyl-3-butyl)-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflavone Kraussianone 3 Kanzonol T 5,7,2’-Trihydroxy-6-(3-hydroxy-3-methylbutyl)-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflavone 5,7,2’,4’-Tetrahydroxy-3’-(2-hydroxy-3-methyl-3-butenyl)-6-prenylisoflavone Lupinisol C 5,7,2’,4’-Tetrahydroxy-6-(2-hydroxy-3-methyl-3-butenyl)-3’-prenylisoflavone Lupinisol B 5,7,2’,4’-Tetrahydroxy-6-(2-hydroxy-3-methyl-3-butenyl)-8-prenylisoflavone Erysenegalensein N 5,7,2’,4’-Tetrahydroxy-8-(2-hydroxy-3-methyl-3-butenyl)-6-prenylisoflavone Erysenegalensein D 5,7,2’,5’’-Tetrahydroxy-6-prenyl-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:4’,3’]isoflavone Lupinisolone B 5,7,4’-Trihydroxy-5’’-(1-hydroxy-1-methylethyl)-6-prenyl-4’’,5’’-dihydrofurano[2’’,3’’:2’,3’]isoflavone Lupinisoflavone J

5,2’,5’’-Trihydroxy-4’’,5’’-dihydro-(2’’,3’’:7,6),(2’’’,3’’’:4’,3’)-bis(6,6-dimethylpyrano)isoflavone 5,7,2’-Trihydroxy-6-(2-hydroxy-3-methyl-3-butenyl)-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]isoflavone 2’-Hydroxy-4’-methoxy-(2’’,3’’:5,6),(2’’’,3’’’:7,8)-bis(4,5-dihydro-6,6-dimethylpyrano)isoflavone

Trivial Name

Formula

436.50 436.50 436.50 436.50 436.50 436.50 436.50 436.50 437.52 438.44 438.48 438.48 438.48 438.48 438.48 438.48 438.48 438.48 438.48 438.48 438.48 438.48 438.48 438.48 438.48

C26H28O6 C26H28O6 C26H28O6 C26H28O6 C26H28O6 C26H28O6 C26H28O6 C26H28O6 C26H29O6N1 C24H22O8 C25H26O7 C25H26O7 C25H26O7 C25H26O7 C25H26O7 C25H26O7 C25H26O7 C25H26O7 C25H26O7 C25H26O7 C25H26O7 C25H26O7 C25H26O7 C25H26O7 C25H26O7

436.50 C26H28O6

436.46 C25H24O7 436.46 C25H24O7 436.50 C26H28O6

Mass

F232 F215 2866 2864 F175 F110 F232 F232 2978 F68 F142 2958 F308 F308 F190 F110 2946 F58 F79 2941 2951 F190 F307 2945 2943

2507

F57 F57 2506

Ref.

1156

778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802

777

774 775 776

Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

828 829 830

827

826

816 817 818 819 820 821 822 823 824 825

814 815

803 804 805 806 807 808 809 810 811 811b 812 813

5,7,4’,5’’-Tetrahydroxy-6-prenyl-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:2’,3’]isoflavone 4’-Methoxy-7-((2E)-6,7-dihydroxy-3,7-dimethyl-2-octaenyloxy)isoflavanone 5,7-Dihydroxy-8,2,4’,5’-tetramethoxy-8-prenylisoflavone 7-Keto-6-methoxy-3’,4’-methylenedioxy-8,8-diprenylisoflavone 2’-Hydroxy-4’,6’-dimethoxy-3’-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5,7,2’-Trihydroxy-4’,5’-methylenedioxy-6,8-diprenylisoflavone 5,7-Dihydroxy-3’,4’-dimethoxy-6,8-diprenylisoflavone 5,7-Dimethoxy-3’,4’-diprenyloxyisoflavone 4’-Amino-5,7,3’-trihydroxy-5’-methoxy-8,2’-diprenylisoflavone 4-Sulfate-2’-hydroxy-6,3’-dimethoxy-5’-(2-propenoic acid)isoflavone 5,7,3’,4’-Tetrahydroxy-5’-methoxy-2’,6’-diprenylisoflavone 5,7-Dihydroxy-6-(2,3-dihydroxy-3-methylbutyl)-5’’-(1-hydroxy-1-methylethyl)-4’’,5’’dihydrofurano[2’’,3’’:4’,3’]isoflavone 5-Hydroxy-2’-methoxy-4’,5-methylenedioxy-6-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 5-Hydroxy-3’,5’-dimethoxy-4’-(1,1,-dimethyl-2-propenyloxy)-5’’-(1-methylethenyl)-4’’,5’’dihydrofurano[2’’,3’’:7,6]isoflavone 5-Hydroxy-3’,5’-dimethoxy-4’-(1,1,-dimethyl-2-propenyloxy)-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 5,7-Dihydroxy-2’-methoxy-4’,5’-methylenedioxy-6,8-diprenylisoflavone 6-Methoxy-3’,4’-methylenedioxy-7-(7-hydroxy-3,7-dimethyl-2(E ),5’’-octadienyloxy)isoflavone 5,4’-Dihydroxy-5’’-(1-hydroxyethyloxy-1-methylethyl)-8-prenyl-4’’,5’’-dihydrofurano[2’’,3’’:7,6]isoflavone 5,7,4’-Trihydroxy-3’,5’-dimethoxy-6,2’-diprenylisoflavone 5,7,4’-Trihydroxy-5’-methoxy-5’’-(1-hydroxy-1-methylethyl)-6’-prenyl-4’’,5’’-dihydrofurano[2’’,3’’:3’,2’]isoflavone 5,7,4’-Trihydroxy-5’-methoxy-5’’-(1-hydroxy-1-methylethyl)-6’-prenyl-4’’,5’’-dihydrofurano[2’’,3’’:3’,2’]isoflavone 5,7,4’-Trihydroxy-5’-methoxy-6’-prenyl-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:3’,2’]isoflavone 5,7,4’-Trihydroxy-5’-methoxy-6’-prenyl-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:3’,2’]isoflavone 5-Hydroxy-2’,4’-dimethoxy-8-(3-hydroxy-3-methylbutyl)-6’’,6’’-dimethyl-4’’,5’’dihydropyrano[2’’,3’’:7,6]isoflavone 5-Hydroxy-3’,4’-dimethoxy-8-(3-hydroxy-3-methylbutyl)-6’’,6’’-dimethyl-4’’,5’’dihydropyrano[2’’,3’’:7,6]isoflavone 5,7,2’-Trihydroxy-6-(2,3-dihydroxy-3-methylbutyl)-5’’-(1-hydroxy-1-methylethyl)-4’’,5’’dihydrofurano[2’’,3’’:4’,3’]isoflavone 5,7,4’-Trihydroxy-5’-((2E)-3,7-dimethyl-2,6-octadienyl)-2’-prenylisoflavone 5,7,4’-Trihydroxy-6,8,3’-triprenylisoflavone 5,7,4’-Trihydroxy-8,3’,5’-triprenylisoflavone Millewanin D Euchrenone b1 Flemiphyllin

Lupinisoflavone N

Pumilaisoflavone A Euchrenone b4 Conrauinone A Eriotriochin Pumilaisoflavone C Erythbigenol A Erythbigenol B Erythbigenone B Erythbigenone A

Euchrenone b3 Pumilaisoflavone B

Lupinisolone C Griffonianone D 6-Prenylisocaviunin Griffonianone C Cajaisoflavone Euchrenone b5 Flemiphilippinin B Glabrescione B Isopiscerythramine Torvanol A Erythbigenin Lupinisoflavone M

C27H28O7 C27H28O7 C27H28O7 C27H30O7 C27H30O7 C26H28O8 C26H28O8 C26H28O8 C26H28O8 C27H32O7

474.60 C30H34O5 474.60 C30H34O5 474.60 C30H34O5

472.49 C25H28O9

468.55 C27H32O7

464.52 464.52 464.52 466.53 466.53 468.50 468.50 468.50 468.50 468.55

F110 2976 2865

2953

2510

2919 2967 F68 2971 2949 F264 F264 F264 F264 2509

2972 2920

2942 F330 2939 F331 2414 2966 F41 2508 F177 F11b F263 2952

Appendix

continued

C25H26O7 C26H30O6 C24H26O8 C27H28O6 C26H26O7 C26H26O7 C27H30O6 C27H30O6 C26H29O6N1 C20H20O10S1 C26H28O7 C25H28O8 462.50 C27H26O7 464.52 C27H28O7

438.48 438.51 442.47 448.51 450.49 450.49 450.52 450.52 451.51 452.43 452.50 456.49

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1157

Isoflavone glycosides 7,4’-Dihydroxyisoflavone 7-O-(2-O-methylrhamnoside) 5,7,4’-Trihydroxyisoflavone 5-O-rhamnoside 5,7,4’-Trihydroxyisoflavone 7-O-rhamnoside 7,4’-Dihydroxyisoflavone 4’-O-glucoside 7,4’-Dihydroxyisoflavone 7-O-glucoside 7,8-Dihydroxy-4’-methoxyisoflavone 7-O-arabinoside 4’-Hydroxy-7-methoxyisoflavone-4’-O-glucoside 5,7-Dihydroxy-6-methoxyisoflavone 7-O-rhamnoside 7-Hydroxy-4’-methoxyisoflavone 7-O-glucoside 5,7,2’-Trihydroxyisoflavone 7-O-glucoside 5,7,4’-Trihydroxyisoflavone 4’-O-glucoside 5,7,4’-Trihydroxyisoflavone 5-O-glucoside 5,7,4’-Trihydroxyisoflavone 7-O-glucoside 6,7,4’-Trihydroxyisoflavone 4’-O-glucoside 7,2’,4 ’-Trihydroxyisoflavone-4’-O-glucoside 7-Hydroxy-3’,4’-methylenedioxyisoflavone 7-O-glucoside

Pseudobaptigenin 7-O-glucoside

Formononetin 7-O-glucoside Isogenistein 7-O-glucoside Genistein 4’-O-glucoside Genistein 5-O-glucoside Genistein 7-O-glucoside Demethyltexasin 4’-O-glucoside

Daidzein G 3 Genestein G 1 Genistein 4’-O-rhamnoside Daidzein 4’-O-glucoside Daidzein 7-O-glucoside Retusin 7-O-arabinoside Isoononin

414.41 416.39 416.39 416.39 416.39 416.39 430.41 430.41 430.41 432.39 432.39 432.39 432.39 432.39 432.39 444.40

C22H22O8 C21H20O9 C21H20O9 C21H20O9 C21H20O9 C21H20O9 C22H22O9 C22H22O9 C22H22O9 C21H20O10 C21H20O10 C21H20O10 C21H20O10 C21H20O10 C21H20O10 C22H20O10

C30H34O6 C30H34O6 C31H34O6 C31H34O6 C31H36O6 C31H36O6 C31H32O7 C31H32O7 C51H78O7

490.59 490.60 502.60 502.60 504.61 504.61 516.48 516.48 803.16

Millewanin C Euchrenone b2 Euchrenone b13 Euchrenone b12 Euchrenone b14 Millewanin B Euchrenone b11 Euchrenone b10 Indicanin D

Formula

488.57 C30H32O6 488.57 C30H32O6

Mass

Euchrenone b16 Flemiphilippinin A

Trivial Name

F93 F93 F224 3110 3108 3215 F351 3191 3113 3148 3141 3207 3139 3117 F179 3118

F110 2977 F175 F175 F175 F110 F175 F175 F184

F175 F41

Ref.

1158

842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857

831 5,2’,4’-Trihydroxy-6,3’-diprenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 832 5,3’,4’-Trihydroxy-8-prenyl-6’’,6’’-dimethyl-5’’-(1,1-dimethyl-2-propenyl) pyrano[2’’,3’’:7,6]isoflavone 833 5,7,3’,4’-Tetrahydroxy-5’-((2E)-3,7-dimethyl-2,6-octadienyl)-2’-prenylisoflavone 834 5,7,2’,4’-Tetrahydroxy-6,8,3’-triprenylisoflavone 835 5,4’-Dihydroxy-2’-methoxy-6,3’-diprenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]isoflavone 836 5,4’-Dihydroxy-2’-methoxy-8,3’-diprenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 837 5,7,4’-Trihydroxy-2’-methoxy-6,8,3-triprenylisoflavone 838 5,7,4’-Trihydroxy-3’-methoxy-5’-((2E)-3,7-dimethyl-2,6-octadienyl)-2’-prenylisoflavone 839 5,5’-Dihydroxy-2’-methoxy-6-prenyl-(2’’,3’’:7,8),(2’’’,3’’’:4’,3’)-bis(6,6-dimethylpyrano)isoflavone 840 5,5’-Dihydroxy-2’-methoxy-8-prenyl-(2’’,3’’:7,6),(2’’’,3’’’:4’,3’)-bis(6,6-dimethylpyrano)isoflavone 841 5,7-Dihydroxy-8-(2-hydroxy-3-methyl-3-butenyl)-4’-(1-(hydroxymethyl) pentacosyloxy)-6-prenylisoflavone

Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891

7,4’-Dihydroxy-6-methoxyisoflavone 7-O-(2-O-methylrhamnoside) 5,4’-Dihydroxy-7-methoxyisoflavone 4’-O-galactoside 5,4’-Dihydroxy-7-methoxyisoflavone 4’-O-glucoside 5,4’-Dihydroxy-7-methoxyisoflavone 5-O-glucoside 5,7-Dihydroxy-3’-methoxyisoflavone 7-O-glucoside 5,7-Dihydroxy-4’-methoxyisoflavone 7-O-glucoside 5,7-Dihydroxy-4’-methoxyisoflavone 8-C-glucoside 6,7-Dihydroxy-4’-methoxyisoflavone 7-O-glucoside 7,3’-Dihydroxy-4’-methoxyisoflavone 7-O-galactoside 7,3’-Dihydroxy-4’-methoxyisoflavone 7-O-glucoside 7,4’-Dihydroxy-5-methoxyisoflavone 4’-O-glucoside 7,4’-Dihydroxy-5-methoxyisoflavone 7-O-glucoside 7,4’-Dihydroxy-6-methoxyisoflavone 7-O-glucoside 7,5’-Hydroxy-3’-methoxyisoflavone-7-O-glucoside 7,8-Dihydroxy-4’-methoxyisoflavone 7-O-glucoside 7,8-Dihydroxy-4’-methoxyisoflavone 8-O-glucoside 5,7,2’,4’-Tetrahydroxyisoflavone 4’-O-glucoside 5,7,2’,4’-Tetrahydroxyisoflavone 7-O-glucoside 5,7,2’,4’-Tetrahydroxyisoflavone 8-C-glucoside 5,7,3’,4’-Tetrahydroxyisoflavone 7-O-glucoside 7,4’-Dihydroxyisoflavone 7-O-(6’’-acetylglucoside) 7-Hydroxy-5,4’-dimethoxy-8-methylisoflavone 7-O-rhamnoside 5,4’-Dihydroxy-6,7-methylenedioxyisoflavone 4’-O-glucoside 5,7-Dihydroxy-3’,4’-methylenedioxyisoflavone 7-O-glucoside 5,7-Dihydroxy-3’,4’-dimethoxyisoflavone 7-O-rhamnoside 5,7-Dihydroxy-6,2’-dimethoxyisoflavone 7-O-rhamnoside 5,7-Dihydroxy-6,4’-dimethoxyisoflavone 7-O-rhamnoside 7-Hydroxy-3’,4’-dimethoxyisoflavone 7-O-glucoside 7-Hydroxy-6,4’-dimethoxyisoflavone 7-O-galactoside 7-Hydroxy-6,4’-dimethoxyisoflavone 7-O-glucoside 7-Hydroxy-8,4’-dimethoxyisoflavone 7-O-glucoside 5,3’,4’-Trihydroxy-7-methoxyisoflavone 3’-O-glucoside 5,7,3’-Trihydroxy-4’-methoxyisoflavone 7-O-glucoside 5,7,3’,4’-Tetrahydroxy-8-methylisoflavone 7-O-glucoside

444.43 446.41 446.41 446.41 446.41 446.41 446.41 446.41 446.41 446.41 446.41 446.41 446.41 446.41 Retusin 7-O-glucoside 446.41 Derriscandenoside A 446.41 2’-Hydroxygenistein 4’-O-glucoside 448.39 2’-Hydroxygenistein 7-O-glucoside 448.39 448.39 Orobol 7-O-glucoside 448.39 Daidzin 6’’-O-acetate 458.42 458.47 Irilone 4’-O-glucoside 460.39 6-Hydroxypseudobaptigenin 7-O-glucoside 460.39 460.44 460.44 Irisolidone 7-O-rhamnoside 460.44 Cladrin 7-O-glucoside 460.44 Afrormosin 7-O-galactoside 460.44 Afrormosin 7-O-glucoside 460.44 8-O-Methylretusin 7-O-glucoside 460.44 462.41 Pratensein 7-O-glucoside 462.41 462.41

Daidzein G 2 Prunetin 4’-O-galactoside Prunetin 4’-O-glucoside Prunetin 5-O-glucoside Mutabilin Biochanin A 7-O-glucoside 4’-O-Methyl-genistein-8-C-glucoside Texasin 7-O-glucoside Calycosin 7-O-galactoside Calycosin 7-O-glucoside Genistein 5-methyl ether 4’-glucoside 7-O-Methylgenistein 7-O-glucoside Glycetein 7-O-glucoside

F93 3213 3155 3212 F55 3149 F2 3123 3205 3121 F194 3211 3124 F34 3190 F218 F240 F240 F234 3156 3109 3197 3161 3159 F61 F226 3192 3126 F198 3128 3131 F129 3162 F61

Appendix

continued

C23H24O9 C22H22O10 C22H22O10 C22H22O10 C22H22O10 C22H22O10 C22H22O10 C22H22O10 C22H22O10 C22H22O10 C22H22O10 C22H22O10 C22H22O10 C22H22O10 C22H22O10 C22H22O10 C21H20O11 C21H20O11 C21H20O11 C21H20O11 C23H22O10 C24H26O9 C22H20O11 C22H20O11 C23H24O10 C23H24O10 C23H2410 C23H24O10 C23H24O10 C23H24O10 C23H24O10 C22H22O11 C22H22O11 C22H22O11

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1159

892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922

5,7,4’-Trihydroxy-3’-methoxyisoflavone 7-O-glucoside 5,7,4’-Trihydroxy-6-methoxyisoflavone 4’-O-glucoside 5,7,4’-Trihydroxy-6-methoxyisoflavone 7-O-glucoside 5,7,4’-Trihydroxy-8-methoxyisoflavone 7-O-glucoside 7-Hydroxy-4’-methoxyisoflavone 7-O-(6’’-acetylglucoside) 4’-Hydroxy-5-methoxy-6,7-methylenedioxyisoflavone 4’-O-glucoside 5,7,4’-Trihydroxyisoflavone 7-O-(6’’-acetylglucoside) 6,3’-Dihydroxy-7-methoxy-4’,5’-methylenedioxyisoflavone 6-O-rhamnoside 6,7-Dihydroxy-3’-methoxy-4’,5’-methylenedioxyisoflavone 6-O-rhamnoside 7-Hydroxy-6-methoxy-3’,4’-methylenedioxyisoflavone 7-O-glucoside 7-Hydroxy-6’-methoxy-3’,4’-methylenedioxyisoflavone 7-O-glucoside 5,7,2’-Trihydroxy-4’,5’-methylenedioxyisoflavone 2’-O-glucoside 5,4’-Dihydroxy-6,7-dimethoxyisoflavone 4’-O-galactoside 5,4’-Dihydroxy-6,7-dimethoxyisoflavone 4’-O-glucoside 5,7-Dihydroxy-6,4’-dimethoxyisoflavone 7-O-galactoside 5,7-Dihydroxy-6,4’-dimethoxyisoflavone 7-O-glucoside 5,7-Dihydroxy-8,4’-dimethoxyisoflavone 7-O-glucoside 7,2’-Dihydroxy-3’,4’-dimethoxyisoflavone 7-O-glucoside 7,3’-Dihydroxy-6,4’-dimethoxyisoflavone 7-O-glucoside 5,6,7,4’-Tetrahydroxy-8-methoxyisoflavone 7-O-glucoside 7,4’-Dihydroxy-6-methoxyisoflavone 7-O-(6’’-acetylglucoside) 5,4’-Dihydroxy-2’-methoxy-6,7-methylenedioxyisoflavone 4’-O-glucoside 5,7-Hydroxy-6-methoxy-3’,4’-methylenedioxyisoflavone 7-O-galactoside 6,3’-Dihydroxy-7-methoxy-4’,5’-methylenedioxyisoflavone 6-O-glucoside 6,7-Dihydroxy-3’-methoxy-4’,5’-methylenedioxyisoflavone 6-O-glucoside 7-Hydroxy-2’,4’,5’-trimethoxyisoflavone 7-O-glucoside 7-Hydroxy-5,6,4’-trimethoxyisoflavone 7-O-glucoside 7-Hydroxy-6,3’,5’-trimethoxyisoflavone 7-O-glucoside 5,7,2’-Trihydroxy-6,4’-dimethoxyisoflavone 7-O-glucoside 5,7,4’-Trihydroxy-6,3’-dimethoxyisoflavone 7-O-glucoside 5,7,4’-Trihydroxy-8,3’-dimethoxyisoflavone 7-O-glucoside

Name

5-Methoxyafrormosin 7-O-glucoside Cladrastin 7-O-glucoside Iristectorigenin A 7-O-glucoside Iristectorigenin B 7-O-glucoside Homotectorigenin 7-O-glucoside

Glycitein 7-O-(6’’-acetylglucoside) Iriflogenin 4’-O-glucoside Dalspinin 7-O-galactoside

Odoratin-7-O-glucoside

Irisolidone 7-O-glucoside

462.41 462.41 462.41 462.41 472.45 474.42 474.42 474.42 474.42 474.42 474.42 476.39 476.44 476.44 476.44 476.44 476.44 476.44 476.44 478.41 488.45 490.32 490.32 490.32 490.32 490.47 490.47 490.47 492.44 492.44 492.44

Mass C22H22O11 C22H22O11 C22H22O11 C22H22O11 C24H24O10 C23H22O11 C23H22O11 C23H22O11 C23H22O11 C23H22O11 C23H22O11 C22H20O12 C23H24O11 C23H24O11 C23H24O11 C23H24O11 C23H24O11 C23H24O11 C23H24O11 C22H22O12 C24H24O11 C23H22O12 C23H22O12 C23H22O12 C23H22O12 C24H26O11 C24H26O11 C24H26O11 C23H24O12 C23H24O12 C23H24O12

Formula

3163 F236 3164 3217 3201 F17 3140 F356 F312 3133 F137 F197 3216 3169 F231 3167 F7 3206 F302 F225 F131 3172 3195 F356 F312 3135 3173 3136 3175 3176 3177

Ref.

1160

7-O-Methyltectorigenin 4’-O-galactoside 7-O-Methyltectorigenin 4’-O-glucoside

Fujikinetin 7-O-glucoside 6’-Methoxypseudobaptigenin 7-O-glucoside

3’-O-Methylorobol 7-O-glucoside Tectorigenin 4’-glucoside Tectorigenin 7-O-glucoside Isotectorigenin 7-O-glucoside Formononetin 7-O-(6’’-acetylglucoside) Germanaism B Genistin 6’’-O-acetate

Trivial Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

922b 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955

7,2’,5’-Trihydroxy-6,4’-dimethoxyisoflavone 2’-O-glucoside 5,7,4’-Trihydroxy-6-prenylisoflavone 7-O-glucoside 7,4’-Dihydroxyisoflavone 7-O-(6’’-malonylglucoside) 7,4’-Dihydroxyisoflavone 8-C-(6’’-malonylglucoside) 4’-Hydroxy-5,3’-dimethoxy-6,7-methylenedioxyisoflavone 4’-O-glucoside 7-Hydroxy-2’,6-dimethoxy-4’,5’-methylenedioxyisoflavone 7-O-glucoside 7-Hydroxy-5,6-dimethoxy-3’,4’-methylenedioxyisoflavone 7-O-glucoside 7-Hydroxy-5,8-dimethoxy-3’,4’-methylenedioxyisoflavone 7-O-glucoside 5,2’,3’-Trihydroxy-7-methoxy-2-hydroxymethyl-6-methylisoflavone 3’-O-glucoside 5,3’-Dihydroxy-7,4’,5’-trimethoxyisoflavone 3’-O-glucoside 5,7-Dihydroxy-6,3’,4’-trimethoxyisoflavone 7-O-glucoside 6,8,3’,5’-Tetrahydroxy-7,4’-dimethoxyisoflavone 6-O-glucoside 7-Hydroxy-4’-methoxyisoflavone 7-O-(2’’,6’’-diacetylglucoside) 5,7,4’-Trihydroxyisoflavone 7-O-(6’’-succinylglucoside) 7-Hydroxy-4’-methoxyisoflavone 7-O-(6’’-malonylglucoside) 5,7,2’,4’-Tetrahydroxy-3’-prenylisoflavone 4’-O-glucoside 5,7,2’,4’-Tetrahydroxy-3’-prenylisoflavone 7-O-glucoside 5,7,2’,4’-Tetrahydroxy-6-prenylisoflavone 7-O-glucoside 5,7,4’-Trihydroxyisoflavone 4’-O-(6’’-malonylglucoside) 5,7,4’-Trihydroxyisoflavone 7-O-(6’’-malonylglucoside) 5,7,4’-Trihydroxyisoflavone 8-C-(6’’-malonylglucoside) 5,7,3’-Trihydroxy-6,4’,5’-trimethoxyisoflavone 7-O-glucoside 5,7,4’-Trihydroxy-6,3’,5’-trimethoxyisoflavone 7-O-glucoside 5,7-Dihydroxy-4’-methoxyisoflavone 7-O-(6’’-malonylglucoside) 7,4’-Dihydroxyisoflavone 7-O-(6’’-succinylglucoside) 5,7,2’,4’-Tetrahydroxyisoflavone 4’-O-(6’’-malonylglucoside) 5,7,2’,4’-Tetrahydroxyisoflavone 7-O-(6’’-malonyl)glucoside 5,7,3’4’-Trihydroxyisoflavone 7-O-(6’’-malonylglucoside) 5,7-Dihydroxy-6,2’,4’,5’-tetramethoxyisoflavone 7-O-glucoside 5,7-Dihydroxy-6,2’,4’,5’-tetramethoxyisoflavone 8-C-glucoside 5,7-Dihydroxy-8,2’,4’,5’-tetramethoxyisoflavone 7-O-glucoside 7,5’-Dihydroxy-5,4’-dimethoxy-3’-prenylisoflavone 7-O-galactoside 7-Hydroxy-6,4’-dimethoxyisoflavone 7-O-(6’’-malonylglucoside) 7,4’-Dihydroxy-6-methoxyisoflavone 7-O-(6’’-succinylglucoside) Afrormosin 7-O-(6’’-malonylglucoside) Glycitein 7-O-(6’’-succinylglucoside)

Biochanin A 7-O-(6’’-malonylglucoside) Daidzein 7-O-(6’’-succinylglucoside) 2’-Hydroxygenisteine 7-O-(6’’-malonylglucoside) 2’-Hydroxygenistein 7-O-(6’’-malonylglucoside) Orobol 7-O-(6’’-malonylglucoside) Caviunin 7-O-glucoside Dalpaniculin Isocaviunin 7-O-glucoside

2’’,6’’-O-Diacetyloninin Genistein 7-O-(6’’-succinylglucoside) Formononetin 7-O-(6’’-malonylglucoside) licoisoflavone A 4’-O-glucoside licoisoflavone A 7-O-glucoside luteone 7-O-glucoside Genistein 7-O-(6’’-O-malonylglucoside) Genistein 7-O-(6’’-malonylglucoside) Genistein 8-C-glucoside 6’’-O-malonate Irigenin 7-O-glucoside

Licoagroside A Genisteone Daidzin 6’’-O-malonate Puerarin 6’’-O-malonate Germanaism A Dalpatein 7-O-glucoside Isoplatycarpanetin 7-O-glucoside Platycarpanetin 7-O-glucoside Mirabijalone C Vavain 3’-O-glucoside Junipegenin 7-O-glucoside

492.44 500.49 502.43 502.43 504.45 504.45 504.45 504.45 506.46 506.46 506.46 508.43 514.48 516.45 516.46 516.49 516.49 516.49 518.43 518.43 518.43 522.46 522.46 532.46 532.46 534.43 534.43 534.43 536.49 536.49 536.49 544.55 546.48 546.48

C23H24O12 C26H28O10 C24H22O12 C24H22O12 C24H24O12 C24H24O12 C24H24O12 C24H24O12 C24H26O12 C24H26O12 C24H26O12 C23H24O13 C26H26O11 C25H24O12 C25H24O12 C26H28O11 C26H28O11 C26H28O11 C24H22O13 C24H22O13 C24H22O13 C24H26O13 C24H26O13 C25H24O13 C25H24O13 C24H22O14 C24H22O14 C24H22O14 C25H28O13 C25H28O13 C25H28O13 C28H32O11 C26H26O13 C26H26O13

Appendix

continued

F141b F202 F135 F135 F17 3138 3178 3179 F316 F189 3194 F208 F92 F294 3116 F240 F240 F240 F240 3147 F135 3181 3196 3154 F294 F240 F240 3187 3182 F214 3184 F328 3214 F294

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1161

5,7,3’-Trihydroxy-4’-methoxyisoflavone 7-O-(6’’-malonylglucoside) 7,4’-Dihydroxyisoflavone 7-O-(6’’-apiosylglucoside) 7,4’-Dihydroxyisoflavone 7-O-glucoside-4’-O-apioside 7-Hydroxy-4’-methoxyisoflavone 7-O-(2’’-p-hydroxybenzoylglucoside) 5,7,4’-Trihydroxyisoflavone 7,4’-bis(3-cymaroside) 7-Hydroxy-4’-methoxyisoflavone 7-O-(2’’-apiosylglucoside) 7-Hydroxy-4’-methoxyisoflavone 7-O-(6’’-xylosylglucoside) 7-Hydroxy-4’-methoxyisoflavone 7-O-(rhamnosylglucoside) 5,7,4’-Trihydroxyisoflavone 7-O-(6’’-apiosylglucoside) 5,7,4’-Trihydroxyisoflavone 7-O-(6’’-arabinosylglucoside) 5,7,4’-Trihydroxyisoflavone 7-O-(6’’-xylosylglucoside) 5,7,4’-Trihydroxyisoflavone 7-O-glucoside-4’-O-apioside 5,7,4’-Trihydroxyisoflavone 7,4’-O-di(2-O-methylrhamnoside) 5,7,4’-Trihydroxyisoflavone 5-O-rhamnoside-7-(2-O-methylrhamnoside) 7-Hydroxy-4’-methoxyisoflavone 7-O-(6’’-rhamnosylglucoside) 4’,7-Dihydroxy-6-methoxyisoflavone 7-O-(6’’-xylosylglucoside) 5,7-Dihydroxy-4’-methoxyisoflavone 7-O-(2’’-apiosylglucoside) 5,7-Dihydroxy-4’-methoxyisoflavone 7-O-(6’’-apiosylglucoside) 5,7-Dihydroxy-4’-methoxyisoflavone 7-O-(6’’-xylosylglucoside) 5,7,4’-Trihydroxyisoflavone 4’-O-(2’’-rhamnosylglucoside) 5,7,4’-Trihydroxyisoflavone 7-O-(2’’-p-coumaroylglucoside) 5,7,4’-Trihydroxyisoflavone 7-O-(6’’-rhamnosylglucoside) 7,4’-Dihydroxy-6-methoxyisoflavone 7-(6’’-xylosylglucoside) 7,4’-Dihydroxyisoflavone 7-O-glucoside-4’-O-glucoside 5,2’-Dihydroxy-8-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]isoflavone 4’-O-glucoside 7-Hydroxy-3’,4’-methylenedioxyisoflavone 7-O-(rhamnosylglucoside) 4’,5-Dihydroxy-7-methoxyisoflavone 3’-O-(3’’-E-cinnamoylglucoside) 5,7-Dihydroxy-4’-methoxyisoflavone 7-O-(6’’-rhamnosylglucoside) 7-Hydroxy-4’-methoxyisoflavone 7-O-(3’’-glucosylglucoside) 7-Hydroxy-4’-methoxyisoflavone 7-O-(6’’-glucosylglucoside) 7-Hydroxy-6,4’-dimethoxyisoflavone 7-O-(2’’-apiosylglucoside)

Mass

Formula

Pratensein 7-O-(6’’-malonylglucoside) 548.46 C25H24O14 Daidzein 7-O-(6’’-apiosylglucoside) 548.50 C26H28O13 Daidzein 7-O-glucoside-4’-O-apioside 548.50 C26H28O13 Formononetin 7-O-(2’’-p-hydroxybenzoylglucoside) 550.52 C29H26O11 Genistein 4’,7-O-bis(3-cymaroside) 558.57 C29H34O11 Formononetin 7-O-(6’’-apiosylglucoside) 562.53 C27H30O13 Formononetin 7-O-(6’’-xylosylglucoside) 562.53 C27H30O13 Daidzein 7-O-rhamnosylglucoside 562.53 C27H30O13 564.50 C26H28O14 Genistein 7-O-(6’’-apiosylglucoside) Genistin 6’’-O-arabinosyl 564.50 C26H28O14 Genistin 6’’-O-xylosyl 564.50 C26H28O14 Genistein 7-O-glucoside-4’-O-apioside 564.50 C26H28O14 Daidzein G 1 574.58 C29H34O12 Genestein G 2 576.56 C28H32O13 Formononetin 7-O-rutinoside 576.56 C28H32O13 578.53 C27H30O14 Coromandelin 578.53 C27H30O14 Biochanin A 7-O-(6’’-apiosylglucoside) 578.53 C27H30O14 Biochanin A 7-O-(6’’-xylosylglucoside) 578.53 C27H30O14 Genistein 7-O-neohesperidoside 578.53 C27H30O14 Genistein 7-O-(2’’-p-coumaroylglucoside) 578.53 C30H26O12 Genistein 7-O-rutinoside 578.53 C27H30O14 Tectorigenin 7-O-(6’’-xylosylglucoside) 578.53 C27H30O14 Daidzein 7,4’-O-diglucoside 578.53 C27H30O14 Auriculatin 4’-O-glucoside 582.60 C31H34O11 Pseudobaptigenin 7-O-rhamnosylglucoside 590.54 C28H30O14 592.55 C31H28O12 Biochanin A 7-O-rutinoside 592.56 C28H32O14 Formononetin 7-O-laminariobioside 592.56 C28H32O14 Formononetin 7-O-gentiobioside 592.56 C28H32O14 Afromosin 7-O-(2’’-apiosylglucoside) 592.56 C28H32O14

Trivial Name

3189 3200 3199 3204 F159 3202 3203 3112 3208 F323 F323 3210 F93 F93 3114 F195 F211 3153 3152 3145 3209 3144 F188 3111 F183 3119 F128 3150 3115 F96 F296

Ref.

1162

956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986

Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020

7,3’-Dihydroxy-4’-methoxyisoflavone 7-O-(rhamnosylglucoside) Calycosin 7-O-rhamnosylglucoside 7,8-Dihydroxy-4’-methoxyisoflavone 7-O-(2’’-rhamnosylglucoside) Retusin 7-O-neohesperidoside 7,8-Dihydroxy-4’-methoxyisoflavone 7-O-(6’’-rhamnosylglucoside) Derriscandenoside B 4’,7-Dihydroxy-6-methoxyisoflavone 7-O-(6’’-xylosylglucoside) 5,6,7,4’-Tetrahydroxyisoflavone 7-O-(rhamnosylglucoside) 6-Hydroxygenistein 7-O-rhamnosylglucoside 5,7,2’,4’-Tetrahydroxyisoflavone 6-C-(2’’-rhamnosylglucoside) Nodosin 5,7,3’,4’-Tetrahydroxyisoflavone 7-O-(rhamnosylglucoside) Orobol 7-O-rhamnosylglucoside 5,7,4’-Trihydroxyisoflavone 7-O-(6’’-apiosylglucoside) Tectorigenin 7-O-(6’’-apiosylglucoside) 5,7,4’-Trihydroxyisoflavone 7-O-(glucosylglucoside) Genistein 7-O-glucosylglucoside 5,7,4’-Trihydroxyisoflavone 7-O-glucoside-4’-O-glucoside Genistein 7,4’-O-glucoside 5,7,4’-Trihydroxyisoflavone 8-C-glucoside-4’-O-glucoside Genistein 8-C-glucoside-4’-O-glucoside 7,2’,4’-Trihydroxyisoflavone 7-O-glucoside-4’-O-glucoside 2’-Hydroxydaidzein 7,4’-O-diglucoside 7-Hydroxy-3’,4’-methylenedioxyisoflavone 7-O-(3’’-glucosylglucoside) Pseudobaptigenin 7-O-laminariobioside 7-Hydroxy-6,4’-dimethoxyisoflavone 7-O-(6’’-rhamnosylglucoside) Derriscandenoside D 7-Hydroxy-8,4’-dimethoxyisoflavone 7-O-(6’’-rhamnosylglucoside) Derriscanoside B 8-Hydroxy-7,4’-dimethoxyisoflavone 8-O-(6’’-rhamnosylglucoside) Derriscandenoside C 5,4’-Dihydroxy-6,7-dimethoxyisoflavone 4’-O-(6’’-apiosylglucoside) 5,7-Dihydroxy-4’-methoxyisoflavone 7-O-(6’’-glucosylglucoside) Biochanin A 7-O-gentiobioside 5,7-Dihydroxy-6,4’-dimethoxyisoflavone 7-O-(2’’-apiosylglucoside) Pubescidin 5,7-Dihydroxy-6,4’-dimethoxyisoflavone 7-O-(xylosylglucoside) Irisolidone 7-O-xylosylglucoside 7,4’-Dihydroxy-5-methoxyisoflavone 7,4’-O-diglucoside Isoprunetin 7,4’-O-diglucoside Germanaism D 5,6,7,4’-Tetrahydroxyisoflavone 4’-O-(6’’-glucosylglucoside) 5,7,2’,4’-Tetrahydroxyisoflavone 7,4’-O-diglucoside 2’-Hydroxygenistein 7,4’-O-diglucoside 5,7,3’,4’-Tetrahydroxyisoflavone 7-O-(2’’-glucosylglucoside) Orobol 7-O-sophoroside 5,7-Dihydroxy-3’,4’-methylenedioxyisoflavone 7-O-(glucosylglucoside) 6,3’-Dihydroxy-7-methoxy-4’,5’-methylenedioxyisoflavone 6-O-(6’’-xylosylglucoside) 6,7-Dihydroxy-3’-methoxy-4’,5’-methylenedioxyisoflavone 6-O-(6’’-xylosylglucoside) 5,4’-Dihydroxy-6,7-dimethoxyisoflavone 4’-O-(rhamnosylglucoside) 7-O-Methyltectorigenin 4’-O-rhamnosylglucoside 5,7-Dihydroxy-6,4’-dimethoxyisoflavone 7-O-(6’’-O-rhamnosylglucoside) Derriscandenoside E 7-Hydroxy-3’,4’-dimethoxyisoflavone 7-O-(3’’-glucosylglucoside) Cladrin 7-O-laminariobioside 7-Hydroxy-6,4’-dimethoxyisoflavone 7-O-(3’’-glucosylglucoside) Afrormosin 7-O-laminariobioside 8-O-Methylretusin 7-O-laminariobioside 7-Hydroxy-8,4’-dimethoxyisoflavone 7-O-(3’’-glucosylglucoside) 5,7,4’-Trihydroxy-6-methoxyisoflavone 4’-O-(6’’-glucosylglucoside) Tectorigenin 4’-O-(6’’-glucosylglucoside) 5,7,4’-Trihydroxy-6-methoxyisoflavone 7-O-(6’’-glucosylglucoside) Tectorigenin 7-O-gentiobioside

592.56 592.56 592.56 594.53 594.53 594.53 594.53 594.53 594.53 594.53 594.53 594.53 606.54 606.58 606.58 606.58 608.54 608.54 608.54 608.54 608.54 610.53 610.53 610.53 622.54 622.54 622.54 622.58 622.58 622.58 622.58 622.58 624.56 624.56

3122 3125 F218 F195 3158 F108 3157 F65 3142 3143 F319 3186 3120 F218 F140 F218 F160 3151 F295 3168 F319 F16 F319 3188 3160 F356 F312 3170 F218 3127 3130 3132 F66 3165

Appendix

continued

C28H32O14 C28H32O14 C28H32O14 C27H30O15 C27H30O15 C27H30O15 C27H30O15 C27H30O15 C27H30O15 C27H30O15 C27H30O15 C27H30O15 C28H30O15 C29H34O14 C29H34O14 C29H34O14 C28H32O15 C28H32O15 C28H32O15 C28H32O15 C28H32O15 C27H30O16 C27H30O16 C27H30O16 C28H30O16 C28H30O16 C28H30O16 C29H34O15 C29H34O15 C29H34O15 C29H34O15 C29H34O15 C28H32O16 C28H32O16

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5,7,4’-Trihydroxy-6-methoxyisoflavone 7-O-glucoside-4’-O-glucoside 4’-Hydroxy-5-methoxy-6,7-methylenedioxyisoflavone 4’-O-(6’’-glucosylglucoside) 7-Hydroxy-6-methoxy-3’,4’-methylenedioxyisoflavone 7-O-(3’’-glucosylglucoside) 5,3’-Dihydroxy-7,4’,5’-trimethoxyisoflavone 3’-O-(6’’-arabinosylglucoside) 5,4’-Dihydroxy-6,7-dimethoxyisoflavone 4’-O-(6’’-glucosylglucoside)

7-Hydroxy-5,8-dimethoxy-3’,4’-methylenedioxyisoflavone 7-O-(3’’-glucosylglucoside) 5,7,3’-Trihydroxy-6,4’,5’-trimethoxyisoflavone 7-(6’’-O-(4-hydroxy-3-methoxybenzoyl)glucoside) 7-Hydroxy-5,6,2’-trimethoxyisoflavone 7-O-(2’’-p-coumaroylglucoside) 5,7-Dihydroxy-6,2’,4’,5’-tetrahydroxyisoflavone 7-O-(rhamnosylglucoside) 5,7,3’-Trihydroxy-6,4’,5’-trimethoxyisoflavone 7-O-(6’’-glucosylglucoside) 5,7-Dihydroxy-8,2’,4’,5’-tetramethoxyisoflavone 7-O-(6’’-glucosylglucoside) 5,7-Dihydroxy-4’-methoxyisoflavone 7-O-(6’’-(5’’’-(apiosyl)-apiosyl)-glucoside)

1043 5,7,4’-Trihydroxyisoflavone 7-O-rhamnoside-4’-O-(2’’-rhamnosylglucoside) 1044 5,7,4’-Trihydroxyisoflavone 7-O-glucoside-4’-O-(2’’-rhamnosylglucoside) 1045 5,7,4’-Trihydroxyisoflavone 7-O-rhamnoside-4’-O-(2’’-glucosylglucoside)

1041 5,7,2’,4’-Tetrahydroxy-6,3’-diprenylisoflavone 5-O-(4’’-rhamnosylrhamnoside) 1042 7-Hydroxy-4’-methoxyisoflavone 7-O-(2’’,6’-di-O-E-p-coumaroyl)-glucoside

1034 1035 1036 1037 1038 1039 1040

1031 7-Hydroxy-6,3’,4’-trimethoxyisoflavone 7-O-(3’’-glucosylglucoside) 1032 5,7,2’-Trihydroxy-6,4’-dimethoxyisoflavone 7-O-(6’’-glucosylglucoside) 1033 5,7,4’-Trihydroxy-6,3’-dimethoxyisoflavone 7-O-(6’’-glucosylglucoside)

Formononetin 7-O-(2’’,6’’-di-O(E-p-coumaroyl)glucoside)

Caviunin 7-O-rhamnosylglucoside Germanaism C Isocaviunin 7-O-gentiobioside Biochanin A 7-O-(6’’-(5’’’(apiosyl)apiosyl)glucoside)

5-Methoxyafrormosin 7-O-laminariobioside Cladrastin 7-O-laminariobioside Iristectorigenin 7-O-gentiobioside Iristectorigenin B 7-O(6’’-glucosylglucoside) Platycarpanetin 7-O-laminariobioside Shegansu A

7-O-Methyltectorigenin 4’-Ogentiobioside 6’’-O-p-Hydroxybenzoyliridin 4’-O-Methylneobavaisoflavone 7-O(2’’-p-coumaroylglucoside)

Tectorigenin 7,4’-O-diglucoside Germanaism E Fujikinetin 7-O-laminariobioside

Trivial Name

Formula

Ref.

C30H34O17 C32H32O16 C34H32O15 C31H38O17 C30H36O18 C31H38O18 C32H38O18

3180 F357 F329 3183 F16 3185 F45

724.66 C33H40O18 F290 740.66 C33H40O19 F290 740.66 C33H40O19 F290

714.75 C37H46O14 F327 722.69 C40H34O13 F251

666.59 672.59 680.61 682.64 684.60 698.64 710.63

652.61 C30H36O16 3137 654.58 C29H34O17 3193 654.58 C29H34O17 F66

650.64 C31H38O15 3198 652.61 C30H36O16 F326 652.61 C30H36O16 3174

642.56 C31H30O15 F112 644.68 C36H36O11 3218

624.56 C28H32O16 F250 636.56 C29H32O16 F16 636.56 C29H32O16 3134 638.58 C29H34O16 F298 638.58 C29H34O16 3171

Mass

1164

1028 5-Hydroxy-7,3’,4’-trimethoxy-8-methylisoflavone 5-O-(2’’-rhamnosylglucoside) 1029 5,7-Dihydroxy-6,3’,4’-trimethoxyisoflavone 7-O-(6’’-rhamnosylglucoside) 1030 7-Hydroxy-5,6,4’-trimethoxyisoflavone 7-O-(3’’-glucosylglucoside)

1026 5,7,3’-Trihydroxy-6,4’,5’-trimethoxyisoflavone 7-(6’’-(4-hydroxybenzoyl)glucoside) 1027 7-Hydroxy-4’-methoxy-3’-prenylisoflavone 7-O-(2’’-p-coumaroylglucoside)

1021 1022 1023 1024 1025

Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072

3-ARYLCOUMARINS 7,2’-Dihydroxy-4’-methoxy-3-phenylcoumarin 7,2’-Dihydroxy-4’,5’-methylenedioxy-3-phenylcoumarin 4’-Hydroxy-4,7,2’-trimethoxy-3-phenylcoumarin 2’-Methoxy-4’,5’-methylenedioxyfurano[2’’,3’’:7,6]-3-phenylcoumarin 2’,4’-Dihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]-3-phenylcoumarin 2’,4’,5’-Trimethoxyfurano[2’’,3’’:7,6]-3-phenylcoumarin 7,4’-Dihydroxy-2’-methoxy-3’-prenyl-3-phenylcoumarin 4,5,7-Trimethoxy-4’,5’-methylenedioxy-3-phenylcoumarin 2’,4’-Dimethoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]-3-phenylcoumarin 8,2’-Dimethoxy-4’,5’-methylenedioxyfurano[2’’,3’’:7,6]-3-phenylcoumarin 4,4’-Dihydroxy-5-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]-3-phenylcoumarin 7,2’-Dihydroxy-5-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]-3-phenylcoumarin 2’,4’-Dihydroxy-5-methoxy-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:7,6]-3-phenylcoumarin 7,2’,4’-Trihydroxy-5-methoxy-3’-prenyl-3-phenylcoumarin 7,2’,4’-Trihydroxy-5-methoxy-6-prenyl-3-phenylcoumarin 7,2’,4’-Trihydroxy-5-methoxy-8-(1,1-dimethyl-2-propenyl)-3-phenylcoumarin 4-Hydroxy-5,6,7-trimethoxy-4’,5’-methylenedioxy-3-phenylcoumarin 2’-Methoxy-3’,4’-methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]-3-phenylcoumarin 4-Hydroxy-5,4’-dimethoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]-3-phenylcoumarin 2’,4’-Dihydroxy-5,7-dimethoxy-6-prenyl-3-phenylcoumarin 4-Hydroxy-5,4’-dimethoxy-5’’-(1-methylethenyl)-4’’,5’’-dihydrofurano[2’’,3’’:7,6]-3-phenylcoumarin 7-Hydroxy-5,2’-dimethoxy-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:4’,3’]-3-phenylcoumarin 2,4’-Dihydroxy-5-methoxy-5’’-(1-hydroxy-1-methylethyl)-4’’,5’’-dihydrofurano[2’’,3’’:7,6]-3phenylcoumarin 1073 2’,4’-Dihydroxy-5-methoxy-6’’-(hydroxymethyl)-6’’-methyl-4’’,5’’-dihydropyrano[2’’,3’’:7,6]-3phenylcoumarin

1046 5,7,4’-Trihydroxyisoflavone 7-O-glucoside-4’-O-(2’’-glucosylglucoside) 1047 4’-Hydroxy-5-methoxy-6,7-methylenedioxyisoflavone 4’-O-(2’’-glucosyl-6’’-rhamnosylglucoside) 1048 3’,4’-Dihydroxy-5-methoxy-6,7-methylenedioxyisoflavone 3’-O-glucoside-4’-O-(2’’-O(4’’’’-acetyl-2’’’’-methoxyphenyl)glucoside) 1049 5,7,4’-Trihydroxyisoflavone 7-O-(4’’-glucosylapioside)-4’-O-(4’’-glucosylapioside)

384.39

Licopyranocoumarin

Neofolin Indicanine B Glyasperin L Isoglycycoumarin Gancaonin W Glycycoumarin Licoarylcoumarin

Eryvarin O Derrusnin

Pervilleanin Robustic acid Glycyrin Indicanine A Gancaonol A Licofuranocoumarin

Melimessanol B Pachyrrhizin Kanzonol W

284.27 298.25 328.32 336.30 336.34 352.34 352.38 356.33 364.40 366.33 366.36 366.36 368.39 368.39 368.39 368.39 372.33 378.38 380.40 382.41 382.41 382.41 384.39

3072

2802 2803 F153 2804 F73 F154 F280 2807 F122 2805 F305 F72 3071 F78 3070 3073 F332 F193 2808 2806 F185 F70 F88

Appendix

continued

C21H20O7

C16H12O5 C16H10O6 C18H16O6 C19H12O6 C20H16O5 C20H16O6 C21H20O5 C19H16O7 C22H20O5 C20H14O7 C21H18O6 C21H18O6 C21H20O6 C21H20O6 C21H20O6 C21H20O6 C19H16O8 C22H18O6 C22H20O6 C22H22O6 C22H20O6 C22H22O6 C21H20O7

C37H46O23 3146

756.66 C33H40O20 F290 782.70 C35H42O20 F16 800.71 C38H40O19 F16

Genistein 7,4’-O-bis(glucosylapioside) 858.76

Germanaism F Germanaism G

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1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100

COUMARONOCHROMONES Coumaronochromone 5,7,3’-Trihydroxycoumaronochromone 5,7,4’-Trihydroxycoumaronochromone 5,4’-Dihydroxy-7-methoxycoumaronochromone 7,4’-Dihydroxy-5’-methoxycoumaronochromone 5,7,4’-Trihydroxy-5’-methoxycoumaronochromone 5,7,5’-Trihydroxy-4’-methoxycoumaronochromone 5,4’-Dihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]coumaronochromone 5,7,4’-Trihydroxy-3’-prenylcoumaronochromone 5,7,4’-Trihydroxy-6-prenylcoumaronochromone 5,4’-Dihydroxy-5’’-(1-hydroxy-1-methylethyl)-4’’,5’’-dihydrofurano[2’’,3’’:7,6]coumaronochromone 5,7-Dihydroxy-5’’-(1-hydroxy-1-methylethyl)-4’’,5’’-dihydrofurano[2’’,3’’:4’,3’]coumaronochromone 3,2’,4’-Trihydroxy-8-prenylfurano[2’’,3’’:7,6]coumaronochromone

4-Hydroxy-5-methoxy-3’,4’-methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]-3-phenylcoumarin 4-Hydroxy-5-methoxy-3’,4’-methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]-3-phenylcoumarin 4,5,4’-Trimethoxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]-3-phenylcoumarin 7,2’4’-Trihydroxy-8,3’-diprenyl-3-phenylcoumarin 4-Hydroxy-5,8,4’-trimethoxy-5’’-(1-methylethenyl)furano[2’’,3’’:7,6]-3-phenylcoumarin 4,5-Dimethoxy-3’,4’-methylenedioxy-5’’-(1-methylethenyl)-4’’,5’’-dihydrofurano[2’’,3’’:7,6]-3phenylcoumarin 4,5-Dimethoxy-3’,4’-methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]-3-phenylcoumarin 4,5-Dimethoxy-3’,4’-methylenedioxy-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]-3-phenylcoumarin 4-Hydroxy-5,8-dimethoxy-3’,4’-methylenedioxy-5’’-(1-methylethenyl)furano[2’’,3’’:7,6]-3-phenylcoumarin 4,4’-Dihydroxy-5-methoxy-6-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]-3-phenylcoumarin 4,4’-Dihydroxy-5-methoxy-8-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]-3-phenylcoumarin 4-Hydroxy-5,3’,4’-trimethoxy-5’’-(1-methylethenyl)-4’’,5’’-dihydrofurano[2’’,3’’:7,6]-3-phenylcoumarin 4-Hydroxy-5,4’-dimethoxy-8-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]-3-phenylcoumarin 4-Keto-4’-hydroxy-5-methoxy-6-prenyl-3-(2-oxopropyl)-6’’,6’’dimethylpyrano[2’’,3’’:7,8]-3-phenylcoumarin

Wrightiadione Coccineone A Lupinalbin A Sophorophenolone Desmoxyphyllin B Desmoxyphyllin A Oblonginol Lupinalbin H Lupinalbin D Lupinalbin B Lupinalbin C Lupinalbin E Erysenegalensein K

Robustin methyl ether Isorobustin 4-methyl ether Thonningine A Scandenin Lonchocarpic acid Thonningin C Lonchocarpenin

Robustin Isorobustin Robustic acid methyl ether Licocoumarin A Thonningine B Glabrescin

Trivial Name

248.23 284.23 284.23 298.25 298.25 314.25 314.25 350.32 352.34 352.34 368.34 368.34 378.38

408.41 408.41 422.39 434.49 434.49 438.43 448.51 490.54

394.38 394.38 394.42 406.47 408.41 408.41

Mass

C16H8O3 C15H8O6 C15H8O6 C16H10O6 C16H10O6 C16H10O7 C16H10O7 C20H14O6 C20H16O6 C20H16O6 C20H16O7 C20H16O7 C22H18O6

C23H20O7 C23H20O7 C23H18O8 C26H26O6 C26H26O6 C24H22O8 C27H28O6 C29H30O7

C22H18O7 C22H18O7 C23H22O6 C25H26O5 C23H20O7 C23H20O7

Formula

F144 F67 3093 F291 F172 F172 F145 F267 3094 3096 3097 3095 F311

2811 3077 3074 2813 2814 F12 2815 F155

2810 3076 2809 F19 3075 2812

Ref.

1166

1080 1081 1082 1083 1084 1085 1086 1087

1074 1075 1076 1077 1078 1079

Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

5,7,4’-Trihydroxy-3’-methoxy-5’-prenylcoumaronochromone 5,7,5’’-Trihydroxy-4’-methoxy-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:3’,2’]coumaronochromone 5,4’-Dihydroxy-8-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]coumaronochromone 5,7,4’-Trihydroxy-6,3’-diprenylcoumaronochromone 5,7,5’-Trihydroxy-6,8-diprenyl-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]coumaronochromone 7,4’,5’-Trihydroxy-3-(3,7-dimethyl-2,6-octadienyl)coumaronochromone 5,4’,5’-Trihydroxy-6-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,8]coumaronochromone 5,5’-Dihydroxy-6’’,6’’,6’’’,6’’’-tetramethyl-4’’,5’’dihydropyrano[2’’,3’’:7,8]-pyrano[2’’’,3’’’:4’,3’]coumaronochromone 5,7,5’-Trihydroxy-8-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]coumaronochromone 3,5,6’-Trihydroxy-8-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:7,6]coumaronochromone 5,7,4’,5’-Tetrahydroxy-6,8-diprenylcoumaronochromone 5,7,4’,5’-Tetrahydroxy-8,3’-diprenylcoumaronochromone 5,7,5’-Trihydroxy-8-prenyl-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:4’,3’]coumaronochromone 5,7,4’-Trihydroxy-5’-methoxy-8,3’-diprenylcoumaronochromone 7,4’-Dihydroxy-5’-methoxycoumaronochromone 7-O-glucoside 5,7,4’-Trihydroxy-5’-methoxycoumaronochromone 7-O-glucoside 5,5’-Dihydroxy-6-prenyl-(2’’,3’’:7,8),(2’’’,3’’’:4’,3’)-bis(6,6-dimethylpyrano)coumaronochromone 5,5’-Dihydroxy-8-prenyl-(2’’,3’’:7,6),(2’’’,3’’’:4’,3’)-bis(6,6-dimethylpyrano)coumaronochromone 5,5’-Dihydroxy-8-prenyl-6’’,6’’,6’’’,6’’’-tetramethyl-4’’,5’’dihydropyrano[2’’,3’’:7,6]pyrano[2’’’,3’’’:4’,3’]coumaronochromone 7,5’-Dihydroxy-8-prenyl-6’’,6’’,6’’’,6’’’-tetramethyl-4’’,5’’dihydropyrano[2’’,3’’:5,6]pyrano[2’’’,3’’’:4’,3’]coumaronochromone 5,7,4’,5’-Tetrahydroxy-6,8,3’-triprenylcoumaronochromone 7,5’-Dihydroxy-8-prenyl-(2’’,3’’:5,6),(2’’’,3’’’:4’,3’)-bis(6,6-dimethyl-4,5dihydropyrano)coumaronochromone 5,7,4’-Trihydroxy-5’-methoxy-6,8,3’-triprenylcoumaronochromone 5,7,5’-Trihydroxy-8-prenyl-6-(3-hydroxy-3-methylbutyl)-6’’,6’’dimethylpyrano[2’’,3’’:7,8]-pyrano[2’’’,3’’’:4’,3’]coumaronochromone 5,7,4’,5’-Tetrahydroxy-6-(3-hydroxy-3-methylbutyl)-8,3’-diprenylcoumaronochromone 5,7,5’,4’’(S),5’’(R)-Pentahydroxy-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:4’,3’]coumaronochromone C25H22O7 C25H24O7 C25H24O7 C25H24O7 C25H24O7 C26H26O7 C22H20O11 C22H20O12 C30H28O7 C30H28O7 C30H30O7

C21H18O7 C21H18O8 C25H22O6 C25H24O6 C25H24O6 C25H24O6 C25H22O7 C25H22O7

Lupinol C Piscerythrol

F266 F266

F149 F148

F149 F148

3101 F149

F149

F173 F311 F173 3099 F149 3100 F172 F172 F174 F174 F148

2512 F264 2513 3098 3102 F170 F173 F148

continued

370.35 C20H18O7 400.38 C21H20O8

522.59 C30H34O8 536.57 C30H32O9

518.60 C31H34O7 520.57 C30H32O8

Euchretin N Formosanatin A Euchretin M Formosanatin B

504.58 C30H32O7 504.58 C30H32O7

502.56 C30H30O7

434.44 436.46 436.46 436.46 436.46 450.49 460.39 476.39 500.54 500.54 502.56

382.27 398.36 418.45 420.46 420.46 420.46 434.44 434.44

Euchretin C Euchretin K

Euchretin J

Euchretin H Erysenegalensein J Euchretin F Euchretin B Euchretin L 8-Dimethylallyllisetin Desmoxyphyllin B 7-O-glucoside Desmoxyphyllin A 7-O-glucoside Euchretin E Euchretin D Formosanatin C

Lisetin Lisetinone Millettin Lupinalbin F Euchretin A Lespedezol C1 Euchretin G Formosanatin D

Appendix

COUMARANOCHROMANONES 1127 (2R,3S)-3,5,7,4’-Tetrahydroxy-6-prenylcoumaranochroman-4-one 1128 (2S,3S)-3,5,7,4’-Tetrahydroxy-5’-methoxy-3’-prenylcoumaranochroman-4-one

1125 1126

1123 1124

1121 1122

1120

1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119

1101 1102 1103 1104 1105 1106 1107 1108

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1167

(2S,3S)-3,5,7,4’-Tetrahydroxy-6,3’-diprenylcoumaranochroman-4-one (2S,3S)-5,7,4’-Trihydroxy-3-methoxy-6,3’-diprenylcoumaranochroman-4-one

PTEROCARPANES (6aS,11aS)-4,9-Dihydroxy-3,8-dimethoxypterocarpan 3,9-Dihydroxypterocarpan 3-Hydroxy-9-methoxypterocarpan 9-Hydroxy-3-methoxypterocarpan 3,4,9-Trihydroxypterocarpan 3,6a,9-Trihydroxypterocarpan 9-Hydroxyfurano[2’,3’:3,2]pterocarpan 3-Hydroxy-8,9-methylenedioxypterocarpan 3,9-Dimethoxypterocarpan 1,9-Dihydroxy-3-methoxypterocarpan 3,10-Dihydroxy-9-methoxypterocarpan 3,4-Dihydroxy-9-methoxypterocarpan 3,6a-Dihydroxy-9-methoxypterocarpan 3,7-Dihydroxy-9-methoxypterocarpan 3,9-Dihydroxy-10-methoxypterocarpan 3,9-Dihydroxy-8-methoxypterocarpan 4,9-Dihydroxy-3-methoxypterocarpan 6a,9-Dihydroxy-3-methoxypterocarpan (6aR,11aR)-3,8-Dihydroxy-9-methoxypterocarpan (6aR,11aR)-3,9-Dihydroxy-8-methoxypterocarpan (6aR,11aR,11bS)-3-Keto-11b-hydroxy-9-methoxy-1,2-dihydropterocarpan 9-Methoxyfurano[2’,3’:3,2]pterocarpan (6aR,11aR)-5’,5’-Dimethyl-4’,5’-dihydrofurano[2’,3’:3,2]pterocarpan 3-Methoxy-8,9-methylenedioxypterocarpan (6aR,11aR)-2-Carboxyaldehyde-9-hydroxy-3-methoxypterocarpan 2,3-Dihydroxy-8,9-methylenedioxypterocarpan

1129 1130

1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156

Name

Lespedezol D1 11b-Hydroxydihydromedicarpin 9-O-Methylneodunol Methyl-oroxylopterocarpan Pterocarpin Erysubin C 2-Hydroxymaackiain

316.31 256.26 270.29 270.29 272.26 272.26 280.28 284.27 284.31 286.29 286.29 286.29 286.29 286.29 286.29 286.29 286.29 286.29 286.29 286.29 288.30 294.31 294.34 298.30 298.30 300.27

438.48 452.50

Mass

C17H16O6 C15H12O4 C16H14O4 C16H14O4 C15H12O5 C15H12O5 C17H12O4 C16H12O5 C17H16O4 C16H14O5 C16H14O5 C16H14O5 C16H14O5 C16H14O5 C16H14O5 C16H14O5 C16H14O5 C16H14O5 C16H14O5 C16H14O5 C16H16O5 C18H14O4 C19H18O3 C17H14O5 C17H14O5 C16H12O6

C25H26O7 C26H28O7

Formula

F147 2608 2609 2610 2611 2680 2640 2612 2613 3021 2615 2616 2681 3018 2614 3020 3023 2682 3034 F171 F22 3030 F8 2617 F275 3036

F266 F266

Ref.

1168

Derricarpin Demethylmedicarpin (
)Medicarpin Isomedicarpin 4-Hydroxydemethylmedicarpin Glycinol Neodunol (
)Maackiain (
)Homopterocarpin Desmocarpin Vesticarpan 4-Hydroxymedicarpin 6a-Hydroxymedicarpin Nissicarpin Nissolin Kushenin Melilotocarpan B 6a-Hydroxyisomedicarpin

Lupinol A Lupinol B

Trivial Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190

3,4-Dihydroxy-8,9-methylenedioxypterocarpan 3,6a-Dihydroxy-8,9-methylenedioxypterocarpan (6aS,11aS)-3,4-Dihydroxy-8,9-methylenedioxypterocarpan 3-Hydroxy-2,9-dimethoxypterocarpan 3-Hydroxy-4,9-dimethoxypterocarpan 3-Hydroxy-8,9-dimethoxypterocarpan 4-Hydroxy-3,9-dimethoxypterocarpan 6a-Hydroxy-3,9-dimethoxypterocarpan (6aR,11aR)-10-Hydroxy-3,9-dimethoxypterocarpan (6aR,11aR)-3-Hydroxy-8,9-dimethoxypterocarpan (6aR,11aR)-3-Hydroxy-9,10-dimethoxypterocarpan (6aR,11aR)-8-Hydroxy-3,9-dimethoxypterocarpan (6R,6aS,11aR)-3-Hydroxy-6,9-dimethoxypterocarpan 7-Hydroxy-3,9-dimethoxypterocarpan 9-Hydroxy-2,3-dimethoxypterocarpan 3,6a,7-Trihydroxy-9-methoxypterocarpan (6aR,11aR,11bS)-3-Keto-11b-hydroxy-8,9-methylenedioxy-1,2-dihydropterocarpan (6aS,11aS)-4-Dihydroxy-3-methoxy-8,9-methylenedioxypterocarpan 8,9-Methyleneoxyfurano[2’,3’:3,2]pterocarpan (6aR,11aS)-(3,4:8,9)-Bis(methylenedioxy)pterocarpan 2-Hydroxy-3-methoxy-8,9-methylenedioxypterocarpan 3-Hydroxy-4-methoxy-8,9-methylenedioxypterocarpan 3-Methoxy-6a-hydroxy-8,9-methylenedioxypterocarpan 4-Hydroxy-3-methoxy-8,9-methylenedioxypterocarpan (6R,6aS,11aR)-3-Hydroxy-6-methoxy-8,9-methylenedioxypterocarpan 2,3,9-Trimethoxypterocarpan 3,4,9-Trimethoxypterocarpan (6aS,11aR)-3,9,10-Trimethoxypterocarpan (6S,6aS,11aR)-3,6,9-Trimethoxypterocarpan 3,6a,7-Trihydroxy-8,9-methylenedioxypterocarpan (6S,6aR,11aS)-3,6,6a-Trihydroxy-8,9-methylenedioxypterocarpan 2,10-Dihydroxy-3,9-dimethoxypterocarpan 2,8-Dihydroxy-3,9-dimethoxypterocarpan 3,7-Dihydroxy-3,9-dimethoxypterocarpan Nissolicarpin

2-Hydroxypterocarpin 4-Methoxymaackiain Pisatin 4-Hydroxypterocarpin Sophoracarpan B 2-Methoxyhomopterocarpin 4-Methoxyhomopterocarpin 3,9-di-O-Methylnissolin 6-Methoxyhomopterocarpin 6a,7-Dihydroxymaackiain 6,6a-Dihydroxymaackiain Mucronucarpan

Neodulin

Sophoracarpan A Fruticarpin Sparticarpin 6a,7-Dihydroxymedicarpin 11b-Hydroxydihydromaackiain

Methylnissolin

2-Methoxymedicarpin 4-Methoxymedicarpin Secundiflorol I 4-Hydroxyhomopterocarpin Variabilin

4-Hydroxymaackiain 6a-Hydroxymaackiain

300.27 300.27 300.27 300.31 300.31 300.31 300.31 300.31 300.31 300.31 300.31 300.31 300.31 300.31 300.31 302.29 302.29 302.29 308.29 312.28 314.29 314.29 314.29 314.29 314.29 314.34 314.34 314.34 314.34 316.27 316.27 316.31 316.31 316.31

C16H12O6 C16H12O6 C16H12O6 C17H16O5 C17H16O5 C17H16O5 C17H16O5 C17H16O5 C17H16O5 C17H16O5 C17H16O5 C17H16O5 C17H16O5 C17H16O5 C17H16O5 C16H14O6 C16H14O6 C16H14O6 C18H12O5 C17H12O6 C17H14O6 C17H14O6 C17H14O6 C17H14O6 C17H14O6 C18H18O5 C18H18O5 C18H18O5 C18H18O5 C16H12O7 C16H12O7 C17H16O6 C17H16O6 C17H16O6

Appendix

continued

2621 2683 F39 2619 2622 F289 2623 2684 F256 F6 2618 3035 3038 3019 2620 2685 F22 F39 2641 F292 2624 2626 2686 2627 3039 2625 2628 F261 3032 2687 F252 2631 2630 3022

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1169

3,9-Dihydroxy-7,10-dimethoxypterocarpan 4,10-Dihydroxy-3,9-dimethoxypterocarpan (6aR,11aR)-4,9-Dihydroxy-3,10-dimethoxypterocarpan (6S,6aS,11aR,11bS)-3-Keto-11b-hydroxy-6,9-dimethoxy-1,2-dihydropterocarpan (6aR,11aR)-3-Hydroxy-5’-(1-methylethenyl)furano[2’,3’:9,10]pterocarpan (6aR,11aR)-5’-Acetyl-3-hydroxyfurano[2’,3’:9,10]pterocarpan 3-Hydroxy-6’,6’-dimethylpyrano[2’,3’:9,10]pterocarpan 3-Hydroxy-6’,6’-dimethylpyrano[2’,3’:9,8]pterocarpan (6aR,11aR)-3-Hydroxy-5’-(1-methylethenyl)furano[2’,3’:9,10]pterocarpan 9-Hydroxy-6’,6’-dimethylpyrano[2’,3’:3,2]pterocarpan 6a-Hydroxy-8,9-methyleneoxyfurano[2’,3’:3,2]pterocarpan 9,10-Dimethoxyfurano[2’,3’:3,2]pterocarpan 3,9-Dihydroxy-10-prenylpterocarpan 3,9-Dihydroxy-2-prenylpterocarpan 3,9-Dihydroxy-8-prenylpterocarpan (6aR,11aR)-3,9-Dihydroxy-6a-prenylpterocarpan 6a-Hydroxy-(3,4:8,9)-bis(methylenedioxy)pterocarpan 2,3-Dimethoxy-8,9-methylenedioxypterocarpan 3,4-Dimethoxy-8,9-methylenedioxypterocarpan (6S,6aS,11aR)-3,6-Dimethoxy-8,9-methylenedioxypterocarpan 1,3-Dihydroxy-2-methoxy-8,9-methylenedioxypterocarpan 3,6a-Dihydroxy-2-methoxy-8,9-methylenedioxypterocarpan 3,6a-Dihydroxy-4-methoxy-8,9-methylenedioxypterocarpan (6aR,11aR)-2,6a-Dihydroxy-3-methoxy-8,9-methylenedioxypterocarpan 3-Hydroxy-7,9,10-trimethoxypterocarpan 4-Hydroxy-2,3,9-trimethoxypterocarpan 4-Hydroxy-3,9,10-trimethoxypterocarpan (6aR,11aR)-10-Hydroxy-3,4,9-trimethoxypterocarpan (6S,6aS,11aR,11bS)-3-Keto-11b-hydroxy-6-methoxy-8,9-methylenedioxy-1,2-dihydropterocarpan 6a-Hydroxy-5’-(1-methylethenyl)furano[2’,3’:3,4]pterocarpan 6a,9-Dihydroxy-5’-(1-methylethenyl)furano[2’,3’:3,4]pterocarpan Melilotocarpan C Odoricarpan Kushecarpin C Clandestacarpin Clandestacarpin

Philenopteran Melilotocarpan D Melilotocarpan E Kushecarpin A Crotafuran A Crotafuran B Phaseollin Isoneorautenol Barbacarpan Neorautenol Neobanol Ambonane Phaseollidin Calocarpin Sophorapterocarpan A Lespedezol D2 Acanthocarpan 2-Methoxypterocarpin 4-Methoxypterocarpin 6-Methoxypterocarpin Trifolian Hildecarpin Tephrocarpin 2-Hydroxypisatin 9-O-Methylphilenopteran

Trivial Name 316.31 316.31 316.31 318.33 320.34 322.31 322.36 322.36 322.36 322.36 324.29 324.34 324.37 324.37 324.37 324.37 328.28 328.32 328.32 328.32 330.29 330.29 330.29 330.29 330.34 330.34 330.34 330.34 332.30 336.34 336.34

Mass

C17H16O6 C17H16O6 C17H16O6 C17H18O6 C20H16O4 C19H14O5 C20H18O4 C20H18O4 C20H18O4 C20H18O4 C18H12O6 C19H16O5 C20H20O4 C20H20O4 C20H20O4 C20H20O4 C17H12O7 C18H16O6 C18H16O6 C18H16O6 C17H14O7 C17H14O7 C17H14O7 C17H14O7 C18H18O6 C18H18O6 C18H18O6 C18H18O6 C17H16O7 C20H16O5 C20H16O5

Formula

2629 3024 3025 F134 F320 F320 2642 3028 F20 2643 2691 2646 2645 2647 2644 F171 2688 2632 2633 3033 2635 3047 2689 F126 2634 2636 3026 3027 F134 2692 3048

Ref.

1170

1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220 1221

Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239 1240 1241 1242 1243 1244 1245 1246 1247 1248 1249 1250 1251 1252 1253 1254 1255

(6aS,11aS)-3,6a-Dihydroxy-5’-(1-methylethenyl)furano[2’,3’:9,10]pterocarpan 3-Hydroxy-9-methoxy-10-prenylpterocarpan 9-Methoxy-6’,6’-dimethylpyrano[2’,3’:3,4]pterocarpan (6aR,11aR)-5’-Acetyl-3,6a-dihydroxyfurano[2’,3’:9,10]pterocarpan 4-Methoxy-8,9-methyleneoxyfurano[2’,3’:3,2]pterocarpan 1,9-Dihydroxy-5’-(1-methylethenyl)-4’,5’-dihydrofurano[2’,3’:3,4]pterocarpan 3,6a-Dihydroxy-6’,6’-dimethylpyrano[2’,3’:9,10]pterocarpan 6a,9-Dihydroxy-5’(R)-(1-methylethenyl)furano[2’,3’:3,2]pterocarpan 6a,9-Dihydroxy-5’(S)-(1-methylethenyl)furano[2’,3’:3,2]pterocarpan 6a,9-Dihydroxy-6’,6’-dimethylpyrano[2’,3’:3,2]pterocarpan 6a,9-Dihydroxy-6’,6’-dimethylpyrano[2’,3’:3,4]pterocarpan 3-Hydroxy-9-methoxy-10-prenylpterocarpan (6aR,11aR)-3-Hydroxy-9-methoxy-8-prenylpterocarpan (6aR,11aR)-9-Hydroxy-3-methoxy-2-prenylpterocarpan 3,6a,9-Trihydroxy-10-prenylpterocarpan 3,6a,9-Trihydroxy-2-prenylpterocarpan 3,6a,9-Trihydroxy-4-prenylpterocarpan 3,9-Dihydroxy-10-(2(R)-hydroxy-3-methyl-3-butenyl)pterocarpan 3,9-Dihydroxy-10-(2(S)-hydroxy-3-methyl-3-butenyl)pterocarpan (6aR,11aR)-3-Hydroxy-5’-(1-hydroxy-1-methylethyl)-4’,5’-dihydrofurano[2’,3’:9,10]pterocarpan (6aR,11aR)-3,8,9-Trihydroxy-6a-prenylpterocarpan (6aR,11aR)-3,9,10-Trihydroxy-4-prenylpterocarpan 2-Hydroxy-3,4-dimethoxy-8,9-methylenedioxypterocarpan 6a-Hydroxy-2,3-dimethoxy-8,9-methylenedioxypterocarpan 2,8-Dihydroxy-3,9,10-trimethoxypterocarpan (6S,6aS,11aR,11bR)-3-Keto-6,11b-dimethoxy-8,9-methylenedioxy-1,2-dihydropterocarpan 9-Hydroxy-10-prenylfurano[2’,3’:3,2]pterocarpan (6aR,11aR)-8,9-Methylenedioxy-5’-(1-methylethenyl)-4’,5’-dihydrofurano[2’,3’:3,2]pterocarpan 8,9-Methylenedioxy-6’,6’-dimethylpyrano[2’,3’:3,2]pterocarpan 8,9-Methylenedioxy-6’,6’-dimethylpyrano[2’,3’:3,4]pterocarpan 3-Hydroxy-2-prenyl-8,9-methylenedioxypterocarpan 3-Hydroxy-9-methoxy-6’,6’-dimethylpyrano[2’,3’:1,2]pterocarpan (6aR,11aR)-10-Hydroxy-9-methoxy-5’-(1-methylethenyl)-4’,5’-dihydrofurano[2’,3’:3,2]pterocarpan (6aR,11aR)-3-Hydroxy-1-methoxy-6’,6’-dimethylpyrano[2’,3’:9,10]pterocarpan Kushecarpin B Erybraedin E Emoroidocarpan Neorautenane Leiocarpin Edunol Bolucarpan D Pervillin 1-Methoxyphaseollidin

Crotafuran C Eryvarin D Hemileiocarpin Crotafuran D Ficinin Apiocarpin Tuberosin Glyceollin III Canescacarpin Glyceollin II Glyceollin I Sandwicensin Prostratol D Orientanol B Sandwicarpin Glyceocarpin Glyceollidin I Dolichinin A Dolichinin B Erystagallin C Lespedezol D3 Bitucarpin B 2-Hydroxy-4-methoxypterocarpin Lathycarpin

336.34 336.38 336.38 338.31 338.32 338.36 338.36 338.36 338.36 338.36 338.36 338.40 338.40 338.40 340.38 340.38 340.38 340.38 340.38 340.38 340.38 340.38 344.32 344.32 346.34 346.34 348.40 350.37 350.37 350.37 352.38 352.38 352.38 352.38

F320 F282 2648 F320 2651 2650 2693 2695 2696 2694 2697 2649 F105 F288 2698 2699 2700 2652 2653 F287 F171 F203 3037 2690 2637 F134 3041 F152 2654 2655 2656 F29 F193 F124

Appendix

continued

C20H16O5 C21H20O4 C21H20O4 C19H14O6 C19H14O6 C20H18O5 C20H18O5 C20H18O5 C20H18O5 C20H18O5 C20H18O5 C21H22O4 C21H22O4 C21H22O4 C20H20O5 C20H20O5 C20H20O5 C20H20O5 C20H20O5 C20H20O5 C20H20O5 C20H20O5 C18H16O7 C18H16O7 C18H18O7 C18H18O7 C22H20O4 C21H18O5 C21H18O5 C21H18O5 C21H20O5 C21H20O5 C21H20O5 C21H20O5

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(6aR,11aR)-3-Hydroxy-8,9-methylenedioxy-4-prenylpterocarpan (6aR,11aR)-8-Hydroxy-9-methoxy-5’-(1-methylethenyl)-4’,5’-dihydrofurano[2’,3’:3,2]pterocarpan 8,9-Methylenedioxy-4’,5’-dihydro-6’,6’-dimethylpyrano[2’,3’:3,2]pterocarpan 9-Hydroxy-1-methoxy-6’,6’-dimethylpyrano[2’,3’:3,2]pterocarpan (6aR,11aR)-3,9-Dimethoxy-4-prenylpterocarpan 6a,9-Dihydroxy-5’-(hydroxymethylethyl)furano[2’,3’:3,2]pterocarpan 3-Hydroxy-9-methoxy-6’,6’-dimethyl-4’,5’-dihydropyrano[2’,3’:1,2]pterocarpan 3,10-Dihydroxy-9-methoxy-8-(1,1-dimethyl-2-propenyl)pterocarpan 3,6a-Dihydroxy-9-methoxy-10-prenylpterocarpan 3,9-Dihydroxy-1-methoxy-10-prenylpterocarpan 3,9-Dihydroxy-1-methoxy-2-prenylpterocarpan 3,9-Dihydroxy-8-methoxy-4-prenylpterocarpan 6a,9-Dihydroxy-3-methoxy-2-prenylpterocarpan (6aR,11aR)-1,9-Dihydroxy-3-methoxy-2-prenylpterocarpan (6aR,11aR)-3,8-Dihydroxy-9-methoxy-6a-prenylpterocarpan (6aR,11aR)-9-Hydroxy-1-methoxy-3-prenyloxypterocarpan 3-Hydroxy-9-methoxy-10-(3-hydroxy-3-methylbutyl)pterocarpan (6aR,11aR)-2,3,4-Trimethoxy-9,8-methylenedioxypterocarpan 8-Hydroxy-3,4,9,10-tetramethoxypterocarpan 3-Sulfate-8,9-methylenedioxypterocarpan 1-Hydroxy-8,9-methylenedioxy-6’,6’-dimethylpyrano[2’,3’:3,2]pterocarpan 3-Hydroxy-8,9-methylenedioxy-6’,6’-dimethylpyrano[2’,3’:1,2]pterocarpan 1,9-Dimethoxy-6’,6’-dimethylpyrano[2’,3’:3,2]pterocarpan (6aR,11aR)-8-Hydroxy-5’-hexylethyl-4’,5’-dihydrofurano[2’,3’:3,2]pterocarpan 3-Hydroxy-8,9-methylenedioxy-4-(4-hydroxy-3-methyl-2-butenyl)pterocarpan 3-Hydroxy-8,9-methylenedioxy-6’,6’-dimethyl-3’,4’-dihydropyrano[2’,3’:1,2]pterocarpan 5’-Hydroxy-8,9-methylenedioxy-6’,6’-dimethyl-4’,5’-dihydropyrano[2’,3’:3,2]pterocarpan 6a-Hydroxy-9-methoxy-5’-(hydroxymethylethyl)furano[2’,3’:3,2]pterocarpan 1,9-Dimethoxy-6’,6’-dimethyl-4’,5’-dihydropyrano[2’,3’:3,2]pterocarpan 3-Hydroxy-1,9-dimethoxy-2-prenylpterocarpan (
)-Maackiain sulfate Neorautenanol Bolucarpan B Edulenane Hexyl-oroxylopterocarpan Cabenegrin A-II Bolucarpan A Neorautanol 9-O-Methylglyceofuran Edulane Edulenol

Lespedezol D4 Asperopterocarpin

4’-Dehydroxycabenegrin A-I Pervillinin Neorautane Edulenanol Bitucarpin A Glyceofuran Bolucarpan C Arizonicanol E Cristacarpin 1-Methoxyphaseollidin Edudiol Eryvarin K Glyceollin IV

Trivial Name 352.38 352.38 352.38 352.38 352.42 354.36 354.40 354.40 354.40 354.40 354.40 354.40 354.40 354.40 354.40 354.40 356.41 358.35 360.37 364.33 366.36 366.36 366.41 366.45 368.39 368.39 368.39 368.39 368.43 368.43

Mass C21H20O5 C21H20O5 C21H20O5 C21H20O5 C22H24O4 C20H18O6 C21H22O5 C21H22O5 C21H22O5 C21H22O5 C21H22O5 C21H22O5 C21H22O5 C21H22O5 C21H22O5 C21H22O5 C21H24O5 C19H18O7 C19H20O7 C16H12O8S C21H18O6 C21H18O6 C22H22O5 C23H26O4 C21H20O6 C21H20O6 C21H20O6 C21H20O6 C22H24O5 C22H24O5

Formula

F46 F193 2657 2658 F203 2703 F29 F289 2701 2659 2660 F276 2702 F229 F171 F124 F120 F166 2638 F196 2661 F29 2662 F8 3031 F29 2663 2704 2665 2664

Ref.

1172

1256 1257 1258 1259 1260 1261 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1273 1274 1275 1276 1277 1278 1279 1280 1281 1282 1283 1284 1285

Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

1295 1296 1297 1298 1299 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317

1286 1287 1288 1289 1290 1291 1292 1293 1294

(6aR,11aR)-9-Hydroxy-1,3-dimethoxy-2-prenylpterocarpan 3-Hydroxy-8,9-methylenedioxy-2-(4-hydroxy-3-methylbutyl)pterocarpan (6aS,11aR,11bS)-3-Keto-6a,11b-dihydroxy-9-methoxy-10-prenylpterocarpan (6aS,11aS,5’S)-3,6a,5’-Trihydroxy-6’,6’-dimethyl-4’,5’-dihydropyrano[2’,3’:9,10]pterocarpan (6aS,11aS)-3,6a-Dihydroxy-9-methoxy-10-(2-keto-3-methylbutyl)-pterocarpan (6aS,11aS)-3,6a,8-Trihydroxy-9-methoxy-10-prenylpterocarpan 2,8-Dihydroxy-3,4,9,10-tetramethoxypterocarpan (6aR,11aR)-8-Hydroxy-5’-heptylethyl-4’,5’-dihydrofurano[2’,3’:3,2]pterocarpan (6aS,11aS)-6a-Hydroxy-8,9-methylenedioxy-5’-(1-hydroxymethylethenyl)-4’,5’dihydrofurano[2’,3’:3,2]pterocarpan 1-Methoxy-8,9-methylenedioxy-4’,5’-dihydro-6’,6’-dimethylpyrano[2’,3’:3,2]pterocarpan 3-Hydroxy-4-methoxy-8,9-methylenedioxy-2-prenylpterocarpan 9-Hydroxy-1,8-dimethoxy-6’,6’-dimethylpyrano[2’,3’:3,2]pterocarpan (6aS,11aS)-3,6a-Dihydroxy-9-methoxy-10-prenylpterocarpan (6aS,11aS)-3,6a,8-Trihydroxy-9-methoxy-10-(3-hydroxy-3-methylbutyl)pterocarpan 3-Hydroxy-2-prenyl-6’,6’-dimethylpyrano[2’,3’:9,10]pterocarpan 6’,6’-Dimethyl-4’,5’-dihydropyrano[2’,3’:3,2]-6’’,6’’-dimethylpyrano[2’’,3’’:9,10]pterocarpan (6aR,11aR)-3-Hydroxy-4-prenyl-6’,6’-dimethylpyrano[2’,3’:9,10]pterocarpan (6aR,11aR)-3-Hydroxy-4-prenyl-6’,6’-dimethylpyrano[2’,3’:9,8]pterocarpan (6aR,11aR)-9-Hydroxy-10-prenyl-6’,6’-dimethylpyrano[2’,3’:3,2]pterocarpan 3,9-Dihydroxy-10-geranylpterocarpan 3,9-Dihydroxy-2,10-diprenylpterocarpan 3,9-Dihydroxy-2,4-diprenylpterocarpan 3,9-Dihydroxy-2,8-diprenylpterocarpan 3,9-Dihydroxy-6a,10-diprenylpterocarpan (6aR,11aR)-3,9-Dihydroxy-2-(1,1-dimethyl-2-propenyl)-10-prenylpterocarpan (6aR,11aR)-3,9-Dihydroxy-4,10-diprenylpterocarpan (6aR,11aR)-3,9-Dihydroxy-4,8-diprenylpterocarpan 3,4-Dimethoxy-8,9-methylenedioxy-2-prenylpterocarpan (6aS,11aS)-6a-Hydroxy-3,8,9-trimethoxy-10-prenylpterocarpan 1,3-Dihydroxy-6’,6’-dimethylpyrano[2’,3’:9,8](1’’-methylphenyl)[3’’,4’’:4’,5’]pterocarpan (6aS,11aS)-3,6a-Dihydroxy-8,9-dimethoxy-10-(3-hydroxy-3-methylbutyl)pterocarpan 3-Hydroxy-9-methoxy-2,10-diprenylpterocarpan Neorautanin Neoraucarpanol Desmodin Orientanol A Sphenostylin C Folitenol Folinin Erybraedin B Erybraedin D Orientanol C Lespedezin Erythrabyssin II Eryvarin J Ficifolinol Lespein Striatin Erybraedin A Erybraedin C Neoraucarpanol Sphenostylin A Tetrapterol B Sphenostylin D Eryvarin E

Heptyl-oroxylopterocarpan Hildecarpidin

Kanzonol P Cabenegrin A-II Hydroxycristacarpone Eryvarin A Erypoegin I Sphenostylin B

382.41 382.41 382.41 388.42 388.42 390.48 390.48 390.48 390.48 390.48 392.50 392.50 392.50 392.50 392.50 392.50 392.50 392.50 396.44 398.46 402.45 402.45 404.51

368.43 370.40 370.40 370.40 370.40 370.40 376.37 380.48 382.37 C22H22O6 C22H22O6 C22H22O6 C21H24O7 C21H24O7 C25H26O4 C25H26O4 C25H26O4 C25H26O4 C25H26O4 C25H28O4 C25H28O4 C25H28O4 C25H28O4 C25H28O4 C25H28O4 C25H28O4 C25H28O4 C23H24O6 C23H26O6 C25H22O5 C22H26O7 C26H28O4

C22H24O5 C21H22O6 C21H22O6 C21H22O6 C21H22O6 C21H22O6 C19H20O8 C24H28O4 C21H18O7

Appendix

continued

2667 2668 2666 F285 3051 2669 2670 3045 3043 F288 2672 2674 F276 2673 2671 F158 3044 3042 2675 3050 F101 3052 F282

F76 3029 F286 F284 F272 3049 2639 F8 3053

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1336 1337 1338 1339 1340 1341 1342 1343 1344

1334 1335

Erystagallin B Dodecanyl-oroxylopterocarpan

Medicarpin 3-O-glucoside Maackiain 3-O-galactoside (þ)-Maackiain 3-O-glucoside (
)Maackiain 3-O-glucoside Methylnissolin 3-O-glucoside Trifolirhizin 6’-monoacetate Medicarpin 3-O-(6’-malonylglucoside) 4-Hydroxymedicarpin 3,4-O-diglucoside

Pterocarpan glycosides (6aR,11aR)-3-Hydroxy-8,9-methylenedioxypterocarpan 3-O-rhamnoside 3-Hydroxy-9-methoxypterocarpan 3-O-glucoside 3-Hydroxy-8,9-methylenedioxypterocarpan 3-O-galactoside 3-Hydroxy-8,9-methylenedioxypterocarpan 3-O-glucoside 3-Hydroxy-8,9-methylenedioxypterocarpan 3-O-glucoside 3-Hydroxy-9,10-dimethoxypterocarpan 3-O-glucoside 3-Hydroxy-9,10-methylenedioxypterocarpan 3-O-(6’-acetylglucoside) 3-Hydroxy-9-methoxypterocarpan 3-O-(6’-malonylglucoside) 3,4-Dihydroxy-9-methoxypterocarpan 3,4-di-O-glucoside

Erysubin E Erycristin Prostratol E 2-Prenyl-6a-hydroxyphaseollidin Erysubin D Gangetinin Nitiducarpin Nitiducol Kanzonol F Erypoegin J Gangetin 1-Methoxyficifolinol Erystagallin A Eryzerin E Lespedezol D5

(6aR,11aR)-1-Hydroxy-2-prenyl-6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:8,9]-6’,6’dimethylpyrano[2’,3’:3,2]pterocarpan (6aS,11aS)-3,6a-Dihydroxy-2-prenyl-6’,6’-dimethylpyrano[2’,3’:9,10]pterocarpan (6aR,11aR)-3-Hydroxy-9-methoxy-2,10-diprenylpterocarpan (6aR,11aR)-3-Hydroxy-9-methoxy-8-((2E)-3,7-dimethyl-2,6-octadienyl)pterocarpan 3,6a,9-Trihydroxy-2,10-diprenylpterocarpan (6aR,11aR)-3,5’-Dihydroxy-2-prenyl-6’,6’-dimethyl-4’,5’-dihydropyrano[2’,3’:9,10]pterocarpan 1-Methoxy-(2’,3’:3,2),(2’’,3’’:9,10)-bis(6,6-dimethylpyrano)pterocarpan 8,9-Methylenedioxy-6’-methyl-6’-prenylpyrano[2’,3’:3,2]pterocarpan 3-Hydroxy-8,9-methylenedioxy-4-geranylpterocarpan (6aR,11aR)-3-Hydroxy-1-methoxy-2-prenyl-6’,6’-dimethylpyrano[2’,3’:9,8]pterocarpan (6aS,11aS)-6a-Hydroxy-9-methoxy-10-prenyl-6’,6’-dimethylpyrano[2’,3’:3,2]pterocarpan 9-Hydroxy-1-methoxy-10-prenyl-6’,6’-dimethylpyrano[2’,3’:3,2]pterocarpan 3,9-Dihydroxy-1-methoxy-2,8-diprenylpterocarpan (6aS,11aS)-3,11a-Dihydroxy-9-methoxy-2,10-diprenylpterocarpan (6aS,11aS)-3,6a-Dihydroxy-9-methoxy-4,10-diprenylpterocarpan (6aR,11aR)-3,8,5’-Trihydroxy-6’-methyl-6’-(4-methyl-3-pentenyl)-4’,5’dihydropyrano[2’,3’:9,10]pterocarpan (6aS,11aS)-3,9,6a-Trihydroxy-1-methoxy-2,10-diprenylpterocarpan (6aR,11aR)-5’-Dodecanyl-5’-methyl-4’,5’-dihydrofurano[2’,3’:3,2]pterocarpan

Trivial Name

430.41 432.43 446.41 446.41 446.41 462.45 488.45 518.48 610.56

438.51 448.64

406.47 406.51 406.51 408.50 408.50 418.49 418.49 420.50 420.50 420.50 420.50 422.51 422.51 422.51 424.50

406.47

Mass

C22H22O9 C22H24O9 C22H22O10 C22H22O10 C22H22O10 C23H26O10 C24H24O11 C25H26O12 C28H34O15

C26H30O6 C30H40O3

C25H26O5 C26H30O4 C26H30O4 C25H28O5 C25H28O5 C26H26O5 C26H26O5 C26H28O5 C26H28O5 C26H28O5 C26H28O5 C26H30O5 C26H30O5 C26H30O5 C25H28O6

C25H26O5

Formula

F228 3229 3233 3231 3232 3235 3234 3230 F235

F287 F8

F275 3040 F105 3054 F275 2677 2676 2678 F74 F272 2679 3046 F287 F277 F171

F230

Ref.

1174

1319 1320 1321 1322 1323 1324 1325 1326 1327 1328 1329 1330 1331 1332 1333

1318

Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

Anhydrotuberosin Erypoegin H Erypoegin E Bryacarpene 2 Bryacarpene 4 3-O-Methylanhydrotuberosin Leiocalycin Andirol A Bryacarpene 3 Bryacarpene 1 Hedysarimpterocarpene B Puemiricarpene Erycristagallin Lespedezol A3 Lespedezol A2 Lespedezol A5

4-Deoxybryaquinone Bryaquinone

PTEROCARPENEQUINONES 9,10-Diketo-3,7-dimethoxypterocarpene 9,10-Diketo-4-hydroxy-3,7-dimethoxypterocarpene

1373 1374

Andirol B Anhydroglycinol

Anhydroglycinol Lespedezol A4 Anhydropisatin Neoduleen

Anhydroglycinol Lespedezol A1 Neorauteen

PTEROCARPENE 3,9-Dihydroxypterocarpene 9-Hydroxy-3-methoxypterocarpene 9-Hydroxyfurano[2’,3’:3,2]pterocarpene 3-Hydroxy-8,9-methylenedioxypterocarpene 3,9-Dimethoxypterocarpene 8,9-Dihydroxy-3-methoxypterocarpene 3-Methoxy-8,9-methylenedioxypterocarpene 8,9-Methyleneoxyfurano[2’,3’:3,2]pterocarpene 3-Hydroxy-4-methoxy-8,9-methylenedioxypterocarpene 3-Hydroxy-8,9-methylenedioxy-6-hydroxymethylpterocarpene 3,9,10-Trimethoxypterocarpene 1,7-Dihydroxy-3,9-dimethoxypterocarpene 3-Hydroxy-6’,6’-dimethylpyrano[2’,3’:9,8]pterocarpene 3,9-Dihydroxy-10-prenylpterocarpene 3,9-Dihydroxy-4-prenylpterocarpene 10-Hydroxy-3,8,9-trimethoxypterocarpene 4-Hydroxy-3,9,10-trimethoxypterocarpene 3-Methoxy-6’,6’-dimethylpyrano[2’,3’:9,8]pterocarpene 2-Hydroxy-1,3-dimethoxy-8,9-methylenedioxypterocarpene 3-Hydroxy-7-methoxy-8,9-methylenedioxy-6-hydroxymethylpterocarpene 3,8,9,10-Tetramethoxypterocarpene 4,10-Dihydroxy-3,8,9-trimethoxypterocarpene 1,3-Dihydroxy-9-methoxy-10-prenylpterocarpene 3,9-Dihydroxy-8-methoxy-7-prenylpterocarpene 3,9-Dihydroxy-2,10-diprenylpterocarpene 3,8-Dihydroxy-6’-methyl-6’-(4-methyl-3-pentenyl)pyrano[2’,3’:9,10]pterocarpene 3,8,9-Trihydroxy-10-(3,7-dimethyl-2,6-octadienyl)pterocarpene 3,8,9-Trihydroxy-7-(methylmethanoate)-10-(3,7-dimethyl-2,6-octadienyl)pterocarpene

1345 1346 1347 1348 1349 1350 1351 1352 1353 1354 1355 1356 1357 1358 1359 1360 1361 1362 1363 1364 1365 1366 1367 1368 1369 1370 1371 1372

312.28 328.28

254.24 268.26 278.27 282.25 282.30 284.26 296.28 306.28 312.28 312.28 312.32 314.29 320.34 322.36 322.36 328.32 328.32 334.37 342.30 342.30 342.35 344.32 352.38 352.38 390.48 404.46 406.47 464.52

2717 2718

2705 F170 2715 3058 2706 F171 2707 2716 2709 F127 2708 F314 3055 F272 F278 2710 2711 3056 2713 F127 2712 2714 F315 F38 3057 F170 F170 F171

Appendix

continued

C17H12O6 C17H12O7

C15H10O5 C16H12O4 C17H10O4 C16H10O5 C17H14O4 C16H12O5 C17H12O5 C18H10O5 C17H12O6 C17H12O6 C18H16O5 C17H14O6 C20H16O4 C20H18O4 C20H18O4 C18H16O6 C18H16O6 C21H18O4 C18H14O7 C18H14O7 C19H18O6 C18H16O7 C21H20O5 C21H20O5 C25H26O4 C25H24O5 C25H26O5 C27H28O7

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COUMESTANES 3,9-Dihydroxycoumestan 3-Hydroxy-9-methoxycoumestan 8,9-Dihydroxy-1-methylcoumestan 1,3,9-Trihydroxycoumestan 2,3,9-Trihydroxycoumestan 3,4,9-Trihydroxycoumestan 3,7,9-Trihydroxycoumestan 3-Hydroxy-8,9-methyledioxycoumestan 3,9-Dimethoxycoumestan 2,9-Dihydroxy-3-methoxycoumestan 3,7-Dihydroxy-9-methoxycoumestan 3,9-Dihydroxy-1-methoxycoumestan 3,9-Dihydroxy-4-methoxycoumestan 3,9-Dihydroxy-8-methoxycoumestan 4,9-Dihydroxy-3-methoxycoumestan 1,3,8,9-Tetrahydroxy-2-prenylcoumestan 1,3,8,9-Tetrahydroxycoumestan 3-Methoxy-8,9-methyledioxycoumestan 3-Hydroxy-7,9-dimethoxycoumestan 3-Hydroxy-8,9-dimethoxycoumestan 1,8,9-Trihydroxy-3-methoxycoumestan 3-Carboxylic acid-5,6-dihydroxy-2-(2’,4’,6’-trihydroxyphenyl)benzofuran 8,9-Methyledioxyfurano[2’,3’:3,2]coumestan 2-Hydroxy-3-methoxy-8,9-methyledioxycoumestan 3-Hydroxy-2-methoxy-8,9-methyledioxycoumestan 3-Hydroxy-4-methoxy-8,9-methyledioxycoumestan 1,9-Dihydroxy-3,8-dimethoxy-2-prenylcoumestan 3,9-Dihydroxy-1,8-dimethoxy-2-prenylcoumestan 3-Hydroxy-6’,6’-dimethylpyrano[2’,3’:9,8]coumestan Sophoracoumestan A

Demethylwedelolactone Flemichapparin C Wairol 3-hydroxy-8,9-Dimethoxycoumestan Wedelolactone Norwedelic acid Erosnin 2-Hydroxyflemichapparin C Tephrosol Sophoracoumestan B

Coumestrol 9-O-Methylcoumestrol Mutisifurocoumarin Aureol Lucernol 4-Hydroxycoumestrol Repensol Medicagol Coumestrol dimethyl ether Melimessanol A Trifoliol Isotrifoliol Pongacoumestan 8-Methoxycoumestrol Sativol

Trivial Name

268.23 282.25 282.25 284.23 284.23 284.23 284.23 296.24 296.28 298.25 298.25 298.25 298.25 298.25 298.25 300.23 300.23 310.26 312.28 312.28 314.25 318.24 320.26 326.26 326.26 326.26 328.28 328.28 334.33

Mass

C15H8O5 C16H10O5 C16H10O5 C15H8O6 C15H8O6 C15H8O6 C15H8O6 C16H8O6 C17H12O5 C16H10O6 C16H10O6 C16H10O6 C16H10O6 C16H10O6 C16H10O6 C15H8O7 C15H8O7 C17H10O6 C17H12O6 C17H12O6 C16H10O7 C15H10O8 C18H8O6 C17H10O7 C17H10O7 C17H10O7 C17H12O7 C17H12O7 C20H14O5

Formula

2774 2775 3090 3078 2777 F182 2776 2778 2779 F153 2780 F88 F324 2781 2782 F32 2783 2784 2785 2786 2787 3082 2792 2788 2789 2790 F32 F32 2793

Ref.

1176

1375 1376 1377 1378 1379 1380 1381 1382 1383 1384 1385 1386 1387 1388 1389 1390 1391 1392 1393 1394 1395 1396 1397 1398 1399 1400 1401 1402 1403

Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

Puerarostan Mirificoumestan Isoglycyrol Corylidin 1-O-Methylglycyrol Mirificoumestan hydrate Mirificoumestan glycol Puerarol Sigmoidin K Lespedezol A6

Licoagroside C 3-Demethylwedelolactone-O-glucoside Coumestrol 3-O-glucoside

Coumestan glycosides 3-Hydroxy-9-methoxycoumestan 3-O-glucoside 1,3,8,9-Tetrahydroxycoumestan 3-O-glucoside 3,9-Dihydroxycoumestan 3-O-glucoside

1432 1433 1434

Tephcalostan Gancaonol B Sojagol Glycyrol

Tuberostan Bavacoumestan B Bavacoumestan A Psoralidin oxide

Plicadin Sojagol Isosojagol Psoralidin Phaseol Isopsoralidin

9-Hydroxy-6’,6’-dimethylpyrano[2’,3’:3,4]coumestan 3-Hydroxy-6’,6’-dimethyl-4’,5’-dihydropyrano[2’,3’:9,8]coumestan 3,9-Dihydroxy-10-prenylcoumestan 3,9-Dihydroxy-2-prenylcoumestan 3,9-Dihydroxy-4-prenylcoumestan 9-Hydroxy-6’,6’-dimethyl-4’,5’-dihydropyrano[2’,3’:3,2]coumestan 9-Hydroxy-1,3,8-trimethoxy-2-prenylcoumestan 3-Methoxy-6’,6’-dimethylpyrano[2’,3’:9,8]coumestan 3-Hydroxy-5’-(1-hydroxy-1-methylethyl)-4’,5’-dihydrofurano[2’,3’:9,8]coumestan 3,3’-Dihydroxy-6’,6’-dimethyl-4’,5’-dihydropyrano[2’,3’:9,8]coumestan 3,9-Dihydroxy-2-(3-methyl-2,3-epoxybutyl)coumestan 2-Hydroxy-1,3-dimethoxy-8,9-methyledioxycoumestan 1,3,8,9-Tetramethoxy-2-prenylcoumestan 8,9-Methylenedioxy-5’-(1-methylethenyl)-4’,5’-dihydrofurano[2’,3’:3,2]coumestan 7-Hydroxy-9-methoxy-6’,6’-dimethylpyrano[2’,3’:3,4]coumestan 9-Hydroxy-1-methoxy-6’,6’-dimethylpyrano[2’,3’:3,2]coumestan 1,9-Dihydroxy-3-methoxy-2-prenylcoumestan 3,9-Dihydroxy-1-methoxy-8-prenylcoumestan 3,9-Dihydroxy-4-methoxy-8-prenylcoumestan 3,9-Dihydroxy-8-methoxy-7-prenylcoumestan 9-Hydroxy-3-methoxy-6’,6’-dimethyl-4’,5’-dihydropyrano[2’,3’:1,2]coumestan 9,4’,5’-Trihydroxy-6’,6’-dimethyl-4’,5’-dihydropyrano[2’,3’:3,2]coumestan 9-Hydroxy-1,3-dimethoxy-2-prenylcoumestan 3,9-Dihydroxy-8-methoxy-7-(3-hydroxy-3-methylbutyl)coumestan 3,9-Dihydroxy-8-methoxy-7-(2,3-dihydroxy-3-methylbutyl)coumestan 3,9-Dihydroxy-2-geranylcoumestan 3,9-Dihydroxy-2,10-diprenylcoumestan 3,8,9-Trihydroxy-10-(3,7-dimethyl-2,6-octadienyl)coumestan

1404 1405 1406 1407 1408 1409 1410 1411 1412 1413 1414 1415 1416 1417 1418 1419 1420 1421 1422 1423 1424 1425 1426 1427 1428 1429 1430 1431

444.39 462.37 430.37

334.33 336.34 336.34 336.34 336.34 336.34 342.30 348.36 352.34 352.34 352.34 356.29 356.33 362.33 364.36 364.36 366.36 366.36 366.36 366.36 366.36 368.34 380.40 384.39 400.39 404.46 404.46 420.46

C22H20O10 C21H18O12 C21H18O10

C20H14O5 C20H16O5 C20H16O5 C20H16O5 C20H16O5 C20H16O5 C18H14O7 C21H16O5 C20H16O6 C20H16O6 C20H16O6 C18H12O8 C19H16O7 C21H14O6 C21H16O6 C21H16O6 C21H18O6 C21H18O6 C21H18O6 C21H18O6 C21H18O6 C20H16O7 C22H20O6 C21H20O7 C21H20O8 C25H24O5 C25H24O5 C25H24O6

Appendix

continued

F141 3238 3237

F216 2794 3080 2795 3081 2796 F32 3079 3084 3083 2797 2791 F32 F123 F70 3092 2798 3088 3089 3086 2799 2800 2801 3085 3087 3090 F181 F171

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1177

1435 1436 1437 1438 1439 1440 1441 1442 1443 1444 1445 1446 1447 1448 1449 1450 1451 1452 1453 1454 1455 1456 1457 1458 1459 1460 1461 1462 1463 1464

ROTENONES 6,9,11-Trihydroxyrotenone (
)-4,9,11,12a-Tetrahydroxyrotenone (
)-4,11,12a-Trihydroxy-9-methoxyrotenone 2,3-Methylenedioxyfurano[2’,3’:9,10]rotenone 2,3,9-Trimethoxyrotenone (
)-4,11,12a-Trihydroxy-9-methoxy-10-methylrotenone (6aR,12aS)-11,12a-Dihydroxy-9,10-dimethoxyrotenone 12a-Hydroxy-2,3-methylenedioxyfurano[2’,3’:9,10]rotenone 2,3-Dimethoxyrfurano[2’,3’:9,10]rotenone 2,3-Dimethoxyrfurano[2’,3’:9,8]rotenone 12-Hydroxy-2,3-dimethoxyfurano[2’,3’:9,8]rotenone (6aR,12aR)-12a-Hydroxy-2,3-dimethoxyfurano[2’,3’:9,8]rotenone (6aR,12aS)-12a-Hydroxy-2,3:8,9-bis(methylenedioxy)rotenone (6aR,12R,12aR)-12,12a-Dihydroxy-12-dihydro-2,3:8,9-bis(methylenedioxy)rotenone 11-Hydroxy-2,3,9-trimethoxyrotenone 12a-Hydroxy-2,3,9-trimethoxyrotenone (6aR,12aS)-4,11,12a-Trihydroxy-9-methoxy-8,10-dimethylrotenone 12a-Methoxy-2,3-methylenedioxyfurano[2’,3’:9,10]rotenone 8-Methoxy-2,3-methylenedioxyfurano[2’,3’:9,10]rotenone 11-Hydroxy-2,3-dimethoxyrfurano[2’,3’:9,8]rotenone 12a-Hydroxy-2,3-dimethoxyfurano[2’,3’:9,10]rotenone (6aS,12aS)-12a-Hydroxy-2,3-dimethoxyfurano[2’,3’:9,8]rotenone (6aR,12aS)-12a-Hydroxy-8,9-dimethoxy-2,3-methylenedioxyrotenone 6,11-Dihydroxy-2,3,9-trimethoxyrotenone (6aR,12aR)-11,12a-Dihydroxy-2,3,9-trimethoxyrotenone (6aS,12aR)-6,12a-Dihydroxy-2,3,9-trimethoxyrotenone (6R,6aS,12aR)-6,9,11,12a-Tetrahydroxy-2,3-dimethoxyrotenone 2,3-Methylenedioxy-5’-(1-methylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone 2,3-Methylenedioxy-6’,6’-dimethylpyrano[2’,3’:9,8]rotenone 12a-Hydroxy-8-methoxy-2,3-methylenedioxyfurano[2’,3’:9,10]rotenone

Name

298.25 316.27 330.29 336.30 342.35 344.32 344.32 352.30 352.34 352.34 354.36 354.36 356.29 358.30 358.35 358.35 358.35 366.33 366.33 368.34 368.34 368.34 372.33 374.35 374.35 374.35 376.31 378.38 378.38 382.33

Mass

C16H10O6 C16H12O7 C17H14O7 C19H12O6 C19H18O6 C18H16O7 C18H16O7 C19H12O7 C20H16O6 C20H16O6 C20H18O6 C20H18O6 C18H12O8 C18H14O8 C19H18O7 C19H18O7 C19H18O7 C20H14O7 C20H14O7 C20H16O7 C20H16O7 C20H16O7 C19H16O8 C19H18O8 C19H18O8 C19H18O8 C18H16O9 C22H18O6 C22H18O6 C20H14O8

Formula

F67 3008 3009 2557 2555 3010 F236 2577 2559 2558 3005 F293 F342 F342 2556 2575 F316 2578 2560 2561 2579 F109 F342 3001 F143 F162 F246 2563 2562 2581

Ref.

1178

Dolineone Munduserone Boeravinone C 9-Methoxyirispurinol 12a-Hydroxydolineone Erosone Elliptone Elliptinol 12a-Hydroxyelliptone Usararotenoid A 12-Dihydrousararotenoid A Sermundone 12a-Hydroxymunduserone Mirabijalone A 12a-Methoxydolineone Pachyrrizone Malaccol 12a-Hydroxyerosone 12a-Hydroxyelliptone Usararotenoid B Dihydrostemonal 6-Deoxyclitoriacetal 11-Deoxyclitoriacetal 9-Demethylclitoriacetal Isomillettone Millettone 12a-Hydroxypachyrrhizone

Coccineone B

Trivial Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

1465 1466 1467 1468 1469 1470 1471 1472 1473 1474 1475 1475b 1476 1477 1478 1479 1480 1481 1482 1483 1484 1485 1486 1487 1488 1489 1490 1491 1492 1493 1494 1495 1496 1497

2,3,12a-Trimethoxyfurano[2’,3’:9,10]rotenone 6,11,12a-Trihydroxy-2,3,9-trimethoxyrotenone 12a-Hydroxy-2,3-methylenedioxy-5’-(1-methylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone 12a-Hydroxy-2,3-methylenedioxy-6’,6’-dimethylpyrano[2’,3’:9,8]rotenone (6aR,12aS)-12a-Hydroxy-2,3-methylenedioxy-6’,6’-dimethoxypyr[2’,3’:9,8]rotenone 2,3-Dimethoxy-5’-(1-methylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone 2,3-Dimethoxy-6’,6’-dimethylpyrano[2’,3’:9,8]rotenone 9-Hydroxy-2,3-dimethoxy-10-(1,4-pentadienyl)rotenone 3-Hydroxy-2-methoxy-5’-(1-hydroxymethyl-1-ethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone 9-Hydroxy-2,3-dimethoxy-8-prenylrotenone 11-Hydroxy-2,3-dimethoxy-5’-(1-methylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone (12R)-12-Hydroxy-2,3-dimethoxy-5’-(1’’-hydroxymethylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone 11-Hydroxy-2,3-dimethoxy-6’,6’-dimethylpyrano[2’,3’:9,8]rotenone 12a-Hydroxy-2,3-dimethoxy-5’-(1-methylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone 12a-Hydroxy-2,3-dimethoxy-6’,6’-dimethylpyrano[2’,3’:9,8]rotenone 2,3-Dimethoxy-5’-(1-hydroxymethylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone 6-Hydroxy-2,3-dimethoxy-5’-(1-methyl-1-ethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone (6aR,12aS)-12a-Hydroxy-9-methoxy-2,3-methylenedioxy-8-prenylrotenone (6R,6aS,12aS)-6-Hydroxy-2,3-dimethoxy-6’,6’-dimethylpyrano[2’,3’:9,8]rotenone 2,3-Dimethoxy-5’-(1-hydroxy-1-methylethyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone 2,3-Dimethoxy-5’-(1-hydroxymethylethyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone cis-9,12a-Dihydroxy-2,3-dimethoxy-8-prenylrotenone 3,12a-Dihydroxy-2-methoxy-5’-(2-hydroxy-1-methylethyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone 6-Acetoxy-11-hydroxy-2,3,9-trimethoxyrotenone 12a-Methoxy-2,3-dimethoxy-5’-(1-methylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone (þ)-2,3,10-Trimethoxy-6’,6’-dimethylpyrano[2’,3’:9,8]rotenone 11,12a-Dihydroxy-2,3-dimethoxy-5’-(1-methylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone 11,12a-Dihydroxy-2,3-dimethoxy-6’,6’-dimethylpyrano[2’,3’:9,8]rotenone 12a-Hydroxy-2,3-dimethoxy-5’-(1-hydroxymethylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone 6,11-Dihydroxy-2,3-dimethoxy-5’-(1-methylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone (6aR,12aR)-11,12a-Dihydroxy-2,3-dimethoxy-6’,6’-dimethylpyrano[2’,3’:9,10]rotenone (6R,6aS,12aR)-6,12a-Dihydroxy-2,3-dimethoxy-6’,6’-dimethylpyrano[2’,3’:9,8]rotenone 12,12a-Dihydroxy-2,3-dimethoxy-5’-(1-hydroxymethylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone 2,3-Dimethoxy-5’-(1-hydroxy-1-hydroxymethylethyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone

Neobanone Clitoriacetal 12a-Hydroxymillettone Millettosin 12a-Epimillettosin Rotenone Deguelin Myriconol 3-O-Demethylamorphigenin Rotenonic acid Sumatrol Dalcochinin Toxicarol 12a-Hydroxyrotenone Tephrosin Amorphigenin 6-Hydroxyrotenone Usararotenoid C Hydroxydeguelin Dalpanol Dihydroamorphigenin cis-12a-Hydroxyrot-2’-enonic acid Volubinol 6-Acetyldihydrostemonal 12a-Methoxyrotenone Erythynone Villosinol 12a-Hydroxytephrosin Dalbinol Villosin 12a-hydroxy-b-toxicarol Hydroxytephrosin 12-Dihydrodalbinol Amorphigenol

382.37 390.35 394.38 394.38 394.38 394.42 394.42 394.42 396.40 396.44 410.42 412.44 410.42 410.42 410.42 410.42 410.42 410.42 410.42 412.44 412.44 412.44 414.41 416.39 424.45 424.45 426.42 426.42 426.42 426.42 426.42 426.42 428.44 428.44

2580 2576 2583 2582 F342 2565 2564 2566 3000 2567 2570 F261b 2569 2585 2584 2568 3003 F334 F150 2572 2571 3006 3007 3002 2586 3004 2589 2588 2587 2573 F11 F150 2590 2574

Appendix

continued

C20H18O7 C19H18O9 C22H18O7 C22H18O7 C22H18O7 C23H22O6 C23H22O6 C23H22O6 C22H20O7 C23H24O6 C23H22O7 C23H24O7 C23H22O7 C23H22O7 C23H22O7 C23H22O7 C23H22O7 C23H22O7 C23H22O7 C23H24O7 C23H24O7 C23H24O7 C22H22O8 C21H20O9 C24H24O7 C24H24O7 C23H22O8 C23H22O8 C23H22O8 C23H22O8 C23H22O8 C23H22O8 C23H24O8 C23H24O8

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1179

(6S,6aS,12aR)-6,12a-Dihydroxy-2,3,9-trimethoxyrotenone 11-O-glucoside (6R,6aS,12aR)-6,11,12a-Trihydroxy-2,3,9-trimethoxyrotenone 11-O-glucoside 2,3-Dimethoxy-5’-(1’’-hydroxymethylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone 1’’-O-glucoside (6aR,12aR)-11,12a-Dihydroxy-2,3-dimethoxy 5’-(1-hydroxy-1-methylethyl)furano[2’,3’:9,8]rotenone 1’’-O-glucoside 1507b (12R)-12-Hydroxy-2,3-dimethoxy-5’-(1’’-hydroxymethylethenyl-4’,5’-dihydrofurano[2’,3’:9,8]rotenone 1’’-O-glucoside 1508 2,3-Dimethoxy-5’-(1’’-hydroxy-1’’-methylethyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone 1’’-O-glucoside 1509 12a-Hydroxy-2,3-dimethoxy-5’-(1’’-hydroxymethylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone 1’’-O-glucoside 1510 12-Hydroxy-2,3-dimethoxy-5’-(1’’-hydroxymethylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]-12dihydrorotenone 1’’-O-glucoside 1511 2,3-Dimethoxy-5’-(1’’-hydroxy-1’’-hydroxymethylethyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone 1’’-O-glucoside 1512 2,3-Dimethoxy-5’-(1’’-hydroxymethylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone 1’’-O-(6’’’-arabinosylglucoside) 1513 2,3-Dimethoxy-5’-(1’’,2’’-dihydroxy-1’’-methylethyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone 1’’-O-(6’’’-arabinosylglucoside) 1514 12a-Hydroxy-2,3-dimethoxy-5’-(1’’-hydroxymethylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone 1’’-O-(6’’’-arabinosylglucoside)

Rotenone glycosides (6aR,12aR)-11,12a-Dihydroxy-2,3,9-trimethoxyrotenone 11-O-glucoside

(6aS,12aS,4’S,5’R)-4’,5’-Dihydroxy-2,3,4’-dimethoxy-6’,6’-dimethyl-4’,5dihydropyrano[2’,3’:9,8]rotenone (þ)-12a-Hydroxy-2,3,10-trimethoxy-6’,6’-dimethylpyrano[2’,3’:9,8]rotenone 6,11,12a-Trihydroxy-2,3-dimethoxy-5’-(1-methylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]rotenone (6aR,12aR)-11,12a-Dihydroxy-2,3,4’-trimethoxy-6’,6’-dimethyl-4’,5-dihydropyrano(2’,3’:9,8]rotenone (6aS,12aS)-12-Keto-12a-hydroxy-3,4-dimethoxy-9-((2E,5E)-7-hydroxy-3,7dimethyl-2,5-octadienyloxy)) rotenone

Formula

C24H24O8 C23H22O9 C24H26O10 C28H32O8

3011 2591 F115 F331

F269

Ref.

590.58 C29H34O13 3228

12-Dihydrodalbinol O-glucoside Amorphigenol O-glucoside

704.69 C34H40O16 3225 720.68 C34H40O17 3227

Dalbinol O-vicianoside

704.69 C34H40O16 3222

Amorphigenin 7-O-vicianoside Amorphigenol O-vicianoside

590.58 C29H34O13 3224

F161 F44 3221 F214

574.58 C29H34O12 3223 588.57 C29H32O13 3226

C25H28O13 C25H28O14 C29H32O12 C29H32O12

Dalpanol O-glucoside Dalbinol O-glucoside

536.49 552.48 572.57 572.57

574.58 C29H34O12 F261b

536.49 C25H28O13 F200

440.45 442.42 474.46 496.55

428.44 C23H24O8

Mass

6-Deoxyclitoriacetal 11-O-glucoside Rotenoid 11a-O-glucoside Clitoriacetal 11-O-glucoside Amorphigenin 7-O-glucoside Dehydrodalpanol O-glucoside Dalcochinin O-glucoside

Griffonianone A

(þ)-12a-Hydroxyerythynone Villol

Derrisin

Trivial Name

1180

1504 1505 1506 1507

1503

1499 1500 1501 1502

1498

Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

(5’R,6S)-6,11-Dihydroxy-2,3-dimethoxy-5’-(1-methylethenyl)furano[2’,3’:9,8]-6a,12a-didehydrorotenone

DEHYDROROTENONES Furano[2’,3’:9,8]-6a,12a-didehydrorotenone 6,9,11-Trihydroxy-10-methyl-6a,12a-didehydrorotenone 1,11-Dihydroxy-9,10-methylenedioxy-6a,12a-didehydrorotenone 6-Oxo-3,9,11-Trihydroxy-10-methyl-6a,12a-didehydrorotenone 9,11-Dihydroxy-6-methoxy-10-methyl-6a,12a-didehydrorotenone 3,6,9,11-Tetrahydroxy-10-methyl-6a,12a-didehydrorotenone 2,3-Methylenedioxyfurano[2’,3’:9,10]-6a,12a-didehydrorotenone 3,6,11-Trihydroxy-9-methoxy-10-methyl-6a,12a-didehydrorotenone 3,9,11-Trihydroxy-6-methoxy-10-methyl-6a,12a-didehydrorotenone 4,6,9,11-Tetrahydroxy-8,10-dimethyl-6a,12a-didehydrorotenone 6-Acetoxy-9,10,11-trihydroxy-6a,12a-didehydrorotenone 8-Methoxy-2,3-methylenedioxyfurano[2’,3’:9,10]-6a,12a-didehydrorotenone 6-Oxo-11-hydroxy-2,3,9-trimethoxy-6a,12a-didehydrorotenone 6-Acetoxy-3,9,10,11-tetrahydroxy-6a,12a-didehydrorotenone 6,11-Dihydroxy-2,3,9-trimethoxy-6a,12a-didehydrorotenone 2,3-Methylenedioxy-6’,6’-dimethylpyrano[2’,3’:9,8]-6a,12a-didehydrorotenone 2,3-Dimethoxy-5’-(1-methylethhenyl)-4’,5’-dihydrofurano[2’,3’:9,8]-6a,12a-didehydrorotenone 2,3-Dimethoxy-6’,6’-dimethylpyrano[2’,3’:9,8]-6a,12a-didehydrorotenone 2,3-Dimethoxy-5’-(1-methylethyl)-4’,5’-dihydrofurano[2’,3’:9,8]-6a,12a-didehydrorotenone 6-Pentanoate-4,9-dihydroxy-10-methyl-6a,12a-didehydrorotenone 11-Dihydroxy-6-ethoxy-2,3,9-trimethoxy-6a,12a-didehydrorotenone 6-Oxo-2,3-dimethoxy-5’-(1-methylethenyl)-4’,5’-dihydrofuran[2’,3’:9,8]-6a,12a-didehydrorotenone 11-Hydroxy-2,3-dimethoxy-5’-(1-methylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]-6a,12a-didehydrorotenone 11-Hydroxy-2,3-dimethoxy-6’,6’-dimethylpyrano[2’,3’:9,10]-6a,12a-didehydrorotenone 11-Hydroxy-2,3-dimethoxy-6’,6’-dimethylpyrano[2’,3’:9,8]-6a,12a-didehydrorotenone 2,3-Dimethoxy-5’-(1-hydroxymethylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]-6a,12a-didehydrorotenone 6-Hydroxy-2,3-dimethoxy-5’-(1-methylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]-6a,12a-didehydrorotenone 2,3-Dimethoxy-5’-(1-hydroxy-1-methylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]-6a,12a-didehydrorotenone 6-Oxo-11-hydroxy-2,3-dimethoxy-5’-(1-hydroxymethylethenyl)furan[2’,3’:9,8]-6a,12a-didehydrorotenone 6-Oxo-11-hydroxy-2,3-dimethoxy-5’-(1-methylethenyl)-4’,5’-dihydrofuran[2’,3’:9,8]-6a,12adidehydrorotenone 6-Oxo-11-hydroxy-2,3-dimethoxy-6’,6’-dimethoxypyran[2’,3’:9,8]-6a,12a-didehydrorotenone 6-Oxo-6a,12adidehydro-a-toxicarol 6a,12a-Dehydrovillosin

C18H10O4 C17H12O6 C17H10O7 C17H10O7 C18H14O6 C17H12O7 C19H10O6 C18H14O7 C18H14O7 C18H14O7 C18H12O8 C20H12O7 C19H14O8 C18H12O9 C19H16O8 C22H16O6 C23H20O6 C23H20O6 C23H22O6 C22H20O7 C21H20O8 C23H18O7 C23H20O7 C23H20O7 C23H20O7 C23H20O7 C23H20O7 C23H22O7 C23H18O8 C23H18O8

424.41 C23H20O8

422.39 C23H18O8

290.27 312.28 326.26 Boeravinone F 326.26 Boeravinone A 326.31 Boeravinone E 328.28 Dehydrodolineone 334.29 Mirabijalone D 342.30 Boeravinone D 342.30 Mirabijalone B 342.30 Repenone 356.29 Dehydropacchyrrhizone 364.31 Stemonone 370.32 Repenol 372.29 Stemonal 372.33 Dehydromillettone 376.37 Dehydrorotenone 392.41 Dehydroguelin 392.41 Dehydrodihydrorotenone 394.42 Diffusarotenoid 396.40 Stemonalacetal 400.38 Rotenonone 406.39 Villosol 408.41 6a,12a-Dehydro-a-toxicarol 408.41 Dehydrotoxicarol 408.41 Dehydroamorphigenin 408.41 Amorpholone 408.41 Dehydroalpanol 410.42 6-Ketodehydroamorphigenin 422.39 Villosone 422.39

Pongarotene Boeravinone B

continued

F207

F146

F249 3015 F250 F136 3016 F136 2595 F316 F136 F316 3013 2596 2592 3014 2593 2597 2599 2598 3017 F84 2594 2600 2604 F147 2603 2602 2601 2605 F258 2606

Appendix

1546

1545

1515 1516 1517 1518 1519 1520 1521 1522 1523 1524 1525 1526 1527 1528 1529 1530 1531 1532 1533 1534 1535 1536 1537 1538 1539 1540 1541 1542 1543 1544

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1181

242.23 242.27 254.29 254.29 256.26 256.26 256.30 270.24 270.29 284.27 284.27 286.29 286.29 286.29 286.29 286.29 298.29 300.27 300.31 308.33

2-ARYLBENZOFURAN 6,2’,4’-Trihydroxy-2-arylbenzofuran 5-Hydroxy-4’-methoxy-2,3-dihydro-2-arylbenzofuran 5-Hydroxy-6-methoxy-3-methyl-2-arylbenzofuran 5,4’-Dimethoxy-2-arylbenzofuran 6,2’-Dihydroxy-4’-methoxy-2-arylbenzofuran 6,4’-Dihydroxy-2’-methoxy-2-arylbenzofuran 5,4’-Dimethoxy-2,3-dihydro-2-arylbenzofuran 2’,4’-Dihydroxy-5,6-methylenedioxy-2-arylbenzofuran 4’-Hydroxy-2’,6-dimethoxy-2-arylbenzofuran 2’-Hydroxy-4’-methoxy-5,6-methylenedioxy-2-arylbenzofuran 6-Hydroxy-2’-methoxy-4’,5’-methylenedioxy-2-arylbenzofuran 5,2’-Dihydroxy-6,4’-dimethoxy-2-arylbenzofuran 5,6-Dihydroxy-2’,4’-dimethoxy-2-arylbenzofuran 6,3’-Dihydroxy-2’,4’-dimethoxy-2-arylbenzofuran 6,4’-Dihydroxy-2’,3’-dimethoxy-2-arylbenzofuran 6,4’-Dihydroxy-2’,5’-dimethoxy-2-arylbenzofuran 3-Carboxyaldehyde-6’-hydroxy-6,4’-dimethoxy-2-arylbenzofuran 2’,4’-Dihydroxy-3’-methoxy-5,6-methylenedioxy-2-arylbenzofuran 5-Hydroxy-6,2’,4’-trimethoxy-2-arylbenzofuran 5,4’-Dihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:2’,3’]-2-arylbenzofuran

1552 1553 1554 1555 1556 1557 1558 1559 1560 1561 1562 1563 1564 1565 1566 1567 1568 1569 1570 1571

Pterofuran Isopterofuran Eryvarin L Melimessanol C Sophorafuran A Methylsainfuran Kanzonol U

Cicerfuran Sainfuran

C14H10O4 C15H14O3 C16H14O3 C16H14O3 C15H12O4 C15H12O4 C16H16O3 C15H10O5 C16H14O4 C16H12O5 C16H12O5 C16H14O5 C16H14O5 C16H14O5 C16H14O5 C16H14O5 C17H15O5 C16H12O6 C17H16O5 C19H16O4

C25H26O13

C24H22O8 C24H24O8 C24H24O9

C23H20O8

Formula

2821 F304 2822 F304 3103 2823 F304 2825 2824 2826 F259 3104 2829 2827 2828 F276 F153 2830 3105 F73

F248

2607 F206 F114

3012x

Ref.

1182

Vignafuran

Corsifuran B Parvifuran Corsifuran C Centrolobofuran 6-Demethylvignafuran Corsifuran A

534.47

Dehydrorotenone glycosides 6,9-Dihydroxy-2,3,10-trimethoxy-6a,12a-didehydrorotenone 9-O-glucoside

1551

438.44 440.45 456.45

2,3-Dimethoxy-6-methoxy-5’-(1-methylethenyl)-4’,5’-dihydrofurano[2’,3’:9,8]-6a,12a-didehydrorotenone 9,11-Dihydroxy-2,3,6-trimethoxy-8-prenyl-6a,12a-didehydrorotenone 11,5’-Dihydroxy-2,3,4’-trimethoxy-6’,6’-dimethyl-4’,5’-dihydropyrano[2’,3’:9,8]-6a,12a-didehydrorotenone

424.41

1548 1549 1550

6-Hydroxy-6a,12adehydro-a-toxicarol Villinol

Mass

(þ)-6,11-Dihydroxy-2,3-dimethoxy-6’,6’-dimethylpyrano[2’,3’:9,8]-6a,12a-didehydrorotenone

Trivial Name

1547

Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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Flavonoids: Chemistry, Biochemistry, and Applications

2-Arylbenzofuran glycosides 6,3’,5’-Trihydroxy-2-arylbenzofuran 3’-O-glucoside 3’,5’,5’’-Trihydroxy -6’’,6’’-dimethyl-4’’,5’’-dihydropyrano[2’’,3’’:6,5]-2-arylbenzofuran 3’-O-glucoside

6,2’-Dihydroxy-6’’,6’’-dimethylpyrano[2’’,3’’:4’,3’]-2-arylbenzofuran 3-Carboxyaldehyde-6,4’-dihydroxy-2’,5’-dimethoxy-2-arylbenzofuran 3-Carboxylic acid methyl ester-4,6,3’,4’-tetrahydroxy-2-arylbenzofuran 6,3’-Dihydroxy-5’-methoxy-4’-prenyl-2-arylbenzofuran 6,4’-Dihydroxy-2’-methoxy-3’-prenyl-2-arylbenzofuran 6,4’-Dihydroxy-2’-methoxy-6-(1,1-dimethyl-2-propenyl)-2-arylbenzofuran 5,3’,5’-Trihydroxy-6-(4-hydroxy-3-methyl-2(E)-butenyl)-2-arylbenzofuran 3-Carboxcyaldehyde-4,3’,4’-trihydroxy-6,2’-dimethoxy-2-arylbenzofuran 2’,4’-Dihydroxy-4-methoxy-6’’,6’’-dimethylpyrano[2’’,3’’:6,5]-2-arylbenzofuran 6,2’,4’-Trihydroxy-4-methoxy-5-prenyl-2-arylbenzofuran 3-Carboxyaldehyde-4,3’-dihydroxy-6,2’,4’-trimethoxy-2-arylbenzofuran 3-Carboxyaldehyde-2’,4’-dihydroxy-6-methoxy-2-arylbenzofuran 2’,4’-Dihydroxy-4,6-dimethoxy-5-prenyl-2-arylbenzofuran 6,2’-Dihydroxy-3,4’-dimethoxy-5-prenyl-2-arylbenzofuran 3-Carboxyaldehyde-4,3’-dihydroxy-2’,4’-dimethoxy-2’’,5’’-dihydrofurano[3’’,4’’:5,6]-2-arylbenzofuran 3’-Hydroxy-4,6,2’,4’-tetramethoxy-3-hydroxymethyl-2-arylbenzofuran 4,3’-Dihydroxy-5,7,2’,4’-tetramethoxy-2-arylbenzofuran 5,4’-Dihydroxy-6-prenyl-6’’,6’’-dimethylpyrano[2’’,3’’:2’,3’]-2-arylbenzofuran 6,3’,5’-Trihydroxy-2’,6’-diprenyl-2-arylbenzofuran 3-Carboxyaldehyde-6,2’,4’-trihydroxy-7,5’-diprenyl-2-arylbenzofuran 5,6,2’,4’-Tetrahydroxy-3-methyl-7-(3,7-dimethyl-2,6-octadienyl)-2-arylbenzofuran 6,3’,5’-Trihydroxy-5-methoxy-4-((2E)-3,7-dimethyl-2,6-octadienyl)-2-arylbenzofuran 6,3’,5’-Trihydroxy-5-methoxy-2-arylbenzofuran 3’-O-glucoside 3’,5’-Dihydroxy-2’,6’-diprenyl-6’’,6’’-dimethylpyrano[2’’,3’’:6,7]-2-arylbenzofuran 6,3’,5’-Trihydroxy-2’-((2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrienyl)-2-arylbenzofuran 6,3’,5’-Trihydroxy-7,2’,6’-triprenyl-2-arylbenzofuran 6,5’-Dihydroxy-3’-methoxy-7-[(2E)-3,7-dimethyl-2,6-octadienyl]-2’-prenyl-2-arylbenzofuran (2’’R)-6,5’-Dihydroxy-7-((2E)-3,7-dimethyl-2,6-octadienyl)-5’’-(1-hydroxy-1-methylethyl)-4’’,5’’dihydrofurano[2’’,3’’:3,2]-2-arylbenzofuran 6,3’,5’-Trihydroxy-5-methoxy-4-((2E)-3,7-dimethyl-2,6-octadienyl)-2’-prenyl-2-arylbenzofuran 6,3’,5’-Trihydroxy-7-prenyl-4’-((1S,5S,6S)-6-(2,4-dihydroxyphenylmethanonyl)-5-(2,4-dihydroxyphenyl)3-methyl-2-cyclohexen-1-yl)-2-arylbenzofuran

Moracin M 3’-O-glucoside Mulberroside C

Mulberrofuran Z Mulberrofuran U

Glyinflanin H Eryvarin P Oryzafuran Artoindonesianin O Bidwillol B Burttinol D w-Hydroxymoracin N Andinermal C Bryebinal Licocoumarone Andinermal A Erypoegin F Gancaonin I Ambofuranol Andinermal B Andinermol Bryebinal Kanzonol V Mulberrofuran V Eryvarin Q Lespedezol B1 Mulberrofuran Y Schoenoside Artoindonesianin Y Mulberrofuran W Artoindonesianin X Sanggenofuran A Mulberrofuran X

404.37 458.47

476.62 648.70

308.33 314.29 316.27 324.37 324.37 324.37 326.34 330.29 338.36 340.38 344.32 352.38 354.40 354.40 356.33 360.37 374.35 376.44 378.46 406.47 408.50 408.50 434.39 444.56 446.58 446.58 460.60 462.58

C20H20O9 C24H26O9

C30H36O5 C39H36O9

F24 F262

F238 F24

F75 F280 F87 F86 F104 F337 F163 F127b 2832 3106 F127b F272 3107 2833 F127b F127 2831 F73 F71 F280 F170 F238 F119 F254 F238 F254 F239 F238

continued

C19H16O4 C17H14O6 C16H12O7 C20H20O4 C20H20O4 C20H20O4 C19H18O5 C17H14O7 C20H18O5 C20H20O5 C18H16O7 C21H20O5 C21H22O5 C21H22O5 C19H16O7 C19H20O7 C19H18O8 C24H24O4 C24H26O4 C25H26O5 C25H28O5 C25H28O5 C21H22O10 C29H32O4 C29H34O4 C29H34O4 C30H36O4 C29H34O5

Appendix

1599 1600

1597 1598

1572 1573 1574 1575 1576 1577 1578 1578b 1579 1580 1580b 1581 1582 1583 1583b 1584 1585 1586 1587 1588 1589 1590 1591 1592 1593 1594 1595 1596

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a-METHYLDEOXYBENZOINS 2,4-Dihydroxy-4’-methoxy-a-methyldeoxybenzoin 2-Hydroxy-4,4’-dimethoxy-’’a -methyldeoxybenzoin 4-Hydroxy-2,4’-dimethoxy-’’a -methyldeoxybenzoin 2-Hydroxy-4’-methoxy-4-[ [1,2,3,4,4a,7,8,8a-octahydro-1,6-dimethyl-4-(1-methylethyl)-1naphthalenyl]oxy]a-methyldeoxybenzoin 6-Hydroxy-4’-methoxy-4-[ [1,2,3,4,4a,7,8,8a-octahydro-1,6-dimethyl-4-(1-methylethyl)-1naphthalenyl]oxy]-a-methyldeoxybenzoin

4-O-T-Cadinylangolensin

Angolensin 4-O-Methylangolensin 2-O-Methylangolensin 4-O-a-Cadinylangolensin

Bryebinalquinone

Eryvarin R Mulberrofuran Z

Ferrugin

476.66

272.30 286.33 286.33 476.66

358.30

316.31 476.62

434.49

Mass

C31H40O4

C16H16O4 C17H18O4 C17H18O4 C31H40O4

C18H14O8

C17H16O6 C30H36O5

C26H26O6

Formula

2820

2816 2818 2817 2819

2834

F280 F237

F50

Ref.

This checklist of isoflavonoids contains various compounds reported in the literature as natural products to the end of 2004. Compounds published before 1991 are referenced to numbered entries in Volume 2 of the Handbook of Natural Flavonoids (J.B. Harborne and H. Baxter), John Wiley & Sons, Chichester 1999, using a number consisting of four digits. Compounds published in the period 1991–2004 are referenced with numbers having F as prefix before the number of the publication found in the reference list.

1609

1605 1606 1607 1608

2-ARYLBENZOFURANQUINONE 3-Carboxyaldehyde-4,7-diketo-3’-hydroxy-6,2’,4’-trimethoxy-5-prenyl-2-arylbenzofuranquinone

3-ARYL-2,3-DIHYDROBENZOFURANS 3-Carboxyaldehyde-6,4’-dihydroxy-2’,5’-dimethoxy-3-aryl-2,3-dihydrobenzofuran (2S,3S)-7,4’-Dihydroxy-3’-methoxy-2-hydroxyethyl-5-hydroxypropyl-2-aryl-2,3-dihydrobenzofuran 4’-O-rhamnoside

2,5-DIARYLBENZOFURAN (2R,3S,3’’S,5’’S)-3,3’’-Dihydroxy-4’-methoxy-2,3-dihydro-2,5’’-diaryl-(cyclopentan[1’’,2’’:2,3]benzofuran)

Trivial Name

1184

1604

1602 1603

1601

Name

APPENDIX Checklist for Isoflavonoids Described in the Literature During the Period 1991–2004 — continued

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REFERENCES Reference list for natural isoflavonoids reported in the period 1991–2004. 1. Abd El-Latif, R.R. et al., A new isoflavone from Astragalus peregrinus, Chemistry of Natural Compounds (Translation of Khimiya Prirodnykh Soedinenii), 39, 536, 2003. 2. Abdel-Halim, O.B. et al., Isoflavonoids and alkaloids from Spartidium saharae, Natural Product Sciences, 6, 189, 2000. 3. Abegaz, B.M. and Woldu, Y., Isoflavonoids from the roots of Salsola somalensis, Phytochemistry, 30, 1281, 1991. 4. Agarwal, D., Sah, P., and Garg, S.P., A new isoflavone from the seeds of Psoralea corylifolia Linn, Oriental Journal of Chemistry, 16, 541, 2000. 4b. Ahn, E.-M. et al., Prenylated flavonoids from Moghania philippinensis, Phytochemistry, 64, 1389, 2003. 5. Aida, M., Hano, Y., and Nomura, T., Constituents of the Moraceae plants. 26. Ficusins A and B, two new cyclic-monoterpene-substituted isoflavones from Ficus septica Barm. F., Heterocycles, 41, 2761, 1995. 6. Al-Hazimi, H.M. and Al-Andis, N.M., Minor pterocarpanoids from Melilotus alba, Journal of Saudi Chemical Society, 4, 215, 2000. 7. Ali, A.A., El-Emary, N.A., and Darwish, F.M., Studies on the constituents of two Iris species, Bulletin of Pharmaceutical Sciences, Assiut University, 16, 159, 1993. 8. Ali, M., Chaudhary, A., and Ramachandram, R., New pterocarpans from Oroxylum indicum stem bark, Indian Journal of Chemistry, 38B, 950, 1999. 10. Alvarez, L. et al., Cytotoxic isoflavans from Eysenhardtia polystachya, Journal of Natural Products, 61, 767, 1998. 11. Andrei, C.C. et al., Dimethylchromene rotenoids from Tephrosia candida, Phytochemistry, 46, 1081, 1997. 11b. Arthan, D. et al., Antiviral isoflavonoid sulfate and steroidal glycosides from the fruits of Solanum torvum, Phytochemistry, 59, 459, 2002. 12. Asomaning, W.A. et al., Isoflavones and coumarins from Milletia thonningii, Phytochemistry, 51, 937, 1999. 13. Asomaning, W.A. et al., Pyrano- and dihydrofurano-isoflavones from Milletia thonningii, Phytochemistry, 39, 1215, 1995. 14. Atindehou, K.K. et al., Three new prenylated isoflavonoids from the root bark of Erythrina vogelii, Planta Medica, 68, 181, 2002. 15. Atta-Ur-Rahman et al., Two new isoflavanoids from the rhizomes of Iris soforana, Natural Product Research, 18, 465, 2004. 16. Atta-ur-Rahman, et al., Isoflavonoid glycosides from the rhizomes of Iris germanica, Helvetica Chimica Acta, 86, 3354, 2003. 17. Atta-ur-Rahman, et al., Isoflavonoid glycosides from the rhizomes of Iris germanica, Chemical & Pharmaceutical Bulletin, 50, 1100, 2002. 18. Ayatollahi, S.M. et al., Two isoflavones from Iris songarica Schrenk. Daru, Journal of Faculty of Pharmacy, Tehran University of Medical Sciences, 12, 54, 2004. 19. Baba, M. et al., Studies of the Egyptian traditional folk medicines. III. A new diprenylated 3-arylcoumarin from Egyptian licorice, Heterocycles, 51, 387, 1999. 20. Babu, U.V., Bhandari, S.P.S., and Garg, H.S., Barbacarpan, a pterocarpan from Crotalaria barbata, Phytochemistry, 48, 1457, 1998. 21. Barragan-Huerta, B.E. et al., Neocandenatone, an isoflavan–cinnamylphenol quinone methide pigment from Dalbergia congestiflora, Phytochemistry, 65, 925, 2004. 22. Barrero, A.F., Cabrera, E., and Garcia, I.R., Pterocarpans from Ononis viscosa subsp. breviflora, Phytochemistry, 48, 187, 1998. 23. Bashir, A. et al., Isoflavones and xanthones from Polygala virgata, Phytochemistry, 31, 309, 1992. 24. Basnet, P. et al., Two new 2-arylbenzofuran derivatives from hypoglycemic activity-bearing fractions of Morus insignis, Chemical & Pharmaceutical Bulletin, 41, 1238, 1993.

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