Naturally Occurring Organohalogen Compounds (Progress in the Chemistry of Organic Natural Products, 121) [1st ed. 2023] 3031266285, 9783031266287

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Progress in the Chemistry of Organic Natural Products

A. Douglas Kinghorn · Heinz Falk · Simon Gibbons · Yoshinori Asakawa · Ji-Kai Liu · Verena M. Dirsch Editors

121 Naturally Occurring Organohalogen Compounds By Gordon W. Gribble

Progress in the Chemistry of Organic Natural Products Series Editors A. Douglas Kinghorn OH, USA Heinz Falk Austria

, College of Pharmacy, The Ohio State University, Columbus,

, Institute of Organic Chemistry, Johannes Kepler University, Linz,

Simon Gibbons , Centre for Natural Products Discovery, Liverpool John Moores University, Liverpool, UK Yoshinori Asakawa , Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan Ji-Kai Liu , School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China Verena M. Dirsch , Department of Pharmaceutical Sciences, University of Vienna, Vienna, Wien, Austria Advisory Editors Giovanni Appendino , Department of Pharmaceutical Sciences, University of Eastern Piedmont, Novara, Italy Roberto G. S. Berlinck , Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, Brazil Jun’ichi Kobayashi, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan Agnieszka Ludwiczuk , Department of Pharmacognosy, Medical University of Lublin, Lublin, Poland C. Benjamin Naman

, Encinitas, San Diego Botanic Garden, CA, USA

Rachel Mata , Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, Distrito Federal, Mexico Nicholas H. Oberlies , Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, NC, USA Dirk Trauner PA, USA

, Department of Chemistry, University of Pennsylvania, Philadelphia,

Alvaro Viljoen , Department of Pharmaceutical Sciences, Tshwane University of Technology, Pretoria, South Africa Yang Ye , State Key Laboratory of Drug Research and Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Shanghai, China

The volumes of this classic series, now referred to simply as “Zechmeister” after its founder, Laszlo Zechmeister, have appeared under the Springer Imprint ever since the series’ inauguration in 1938. It is therefore not really surprising to find out that the list of contributing authors, who were awarded a Nobel Prize, is quite long: Kurt Alder, Derek H.R. Barton, George Wells Beadle, Dorothy Crowfoot-Hodgkin, Otto Diels, Hans von Euler-Chelpin, Paul Karrer, Luis Federico Leloir, Linus Pauling, Vladimir Prelog, with Walter Norman Haworth and Adolf F.J. Butenandt serving as members of the editorial board. The volumes contain contributions on various topics related to the origin, distribution, chemistry, synthesis, biochemistry, function or use of various classes of naturally-occurring substances ranging from small molecules to biopolymers. Each contribution is written by a recognized authority in the field and provides a comprehensive and up-to-date review of the topic in question. Addressed to biologists, technologists, and chemists alike, the series can be used by the expert as a source of information and literature citations and by the non-expert as a means of orientation in a rapidly developing discipline. All contributions are listed in PubMed.

Progress in the Chemistry of Organic Natural Products Volume 121

A. Douglas Kinghorn · Heinz Falk · Simon Gibbons · Yoshinori Asakawa · Ji-Kai Liu · Verena M. Dirsch Editors

Naturally Occurring Organohalogen Compounds

By Gordon W. Gribble

Editors A. Douglas Kinghorn College of Pharmacy Ohio State University Columbus, OH, USA

Heinz Falk Institute of Organic Chemistry Johannes Kepler University of Linz Linz, Austria

Simon Gibbons Centre for Natural Products Discovery Liverpool John Moores University Liverpool, UK

Yoshinori Asakawa Faculty of Pharmaceutical Sciences Tokushima Bunri University Tokushima, Japan

Ji-Kai Liu School of Pharmaceutical Sciences South Central University for Nationalities Wuhan, China

Verena M. Dirsch Department of Pharmaceutical Sciences University of Vienna Vienna, Austria

ISSN 2191-7043 ISSN 2192-4309 (electronic) Progress in the Chemistry of Organic Natural Products ISBN 978-3-031-26628-7 ISBN 978-3-031-26629-4 (eBook) https://doi.org/10.1007/978-3-031-26629-4 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

About This Book

The present volume is the third in a trilogy that documents naturally occurring organohalogen compounds, bringing the total number—from fewer than 25 in 1968—to approximately 8,000 compounds to date. Nearly, all of these natural products contain chlorine or bromine, with a few containing iodine and, fewer still, fluorine. Produced by ubiquitous marine (algae, sponges, corals, bryozoa, nudibranchs, fungi, bacteria) and terrestrial organisms (plants, fungi, bacteria, insects, higher animals), and universal abiotic processes (volcanos, forest fires, geothermal events), organohalogens pervade the global ecosystem. Newly identified extraterrestrial sources are also documented. In addition to chemical structures, biological activity, biohalogenation, biodegradation, natural function, and the future outlook are presented.

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Content

Naturally Occurring Organohalogen Compounds—A Comprehensive Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gordon W. Gribble

1

vii

Naturally Occurring Organohalogen Compounds—A Comprehensive Review Gordon W. Gribble

Contents 1 2

3

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Origins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Marine Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Terrestrial Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Extraterrestrial Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Simple Alkanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1 Chloromethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2 Dichloromethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3 Chloroform (Trichloromethane) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.4 Carbon Tetrachloride (Tetrachloromethane) . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.5 Other Chloroalkanes and Chloroalkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.6 Bromomethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.7 Dibromomethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.8 Bromoform (CHBr3 ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.9 Iodoalkanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.10 Mixed Chloro-, Bromo-, and Iodoalkanes . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Other Functionalized Acyclic Organohalogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Simple Functionalized Cyclic Organohalogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1 Cyclopentanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2 Cyclitols and Benzoquinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Terpenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1 Monoterpenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2 Sesquiterpenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.3 Diterpenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.4 Higher Terpenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5 Steroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6 Marine Nonterpenes: C15 Acetogenins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3 4 4 6 7 9 9 9 11 11 13 13 16 16 17 17 18 18 22 22 24 42 43 45 64 93 99 106

G. W. Gribble (B) Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. D. Kinghorn, H. Falk, S. Gibbons, Y. Asakawa, J.-K. Liu, V. M. Dirsch (eds.), Naturally Occurring Organohalogen Compounds, Progress in the Chemistry of Organic Natural Products 121, https://doi.org/10.1007/978-3-031-26629-4_1

1

2

G. W. Gribble 3.7 3.8 3.9 3.10 3.11 3.12 3.13 3.14

4

5

Iridoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lipids, Fatty Acids, and Marine Polyacetylenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fluorine-Containing Natural Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prostaglandins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Furanones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Amino Acids and Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Heterocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.14.1 Pyrroles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.14.2 Indoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.14.3 Carbazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.14.4 Indolocarbazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.14.5 Carbolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.14.6 Quinolines and Other Nitrogen Heterocycles . . . . . . . . . . . . . . . . . . . . . . . . 3.14.7 Benzofurans and Related Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.14.8 Pyrones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.14.9 Coumarins and Isocoumarins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.14.10 Flavones, Isoflavones, and Chromones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.15 Polyacetylenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.15.1 Terrestrial Polyacetylenes and Derived Thiophenes . . . . . . . . . . . . . . . . . . . 3.15.2 Marine Polyacetylenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16 Enediynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.17 Macrolides and Polyethers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.18 Naphthoquinones and Higher Quinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.19 Tetracyclines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.20 Aromatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.21 Simple Phenols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.21.1 Terrestrial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.21.2 Marine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.22 Complex Phenols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.22.1 Diphenylmethanes and Related Compounds . . . . . . . . . . . . . . . . . . . . . . . . . 3.22.2 Diphenyl Ethers and Related Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.22.3 Tyrosines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.22.4 Depsides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.22.5 Depsidones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.22.6 Xanthones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.22.7 Anthraquinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.22.8 Griseofulvin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.22.9 Miscellaneous Fungal Metabolites and Other Complex Phenols . . . . . . . . 3.23 Glycopeptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.24 Orthosomycins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.25 Dioxins and Dibenzofurans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.26 Humic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biohalogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Chloroperoxidase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Bromoperoxidase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4 Halogenases, Other Haloperoxidases, and Peroxidases . . . . . . . . . . . . . . . . . . . . . . . . 4.5 Myeloperoxidase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6 Abiotic Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7 Biofluorination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8 Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biodegradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

115 122 150 152 152 157 194 198 198 221 251 253 254 258 265 266 268 271 275 275 277 278 280 295 303 304 306 307 313 324 324 326 332 362 362 365 367 372 373 384 385 385 389 390 390 390 392 393 395 396 396 397 398

Naturally Occurring Organohalogen Compounds … 6 Natural Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3 400 402 403 405

1 Introduction The previous two surveys documented a combined total of 4714 naturally occurring organohalogen compounds, both biogenic and abiotic [1, 2]. In the subsequent two decades, an additional 3243 compounds have been described that contain chlorine, bromine, iodine, or, in a very few cases, fluorine. The organization follows exactly as that used in the two previous monographs. Thus, the compounds are arranged by structural type, which may seem to be arbitrary, but which follows those decisions made in the two previous surveys. As before, a discussion of individual compounds is limited, and space limitations precludes the illustration of syntheses beyond citations. In addition to the author’s two surveys [1, 2], a number of short reviews of naturally occurring organohalogens are available [3–8]. Noteworthy are the excellent annual reports on marine natural products [9–22], that of course, include halogenated compounds. Other relevant reviews cover halogen-containing alkaloids [23], indoles [24], organoiodines [25], and organochlorines [26]. More general surveys cover the natural products of sponges [27–41], marine algae [42–47], lichens [48], marine and terrestrial fungi [35, 49–53], marine and terrestrial bacteria [30, 54–63], cyanobacteria [64–71], ascidians [72, 73], crinoids [74], sea hares [75], bryophytes [76–78], nudibranchs [79], gastropods [80], and gorgonian corals [81]. Other reviews within the time period include antifouling compounds [82–86], deep-sea [87, 88] and coldwater natural products [89, 90], and those in marine benthic environments [91] and the hydrosphere [92]. Several studies of mangrove sediments have been described [93–96], and the specific areas of the Red Sea [97] and Okinawa [97] are reviewed. Reviews on synthesis aspects of marine natural products [98], and marine tricyclic sesquiterpenes [99] have appeared. Organic guanidines, which feature prominently in many halogenated natural products are reviewed [100, 101], as are marine isonitrile natural products [102]. A short review on halogenated natural products in German has appeared [103]. It should be emphasized that a 2016 review on the prodigious Laurencia genus of red algae is the “pièce de résistance” for this ubiq-

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G. W. Gribble

uitous collection of marine natural products [47]. An important recognition among natural products researchers is that bacterial symbionts of eukaryotic hosts (sponges, fungi, nematodes, insects, terrestrial plants, animals, even humans) may be the actual “biosynthesizers” of the respective organohalogens [104]. Coverage in this present contribution begins from volume 91 [2] in 2010 to references in 2021 and some from 2022.

2 Origins The abundance of fluoride/fluorine, chloride/chlorine, bromide/bromine, and iodide/ iodine on earth and in our solar system has provided an extraordinarily rich collection of halide/halogen chemical structures. Table 1 summarizes the distribution of halides in the earthen environment. For background material on this topic the reader is referred to the two prior accounts [1, 2].

2.1 Marine Environment Extensive studies show that halogen chemistry as generated, for example, from sea-salt spray, plays a significant role in photochemical tropospheric ozone loss [111–114]. The major source of tropospheric chlorine atoms is the reaction between hydroxyl radicals and hydrogen chloride derived from sea salt, where the concentration of chlorine atoms in the marine troposphere is about 1000/cm3 [115]. There is evidence that other inorganic chlorine gases exist in marine surface air, such as hypochlorous acid (HOCl) [116], nitryl chloride (ClNO2 ) [117–119], and nitrosyl

Table 1 Distribution of halides in the environment Halide

Oceans [105, 106] (mg/dm3 )

Sedimentary rocks [106, 107] (mg/kg)

Cl–

19,000

10–320

Br–

65

1.6–3

I–

0.05

0.3

F–

1.4

270–740

Fungi [108] (mg/kg)

100

Wood Pulp [109] (mg/ kg)

Plants [106, 110] (mg/kg)

70–2100

200–10,000

Naturally Occurring Organohalogen Compounds …

5

chloride (NOCl) [120], each of which is assumed to initiate atmospheric photochemical oxidations. However, the reaction details by which inorganic halides are converted into reactive halogens such as chlorine (bromine, iodine) atoms are unclear. A study of New England coastal air concluded that sea-salt is the primary source of inorganic chloride and bromide [121]. Similar investigations of salt lakes in Western Australia [122], the southern California coast [123], and the Great Salt Lake, Utah [124], have been described. The latter research uncovered the first direct observation of chlorine oxide (ClO) in the mid-latitude boundary layer along with bromine oxide (BrO). The authors ventured that these reactive halogens originate from salt on the flats surrounding the Great Salt Lake. Bromine oxide was previously observed in high concentrations in the boundary layer of the Dead Sea [125]. Likewise, both chlorine and bromine atoms were detected in the Arctic troposphere [126], and the latter are implicated in boundary-layer ozone depletion [127]. A study of the Arctic surface snowpack concludes that photochemical oxidation of bromide to molecular bromine (or bromine oxide) leads to the depletion of tropospheric ozone [128]. A laboratory study has shown chlorine atom formation from sea-salt aerosol induced by the photoreduction of Fe(III) to Fe(II) [129]. A similar model study involving the production of reactive bromine species (Br2 , BrO, HOBr) and subsequent quenching by ozone was reported [130]. Another investigation found that reactive bromine is produced biotically in two eutrophic lakes in Germany, requiring only light and algae to produce organobromine compounds [131]. The authors assume that haloperoxidases are involved. Bromine biogeodynamics in the wetland ecosystems of Western Portugal have been investigated. Both brackish and freshwater wetlands in several storage compartments (waters, soils, sediments, and plants) contain bromine [132]. A study of the occurrence of the dibromide radical (Br2 –• ) in natural waters has been published [133]. Thus, as we have seen, bromide ion is oxidized by hydroxyl radical to give the bromine atom, which can react further with bromide ion to give the dibromide radical (Br2 –• ), a reasonably strong oxidant. As alluded to earlier, the reaction of ozone with surface sea water forms reactive bromine and chlorine. Moreover, the reaction between ozone and iodide is thought to be the dominant emission of global iodine [113] and, thus, an important source of ozone depletion in the lower stratosphere [134]. Furthermore, abiotic tropospheric iodine oxide (IO) in the Dead Sea Valley has led to total ozone loss [135]. A major source of iodide and iodine is brown algae of the Laminaria genus. The authors concluded that iodide is “the chemically simplest antioxidant … with a central role for marine and atmospheric processes through the provision of condensation nuclei and the removal of ozone” [136]. Iodine oxide has been detected in the marine boundary layer at Mace Head, Ireland [137], and biogenic iodine emissions lead to marine aerosol and cloud condensation nuclei formation [138].

6

G. W. Gribble

2.2 Terrestrial Environment While fluorine (as fluoride) is the most abundant halogen on earth [139], the enormous reactivity of elemental fluorine (F2 ) has thwarted its discovery in Nature until 2012 when it was positively identified as a gas in the mineral antozonite [140]. The other three main halogens (as halides), with the exception of astatine, are abundant to varying degrees in sedimentary rocks [141, 142]. Marine sediments are a source of both organochlorines [143] and organobromines [144, 145]. It has been concluded that the largest natural sources of bromine/bromide are the oceans, which contain an average of 65 mg/dm3 of bromide. Much greater are the concentrations of bromine/ bromide in the Dead Sea of 4000 mg/dm3 [144]. These aquatic sediments play an important role in the cycling of bromine in the biosphere, acting as both sinks and sources of bromine/bromide. Other investigations have found a similar bromine biogeochemical cycle in terrestrial ecosystems involving brominated humic acid from decayed plant materials [146, 147]. The structures of these organobromines will be presented below. Chlorine has been recognized as cycling between inorganic and organic forms in the wet tundra soils in the Arctic Coastal Plain, providing evidence that natural chlorine/chloride recycling is widespread in other ecosystems [148]. Most of such chloride/chlorine cycling studies have been executed in terrestrial forests and the soils therein [149– 160]. These studies show that most of the chloride originates from the sea, that the organic chlorine derives from inorganic chloride during the decay and humidification of plant material, and that both biotic and/or abiotic in situ chlorination pathways may be involved, although most researchers prefer the former. Another terrestrial reservoir of halide/halogens is peatlands, and halogenated organic matter is the predominant pathway for release of organoiodines and organobromines from peat. In porewater, chlorine is mainly released as chloride [161, 162]. A significant source of terrestrial halogens and halides is volcanic emissions [163– 166]. Early studies found HCl, HF, Cl2 , and F2 to varying extents in the plumes of Hawaiian, Central American, American, and other volcanos (Table 2) [163]. Apparently, the first measurement of Cl2 and HCl was recorded in emissions from the Tolbachik volcanos of Kamchatka, Russia [166]. The authors propose a catalytic oxidation of chloride by crystals of Fe2 O3 , in what may be the first abiogenic catalysis in gas-rock interactions in Nature. The 2009–2010 eruption of the Gaua volcano in the Vanuatu archipelago discharged a large quantity of chlorine and fluorine [167], and in 1987 the White Island volcano in New Zealand emitted “paralava bombs” rich in chlorine and fluorine (mainly halite) [168]. Both chlorine- and bromine-containing gases from the large explosive volcanic eruptions in Nicaragua and other parts of Central America

Naturally Occurring Organohalogen Compounds …

7

Table 2 Concentrations of Cl2 , HCl, F2 , and HF reported in volcanic gases (recalculated to weight percent) Source

Cl2

Surtsey, Iceland

HCl

F2

HF

1

Mt. Pelée, West Indies

1.3

5.7

Lassen Peak, California

0.75

2

Mauna Loa, Hawaii

0.64

0

Niuafo’ou, Tonga

1.2

Kilauea, Hawaii

0.22

0 0.41

0.17

have led the authors to suggest that these events “have the potential to substantially deplete ozone on a global scale, eventually forming future ozone holes” [169–171]. Iodine is present in Central American volcanic fluids at concentrations higher than those found in seawater or meteoric fluids [172], and both iodine and bromine are present in volcanic ash soil [173], and granitoid rocks [174]. Gas plumes from the active Mt. Etna volcano on Sicily, which is one of the largest point sources of halogens on Earth, contain HBr, HI, BrO, and ClO2 among other gases [175, 176]. Bromine monoxide has also been observed in the plume of Soufrière Hills volcano on Montserrat [177], and both BrO and ClO2 were measured in the gases from Mount Pagan volcano in the Mariana Islands [178]. This volcano was active from 1981 to 2015. Chlorine was found as glass inclusions in crystals in ancient basaltic lavas (65–67 million years ago) [179], and the amazing complexity of the global deep halogen cycle has been summarized [180].

2.3 Extraterrestrial Environment Recent years have witnessed stunning discoveries in the chemistry of the interstellar medium, notably with regard to halogen. In 1967 traces of HCl and HF were found in the atmosphere of Venus, our closest neighbor, by means of a Michelson interferometer for high-resolution planetary infrared spectroscopy [181]. The levels detected were 10 μM [715]. One of the 50 fundamental herbs of traditional Chinese medicine is “Huang Bai”, the dried bark of Phellodendron chinense (Plate 24), and a study of the fruits of this plant yielded the new 795 with an uncommon chlorine at the C-20 position [716]. In a collection of the plant Physalis nicandroides from Morelos, Mexico, physanicandrolide C (796) was identified. An X-ray crystallographic study of the 6-OAc derivative was executed [717]. Aeropon-

Naturally Occurring Organohalogen Compounds …

103

ically grown Physalis acutifolia affords the new 5α-chloro-6β-hydroxyphysalin C (797) [718] and the closely related known chlorohydrin physalin H [2, 719, 720]. Both compounds are potent in four cytotoxicity assays, PC-3, MCF-7, NCI-H460, SF-268 (IC 50 0.5–2.1 μM) [718]. The Bolivian plant Salpichroa scandens contains the novel withanolide salpichrolide V (798), which shows weak cytotoxicity against the LNCaP, PC-3, and T47D cell lines (IC50 40–54 μM) [721]. The antiproliferative activity of 22 natural withanolides (of all types) against human cancer cell lines is summarized [722].

Plate 24 Phellodendron chinense (Photograph courtesy of Daderot; Kunming Botanical Garden, Kunming, Yunnan, China; Public domain)

104

G. W. Gribble OH HO OH

Cl O O

O

O

O

O

OAc

OH OAc O HO

Cl

OH Cl 795

794

O

O

OH

796 (physanicandrolide C)

O O

O

HO

O OH O

Cl

OH

797 (5α -chloro-6β-hydroxyphysalin C)

OH

O

O

O HO

Cl 798 (salpichrolide V)

Although few in number, halogenated marine steroids are known [723], and new examples are described herein. The marine sponge of genus Topsentia in Vang Fong Bay, Vietnam, provides the novel chlorotopsentiasterol sulfate D (799) and iodotopsentiasterol sulfate D (800), which is the first natural iodine-containing steroid. Metabolite 799 is an effective inhibitor of endo-1,3-β-d-glucanase from the marine mollusk Spisula sachalinensis [724]. A new chlorinated sterol disulfate, chalinulasterol (801), is found in the Bahamian sponge Chalinula molitba. Unlike the related solomonsterols A and B that have a sulfate replacing the chlorine, compound 801 is not an agonist of the PXR nuclear receptor [725]. The Vietnamese sponge Halichondria vansoesti yields the three new halogenated furano trisulfated steroids 802–804 [726]. These three compounds inhibit PSA (prostate-specific antigen) in 22Rv1 human drug-resistant prostate cancer cells and suppress glucose uptake in these cells. A Vietnamese Penares sp. sponge contains the chlorinated nor-lanostane 805. The authors suggest that this chlorohydrin may be an artifact formed from the corresponding epoxide, which is not found in the sponge [727]. A sponge of the genus Myrmekioderma from Kauai, Hawaii, afforded the new chlorine-containing pregnane 806, which (weakly) inhibits BACE1 (IC 50 82 μM) [728].

Naturally Occurring Organohalogen Compounds …

105

R Cl

O –O SO 3

–O SO 3

–O SO 3

–O3SO

HO

OSO3–

799 R = Cl (chlorotopsentiasterol sulfate D) 800 R = I (iodotopsentiasterol sulfate D)

801 (chalinulasterol)

R1

OH

O

O

Cl

O

R2

–

O3SO

O –O SO 3

O HO

OSO3– 805

802 R1 = Br, R2 = H (bromotopsentiasterol sulfate D) 803 R1 = R2 = Cl (dichlorotopsentiasterol sulfate D) 804 R1 = Cl, R2 = Br (bromochlorotopsentiasterol sulfate D)

O O

HO Cl 806

O

O O

O

O O H2N

Cl

O O

OH

Cl OH

H2N

O

O

O

807 (cyanobufalin A)

808 (cyanobufalin B) O O

HO

O Cl

O O

OH O

809 (cyanobufalin C)

106

G. W. Gribble

The three novel cyanobufalins A–C (807–809) are found in the Ohio cyanobacterial blooms of Planktothrix agardhii in Grand Lake St. Marys and Planktothrix sp. in Buckeye Lake. This is the first account of naturally occurring cardioactive steroids in the aquatic environment. Compounds 807 and 808 are potent and indiscriminate cytotoxins to 26 human normal and cancer cell lines, and 807 is an acute cardiotoxin at levels of as low as 8 nM [729]. The earlier proposed structures for the Cliona nigricans burrowing sponge metabolites clionastatins [2] have been corroborated through synthesis [730]. In contrast, the structures of nakiterpiosin and nakiterpiosinone [2] have been (slightly) reassigned as shown (confirmed by synthesis) [731], and their chemistry and biology is reported [732, 733]. O O O

Cl

Cl

O

O O

O HO

Cl

Cl

O

O

OH

OH O

HO Br

Br nakiterpiosin

nakiterpiosinone

3.6 Marine Nonterpenes: C15 Acetogenins The halogenated C15 acetogenins are a very large class of marine natural products. The first two surveys documented 175 examples, following the initial report of the oxocin laurencin from the red alga Laurencia glandulifera in 1965. The present survey continues with this large output [734]. Space does not permit presentation of the numerous elegant syntheses of these compounds, except where a structural revision is reported, but, unfortunately, this has been all too common in this class of marine natural products. Newly isolated compounds are presented first. As in previous sections, the red algae genus Laurencia is a major producer of C15 acetogenins. A sample of Laurencia glandulifera from waters off the island of Crete produces five new cyclic ethers, 810–814, along with the related known compound, the dideacetyl 811. Only 811 shows significant antibacterial activity against five multidrug and methicillin-resistant Staphylococcus aureus bacteria (MIC 8–16 μg/cm3 ) [735]. Another study of this Greek red alga finds the new tetrahydrofurans 815–819 and linear precursor 820. Metabolites 815, 816, 818, and 820 show no discernible cytotoxicity against HT-29, MCF-7, PC-3, HeLa, and A431 cells, but the results are negative (IC 50  10 μM) [736]. A Spanish specimen of the sea hare Aplysia fasciata contains the acetogenin 821 [504].

Naturally Occurring Organohalogen Compounds … R1O

Br

AcO

107

R2

R1 O Cl

Br

O

O Cl

Cl

R2 815 R1 = OAc, R2 = Cl 816 R1 = OH, R2 = OH

811 R1 = Ac, R2 = OAc 812 R1 = Ac, R2 = OH 813 R1 = H, R2 = OAc 814 R1 = Ac, R2 = Br

810

AcO

Br

O

O

Cl

Cl R 817 R = Br 818 R = OMe

819 OH

AcO

Cl O

820

Cl 821

A collection of Laurencia marilzae from the Canary Islands discovered eight new C15 acetogenins (822–829), along with the known obtusallene IV. All are essentially inactive towards human solid tumor cell lines (GI 50 > 10 μg/cm3 ) [737].

O

O Br

Br O

O

O

Br

C

OH

O

O

O Br

MeO2C

Br

Cl

Cl

822 (12-epoxyobtusallene IV) R3

O

Cl 824 (obtusallene X)

823 Cl

Br

C

threo

threo

Br Cl

Cl OH

C R2

R1

825 R1 = Br, R2 = H, R3 = (4R)-OH (marilzallene) 826 R1 = Br, R2 = H, R3 = (4R)-OAc ((+)-4-acetoxymarilzallene) 827 R1 = H, R2 = Br, R3 = OAc ((–)-4-acetoxymarilzallene)

828 ((Z)-adrienyne) 829 ((E)-adrienyne)

The red alga Laurencia obtusa from the Red Sea coast of Saudi Arabia yields three new maneonenes 830–832, which exhibit varying degrees of apoptosis to blood neutrophils [738]. The new dihydroitomanallene B (833) is found in Laurencia nagii Masuda, collected from Sabah, Borneo. This metabolite is a dihydro derivative of the known itomanallene B [739]. The earlier presented metabolites of Laurencia okamurai from China includes the new C12 acetogenin desepilaurallene (834) [511].

108

G. W. Gribble

Another collection of Laurencia okamurai mentioned earlier, with regard to its sesquiterpene content contains the C12 -acetogenin okamuragenin (835) [512]. Cl

O

O

O

O

Cl

O

O

Br

Cl Br

Br 830 ((12Z)-cis-maneonene-D)

831 ((12E)-cis-maneonene-E)

832 ((12Z)-trans-maneonene-C)

O

O

Br

Br C

AcO

O

O O

CHO O

Br Br 835 (okamuragenin)

834 (desepilaurallene)

833 (dihydroitomanallene B)

Examination of Laurencia chondrioides from Kefalonia Island, Greece, leads to the novel marilzallene (836) and the unusual chondrioallene (837) [740]. A Canary Islands collection of Laurencia marilzae afforded a group of C15 acetogenins (838– 842) [741], and the three new obtusallenes 843–845 [742]. O Cl Cl

OH

OH

O

HO

O O

O

Br

O

C

C

C Br

Br

Br

836 (marilzallene B)

Cl

Cl

Cl

OH

OH

O

O

O Br

OR

838 (marilzafurollene A)

837 (chondrioallene)

OH

C

Br

842 (12-acetoxy-marilzafurenyne)

841 (marilzafurollene D)

OH

O

O

Cl

O

O O

Br

Cl

O MeO2C

C

O

O Br Br

Br 843 (marilzanin)

Br

Br

Br 839 R = H (marilzafurollene B) 840 R = Me (marilzafurollene C)

Br

AcO

C

Cl 844 ((12S,13S)-epoxyobtusallene IV)

Cl 845

Salman’s Gulf, Saudi Arabia, in the Red Sea provided Laurencia obtusa that contains the novel jeddahenyne A (846) and 12-debromo-12-methoxy isomaneonene

Naturally Occurring Organohalogen Compounds …

109

A (847). Both compounds are apoptopic towards blood neutrophils (IC 50 , 846, 15.9 μM; dexamethasone, 0.9 μM) [743]. Another collection of this red alga from this part of the Red Sea affords the undescribed isolaurenidificin (848) and bromolaurenidificin (849), of which both show apoptosis as found above [744]. Metabolite 848 is an isomer of the known laurenidificin (850) which is a Chinese sample of Laurencia nidifica [745], and confirmed by asymmetric total synthesis [746]. In addition to the identification of 23 known compounds from a Corsican collection of Laurencia obtusa, the new sagonenyne (851) is present [747].

O O

O

O O

O

847

846 (jeddahenyne A)

(S) Br

(R) O (R) OH (R)

O

Br Br

O

Br

R2

848 R1 = OH, R2 = Br (isolaurenidificin) 849 R1 = R2 = Br (bromolaurenidificin)

Br

HO AcO

(R) O (R)

O Br

850 (laurenidificin)

851 (sagonenyne)

Three novel laurendecumallenes A–B (852, 853) and laurendecumenyne A (854) are present in Laurencia decumbens from Weizhou Island, China. These metabolites are inactive towards A-549 cells (human lung adenocarcinoma; IC 50 > 10 μg/cm3 ). The known elatenyne (Br in place of Cl in 855) is also present in this seaweed [748]. However, following the reassignment of elatenyne (vide infra), the structure of “laurendecumenyne B” is incorrect and subsequent work identified this compound as the known notoryne [1, 749]. The anti-fouling omaezallenes 855–857 are present in Laurencia sp. from Japan, and the structures and absolute configurations of 855 and 856 are confirmed by synthesis. Both metabolites are active against the barnacle Amphibalanus amphitrite [750].

110

G. W. Gribble HO

HOO O

HO

HO

HO

O

O

O C Br

C

O

Br

O

Br

Br

852 (laurendeccumallene A)

Br

854 (laurendecumenyne A)

853 (laurendeccumallene B) Br

O Br

O

Br

Cl

C OH

O

Br

HO

"laurendecumenyne B"

855 ((E)-omaezallene)

Br

Br O

OH

Br

O

Br

C

C OH

Br

HO

Br

HO 857

856 ((EZ)-omaezallene)

Cl

Cl R1

HO C

O

Br

Br

C

O

Br

O

O

Br

R2

HO

858 R1 = R2 = OH (marilzabicycloallene A) 860 R1 = OMe, R2 = OH (marilzabicycloallene C) 861 R1 = R2 = Cl (marilzabicycloallene D)

O

Br

BrHC

Br

Br

O

C

859 (marilzabicycloallene B)

Br

O Br O

O

OH

OH 862

O Br

863 O

C Br

O

OH

864 (hachijojimallene A)

Br O

O Br

C

Br 865 (hachijojimallene B)

The complex bicyclotridecane C15 norterpenoids marilzabicycloallenes A–D (858–861) are present in the Canary Islands Laurencia marilzae. None of these metabolites (858, 859) show significant activity against six human tumor cell lines [751]. In a brilliant tour-de-force of a proposed biosynthesis of the obtusallene family by Braddock [752], this researcher confirmed the structures of marilzabicycloallenes

Naturally Occurring Organohalogen Compounds …

111

C (860) and D (861) by total synthesis, along with syntheses of epoxyobtusallene IV, 12-epoxyobtusallene II, and obtusallene X [753]. A population of Laurencia obtusa from Corsica contains the new C15 -acetogenins 862 and 863, which are similar to sagonenyne (851) with regard to the pyran ring [754]. The collections of the Japanese Laurencia sp. that contain omaezol (487) and intricatriol (770) also produce the new hachijojimallenes A (864) and B (865); the names derive from Hachijojima Island where some algae were collected [577]. An examination of the red alga Laurenciella sp. from Corsica reveals the five new compounds 866–870, one of which, 870, is a new member of the bicyclo[5.5.1]tridecane ring system group similar to the marilzabicycloallenes (858– 861) [755]. Laurencia viridis from the Canary Islands contains the new pinnatifidenynes 871–873 and pinnatifidehyde (874), a rare C-12 acetogenin. Metabolite 873 is the most potent against four of the human solid tumor cell lines used (GI 50 13– 48 μM; A549, HBL-100, HeLa, SW1573, T-47D, WiDr) [756]. The coastal waters of Semporna, Malaysia, provides Laurencia nangii, which contains the two nangallenes A (875) and B (876), which have potent antifungal activity against Haliphthoros sabahensis and Lagenidium thermophilum (MIC 25 μg/cm3 ) [757]. Cl

R1

R2

Cl

O O C

Br

O

Br

O

Br

O

Br

Br

3

O

Br

866 R1 = OMe, R2 = OAc 867 R1 = Cl, R2 = OAc 868 R1 = Br, R2 = OAc 869 R1 = Cl, R2 = OH

871 ((3R,4S)-epoxy-pinnatifidenyne) 872 ((3S,4R)-epoxy-pinnatifidenyne)

870

O

O

Cl

Cl

O Br

O

4

C

Br

O

O

O

Br

873 ((9R,10S)-epoxy-(Z)-pinnatifidenyne)

Br C

O

875 (nangallene A)

874 (pinnatifidehyde) OH O Br

Cl O

Br C

876 (nangallene B)

The unusual rearranged C15 -acetogenin vagiallene (877) is found in Laurencia obtusa from Lefkada Island in the Ionian Sea, and a biogenesis of 877 from obtusallene I is proposed [758]. New C15 acetogenins from Laurencia sp. are thuwalallenes A–E (878–882) and thuwalenynes A–C (883–885), named after the Village of Thuwal in the Red Sea off Saudi Arabia. Only 883 did not exhibit anti-inflammatory activity

112

G. W. Gribble

in a standard nitric oxide release assay, whereas 880 and 882 were the most effective (IC 50 4.2 and 4.0 μM, respectively) [759]. Br OH

O

O

O

O

Br

O

Br

O

C

Br

O

O

O

C

O

C

Br 877 (vagiallene)

Br

878 (thuwalallene A)

O

Br

Br

O

Cl O

Br

Br

883 (thuwalenyne A)

Br

882 (thuwalallene E)

O

O Br

C

OH

881 (thuwalallene D)

880 (thuwalallene C)

O

O

O

C

O

Br

C

O

Br

Br

879 (thuwalallene B)

O

Br

884 (thuwalenyne B)

Br

OH

885 (thuwalenyne C)

A new collection of Laurencia obtusa, from the Red Sea, identified another rare C12 acetogenin, 886, together with two nonhalogenated analogs. All three of these metabolites inhibit the inflammatory cytokine release from peripheral blood mononuclear cells (e.g., TNF-α, IL-6, and TGF-β) [760]. A further Red Sea sample of Laurencia obtusa discovered the new laurentusenin (887) and laurenfuresenin (888), and the latter exhibits the most potent apoptotic cell death percentage [761]. The seldom studied Laurencia japonensis obtained as a sample from the Yoshio coast of Japan revealed the new katsuurenynes A (889) and B (890) [762]. The new 5-epi-maneolactone (891) is part of a contingent of halogenated metabolites (i.e., 492–495) found in the Red Sea Laurencia papillosa [580].

Naturally Occurring Organohalogen Compounds …

113 Br Br

Cl

O

O

Br OAc

OH

Br

O

O

CO2H

C Cl

886

888 (laurenfuresenin)

887 (laurentusenin)

O O

O

O

Br

Br

Br

O

Br

Br

Cl

O O

890 (katsuurenyne B)

889 (katsuurenyne A)

891 (5-epi-maneolactone)

The interesting set of nine new polyhalogenated acetogenins, ptilonines A–F (892–897), magellenediol (898), and pyranosylmagellanicus D and E (899, 900), are found in the red alga Ptilonia magellanica from Chile. The absolute configuration of the known pyranosylmagellanicus A was determined [763]. O Br Br

O O

O Br

O

Br

Br

O

O Br

O

O

Cl

Br

O

OH Br

R

R

892 R = Br (ptilonine A) 893 R = Cl (ptilonine B) 894 R = H (ptilonine C) OH

895 (ptilonine D)

Cl

Br Br

OH

OAc

OH

Cl

896 R = Br (ptilonine E) 897 R = Cl (ptilonine F)

OH Br

O Br

898 (magellenediol)

899 (pyranosylmagellanicus D)

O HO

Br Br

900 (pyranosylmagellanicus E)

A Philippines collection of Laurencia sp. afforded the set of laurefurenynes A–F, two of which, E (901) and F (902), are brominated. The latter metabolite is moderately cytotoxic towards three solid tumor cell lines, murine colon 38, human colon H116, and human lung H125, as well as leukemia L1210 cells [764]. Subsequently, these structures have been reassigned through a combined synthetic-spectroscopic effort, which culminated in reversing the configuration of the C-10 hydroxy group in 901 and 902. The other laurefurenynes are also reassigned [765]. An asymmetric total synthesis of (–)-bisezakyne A, which was isolated in 1999 from Laurencia sp. and Aplysia oculifera, leads to the reassignment of this C15 acetogenin and its absolute configuration [766]. The first total synthesis of (–)-aplysiallene, isolated in 1985 from Laurencia okamurai Yamada, led to its revision as shown [767]. Both (–)-bisezakyne A and (–)-aplysiallene were “counted” in the last survey [2].

114

G. W. Gribble HO

HO

3 4

O 10

Br

901 902

3 4

O 10

3,4

cis (laurefurenyne E) 3,4 trans (laurefurenyne F)

O

Br

O reassigned

original Cl

Cl (–)-bisezakyne A

O

O

Br

Br

reassigned

original

O

O C

Br

C

(–)-aplysiallene

O

Br

O Br

Br reassigned

original

The first C15 acetogenin cited in the previous survey happened to be the Laurencia elata pyrano[3,2-b]pyranyl vinyl acetylene named “elatenyne” isolated in 1986 from the coast of Victoria [2]. Following (1) the synthesis of the purported elatenyne structure [768, 769], (2) the realization that elatenyne was likely to possess the isomeric 2,2 -bifuranyl ring system [769, 770], (3) predictions as to the correct elatenyne diastereomer [770, 771], (4) total synthesis of the correct elatenyne structure [772], and (5) determination of the absolute configuration of elatenyne by X-ray analysis [773], this incredible detective story was concluded.

Br

Br

O

O

elatenyne O

Br

O

reassigned (absolute configuration)

original

O

Br O

Br

(+)-itomanallene A

O

Br O

4

4

C

C

Br original (+ enantiomer)

Br reassigned

The synthesis of (+)-itomanallene A led to the revision at C-4 of this Laurencia nipponica metabolite isolated in 1982 [774].

Naturally Occurring Organohalogen Compounds …

115

An elegant combination of GIAO-based density functional predictions, total synthesis, and X-ray crystallography required the structural revision of obtusallenes V–VII [775, 776]. obtusallene VI

obtusallene V Y

obtusallene VII

Y

Y

OH

Br O

O

H

O O

H

Br

H O

O

O O

C

X X

Br

X = Cl, Y = Br original X = Br, Y = Cl reassigned

X

C

C Br

Br

X = Cl, Y = Br original X = Br, Y = Cl reassigned

X = Cl, Y = Br original X = Br, Y = Cl reassigned

Some total syntheses of C15 acetogenins that were reported during this time frame include (+)-brasilenyne [777, 778], (+)-microcladallene B [779], (+)-scanlonenyme [780], (–)-laurefucin [781], (±)-laurefucin [782], (+)-(3E)-isolaurenfucin methyl ether [783], (+)-(3Z)-laureatin and (+)-(3Z)-isolaureatin [784], (+)-laurencin [785], (–)-kumausallene [786], (+)-(3E)-pinnatifidenyne [787], (±)-(E)- and (±)-(Z)pinnatifidenyne [782], (±)-panacene [788], (+)-(3Z)-dihydrohodophytin [789], (–)-isolaurallene, (+)-neolaurallene, (+)-itomanallene A, (+)-laurallene, and (+)pannosallene [790], (–)-isolaurepinnacin and (+)-rogioloxepane A [791], (+)bermudenynol [792], (±)- and (–)-aplysiallene [793], (+)-intricenyne [794], (+)srilankenyne [795], (+)-laurendecumallene B [796], laurallene [797], (Z)-notoryne [798, 799], 6-chlorotetrahydrofuran acetogenin [800], and (+)-(3E)- and (–)-(3Z)bromofucin [801], each of which supports the structures of the respective natural products.

3.7 Iridoids A group of plant metabolites are the iridoids, a few of which contain chlorine [802, 803]. The first two surveys documented 28 such compounds, which have an isoprenoid skeleton and are believed to be derived from mevalonic acid [1, 2]. The roots of the Chinese medicinal plant Patrinia rupestris (Plate 25) contain five new iridoids, three of which are chlorohydrins, rupesins A–C (903–905). Rupesins A and B show significant antibacterial activity against Escherichia coli, and C is active towards Staphylococcus aureus [804]. The Chinese perennial herbaceous Chinese plant Veronica sibirica, which is used for a variety of aliments (rheumatism, inflammation, cystitis, wound treatment), yields the new glycoside versibirioside (906) having a rare iridoid skeleton [805]. The New Zealand flowering plant Veronica catarractae contains catarractoside (907), an α-rhamnopyranosyl glucoside of the known

116

G. W. Gribble

Plate 25 Patrinia rupestris (Photograph courtesy of Michael Wolf)

asystasioside E [806]. The 10-O-cinnamoyl ester of asystasioside E, baldaccioside (908), is present in Wulfenia baldaccii [807].

O

Cl

O

HO

O

HO

Cl

905 (rupesin C)

904 (rupesin B)

O

OH O

α-Rha-O

O O

HO

Cl Cl

Ph

O O

O

O 903 (rupesin A)

O

O

AcO HO

OH

O

O

O Cl

O

O

O

O

O

O

OH

Ph

O

HO HO

O Cl

O

HO OGlu

HO

OGlu

OGlu 906 (versibirioside)

907 (catarractoside)

908 (baldaccioside)

Naturally Occurring Organohalogen Compounds …

117

An examination of the leaves of Myoporum bontioides from Okinawa discovered the new myopochlorin (909) and myobontioside A (910) [808]. The world-wide genus Valeriana and a Chinese sample of Valeriana wallichii contains the iridoid 1,5-dihydroxy-3,8-epoxyvalechlorine A [809]. Cultivation of Valeriana officinalis (Plate 26) seeds from China yields the new volvaltrate B along with several known iridoids and sesquiterpenoids [810]. However, the original proposed structures (not shown) have been revised at one chiral center (as shown), 911 and 912, respectively [811]. A more recent examination of Veronica longifolia reveals two new derivatives of asysatasioside E, longifolioside A (913) and B (914) [812]. The new iridoids valeriandoids A (915) and B (916) are present in the roots of Valeriana jatamansi Jones (Plate 27) growing in Sichuan Province, China [813]. Compound 915 shows moderate neuroprotective effects against 1-methyl4-phenylpyridinium-induced neuronal cell death in dopaminergic neuroblastoma (SH-SY5Y) cells [813]. Another collection of this source of Valeriana jatamansi revealed the new jatamandoid A (917) along with representative known analogs. Similar to 915, compound 917 exhibits neuroprotective effects without cytotoxicity, suggesting possible utility in Alzheimer’s, Parkinson’s, and Huntington’s diseases [814]. A sample of Valeriana jatamansi from Guizhou Province, China, proved to be a treasure trove for new chlorine-containing iridoids. Thus, 15 new chlorovaltrates A–O (918–932) are present in this plant together with six known analogs. Most of these compounds are cytotoxic towards the A-549, PC-3M, HCT-8, and Bel 7402 cell lines with IC 50 values of 0.89–9.76 μM [815].

Plate 26 Valeriana officinalis (Photograph courtesy of Ivar Leidus; Creative Commons AttributionShare Alike 4.0 International)

118

G. W. Gribble HO

HO

OH

Cl

HO

O

AcO

O

HO

Cl O

909 (myopochlorine)

HO

OGlu

7

O

O

Cl

OH

911 (1,5-dihydroxy-3,8-epoxyvalechlorine)

910 (myobontioside A)

O O O HO AcO Cl

HO

O

O

O HO

8 HO

O

O HO

O

HO

Cl

O

O

HO

Cl

O HO

HO OGlu

HO

OGlu

O 912 (volvaltrate B)

913 (longifolioside A)

914 (longifolioside B)

Plate 27 Valeriana jatamansi (Photograph courtesy of Daderot; Kunming Botanical Garden, Kunming, Yunnan, China; Public Domain)

Naturally Occurring Organohalogen Compounds …

119 O O HO

O

O HO

AcO

O

O

HO

O

HO

O

O

HO

HO OAc

Cl

O

OAc

O

O

Cl

O

Cl

O

O 915 (valeriandoid A)

916 (valeriandoid B)

HO AcO

HO

O

O

Cl HO

O

HO

O

O

OEt

AcO

O

Cl Cl

HO

OR

AcO

O

917 (jatamandoid A)

OEt

O

918 (chlorovaltrate A)

921 (chlorovaltrate D)

919 R = Me (chlorovaltrate B) 920 R = Et (chlorovaltrate C)

O O

O

O HO

HO O

HO

AcO

O

Cl

HO

OR

AcO

O

Cl

HO

O

O

O

OAc O

O

O HO

O

O O

Cl

HO

O 924 R = H (chlorovaltrate G) 925 R = Me (chlorovaltrate H) 926 R = Et (chlorovaltrate I)

923 (chlorovaltrate F)

922 (chlorovaltrate E)

O

Cl

O

O

RO

HO

O

O Cl

O

O 927 R = H (chlorovaltrate J) 928 R = Ac (chlorovaltrate K)

OH O

O HO

AcO

O Cl

O

930 (chlorovaltrate M)

929 (chlorovaltrate L)

OH

OAc

O Cl

O

O

O HO

O Cl

O O

931 (chlorovaltrate N)

O O

O

O

O HO

HO

O O

932 (chlorovaltrate O)

A Sichuan collection of Valeriana jatamansi contains an additional five new iridoids including the three chlorovaltrates P (933), Q (934), and R (935). Two other new “chlorovaltrates” are not chlorinated [816]. An examination of Phlomis likiangensis from Yunnan, China, yields six new iridoid glycosides, two of which contain

120

G. W. Gribble

chlorine, phloloside E (936) and F (937). Both compounds are weakly antimicrobial against Staphylococcus aureus (MIC 20.8 and 21.7 μg/cm3 , respectively) [817]. The roots of Patrinia scabra from Korea afford five novel patriscabrins A–E, one of which, A (938), is chlorinated [818]. HO HO CO2Me Cl

R HO

O

Cl

HO

O O

O

Cl

O

O

HO O

O O

O

O

OR

OH

HO OH

935 (chlorovaltrate R)

933 R = H (chlorovaltrate P) 934 R = OH (chlorovaltrate Q)

936 R = Me (phloloside E) 937 R = Et (phloloside F)

O O O

O OH Cl 938 (patriscabrin A)

The biosynthesis of the iridoid lamalbid was investigated using 13 C-labeled intermediates of the two pathways, MVA (mevalonic acid) and MEP (2-methyl-derythritol 4-phosphate). Based on the resulting 13 C-labeling pattern of lamalbid and the incorporation data, it is concluded that in the plant Lamium barbatum lamalbid is biosynthesized through the MEP pathway and not the (classic) MVA pathway (Scheme 2) [819].

OH

OH

O OH

OPPP OP

OP OH

OH OPPP OH

O O

OPP

OH

O HO

O O

CO2Me

HO

O

HO

OGlu lamalbid

Scheme 2 Biosynthesis of lamalbid

O O

Naturally Occurring Organohalogen Compounds …

121

Plate 28 Catharanthus roseus (Photograph courtesy of Joydeep; Creative Commons AttributionShare Alike 3.0 Unported)

O O

O

OH

iridoid synthase

O O

O

O

NAD(P)H

cis/trans nepetalactol

cis-iridodial

trans-iridodial

Scheme 3 Action of iridoid synthase

A novel enzyme, iridoid synthase, is found in plants that contain iridoids, such as Catharanthus roseus (Plate 28) and may be involved in iridoid biosynthesis. A reaction is shown in Scheme 3 [820]. Although not iridoids in the strictest sense, the new alcyopterosins 939–944 are included here. These are found in the Antarctic soft coral Alcyonium grandis and are of the illudalane sesquiterpenoid class. Crude extracts of this coral are feeding deterrents to the Antarctic predatory sea star Odontaster validus [821].

OR Cl

Cl

OR

OAc

939 R = COMe 940 R = CO(CH2)Me

941 R = COMe 942 R = CO(CH2)2Me

OH Cl

Cl OH 943

O

O

944 (alcyopterosin P)

122

G. W. Gribble

3.8 Lipids, Fatty Acids, and Marine Polyacetylenes As was the decision in the previous survey [2], the Sect. 3.15.2 Marine Polyacetylenes is adopted into this section. Halogenated lipids, fatty acids, and polyacetylenes are predominantly of marine origin [822, 823]. The organization is by type of producing organism. The marine sponge Phakelina carduus from Australia contains several acetylenic acids, carduusynes A–E, of which two are brominated, and with B (945) and D (946) isolated as the ethyl esters [824]. The Philippines sponge Diplastrella sp. yields the brominated diplynes A–E (947–951) and three sulfated analogs (948a–950a) [825]. Total syntheses of the diplynes A, C–E confirm the structures and establish absolute configuration for the natural (–)-diplyne A (shown) and inferred for diplynes B–E [826, 827]. O HO Br

R 945 R = H (carduusyne B) 946 R = OH (carduusyne D) R2 R1

Br

OH

OH

OR3

OR

947 R1 = H, R2 = Br, R3 = H (diplyne A) 948 R1 = Br, R2 = H, R3 = H (diplyne B) 948a R1 = H, R2 = Br, R3 = SO3H (diplyne A 1-sulfate)

Br

R1

949 R = H (diplyne C) 949a R = SO3H (diplyne C 1-sulfate)

Br OH OR2

950 R1 = OH, R2 = H (diplyne D) 950a R1 = H, R2 = SO3 H (2-deoxydiplyne D sulfate)

951 (diplyne A)

OH

The San Diego sponge Haliclona lunisimilis contains three new chlorinated acetylenes, 952–954 [828]. An earlier study of the nudibranch Diaulula sandiegensis living in the same area identified six related chlorinated acetylenes, which are believed to have originated from Haliclona lunisimilis as a likely diet for this animal. An Indonesian Haliclona sp. sponge yielded the new brominated fatty acid 955 [829],

Naturally Occurring Organohalogen Compounds …

123

and a Red Sea collection of Haliclona sp. found the two new metabolites 956 and 957; the former is moderately cytotoxic against MCF-7 cells (IC 50 32.5 μM) [830]. The carboxylic acid corresponding to 956 is known [1]. The new polyunsaturated bromo lipid 958 is present in a South China Sea Haliclona sp. sponge [831]. Cl

Cl

OAc RO

3 952 R = H, (3Z) 953 R = Ac, (3E)

954 Br

CO2H

955 Br Br 956 Br CO2Me 957 Br O

958

A collection of new brominated fatty acids was isolated, converted to methyl esters, from a Papua New Guinea unidentified sponge, metabolites 959–964, along with an array of known related fatty acids [832].

124

G. W. Gribble Br O

O HO

HO

960

959

Br

O

Br

Br HO

O OH

962

961

Br O HO

963

O

Br

HO

Br 964

A sample of the sponge Xestospongia muta (Plate 29) from the Bahamas revealed seven new brominated mutafurans A–G (965–971). The isolated fatty acids were methylated prior to structural elucidation. The absolute configuration of the tetrahydrofuran ring in 965, 967, and 968 was established as (5R,8S). Several of these compounds exhibit moderate antifungal activity against Cryptococcus neoformans var. grubii (MIC 4–16 μg/cm3 ) [833].

Plate 29 Xestospongia muta (Photograph courtesy of NOAA Photo Library 2: reef3860; Cayman Islands; Creative Commons Attribution 2.0 Generic)

Naturally Occurring Organohalogen Compounds …

125

3 Br O

5

O 965 (mutafuran A)

OH

Br Br

Br 967 (mutafuran C)

966 (mutafuran B)

970 (mutafuran F)

Br

Br Br

Br

971 (mutafuran G)

969 (mutafuran E)

968 (mutafuran D)

The marine sponge Xestospongia testudinaria is an enormously productive source of brominated lipids, especially sponge samples obtained in Chinese waters. This sponge contains 12 new xestospongienols A–L (972–983). Only weak cytotoxicity is observed against the Bel-7420, BGC-823, HeLa, and HL-60 human tumor cell lines [834]. Br Br Br

OH 9 10 OH

CO2H

Br

OH 9

Br

CO2H

10 OH 976 ((9S,10R)-xestospongienol E) 977 ((9R,10S)-xestospongienol F) 978 ((9R,10R)-xestospongienol G) 979 ((9S,10S)-xestospongienol H)

972 ((9S,10R)-xestospongienol A) 973 ((9R,10S)-xestospongienol B) 974 ((9R,10R)-xestospongienol C) 975 ((9S,10S)-xestospongienol D) Br

OH 9

CO2H

10 OH 980 ((9S,10R)-xestospongienol I) 981 ((9R,10S)-xestospongienol J) 982 ((9R,10R)-xestospongienol K) 983 ((9S,10S)-xestospongienol L)

Another collection of this Chinese sponge by the same team, in an heroic effort, uncovered an additional 39 new bromine-containing lipids, the xestospongienes A–Z and Z1 –Z13 (984–1021) [835].

126

G. W. Gribble R Br

R

H

7

Br

5

4 O

Br

Br

H 4 O

O

O

984 R = OH ((4S,7R)-xestospongiene A) 985 R = OH ((4R,7S)-xestospongiene B) 986 R = OH ((4R,7R)-xestospongiene C) 987 R = OH ((4S,7S)-xestospongiene D) 988 R = OMe ((4R,7S)-xestospongiene E) 989 R = OMe ((4S,7R)-xestospongiene F) 990 R = OMe ((4R,7R)-xestospongiene G) 991 R = OMe ((4S,7S)-xestospongiene H)

992 R = OH ((4R,5S)-xestospongiene I) 993 R = OH ((4S,5R)-xestospongiene J) 994 R = OH ((4R,5R)-xestospongiene K) 995 R = OH ((4S,5S)-xestospongiene L) 996 R = OMe ((4R,5S)-xestospongiene M) 997 R = OMe ((4S,5R)-xestospongiene N)

OH Br

OH 4

7 Br

CO2H

Br

998 ((7R)-xestospongiene O) 999 ((7S)-xestospongiene P) O

Br

Br

OH

CO2H

Br O

1003 ((7E,9R,10S)-xestospongiene T) 1004 ((7E,9S,10R)-xestospongiene U) 1005 ((7E,9S,10S)-xestospongiene V) 1006 ((7E,9R,10R (xestospongiene W) 1007 ((7Z,9R,10S)-xestospongiene X) 1008 ((7Z,9S,10R)-xestospongiene Y)

OH

1009 (xestospongiene Z)

OH

Br

10 5

8 7 Br

Br

CO2R

O

CO2H

9 Br

6 OH

1000 R = H ((6R*,7S*)-xestospongiene Q) 1001 R = H ((6R*,7R*)-xestospongiene R) 1002 R = Me ((6R*,7S*)-xestospongiene S)

7

10

7 Br

O

Br

CO2H

OH

Br

CO2H

Br

OH

1014 ((5R,10S)-xestospongiene Z5) 1015 ((5S,10R)-xestospongiene Z6) 1016 ((5R,10R)-xestospongiene Z7) 1017 ((5S,10S)-xestospongiene Z8)

1010 ((7S,8S)-xestospongiene Z1) 1011 ((7R,8R)-xestospongiene Z2) 1012 ((7S,8R)-xestospongiene Z3) 1013 ((7R,8S)-xestospongiene Z4) OH CO2H

5 Br

Br

O

CO2H

O

Br

Br

Br

1018 ((5R)-xestospongiene Z9) 1019 ((5S)-xestospongiene Z10)

O

O

1020 (xestospongiene Z11)

O

O

CO2H

Br 1021 (xestospongiene Z12)

Naturally Occurring Organohalogen Compounds …

127

Another investigation of this prolific sponge discovered one new brominated metabolite, mutafuran H (1022), off the coast of Hainan in the South China Sea. The absolute configuration is deduced as shown. It inhibits acetylcholinesterase at a level of IC 50 0.64 μM, whereas the positive control tacrine has IC 50 0.41 μM [836]. A Japanese sample of Xestospongia testudinaria yielded five new brominated fatty acids, 1023–1027 [837].

Br O

HO2C

O

Br

Br

O

1023 (testufuran A)

1022 (mutafuran H)

HO2C Br 1024 HO2C

1025

Br

HO2C

1026

Br

HO2C

Br 1027

Another study of Xestospongia testudinaria from China identified eight new brominated acetylenic fatty acids, xestonarienes A–H (1028–1035), which are typically methylated with diazomethane to form the respective methyl esters prior to structural determination [838]. Subsequent studies of this sponge by this Chinese team afforded 1036 [839], and xestonarienes I (1037) [840] and J (1038) [841]. These metabolites were isolated as methyl esters. It is also found that several methyl esters of these brominated acetylenic lipids are strong inhibitors of pancreatic lipase, such as the known methyl xestospongoate [842]. The first total synthesis of xestospongenyne is recorded, and it also is a potent pancreatic lipase inhibitor [843]. This compound would appear to be the methyl ester of 1026, isolated by the Japanese group [837].

128

G. W. Gribble CO2H Br 1028 (xestonariene A) CO2H

OH

9

10 Br

Br

1029 ((9R*,10S*)-xestonariene B) 1030 ((9S*,10S*)-xestonariene C) CO2H

Br 13 14 Br

OH 1031 ((3R*,14S*)-xestonariene D) 1032 ((13R*,14R*)-xestonariene E) CO2H

O

Br

1033 (xestonariene F) CO2H O Br 1034 (xestonariene G) CO2H

OH

Br

1035 (xestonariene H) Br Br

CO2H

Br

1036

Br

Br

Br

CO2H

Br

1037 (xestonariene I) CO2Me

CO2H

1038 (xestonariene J)

Br

methyl xestospongoate

Br

CO2Me xestospongenyne

Naturally Occurring Organohalogen Compounds …

129

The Red Sea version of Xestospongia testudinaria furnished the new xestosterol ester 1039 [844], and metabolites 1040 and (the unusual) xestospongiamide (1041) are found in the Red Sea sponge Xestospongia sp. Both of these latter metabolites are active against multidrug-resistant bacteria (MIC 2.2–4.5 μM) and 1041 shows excellent antifungal activity towards Aspergillus niger and Candida albicans (MIC 2.2–2.5 μM), as well as cytotoxic activity against Ehrlich ascites carcinoma and lymphocytic leukemia (IC 50 5.0 μM) [845]. An Indonesian collection of the sponge Theonella swinhoei contains the chlorinated fatty acid auranoic acid (1042) [846]. The new aurantoside J (1043) is present in this same collection of this Indonesian sponge, along with three known aurantosides that also contain auranoic acid in the polyene moiety [847]. A Japanese sample of Theonella swinhoei affords bromotheoynic acid (1044), which inhibits starfish oocyte maturation and the cell division of fertilized starfish eggs, and inhibits the proliferation of human leukemia cells (U937 and HL60), human lung cancer cells (A549 and H1299), and human embryonic kidney cells (HEK 293) [848].

Br O O 1039 Br O O

O

O HO O

OH

Br

O HO

OH 1040 H N O

Br

Cl NH2

1041 (xestospongiamide)

Cl

Cl

OH

O

OH

CO2H

O

N HO

O 1042 (aurantoic acid)

1043 (aurantoside J)

H2 N O

Br

CO2H 1044 (bromotheoynic acid)

OH

130

G. W. Gribble

A collection of the sponge Dysidea fragilis from Pohnpei, Micronesia, contains the three novel 2H-azirines 1045–1047. The terminal (Z)-1-bromo-1-chlorovinyl group in 1045 and 1046 is unique for a marine invertebrate. Metabolites 1045 and 1046 are moderately active towards HCT-116 cells (IC 50 13.6–15.2 μM) [849]. An Indonesian sponge Dysidea sp. provided two new compounds, biaketide (1048) and debromoantazirine (1049), both of which are cytotoxic to NBT-T2 cells (IC 50 8.3 and 4.7 μg/cm3 , respectively) [850]. CO2Me

CO2Me

CO2Me

N

N

N

Cl

Cl

Cl

Cl

Br

Br 1045

1047

1046

N O O Cl 1048 (biaketide)

CO2Me

Br 1049 (debromoantazirine)

A Fijian sponge, Siliquariaspongia sp., has yielded six motualevic acids A– F (1050–1055) and (4E,R)-antazirine (1056). The former six metabolites inhibit the growth of Staphylococcus aureus and methicillin-resistant S. aureus at 1.2– 10.9 μg/cm3 [851]. Total syntheses [852–854] and further biological studies of these compounds and analogs are reported [852]. Penasin B (1057) is found in a Penares sp. sponge from Japan along with four nonhalogenated analogs. The absolute configuration is depicted. This metabolite shows some cytotoxicity towards HeLa cells (IC 50 10 μg/cm3 ) [855]. A sponge complex of Geodia sp. encrusted with Halichondria sp. in a deep water collection in the Great Australian Bight afforded franklinolides A–C (1058–1060). Of these novel polyketides that incorporate the 3-O-methylglyceric acid phosphodiester unit, only franklinolide A is the dominant cytotoxic compound towards HT-29 and AGS cancer cell lines (GI 50 0.1–0.3 μM) [856].

Naturally Occurring Organohalogen Compounds … O

R

O N H

131 O CO2H

NHCH2CO2H Br

Br Br

Br Br

Br

1050 R = OH (motualevic acid A) 1052 R = NH2 (motualevic acid C) 1053 R = NMe2 (motualevic acid D)

1054 (motualevic acid E)

1051 (motualevic acid B)

CO2R O

N

14 Br

Cl H2N

OH

Br 1055 R = H (motualevic acid F) 1056 R = Me ((4E),(R)-antazirine)

1057 (penasin B)

12 HO

14

Cl

OH

O O

O

P

O

O

O

O

CO2H 1058 ((12Z,14Z)-franklinolide A) 1059 ((12E,14E)-franklinolide B) 1060 ((12E,14Z)-franklinolide C)

A Bahamian sponge Diplastrella sp. yielded the three faulknerynes A–C (1061– 1063), which are related to the diplynes presented earlier [857]. Another Bahamian sponge, Spirastrella mollis, contains mollenyne A (1064) [858], later to be followed by the identification of mollenynes B–E (1065–1068) from this sponge [859]. Mollenyne A is significantly cytotoxic towards human colon cancer cells, HCT-116 (IC 50 = 1.3 μg/cm3 ), and its absolute configuration was determined [858]. OH OH

OH OH

Br Br 1062 (faulkneryne B)

1061 (faulkneryne A) OH OH H2N

O

H N NH

4

N H

OH

Br

Cl

Br

Br 1063 (faulkneryne C)

1064 (mollenyne A)

132

G. W. Gribble O

H N

H2 N

4 NH

N H

OH

Br

Br

Cl

1065 (mollenyne B)

H2 N

O

H N 4 NH

N H

Br

Br

Cl

1066 (mollenyne C) O

H N

H2N

4 NH

N H

OH

Br

Cl

1067 (mollenyne D)

H2 N

O

H N 4 NH

N H Br

Cl

1068 (mollenyne E)

The Indonesian sponge Plakortis cfr. lita contains several manadoperoxides, two of which, J (1069) and K (1070) are chlorinated. Metabolite 1070 and some of the nonhalogenated manadoperoxides have excellent antiprotozoal activity against Trypanosoma brucei rhodesiense and Leishmania donovani, into the low ng/cm3 range [860]. A Fijian sponge Melophlus sp. contains the new teramic acid glycoside aurantoside K (1071) [861]. The new peptide-ketide hybrids smenamides A (1072) and B (1073) were isolated from the Bahamas sponge Smenospongia aurea, but these compounds may actually be metabolites from the cyanobacterium Synechococcus spongiarcum that is present in the sponge. Both compounds have potent activity towards lung cancer cells (Calu-1) (IC 50 48 nM) [862] as do some synthetic analogs [863].

Naturally Occurring Organohalogen Compounds … O

133

O

OH

O

O O

O Cl

O

CO2Me

O

Cl

1070 (manadoperoxide K)

1069 (manadoperoxide J) Cl

OH

O O

N O

O

OH

OH OH OH

H2N

O O

O

HO 1071 (aurantoside K) Cl N

N

1072 (smenamide A)

OH

N

Ph

O O

O

O

Cl

Ph

O

O

CO2Me

O

N

O

1073 (smenamide B)

O

O

A Madagascan sponge Lithoplocamia lithistoides possesses the novel polyketide PM050489 (1074), which was synthesized and shown to have subnanomolar cytotoxic activity against HT-29, A-549, and MDA-MB-0231 cells. The dechloro analog is also in this sponge and is a promising drug candidate undergoing clinical trials [864]. The four iodine-containing fatty acids 1075–1078 are found in the South Korean sponges Suberites mammilaris and Suberites japonicus. The methyl esters of these metabolites have anti-inflammatory effects, especially those of 1077 and 1078 [865]. Another Korean sponge, Placospongia sp., afforded phosphoiodyns A (1079) and B (1080) [866] (corrected structures shown [867]), and, subsequently, placotylenes A (1081) and B (1082) [868]. Interestingly, only placotylene A shows inhibitory activity against RANKL-induced osteoclast differentiation at 10 μM, whereas placotylene B shows no significant activity up to 100 μM. Total syntheses of 1079 and 1081 confirm the structures [869].

134

G. W. Gribble O O

O O

NH2

O

O N H

O HN Cl

1074 (PM050489) I

CO2H I 1075

I

CO2H I 1076 CO2H I 1077 CO2H I 1078 I

O P O OH

H2 N

1079 (phosphoiodyn A) I O H2N

O

P O OH 1080 (phosphoiodyn B) X Y

HO 1081 X = I, Y = H (placotylene A) 1082 X = H, Y = I (placotylene B)

The aforementioned Bahamian sponge Smenospongia aurea also contains the chlorinated thiazoles smenothiazoles A (1083) and B (1084), both of which display potent cytotoxicity towards the A2780 ovarian carcinoma cell line, inducing apoptosis at 70–100 μM [870]. These structures are confirmed by total synthesis [871]. Further examination of a Bahamas sponge, Smenospongia conulosa, identified two new thiazole-containing polyketide-peptides, conulothiazoles A (1085) and B (1086) [872]. Another study of this Smenospongia aurea sponge in combination with the cyanobacterium Trichodesmium sp., also in the Bahamas, uncovered the new smenolactones A–D (1087–1090) from the sponge, and the new isoconulothiazole B (1091) and conulothiazole C (1092) from the cyanobacterium [873]. Subsequently, smenamides C–G (1093–1097) have been identified in this sponge [874, 875].

Naturally Occurring Organohalogen Compounds … Cl

135 Cl

O

Ph

O

N

N H

N

N H

O

O

S

N

1084 (smenothiazole B)

1083 (smenothiazole A)

O

Cl

O

Ph

Cl S

N H

R

O

Ph

O

N

1085 R = H (conulothiazole A) 1086 R = Me (conulothiazole B)

1087 (smenolactone A) O

O Cl

Cl

O

OH

Ph

O 1089 (smenolactone C)

1088 (smenolactone B) O

Cl

O

OH

O

OH

Ph

O

Cl

S

N

O

Ph

Ph

Cl

O

Ph

N

O

O

N

O 1093 ((13E)-smenamide C) 1094 ((13Z)-smenamide D)

1092 (conulothiazole C)

OH

O

N

S

N H

Cl

N

1091 (isoconulothiazole B)

1090 (smenolactone D) Cl

S

N H

O

Cl

O

N

OH

N

Ph

O

N

N

O

O

O

O

O

O

1096 (smenamide F)

1095 (smenamide E) Cl

OH

Ph

O

N

N

O

O O 1097 (smenamide G)

A series of thiazole-containing polyketides, biakamides A–D (1098–1101) are in the Indonesian sponge Petrosaspongia sp. These novel metabolites show selective antiproliferative activity against PANC-1 cells [876]. The Thai sponge Hyrtios erectus contains the novel phenolic erectusenols A–C (1102–1104) and F (1105), together with nonchlorinated analogs. Of these metabolites, only B (1103) shows modest activity against acute lymphoblastic leukemia (MOLT-3) (IC 50 18 μM), among several tumor cell lines [877].

136

G. W. Gribble O

N 9

N S O

OH

N

Cl 1098 ((9E)-biakamide A) 1099 ((9Z)-biakamide B) O

N N

9

S O

N

O

Cl 1100 ((9E)-biakamide C) 1101 ((9Z)-biakamide D)

Cyanobacteria (blue-green algae) are a rich source of halogen-containing metabolites [1, 2], and some were already cited in the previous section, such as the smenamides from the cyanobacterial genus Trichodesmium in concert with the Bahamian sponge Smenospongia aurea [873, 874]. For a brief introduction to these classes of metabolites from cyanobacteria and marine algae: malyngamides, coibactins, honauctins, laurenciones, and tumonic acids, see [878]. A major contributor of halogenated fatty acids is the cyanobacterium genus Lyngbya (reclassified as genus Moorea as of 2012 [879]) and many new metabolites from this cyanobacterium have been discovered since the previous surveys [1, 2]. A collection of Moorea producens (formerly Lyngbya majuscula) (Plate 30) from Grenada affords the new grenadamides A (1106) and B (1107), along with new depsipeptides (Sect. 3.12). Both compounds are marginally active against the beet armyworm (Spodoptera exigua) [880]. A new malyngamide C, 8-epi-malyngamide C (1108), is present in Moorea producens sourced at Dry Tortugas, Florida. Both 1108 and malyngamide C are cytotoxic towards HT-29 colon cancer cells (IC 50 15.4 and 5.2 μM, respectively). The absolute configuration of 1108 is established as shown [881]. Both 1108 and the corresponding acetate (1109) are found in a Grenada sample of this cyanobacterium. These are active against the human lung cancer cell line H-460 and neuro-2a cancer cell line (IC 50 4.2–10.9 μg/cm3 ) [882]. A Papua New Guinea specimen of Moorea producens affords the new malyngamide 2 (1110), which exhibits anti-inflammatory activity in LPS-induced RAW macrophage cells (IC 50 8.0 μM) with only modest cytotoxicity to mammalian cells [883].

Naturally Occurring Organohalogen Compounds …

137

Plate 30 Moorea producens, Kahe Beach Park HI (Photograph courtesy of David R, Creative Commons) Cl

OR Cl

OH

OAc

OH

OH 1102 R = H (erectusenol A) 1103 R = Ac (erectusenol B) Cl

1104 (erectusenol C)

OH O Cl

N H

R O

1106 R = H (grenadamide B) 1107 R = Cl (grenadamide C)

OH 1105 (erectusenol F)

OH

O N H O

O

O

Cl O

RO

1108 R = H (8-epi-malyngamide C) 1109 R = Ac (8-O-acetyl-8-epi-malyngamide C)

HO N H

O

OH Cl

O

1110 (malyngamide 2)

A Guam sample of Moorea producens furnished malyngamide 3, which has marginal cytotoxicity towards MCF-7 and HT-29 cancer cells (IC 50 29 and 48 μM, respectively) (1111) [884]. A Red Sea Moorea producens from Saudi Arabia yields malyngamide 4 (1112), which is only modestly cytotoxic against three cancer cell lines [885]. A Taiwanese Moorea producens contains isomalyngamide A-1 (1113).

138

G. W. Gribble

This study also features several synthetic analogs, but noteworthy is that both 1113 and isomalyngamide A significantly suppress tumor migration, rather than proliferation [886]. Isomalyngamide K (1114) is found in Moorea producens from Papua New Guinea [887], and a Florida collection of Moorea producens yields (+)-malyngamide Y (1115), which is cytotoxic to the human lung cancer cell line H-460 (EC 50 1.45 × 10–5 μM) [888]. The first reported malyngamide with hydroxy-substitution at the fatty acid chain is 1116, which was isolated from a Hawaiian Moorea producens cyanobacterium sample. This metabolite is 10–100 times less cytotoxic than, for example, isomalyngamides A and B, which have a methoxy group at C-7 [889].

O N O

Cl

O

N

O

O

H N

O N

O

OH CO2Me

O

Cl

1111 (malyngamide 3)

O

1112 (malyngamide 4) O

O

O

N O O

N

N H

O

O

O

Cl

O Cl

1114 (isomalyngamide K)

1113 (isomalyngamide A1)

O O

O

O

O

N H Cl

O

O

N

HO 7 1115 ((+)-malyngamide Y)

N

O Cl

1116

Three new members of the malyngamide family are present in Moorea producens from Okinawa, 1117–1119. Metabolite 1117 shows potent activity and activated monophosphate-activated protein kinase (AMPK) [890]. Following the characterization of columbamides A–C (1120–1122) from a laboratory culture of Moorea bouillonii [891], two studies of a Malaysian collection of Moorea bouillonii found the new columbamides D–H (1123–1127) [892]. The structure of 1123 is confirmed by total synthesis of all four stereoisomers and the absolute configurations of 1123 and 1125 are established [892, 893].

Naturally Occurring Organohalogen Compounds …

139

OR O N H Cl

O

1119 (N-demethyl-isomalyngamide I)

R

Cl N

Cl

3

OR2

3 O

Cl N 20

Cl

5

10

1120 R1 = H, R2 = Ac (columbamide A) 1121 R1 = Cl, R2 = Ac (columbamide B) 1122 R1 = R2 = H (columbamide C)

OH

3 O

O

R1

O

Cl

O

1117 R = Ac (6,8-di-O-acetylmalyngamide 2) 1118 R = H (6-O-acetylmalyngamide 2) R1

O N H

OAc

O

OH

O

HO

O

1123 R = H ((10R,20R)-columbamide D) 1125 R = Cl ((10R,20R)-columbamide E)

Cl N

R2

5

OR3

3 O

O

1124 R1 =H, R2 = Cl, R3 = Ac (columbamide F) 1126 R1 = R2 = Cl, R3 = Ac (columbamide G) 1127 R1 = R2 = R3 = H (columbamide H)

A mixed Fijian collection of Moorea producens and Schizothrix sp. led to the discovery of 11 novel chlorinated lipids, taveuniamides A–K (1128–1138). The most potent of these are F, G, and K in the brine shrimp (Artemia salina) assay (LD50 1.7–1.9 μg/cm3 ) [894]. NHAc

Cl

Cl

NHAc

Cl R

4

Cl Cl

CO2Me

CO2Me 1130 (taveuniamide C)

1128 R = H (taveuniamide A) 1129 R = Cl (taveuniamide B) NHAc

Cl

Cl

Cl

NHAc

Cl

CO2Me

1131 (taveuniamide D) NHAc

1132 (taveuniamide E)

4

NHAc

Cl

Cl

Cl

Cl

1133 (taveuniamide F)

R1

1135 R1 = R2 = H (taveuniamide H) 1136 R1 = Cl, R2 = H (taveuniamide I) 1137 R1 = R2 = Cl (taveuniamide J)

Cl Cl

1134 (taveuniamide G)

NHAc

Cl

Cl Cl

Cl CO2Me

Cl

Cl Cl

Cl R2

Cl Cl Cl NHAc 1138 (taveuniamide K)

140

G. W. Gribble

The suspected toxic cyanobacterium Trichodesmium thiebautii contains trichotoxins A (1139) and B (1140) [332, 895], but the former structure was subsequently revised [895]. Blooms of this cyanobacterium are suspected in hundreds of human illnesses, marine mammal deaths, and other marine toxicities [333]. Subsequent study of this cyanobacterium found trichophycin A (1141), which is significantly more cytotoxic than the trichotoxins A and B; for example, towards Neuro-2A and HCT-116 cells (EC 50 6.5 and 11.7 μM, respectively) [896]. Also isolated from a Trichodesmium bloom is trichothiazole A (1142), which shows modest cytotoxicity to Neuro-2A cells (EC 50 13 μM) [897]. Cl

Cl

OH

OH

Ph

1140 (trichotoxin B)

1139 (trichotoxin A) Cl

OH

OH

Cl

OH N

Ph

Cl

S

1141 (trichophycin A) (proposed absolute configuration [902])

1142 (trichothiazole A)

A bloom of Trichodesmium in the Gulf of Mexico generates the new trichophycins B–F (1143–1147), with the proposed absolute configurations shown [898]. A further study revealed isotrichophycin C (1148/1149) and trichophycins G–I (1150–1152) [899]. O Cl

Cl

O

OH

Ph

OH

OH

Ph

O

Cl

1144 (trichophycin C)

1143 (trichophycin B)

O Cl

R

Cl

OH

OH

Cl

O

N

O

O 1147 (trichophycin F)

1145 R = H (trichophycin D) 1146 R = Br (trichophycin E) Cl

Cl OH

OH

Ph

Cl

1148 (isotrichophycin C)

Cl

OH

OH

OH 7

Ph

10

5

4

R

1149 R = Cl ((4S,5R,7R,10R)-isotrichophycin C) 1150 R = H (trichophycin G) OH

Cl

OH

OAc

Ph

1151 (trichophycin H)

1152 (trichophycin I)

Naturally Occurring Organohalogen Compounds …

141

A Papua New Guinea sample of Trichodesmium sp. nov. furnishes the new credneramides A (1153) and B (1154) along with their putative precursor credneric acid (1155). Both credneramides inhibit spontaneous calcium oscillations in murine cerebrocortical neurons (IC 50 3.8–4.0 μM) [900]. A Panamanian cyanobacterium Oscillatoria sp. contains coibactins A (1156) and B (1157) along with two nonhalogenated cyclopropane analogs. All four showed potent activity against axenic amastigotes of Leishmania donovani especially one of the nonchlorinated analogs (IC 50 2.4 μM) [901]. A Hawaiian cyanobacterium Leptolyngbya crossbyana contains the honaucins A–C (1158–1160), which inhibit bioluminescence in Vibrio harveyi BB120 and nitric oxide production in LPS-stimulated RAW264-7 macrophage cells (IC 50 4.0–7.8 μM) [902], via activation of the Nrf2-antioxidant pathway [903]. The new jamaicamides D (1161) and F (1162) are found in laboratory cultures of Moorea producens [904].

O

O Cl

Cl

R

N H

Cl O

OH O

1155 (credneric acid)

1153 R = Ph (credneramide A) 1154 R = i-Pr (credneramide B)

O Cl

O

O

O

O O

O

O

N O

O

OH O

RO

Cl

O

Cl O

1158 (honaucin A)

1157 (coibacin D)

1156 (coibacin C)

1159 R = Et (honaucin B) 1160 R Me (honaucin C) R1

R2

N H 1161 R1 = H, R2 = Br (jamaicamide D) 1162 R1 = Cl, R2 = I (jamaicamide F)

A mixed collection of cyanobacteria from Curacao and Papua New Guinea results in the identification of the new janthielamide A (1163), kimbeamides A–C (1164– 1166), and kimbelactone A (1167). Both 1163 and 1164 exhibit moderate sodiumchannel blocking activity in murine Neuro-2a cells [905]. A Guamanian cyanobacterium similar to Moorea sp. yields the new pitinoic acids B (1168) and C (1169) that inhibit quorum sensing in Pseudomonas aeruginosa, perhaps by acting as a prodrug (1168) for the nonchlorinated (active) pitinoic acid [906]. Laboratory cultivation of the cyanobacterium Nodosilinea sp. LEGE 06,102 affords the new bartolosides A–D (1170–1173), which again illustrates the power of genomics in the structure elucidation of “hidden” natural products [907].

142

G. W. Gribble Cl Cl O

O Cl

N H

N H

4

1164 ((4E,2’Z)-kimbeamide A) 1165 ((4Z,2’Z)-kimbeamide B) 1166 ((4Z,2’E)-kimbeamide C)

1163 (janthielamide A)

O

O Cl

2'

O

O

OH Cl

HO2C

O

1168 (pitinoic acid B)

1167 (kimbelactone A)

Cl

HO2C

1169 (pitinoic acid C) OH OH

O HO HO Cl

O

O OH

H

HO O

R1 4

7

3

5

3 Cl

4

HO R2

3

Cl

O

3 OH HO HO

O

OH 1170 (bartoloside A)

1171 R1 = Cl, R2 = H (bartoloside B) 1172 R1 = R2 = H (bartoloside C) 1173 R1 = R2 = Cl (bartoloside D)

A Guam sample of the cyanobacterium Hydrocoleum majus affords the new (1E)- and (1Z)-pitiamides (1174, 1175) [908], and a Panamanian cyanobacterium cf. Symploca sp. yields caracolamide A (1176), having the somewhat rare dichlorovinyl function (confirmed by total synthesis) [909]. An Okinawan cyanobacterium Okeania sp. contains the new lipopeptide ypavamide C (1177), along with a dechloro analog. Both compounds stimulate glucose uptake in a dose-dependent and an insulin-independent manner in cultured L6 myotubes [910]. The polychlorinated peptide-poyketide hybrids, aranazoles A–D (1178–1181) are produced by the cyanobacterium Fischerella sp. PCC 9339 [911].

Naturally Occurring Organohalogen Compounds …

143 H N

Cl O

O

1174 ((1E)-pitiamide B) Cl

O

H N O

Cl O

Cl

1176 (caracolamide A)

1175 ((1Z)-pitiamide B) Cl

O

H N

N Cl

Cl

Cl

O

O

Ac

S

O 1178 (aranazole A)

1177 (ypaoamide C) OH

OR

Cl

Cl N

Cl Cl

OH

Cl

O Cl

O

O N

Ph

N H

3

Cl

Cl

Cl

O

O

1179 R = H (aranazole B) 1180 R = Me (aranazole C)

S

OH O

O

Cl

N

Ac Cl

Cl

O

O

Ac

S

1181 (aranazole D)

Another genome mining investigation, of the cyanobacterium Moorea producens, afforded the vatiamides A–F (1182–1187) [912], and the laboratory culture of cyanobacterium Sphaerospermopsis sp. LEGE 00249 produces chlorinated fatty acid lactylates, chlorosphaerolactylates A–D (1188–1191) [913]. In a subsequent study of the biosynthesis of these lactylates, three additional chlorinated analogs were isolated but the position of the midchain-chlorine atom could not be ascertained so these are not included here [914]. A similar genome-guided mining of Nodularia sp. LEGE 06071 discovers the lactylate-nocuolin A hybrids, nocuolactylates, two of which contain chlorine, A (1192) and B (1193) [915].

144

G. W. Gribble Cl

R

CO2Me

O N

1182 R = H (vatiamide A) 1183 R = Br (vatiamide B) Cl

R

O

O

HO N H

O

O O O

1184 R = H (vatiamide C) 1185 R = Br (vatiamide D)

Cl

R

O

O

O N

N H

NH2

O

1186 R = H (vatiamide E) 1187 R = Br (vatiamide F) O HO

R2

O 1

3

R

O

R

1188 R = R = Cl, R = H (chlorosphaerolactylate A) 1189 R1 = R3 = H, R2 = Cl (chlorosphaerolactylate B) 1190 R1 = Cl, R2 = R3 = H (chlorosphaerolactylate C) 1191 R1 = R2 = R3 = Cl (chlorosphaerolactylate D) 1

2

3

N

O Cl R

5

O

O O

N

O

O

1192 R = H (nocuolactylate A) 1193 R= Cl (nocuolactylate B)

Several new karlotoxins have been isolated from Karlodinium veneficum and from other harmful algal bloom dinoflagellate Karlodinium sp. and Amphidinium sp. in recent years [916–919]. These powerful toxic ichthyotoxins, including karlotoxin 2 (= KmTx 2) (1194) [917, 919], (65E)-chloro-KmTx 1 (1195) [916], and (64E)chloro-KmTx 3 (1196) [916], are responsible for massive fish kills and significant economic losses to the seafood industry.

Naturally Occurring Organohalogen Compounds …

145 OH HO OH

Cl

OH

OH

OH OH

O OH

OH

O

OH

HO OH

OH

OH HO OH

OH

OH

OH

OH

OH

OH

1194 (karlotoxin 2) (KmTx2) OH

OH

OH

OH OH

HO OH

OH

OH

OH

OH

OH

OH

OH

HO OH Cl

OH

O

OH OH

OH O

OH

OH

1195 ((65E)-chloro-KmTx1) OH

OH

OH

OH OH

HO OH

OH

OH

OH

OH

OH

OH

OH

HO OH

Cl

OH OH

O

OH OH

O OH

OH

1196 ((64E)-chloro-KmTx3)

The unique polyhydroxylated polyene antibiotics “enacyloxins” from the bacterium Frateuria sp. W-315 continue to be of interest since their early discovery [1, 2]. The absolute configurations of the known enacyloxins Ia, IIa, IIIa, IVa, and the new decarbamoyl enacyloxin IIc (1197) have been determined [920]. Studies of the polyketide synthase chain release for the biosynthesis of enacyloxins are reported [921, 922].

146

G. W. Gribble HO2C R

OH O

H2N

O

OH

O

OH

OH

O

Cl

O R = H enacyloxin Ia R = Cl enacyloxin IIa HO2C R

OH O

O

H2N

OH

OH

OH

Cl

OH

O

O R = H enacyloxin IIIa R = Cl enacyloxin IVa HO2C HO O

OH O OH

Cl

Cl

OH

O

OH 1197 (decarbamoylenacyloxin IIa)

Fermentation of the Gram-negative bacterium Burkholderia thailandensis MSMB43 affords thailanstantins A–C, two of which contain chlorine (1198, 1199), and the third is a corresponding epoxide [923]; the structures are confirmed by total synthesis [924]. All three compounds show excellent antiproliferative activity towards human cancer cell lines (DU-145, H-232A, MDA-MB-231, SKO-3) as low as GI 50 1.1–2.7 nM for thailanstantin A (the epoxide) [923]. The fungus Gymnascella dankaliensis living within the Japanese sponge Halichondria japonica contains new examples of gymnastatins, Q (1200) and R (1201), and dankastatins A (1202) and B (1203), all of which retard the growth of P388 cancer cells (ED50 0.15–2.8 μg/cm3 ) [925]. Syntheses of gymnastatins Q and the known F [2] are described [926]. When the culture medium of this fungus contains bromide, the new brominated gymnastatins I–K are obtained. As “forced” metabolites, these are not counted as natural. Gymnastatin I is a mixture of two stereoisomers [927].

Naturally Occurring Organohalogen Compounds …

147

R O

R

O

O

O

O

HO

N H

OH

1198 R = H (thailanstatin B) 1199 R = Me (thailanstatin C) HO

CO2H

Cl

HO

Cl O

O

O

N H

OH

Cl

O O

N H

Cl

1200 (gymnastatin Q)

OH

Cl

1201 (gymnastatin R) Cl

Cl O

O

HO

HO

O

Cl

O

1203 (dankastatin B)

O

O

O

Br

Br

O N H

O

N H

O

1202 (dankastatin A)

O

Cl

O

N H

Br

Br

R1

gymnastatin I R1 = OH, R2 = H gymnastatin I R1 = H, R2 = OH

O

O N H gymnastatin J

Br OH

HO

HO R2

Br

O

O

O N H

O

gymnastatin K

The fungus Isaria tenuipes BCC 12625, which is a parasite to larvae of Lepidopteran insects, contains isariotin F (1204), and is active against the malaria parasite Plasmodium falciparum K1 (IC 50 5.1 μM) and cytotoxic to the cell lines KB, KC, and H-187 (IC50 15.8, 2.4, and 1.6 μM, respectively) [384]. A subsequent examination of this fungus reveals three new chlorinated isariotins G–I (1205–1207) [928]. Likewise, another study of the sponge-derived Gymnascella dankaliensis uncovered dankastatin C (1208), which is highly active against the murine P388 lymphocytic leukemia cell line (ED50 57 ng/cm3 ) [929]. The fungal genus Pestalotiopsis is found worldwide and some species are disease-causing in plants. The ambuic acid analog 1209 is produced by Pestalotiopsis sp. cr013 [930]. The fungus Emericella variecolor associated with the sponge Cinachyrella sp. from the South China Sea affords one chlorinated metabolite, varioxiranol D (1210) with a host of nonhalogenated analogs [931]. Cultures of a mangrove-derived Penicillium variabile HXQ-H-1 yield varitatin A (1211), which is both cytotoxic to HCT-116 cells (IC 50 2.8 μM) and inhibits two protein tyrosine kinases with inhibitory rates of 40–50% at 1 μM [932].

148

G. W. Gribble Cl O

O

O

HO

HO

HO

Cl

O R 7

Cl

O R

O

N H

5

OH

O

N H

OH

1206 R = H (isariotin H) 1207 R = OH (isariotin I)

1204 R = H (isariotin F) 1205 R = OH (isariotin G)

Cl

O

O

N H

O

O

1208 (dankastatin C)

O Cl

O

O

HN

O OH HO

OH

OH

Cl OH OH

O O

OH

HO

OH

Cl CO2H

1209

1210 (varioxiranol D)

1211 (varitatin A)

The sea grass Zostera marina-derived fungus Penicillium thomii Maire KMM 4675 contains eleven new polyketides including the chlorine-containing pallidopenilline E (1212) [933]. A fungal strain of Phoma sp. NTOU4195 associated with the red alga Pterocladiella capillacea contains the new phomaketides A (1213) and B (1214), the former of which displays most potent anti-inflammatory activity in suppressing the tube formation of endothelial progenitor cells with IC 50 8.1 μM [934]. Oxirapentyn L (1215) was isolated from a mixed culture of Isaria felina KMM 4639 and Aspergillus sulphureus KMM 4640, and would appear to be the first natural product having the chloroallenic moiety [935]. Of several novel shishididemniols from a Didemnidae tunicate, two are chlorohydrins (1216, 1217) [936, 937]. OAc O O OH

O

O

O

OH O

OH HO

Cl OH

OH

Cl

O

O

1213 (phomaketide A)

1212 (pallidopenilline E)

O

O

Cl OH

1214 (phomaketide B) O HN

R HO

OH

O OH C

O HO

O

OH

Cl

HO

NH2

HN

OH

O

9

5 OH

1215 (oxirapentyn L)

O

OH

Cl

OH

1216 R = Et (shishididemniol B) 1217 R = Me (shishididemniol D)

Naturally Occurring Organohalogen Compounds …

149

A large group of natural lipids are the chlorosulfolipids found in freshwater algae and toxic mussels [938]. A new chlorosulfolipid 1218 is found in the micro alga Ochromonas danica [939]. Another culture of this alga yielded eight chlorosulfolipids, including five new examples (1219–1223), and establishing the absolute configurations of 1219–1222. Lipid 1219 is the most toxic to brine shrimp larvae (Artemia salina) (LC 50 0.27 μg/cm3 ) [940]. The absolute configuration is established for the most commonly known chlorosulfolipid, 2,2,11,13,15,16hexachlorodocosane-1,14-disulfate [1]. Two new polychlorinated lipids, 1224 and 1225, are found in the octocoral Dendronephthya griffin from Formosa [941]. HO3SO

Cl

Cl

Cl

OR

Cl

OSO3H OSO3H

Cl

5

Cl

R3

Cl

OR2

Cl

1224 R = SO3H 1225 R = H

1218

Cl

Cl

Cl

Cl

Cl 7 R4 R4

1219 R1 = SO3H, R2 = H, R3 = R4 = Cl 1220 R1 = R2 = H, R3 = R4 = Cl 1221 R1 = R2 = SO3H, R3 = Cl, R4 = H 1222 R1 = R2 = SO3H, R3 = R4 = H

Cl

OR1

OSO3H

Cl 5

Cl

OSO3H

Cl

1223

The linear structure of the chlorosulfolipids with multiple chiral centers poses an enormous synthesis challenge! Some groups have accepted and met this challenge [942–944], and a few seminal examples are listed. The revision of malhamensilipin A isolated from the freshwater alga Poterioochromonas malhamensis [1] is reported and the absolute configuration is established [945]. An asymmetric total synthesis of (+)-hexachlorosulfolipid [2] confirms the proposed absolute configuration [946], and several syntheses of danicalpin A, a major component of Ochromonas danica, are published [947–951]. Other chlorosulfolipids that have been synthesized are mytilipin A [948, 952], malhamensilipin A [948], and the complex undecachlorosulfolipid A [2], the synthesis of which led to its revision at C-23 [953]. If Ochromonas danica is cultured in the presence of excess bromide, then the forced metabolite bromodanicalipin A is formed [954].

150

G. W. Gribble SO3H Cl

O

Cl

Br

Cl

OSO3H

Br

Br OSO3H

5 Cl

Cl

Cl

7

5

3

OSO3H

Br

Br

"bromodanicalipin A"

malhamensilipin A C15H31 O

Br

SO3H

O

Cl

O

Cl

OH

OH

Cl

OH

Cl OH

Cl

Cl

Cl

Cl Cl

Cl

Cl

OH

undecachlorosulfolipid A

An outgrowth of the chlorosulfolipid synthesis efforts is the discovery of an unprecedented [1, 3]-sigmatropic shift of an allylic chloride shown below [955]. Also noteworthy is the observation of chlorine “Neighboring Group Participation” via a 5-membered ring “chloronium ion” in the synthesis of a chlorosulfolipid as summarized below [956]. This species previously had only been seen under strongly acidic conditions like the more common 3-membered ring chloronium ion [957, 958]. Cl

OTBS

Cl

Cl

OTBS

Cl

SiO2 (flash chromatography)

Cl

Cl

OTBS

C6H13 Cl

7

Cl

OTBS

C6H13

n-hexane/toluene

Cl

Cl

7

62% (one diastereomer)

SiMe3

Cl

Cl

Cl

O Cl

OH

Cl– Me3SiO R

Cl

Cl–

Cl

Cl

R

R

chloronium ion

Several total syntheses of the malyngamide family of lipids have been achieved, including malyngamides O, P, Q, R [959], M and isomalyngamide M [960], K, L, 5 -epi-C, and the absolute configuration of malyngamide L [961]. The first syntheses of credneramides A (1153) and B (1154) are described [962], as are total syntheses of aurantoside G [963] and (+)-majusculoic acid [964].

3.9 Fluorine-Containing Natural Products The fascinating history of the natural fluoroacetic acid and the equally toxic natural even-numbered ω-fluorinated carboxylic acids was discussed in detail earlier [1, 2]. A study of 13 Gastrolobium species in Western Australia reveals significant variations in total fluorine content, mainly as organic fluorine, ranging from 1.6

Naturally Occurring Organohalogen Compounds …

151

Plate 31 Gastrolobium spinosum (Photography courtesy of jeans_Photos; https://www.flickr.com/ photos/63479603 @N00/48825099826; Creative Commons Attribution 2.0 Generic)

to 1064 mg/kg in Gastrolobium spinosum (Plate 31) and Gastrolobium cuneatum, respectively. Interestingly, the organofluorine is mainly concentrated in the plant cotyledons (embryonic leaves) to the extent of 87%. This suggests a chemical defense strategy whereby the plant is protecting the newly germinated seedling rather than the seed itself [965]. In accord with the proposed biosynthesis of fluoroacetate and fluorothreonine [2], the third intermediate in the biosynthesis pathway, (3R,4S)-5-fluoro-5-deoxy-dribulose-1-phosphate is found in Streptomyces cattleya [966, 967]. A new enzyme capable of degrading fluoroacetate is fluoroacetate dehalogenase that was isolated and purified from Pseudomonas fluorescens DSM 8341 and is specific for fluoroacetate [968]. The enzyme fluoroacetyl-coenzyme A (CoA)-specific thioesterase (F1K) from Streptomyces cattleya is highly specific for fluoroacetyl-CoA over acetyl-CoA by a factor of 106 -fold, thus protecting its host from fluoroacetate toxicity. Crystallographic and biochemical studies on this enzyme have been detailed [969]. Fluorinase, the enzyme from Streptomyces cattleya that initiates the conversion of S-adenosine-l-methionine (SAM) to fluoroacetate, has been employed via its gene to create the unnatural fluorosalinosporamide by a replacement of the chlorinase gene salL from Salinispora tropica with the fluorinase gene flA in the presence of fluoride [970]. Employing the action of fluorinase with [18 F]-fluoride provides both a chemoenzymatic synthesis of 5 -[18 F]-fluoro-5 -deoxyadenosine and then sodium [18 F]-fluoroacetate [971]. Similar engineering with fluorinase is used to prepare [18 F]-5-fluoro-5-deoxyribose for use in positron emission tomography (PET) imaging [972]. Highly enantioselective (>95% ee) syntheses of (R)- and (S)-[2 H1 ]-fluoroacetate sodium salts are reported [973]. The biosynthesis of fluoroacetate in the marine-derived bacterium Streptomyces xinghaiensis NRRL B-24674 revealed a fluorinase enzyme. Production of fluoroacetate in this organism is sea-salt dependent (fluoride averages 1.3 ppm in surface ocean water) but 4-fluorothreonine is not produced [974, 975].

152

G. W. Gribble

The new organofluorine (2R,3S,4S)-5-fluoro-2,3,4-trihydroxypentanoic acid (1226) is found in the soil bacterium Streptomyces sp. MA37. This metabolite is thought to form from 5-deoxyribose phosphate → 5-fluoro-5-deoxyribose → 5-fluoro-5-deoxy-d-ribono-γ-lactone → 1226, a pathway supported by synthesis [976]. F

O

O

–PO4

F

O

O P O– HO OH

O–

HO OH

F OH

NAD+

O

HO OH

O

H2O

OH

OH

F

CO2H OH 1226

In contrast to the clear and convincing evidence for the natural formation and occurrence of fluoroacetic acid/fluoroacetate, there is considerable controversy regarding the existence of natural trifluoroacetic acid (TFA), although this compound was “counted” in the earlier survey [2]. The debate revolves around whether the observed TFA is anthropogenic, formed, for example, from Freon replacements (HCFC-134a, HCFC-123, HCFC-124), or from natural processes. Several studies find TFA in Canadian Lake waters [343], natural Switzerland waters [344], in the Great Lakes [345], and much lower concentrations in Lake Malawi in Africa [345]. The conclusions from two studies [343, 345] are that the TFA is from proximate urban and/or industrial areas. An examination of pre-industrial (>2000-year-old) freshwater from Greenland and Denmark found no detectable TFA (100 μg/dm3 concluded that wastewater treatment plants among other sources are TFA dischargers [979]. A critical review of TFA in the environment from all possible sources concludes that there is “insufficient evidence for the existence of natural trifluoroacetic acid” [980].

3.10 Prostaglandins Following the discovery of some 50 halogenated punaglandins, vulones, and related prostanoids in the earlier surveys [1, 2], no additional analogs are to be reported herein.

3.11 Furanones Reviews on naturally occurring furanones and their antifouling action are available [981, 982], the inhibition of biofilm formation by brominated furanones is reported

Naturally Occurring Organohalogen Compounds …

153

[982–984], and intercellular communication by these metabolites is of interest [985– 987]. A brominated furanone inhibits cystathionine beta-synthase, an enzyme that regulates homocysteine levels [988], and another brominated furanone covalently modifies and inactivates LuxS ((S)-ribosylhomocysteine lyase), the enzyme that produces autoinducer-2, a signaling molecule [989]. A paper on the evolution of quorum sensing inhibitory drugs as new antimicrobials has appeared [990]. More than 85 halogenated furanones are presented in the earlier surveys [1, 2], and many new examples have been discovered in the interim. The Korean tunicate Pseudodistoma antinboja contains the six novel cadiolides 1227–1234, several of which have significant antibacterial activity against a range of drug- and non-drug-resistant strains [991]. A second study of this organism uncovered cadiolides J–M (1235–1239) also with antibacterial activity comparable to vancomycin and linezolid. The known cadiolide H is also in this animal [992]. HO Br Br O

O O O

5

Br

O

O

R3 OR2

5

Br

Br HO

HO

R

R1

1230 R1 = R2 = R3 = H (cadiolide C) 1231 R1 = Br, R2 = R3 = H (cadiolide D) 1232 R1 = R2 = H, R3 = Br (cadiolide E) 1233 R1 = R3 = H, R2 = Me ((5E)-cadiolide F) 1234 R1 = R3 = H, R2 = Me ((5Z)-cadiolide F)

1227 R = Br ((5E)-rubrolide P) 1228 R = Br ((5Z)-rubrolide P) 1229 R = H (rubrolide Q)

R5O Br Br O O

HO

R2 OR3

5

Br

R4 HO

R1

1235 R1 = R2 = Br, R3 = R5 = Me, R4 = H ((5E)-cadiolide J) 1236 R1 = R2 = Br, R3 = R5 = Me, R4 = H ((5Z)-cadiolide J) 1237 R1 = R2 = Br, R3 = R4 = H, R5 = Me (cadiolide K) 1238 R1 = R3 = H, R2 = R4 = Br, R5 = Me (cadiolide L) 1239 R1 = R2 = R4 = Br, R3 = R5 = H (cadiolide M)

Several of the aforementioned cadiolides (i.e., C, D, E, F) [991] were independently isolated from the Korean tunicate Synoicum sp., including also the new cadiolides G–I (1240–1243), and the new synoilides A (1244, 1245) and B (1246, 1247). For both sets of metabolites, (E) and (Z) isomers are found, but favoring the (Z) isomer in each case. Several of these metabolites significantly inhibit the Candida albicans-derived isocitrate lyase and Na+ /K+ -ATPase, but all are inactive against the

154

G. W. Gribble

K-562 and A-549 tumor cell lines [993]. The isocitrate lyase activities of these cadiolides and synoilides are studied in depth, and cadiolides E (1232), H (1241), and I (1243) are particularly inhibitory (IC 50 7.62, 17.16, 10.36 μM, respectively) [994]. A South African tunicate Synoicum sp. produces four new rubrolides 1248–1251, along with the known rubrolides E and F. Both 1241 and ruberolide E are active towards methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis [995]. Br

O

HO

Br Br

O Br

O

O O

HO

OR3

5

Br

OH

Br Br

R2 HO

Br

MeO2C

HO

R1

1240 R1 = R3 = H, R2 = Br ((5Z)-cadiolide G) 1241 R1 = Br, R2 = H, R3 = Me ((5Z)-cadiolide H) 1242 R1 = Br, R2 = H, R3 = Me ((5E)-cadiolide H)

Br

1243 (cadiolide I)

OH Br

Br O O O

Br

2 CO2Me CO2Me

R2 HO R1

OR3

HO R 1244 R = Br ((2Z)-synoilide A) 1245 R = Br ((2E)-synoilide A) 1246 R = H ((2Z)-synoilide B) 1247 R = H ((2E)-synoilide B)

1248 R1 = H, R2 = Br, R3 = Me (3"-bromorubrolide F) 1249 R1 = Br, R2 = R3 = H (3'-bromorubrolide E) 1250 R1 = Br, R2 = H, R3 = Me (3'-bromorubrolide F) 1251 R1 = R2 = Br, R3 = H (3',3"-dibromorubrolide E)

An Indian Ocean tunicate Synoicum from the Bay of Bengal contains a new member of the ruberolide family, R (1252) (isolated as its diacetate), along with the known rubrolide A, cadiolide B, and prunolide A [996]. The fungus Xylotumulus gibbisporus, originally found in the Bird Park in the Hawaii Volanoes National Park, was cultured to produce several γ-lactone polyketides including the chlorinated xylogiblactone A (1253) and several nonhalogenated analogs [997]. Three new chlorinated cembranolides (1254–1256) are found in a Panamanian Leptogorgia sp., and 1254 and 1255 activate the proliferation of pancreatic insulin-producing cells [998].

Naturally Occurring Organohalogen Compounds … HO

155

Br

O

Br

HO Br

OH

HO

O

O O

Cl

Cl

O

O

O OH

O O Br HO 1253 (xylogiblactone A)

1252 (rubrolide R)

1254

O O

O

HO HO

O Cl

HO

O Cl

O

O O

O

1255

1256

The Australian ascidan Polycarpa procera contains six new brominated butenolides, procerolides A–D (1257–1260) and procerones A (1261) and B (1262). Metabolites 1257 and 1261 exhibit potent bioactivity (EC 50 23 and 29 μM, respectively) in a yeast-based anti-prion assay, results comparable to guanabenz [999]. O

OR2 O Br

O R1

OH

R

OH

Br O

Br

O Br

1257 R1 = R2 = H (procerolide A) 1258 R1 = Br, R2 = H (procerolide B) 1259 R1 = H, R2 = Me (procerolide C) 1260 R1 = Br, R2 = Me (procerolide D)

Br

HO

Br 1261 R = H (procerone A) 1262 R = Br (procerone B)

The new isocadiolides A–H (1263–1270) and cadiolide N (1271) are found in a Korean Synoicum sp. Cadiolide H is a new member of the cadiolide family bearing a γ-hydroxyfuranone moiety. Several of these metabolites show some antibacterial activity and moderate abilities to inhibit sortase A and isocitrase lyase [1000].

156

G. W. Gribble Br

R

Br

R3

OH

HO

OH

HO

O

O Br

R2 5

Br

Br

O

Br

R1

Br

MeO2C MeO2C

O OH

OH

Br

Br

1263 R1 = CO2Me, R2 = R3 = Br (isocadiolide A) 1264 R1 = CO2Me, R2 = R3 = H, ((5S)-isocadiolide B) 1265 R1 = H, R2 = R3 = Br (isocadiolide C) 1266 R1 = CO2Me, R2 = Br, R3 = H, ((5S)-isocadiolide D) 1267 R1 = CO2H, R2 = H, R3 = Br (isocadiolide E)

1268 R = Br (isocadiolide F) 1269 R = H (isocadiolide G)

Br

O

HO

O

Br

Br

O

Br

O O

MeO2C

OH

O Br Br

Br OH

1270 (isocadiolide H)

O

HO

O

Br HO

Br

HO Br 1271 (cadiolide N)

The New Zealand tunicate Synoicum kuranui (Plate 32) yields the two new rubrolides T (1272) and (Z/E) U (1273/1274), which each are strongly inhibitory towards the growth of Bacillus subtilis (MIC 0.41–0.91 μM) [1001]. Another examination of this New Zealand tunicate found rubrolides V (1275) and W (1276) [1002].

Plate 32 Synoicum kuranui (Photograph courtesy of Tangatawhenua; Otaipango, Henderson Bay, Northland, New Zealand; Attribution-NonCommercial 4.0 International)

Naturally Occurring Organohalogen Compounds … O

157 O

O R2

O

Br

Br O

HO Br

R

O

Br HO

OH

HO Br O

1272 R = Br (rubrolide T) 1273 R = H ((Z)-rubrolide U)

O

Br

Br Br

1274 ((E)-rubrolide U)

OH R1

1275 R1 = Br, R2 = H (rubrolide V) 1276 R1 = H, R2 = Cl (rubrolide W)

Several syntheses of the halogenated furanones are reported. These include the fimbrolides [1003], rubrolides L [1004], C and E [1005], B, I, K, and O [1006], and novel fimbrolide-nitric oxide donor hybrids [1007]. For the rubrolide syntheses, the structures are confirmed in each instance.

3.12 Amino Acids and Peptides The organization of this section follows the two previous surveys [1, 2]. This collection of natural halogenated amino acids and peptides is enormous, and some examples are presented in other portions of this monograph. However, amino acids and peptides that incorporate heterocycles (e.g., pyrroles, indoles) or phenols are typically included in this section. Space does not permit inclusion of syntheses, except for important citations and structure revisions. The previous two surveys led this section with the naturally occurring chloramphenicol, which is also a commercial antibiotic [1, 2]. This simple compound continues to be of interest. The new chloramphenicols 1277–1279 are uncovered by functional metagenomics [1008]. A new chloramphenicol-producing strain, Saccharothrix sp. PAL54, is found in the Sahara desert in Algeria [1009]. During an investigation of the environmental occurrence of natural chloramphenicol, eight isomers of both chloramphenicol and its meta-isomer were distinguished by chiral liquid chromatography [1010, 1011]. A review of the health risks of chloramphenicol has appeared [1012]. The Indonesian Dysidea sp. sponge contains the chlorinated sintokamides A–E (1280–1284); 1280 is an inhibitor of N-terminus transaction of the androgen receptor in prostate cancer cells. The presence of the trichloromethyl groups on a leucine unit may implicate a cyanobacterial metabolism and bacterial origin [1013]. Another Indonesian sponge, Callyspongia sp., yields the new callyspongiamides A (1285) and B (1286). Both inhibit sterol O-acyltransferase [1014]. The predatory bacterium Herpetosiphon aurantiacus produces the simple chlorophenolic amide auriculamide (1287) [1015].

158

G. W. Gribble O R1

NH O

OR1 OR2 Cl HN

O2N

Cl

O

O

R2

chloramphenicol R1 = R2 = H 1277 R1 = Ac, R2 = COCH2CH3 1278 R2 = Ac, R2 = COCH2CH2CH3 1279 R1 = COEt, R2 = COCH2CH2CH3

N

H N

Cl3C O

N

O

1280 R1 = CCl3, R2 = CHCl2 (sintokamide A) 1281 R1 = CCl3, R2 = CCl3 (sintokamide B) 1282 R1 = CHCl2, R2 = CHCl2 (sintokamide C) 1283 R1 = CCl3, R2 = CH2Cl (sintokamide D) 1284 R1 = CCl3, R2 = CH3 (sintokamide E)

CCl3

H N

Cl3C O

O

CCl3

O

1286 (callyspongiamide B)

1285 (callyspongiamide A) Cl

OH O

OH

N H

O

1287 (auriculamide)

Fermentation of the marine actinomycete Salinispora tropica (Plate 33), which produces the highly active salinosporamide A [2], now yields 1288, which is identical to the synthetic product antiprotealide [1016]. A review on salinosporamide natural products is available [1017]. The new 4-O-demethylbarbamide (1289) is found as the result of heterologous expression of the cyanobacterium Moorea producens [1018]. The new bactobolin D (1290) is found in the quorum-sensing-regulated bactobolin producer Burkholderia thailandensis E264. Bactobolin D shows weaker antibacterial activity against selected strains than bactobolins A–C [1019]. The Korean ascidian Aplidium sp. contains six new iodine- and bromine-containing apliamides A–E (1291–1295) and apliamine A (1296). These compounds show moderate cytotoxicity against the human cancer cell lines K-562 and A-549, and apliamide D is significantly inhibitory towards the enzyme Na+ /K+ -ATPase [1020].

Naturally Occurring Organohalogen Compounds …

159

Plate 33 Salinispora tropica (Photograph courtesy of Paul Jensen)

OH O

H N O

H N

N

Ph

O

O

OH O O

O N

Cl

Cl salinosporamide A

1288

CCl3 O

S

1289 (4-O-demethylbarbamide) I

NHR HN

N

H N

O

R3

O I

HO O OH

CHCl2

O

R1 R2

O

1291 R1 = R2 = R3 = H (apliamide A) 1292 R1 = R2 = H, R3 = Me (apliamide B) 1293 R1 = OMe, R2 = I, R3 = Me (apliamide C)

1290 R = L-alanine (bactobolin D) I O Ph

H N

I O

1294 (apliamide D)

Ph

N

H N

I

NH N

O 1295 (apliamide E)

Br

O I

1296 (apliamine A)

A Streptomyces sp. Sp080512GE-23 from a Haliclona sp. sponge contains the indole tetrapeptides JBIR-34 (1297) and JBIR-35 (1298), having the absolute configurations shown [1021]. An additional three JBIRs, 126 (1299), 148 (1300), and 149 (1301) are found in Streptomyces sp. NBRC 111228 collected in Okinawa [1022].

160

G. W. Gribble

The novel tetrapeptides (1302–1304) are produced by a Streptomyces sp. [1023], and a cyanobacterium from Guam, Hormoscilla sp., contains anaenamides A (1305) and B (1306), along with the presumed precursor anaenoic acid (structures confirmed by total synthesis). Both isomers are active against HCT-116 cells (IC 50 4.5 and 8.7 μM, respectively, for 1305 and 1306) [1024].

NH O O

N H

N

OH

H N

O COOH O

O

N

Cl

N

OH

OH

R

H N

N H

CO2H

O

OH

N

Cl

1299 (JBIR-126)

1297 R = Me (JBIR-34) 1298 R = H (JBIR-35)

R NH

HN

O O OH

N

O

N H

N

Cl

O

H N O H2N

N H OH

O

H N

CO2H H N

O HO

Cl N

X

1302 R = H, X = O (factor A) 1303 R = NH2, X = O (factor B) 1304 R = NH2, X = NH (factor B1)

1300 R = H (JBIR-148) 1301 R = Me (JBIR-149)

O

O O

O O

N

OH

OR

N H

O

O N H

1305 (anaenamide A)

O

O

Cl CO2Me

O

O

O

CO2Me N H

Cl

1306 (anaenamide B)

The cold-water sponge Geodia barretti collected in the Swedish Koster Fjord contains the novel barettin cyclopeptide 1307, which is antifouling towards the barnacle larvae of Balanus improvisus (EC50 15 nM) [1025]. The new polyketide PM050489 (1308) is found in the Madagascan sponge Lithoplocamia lithistoides, together with the dechloro analog. Both compounds, which were synthesized, have subnanomolar antitumor activity in three human cancer cell lines. The dechloro analog is in clinical cancer trials [1026].

Naturally Occurring Organohalogen Compounds …

161

O O

O

O Br O

N H Br N H

O

NH

HO HN O

H N

NH2

O

O

O N H

NH

1307 (bromobenzisoxazolone barettin)

NH2

O HN Cl

1308 (PM050489)

The aeruginosins are a large family of serine protease inhibitors found in cyanobacteria that often consist of an N-terminal acidic or hydroxy group, a bulky hydrophobic amino acid, a 2-carboxyperhydroindole core, and a C-terminal guanidine-containing group. For reviews, see [864, 1027]. The freshwater cyanobacterium Microcystis sp. from a water reservoir in Israel yields the novel aeruginosins KY642 (1309) and KY608 (1310) [101] along with the known aeruginosin 98A [2]. A different reservoir in Israel affected with a Microcystis aeruginosa (Plate 34) bloom produced seven chlorinated protease inhibitory micropeptins (1311–1317). These compounds inhibit trypsin (IC 50 0.7–5.2 μM) and chymotrypsin (IC 50 2.8– 72 μM) [1028]. Another Israeli bloom in the Valley of Armageddon contains the microginin AL584 (1318), also a protease inhibitor [1029].

Plate 34 Microcystis aeruginosa (Photograph courtesy of Bidgee; Lake Albert, Australia; Creative Commons Attribution-Share Alike 3.0 Australia)

162

G. W. Gribble O Cl OH HO

HO

O

N H

HN

H N

N

NH2

O

R

HN 1309 R = Cl (aeruginosin KY642) 1310 R = H (aeruginosin KY608)

NH2 H2 N

NH OR3 O

OR4 R5O

O

NH

N H O

H N

N O

O O

O

Cl

N

H N

OR2 O

R1 1

1311 1312 1313 1314 1315 1316 1317

R Me Me H H H H Me

R2

R3

R4

Me Me H Me Me Me H

H H H H H Me H

SO3– H SO3– H H H H

R5 SO3– SO3– SO3– SO3– H H H

(micropeptin HU1069) (micropeptin HU989) (micropeptin HU1041) (micropeptin HU975) (micropeptin HU895A) (micropeptin HU909) (micropeptin HU895B) OH

NH2 O Cl OH

O N H

N O

N H

CO2H

1318 (microginin AL584)

Further studies of Microcystis aeruginosa and Microcystis spp. blooms in Israel and India discovered the novel aeruginosins 1319–1328, containing both chlorine and bromine. Several of these compounds are strongly inhibitory (IC 50 ) towards trypsin (1321, 2.3 μM), thrombin (1326, 1.8 μM), and chymotrypsin (the nonchlorinated microviridin, 2.8 μM) [1023–1032].

Naturally Occurring Organohalogen Compounds …

163

R2O

O R1 OH

HO

N

N H

O

NH

H N

N H

O

NH2

Br

1319 R1 = Cl, R2 = H (aerugiosin GE686) 1320 R1 = Cl, R2 = SO3H (aerugiosin GE766) 1321 R1 = Br, R2 = H (aerugiosin GE730) 1322 R1 = Br, R2 = SO3H (aerugiosin GE810) HO

HO

O R1 OH

HO

O N H

N O

NH

H N

N H

O

NH2

OH

HO

R2

Cl

1323 R1 = R2 = Cl (aerugiosin GE642) 1324 R1 = Cl, R2 = H (aerugiosin GE608) 1325 R1 = Br, R2 = H (aeerugiosin GE652)

N H

N O

O

N H

N R

NH NH2

1326 R = α-OMe (aeruginosin LH650A) 1327 R = β-OMe (aeruginosin LH650B) HO

O

OH

HO

N H

N O

O

Cl

N

N H HN

NH2

1328 (aeruginosin LH606)

As seen with 1318, microginins are also ubiquitous in cyanobacterial blooms [1033], and four new chlorinated microginins 1329–1332 were identified in the Kishon Reservoir, Israel. These compounds inhibit zinc-containing metalloproteases (IC 50 0.1–5.7 μM) [1034]. A Red Sea sample of Okeania sp. cyanobacterium produces two lyngbyabellins O (1333) and P (1334) along with the known lyngbyabellins F and G [1035].

164

G. W. Gribble

R1

OH

Cl NH

R2

O

H N

O

H N

N

N O

CO2H

O

OH R1

OH

R2

1329 = H, = Me (microginin KR801) 1330 R1 = Cl, R2 = Me (microginin KR835) 1331 R1 = H, R2 = H (microginin KR787)

OH Cl NH

H N

O N

N

CO2H

O

O

OH 1332 (microginin KR638) O HO

OH

O

OH

HN O O

S O

S O

S

N O

HO

O

OH

O

N O

Cl

Cl

S

N O

O HO 1333 (lyngbyabellin O)

N O

O

Cl

Cl

O 1334 (lyngbyabellin P)

An Okinawan Lyngbya sp. cyanobacterium affords bisebromoamide (1335), which displays cytotoxicity towards HeLa S3 cancer cells (IC 50 0.04 μg/cm3 ) [1036]. The original structure has been revised at the methyl-group position in the thiazoline ring (as shown) [1037, 1038]. The solitary tunicate Herdmania momus contains the two brominated herdmanines E (1336) and F (1337) [1039]. The marine sponge Ircinia sp. from the Great Barrier Reef, Australia, yields polydiscamides B–D (1338– 1340), which are potent agonists against the human sensory neuron-specific G protein couple receptor. These are the first non-endogenous human SNSR agonists [1040].

Naturally Occurring Organohalogen Compounds …

165

O N S

N

O

N H

N

NH

O

O O

N

N

O

O OH Br 1335 (bisebromoamide) O HO

O

H N

N H

O

Br

CO2H

NH2

Br

H N

N H

NH

O N H

CO2H

NH2 NH

HO

1336 (herdmanine E)

1337 (herdmanine F)

CHO NH Br

HN

O

CONH2

NH

O

R1

O

H N

N N H

O

O

R2

H N

N H

O

SO3H

O N H

O

H N

H N

N O

O O

HN

H N

N

O

O HN

NH2

O CO2H

1338 R1 = t-Bu, R2 = Me2CCH2CH3 (polydiscamide B) 1339 R1 = i-Pr, R2 = Me2CCH2CH3 (polydiscamide C) 1340 R1 = i-Pr, R2 = t-Bu (polydiscamide D)

A culture of Streptomyces sp. produces the novel siderophores, chlorocatechelins A (1341) and B (1342) [1041]. A large group of natural products contain a diketopiperazine ring often with bridging sulfur linkages [1042]. Many of these compounds contain halogen, such as the novel epidithiodiketopiperazine N-methylpretrichlorodermamide B (1343), found in a Penicillium sp. from a hypersaline Egyptian lake sediment. This compound is significantly cytotoxic towards the murine lymphoma L5178Y cell line (IC 50 2 μM) [1043]. A Chinese sponge-derived Penicillium adametzioides AS-53 sample delivered “adametizine A” upon cultivation [1044]. Adametizine A is identical with Nmethylpretrichlorodermamide B. A Palauan red alga-derived fungus Trichoderma cf. brevicompactum produces chlorotrithiobrevamide (1344) [1045], and when the fermentation of this fungus is performed in the presence of halide (NaBr, NaI) then the corresponding halogenated analogs are obtained [1046]. A mangrove-derived fungus, Penicillium janthinellum HDN13-309 affords penicisulfuranols A (1345) and D (1346), the former of which is significantly cytotoxic against HeLa and HL-60 cells (IC 50 0.5 and 0.1 μM, respectively) [1047].

166

G. W. Gribble OH Cl

OH N O

NH2

NH

O

OH HO

NH2

N H

HO

CO2H

O

Cl

O

OH

H N

H N

N H

Cl N

CO2H

O

CHO

N

OH

OH 1342 (chlorocatechelin B)

1341 (chlorocatechelin A)

Cl

O

OH

O

N

S

Cl O

N

OH

O O S

HO

CHO

OH

O

O S

S NH S

N

HO

O

OH O O

1343 (N-methylpretrichodermamide B) (= adametizine A)

Cl

S O

OH

1344 (chlorotrithiobrevamide)

Cl

S

OH

S

O N

N O HO

N O

O

O

HO O

O

1345 (penicisulfuranol A)

S

N O

O O

O

1346 (penicisulfuranol D)

Genome mining of the marine Streptomyces sp. NA03103 led to the new ashimide B (1347) and the hydroxy group analog [1048]. An examination of five bacterial strains from Eastern Mediterranean marine sediments uncovered the three new chlorinated 2,5-diketopiperazines 1348–1350 [1049]. The marine fungus Penicillium janthinellum HDN13-309 contains the new N-methyl-trichodermamide B (1351), which exhibits antioxidant activity via the Nrf2 pathway [1050]. In this regard the cytotoxicity and mechanism of action of trichodermamide B has been investigated [1051]. A study of the soil bacteria Myxococcus sp. and Pyxidicoccus sp. has uncovered several novel tetrapeptides incorporating a 6-chloromethyl-5-methoxypipecolic acid moiety (1352–1356) [1052].

Naturally Occurring Organohalogen Compounds …

167

O N Cl O

N

O

O

N H

Cl

O

O

H N

O

N

HN

HO

HN

HO

OH O

O Cl

N

O

O

OH 1348

1347 (ashimide B)

1349 O

O

Cl

Cl OH

NH

O

O

OH

O

N

HN

O O

N

O

OH 1350

1351 (N-Me-trichodermamide B) R OH

O Cl

N H

H N

O

O

N

O CO2H

N

Cl

N H

O

O N H

H N

O

O

N

N

O

1355 (chloromyxamide D)

CO2H

N

O

O CO2H

O

N

1354 (chloromyxamide C)

1352 R = H (chloromyxamide A) 1353 R = Me (chloromyxamide B)

Cl

H N

O

Cl

N H

H N

O

O N

N CO2H

O

1356 (chloromyxamide E)

A Guamanian cyanobacterium, Moorea bouillonii, contains the brominated bouillomide B (1357) along with the debromo analog. Both inhibit elastase and chymotrypsin, but not trypsin [1053]. A study of Moorea producens from Grenada identified the new itralamides A (1358) and B (1359) [1054]. A reported synthesis of itralamide B and four stereoisomers would indicate that the proposed structure of 1359 is incorrect [880, 1055]. The Grenada study also found the new grenadamides B (1360) and C (1361) [1054]. Several samples of Microcystis spp. living in fishpond water in Israel contain the new microginin GH787 (1362) and the micropeptin HA983 (1363) [1056]. A strain of Microcystis aeruginosa furnished microginins 680 (1364) and 646 (1365), which are inactive in standard protease assays [1057]. The Okinawan marine cyanobacterium Okeania sp. contains odobromoamide (1366) having a terminal alkynyl bromide. This novel metabolite was cytotoxic towards HeLa S3 cancer cells (IC 50 0.31 μM) [1058].

168

G. W. Gribble Br O HO N

O

O N

O

O

N H

N H O

O HN

H N

O

H N

N H

O

O

HO

1357 (bouillomide B)

O

O

H N

N N

O O O

R2

N H

R1

O

O Cl

N H

N

R O

N R3

O

1360 R = H (grenadamide B) 1361 R = Cl (grenadamide C)

O Cl Cl

HO

1358 R1 = Me, R2 = Me, R3 = i-Pr (itralamide A) 1359 R1 = i-Pr, R2 = i-Pr, R3 = Me (itralamide B)

H N NH2 O

Cl OH

CO2H

N O

N

N H

O

O

OH

NH2 O

Ac

O

H N

O

NH

1362 (microginin GH787)

OH

O N

N H

HO

Ph O

O N

N H

NH2 O O

HN

Cl O R

O O

NH2

Cl

OH

CO2H

O N H

N

N

O

OH OH

1363 (micropeptin HA983)

1364 R = Cl (microginin 680) 1365 R = H (microginin 646) H N

Br

O

O

O

N

O

O

N

O O O

N 1366 (odobromoamide)

Several sponges of genus Jaspis produce cyclic peptides containing a 2bromotryptophan unit, known as jaspamides (= jasplakinolides), and several new members of this class are known since their discovery [1, 2]. An exhaustive examination of Jaspis splendens from Tonga, in the South Pacific Islands, led to the new jaspamides D–N (1367–1376) [1059–1061]. Jaspamide and jaspamides D, E,

Naturally Occurring Organohalogen Compounds …

169

and M are the most active in the MCF-7 and HT-29 cancer cell assays used (IC 50 0.02–0.18 μM) [1061]. OH

OH

O

O HN

HN

O

O

O HN

N

O

R

R2 NH

Br

O

N

HN

R4

O

Br

R3

H

NH O

R1

O

O

1367 R = α -Et, R1 = R3 = R4 = Me, R2 = H (jaspamide D) 1368 R = β-CH2OH, R1 = R3 = R4 = Me, R2 = H (jaspamide E) 1369 R = β-Me, R1 = R2 = R3 = H, R4 = Me (jaspamide F) 1371 R = β-Me, R1 = R3 = Me, R2 = R4 = H (jaspamide H) 1372 R = β-Me, R1 = R2 = H, R3 = R4 = Me (jaspamide J) 1373 R = β-Me, R1 = R3 = R4 = Me, R2 = OH (jaspamide K) 1374 R = β-Me, R1 = R4 = Me, R2 = H, R3 = CH2OH (jaspamide L)

1370 (jaspamide G)

OH

O HN R R1

1375 R =

R1 = H (jaspamide M)

Br

R1 = Me (jaspamide N)

HO

O N

Br N H

O

O 1376 R = N H

HN O

A study of Jaspis splendens from Indonesia led to the new jaspamide R (1377), along with jaspamide and the didebromo analog [1062]. This structure was revised (and reassigned at R1 , shown) having the second bromine at C-6 in the indole ring, rather than at C-5 as originally proposed [1063]. A collection of Jaspis splendens and the sponge Auletta sp. from Fiji and Papua New Guinea, respectively, affords several new jasplakinolides (aka jaspamides), including the brominated jasplakinolides Ca (1378) and Cb (1379) [1064]. Further study of the Fijian Jaspis splendens revealed the new jasplakinolides Z3 (1380), Z4 (1381), V (1382), and Z5 (1383) [1063]. A similar group of jasplakinolides is found in an Indonesian Jaspis splendens, including the new jasplakinolide Z6 (1384) [1065]. To save space, the basic structure is depicted differently from the earlier presentation.

170

G. W. Gribble OH

OH

O

O Br

HN

HN

O

O O

O N

HN

O

N

HN

O

R

Br

Br

NH

NH

O

O

1378 R = β-OH (jasplakinolide Ca) 1379 R = α-OH (jadplakinolide Cb)

1377 (jaspamide R)

Br

NH OH

OH

R2 R1

H N

HO N O

O

R1 = H

O O

O

= R1

NH R2 =

= R2

EtO

1381

1380 (jasplakinolide Z3)

R1

=

R2

= H (jasplakinolide Z4)

OH HO

= R2

O =

1382 (jasplakinolide V)

OH

HO

R1

O

O

R2

=H

1383 (jasplakinolide Z5)

R1

=H

HO

O

1384 (jasplakindolide Z6)

The true structure of the well-known cyclocinamide A [2, 1066] (counted in Ref. [2]) has now been confirmed through extensive synthesis efforts [1066–1068] as having the structure shown [1069], although the stereostructure of the Papua New Guinea companion Psammocinia aff. bulbosa sponge metabolite cyclocinamide B remains unknown [1068]. A collection of an Ircinia sponge from the “Thousand Islands” in Indonesia found the new haloirciniamide (1385) and seribunamide (1386). The former is the first dibromopyrrole cyclopeptide having a chlorohistidine ring, and the latter is a rare tribromopyrrole peptide. Both compounds are not significantly cytotoxic towards four human tumor cell lines [1070]. The Streptomyces canus CA091830 strain from the Kalahari Desert in South Africa contains krisynomycin C (1387) [1071] and krisynomycin (1388) [1072]. These compounds are only weakly antibacterial [1071].

Naturally Occurring Organohalogen Compounds …

171

Cl N HN

HN

O

Br

O

O

HN

N H

O

HN

NH

H2N

O

O

H N

OH

O

cyclocinamide A

H2N O OH

N

N

O HN O NH

HN

H N

NH

N

N O

Br

HN

O Cl

N H

Br

HN

O

O

Br

O

Br

O

O

HN

O NH2

N

O

Br

O

1385 (haloirciniamide)

NH2 OH

1386 (seribunamide A) SO3H O Cl

N O HO

O N H

H N

O

O O

N H O

O

H N

NH

O

O

NH

HN

HO NH O

H N

HN

O

N H

R

O

1387 R = H (krisynomycin C) 1388 R = Cl (krisynomycin)

The bacterium Pseudoalteromonas maricaloris KMM 636T living in the Australian sponge Fascaplysinopsis reticulata produces bromoalterochromides 1389–1391. Not shown are the respective bromoalterochromides A (1392–1394) where leucine has replaced isoleucine [1073]. The polypeptide (–)-psymbamide A (1395) is found in the sponge Psammocinia aff. bulbosa from Papau New Guinea [1074]. The related paltolide C (1396) is produced by the Palau sponge Theonella swinhoei, and the two related paltolides (1397, 1398) are described in a patent [1075].

172

G. W. Gribble O 1a OH H2N

O

O

Br O

NH O

O

H2N

N H

O O

N H

1b

O OH

H N O

Br

N H

O 1c

1389–1391 (1a–1c) (bromoalterochromides A) OH (in 1392–1394 leucine is replaced by isoleucine)

Br

NH Br N N

NH

O

O NH O

Ph

O HN

O

NH

HN

O

Y

O N H

N H

CO2H

HN N H

X

NH

O O

NH

H2N

NH O

HN

O N H

O N H

O OH

1396 X = Br, Y = H (paltolide C) 1397 X = Cl, Y = OH 1398 X = Cl, Y = H

1395 ((–)-psymbamide A)

O

H N

Cl N Cl

O O HO

Ph N H

O H N

OH

NH

O HO

1399 (hydroxycyclochlorotine)

The new astin analog hydroxycyclochlorotine (1399) is present in Penicillium islandicum, and its absolute configuration was determined [1076]. The familiar marine cyanobacterium Oscillatoria sp. from Key Largo, Florida, contains the seven new depsipeptides, and four contain halogen, largamides D–G (1400–1403), which inhibit chymotrypsin (IC 50 4–25 μM) [1077]. Two groups independently uncovered the piperazimycins, hexadepsipeptides from a marine-derived Streptomyces sp. from Guam (1404–1406) [1078] and from the Gulf of Mexico (1404, 1405) [1079]. Piperazimycin A displays potent cytotoxicity against multiple human tumor cell lines with a mean of GI 50 value of 100 nM [1078]. A soil sample from the Shaanxi province of China containing Streptomyces alboflavus produces the cyclic

Naturally Occurring Organohalogen Compounds …

173

hexadepsipeptide NW-G01 (1407) [1080–1082] and the related NW-G03 (1408) [1083], which display strong antibacterial activity. Four subsequent studies identified an additional group of NM-G01 analogs each incorporating the same chloropyrroloindoline unit as in NW-G01 (1407): NW-G05–NW-G07 (1409–1411) [1084], NW-G08 and NW-G09 (1412, 1413) [1085], NW-G10 and NW-G11 (1414, 1415) [1086], cp06 (1416), ep08 (1417), cp09 (1418), and cp12 (1419) [1087]. For brevity, these structures are not shown. Total syntheses of piperazimycin A (1404) [1088] and the previously described [2] dimeric cyclohexapeptide chloptosin [1089, 1090] have been achieved. Two different cyanobacteria species, Symploca cf. hydnoides from Guam [1091] and Oscillatoria margaritifera from Panama [1092], contain the same collection of cyclic depsipeptides, the veraguamides, several of which feature the rare bromoacetylene function. Veraguamides A (1420) and B (1421) are found in both species, while K (1422) and L (1423) are only characterized in the Panamanian cyanobacterium. Veraguamide A (1420) is quite potent against the H-460 human lung cancer cell line (LD50 0.14 μM) [1092]. The structure proposed for veraguamide A may be suspect; a synthesis of this structure did not match that of the natural product [1093]. HO O R OH

O

OH

O

H N

N H

N H

O

H N O

OH OH

N H

HN

N O

O O

N

H N

O

O

O 1400 X = Br, R = CHMe2 (largamide D) 1401 X = Cl, R = CHMe2 (largamide E) 1402 X = Br, R =

1403 X = Br, R =

HO

HN

O O

OH (largamide G)

N

HN N

N O O O

OH HN N

O O

O O O

NH

O O O

N NH

N HN

R2

CH2

N N

HN

X OH

OH (largamide F)

NH

H N

N

OH

R1

Cl

1404 R1 = OH, R2 = Me (piperazimycin A) 1405 R1 = H, R2 = Me (piperazimycin B) 1406 R1 = OH, R2 = Et (piperazimycin C)

1407 (NW-G01)

Cl

174

G. W. Gribble O

O O N

O O

O

N O

HN O

O

N

N

O

N O

O

Br

Br

O

O

N

O

HN

O

1421 (veraguamide B)

1420 (veraguamide A) R O N O

N

O

OH

O N

O O

Br

N H

O

O 1422 R = Me (veraguamide K) 1423 R = H (veraguamide L)

A sponge from Chuuk Lagoon, Micronesia, Siliquariaspongia mirabilis contains the new depsipeptides mirabamides, three of which are chlorinated, A–C (1424– 1426) [1094]. Four additional mirabamides E–H (1427–1430) along with C (1426) are found in the Australian Torres Strait sponge Stelletta clavosa [1095]. Mirabamides E and F are l-rhamnosyl derivatives of G and H, respectively. The main difference between the two sets of mirabamides is that the threonine unit in A–C is replaced with its dehydration product 2-amino-2-butenoic acid in E–H. Only G (1429) and H (1430) are shown. Interestingly, only mirabamides E–H show strong inhibition of HIV-1 (IC 50 41–121 nM) [1095]. OH

HO

O

OH

H N

N H

O HN

O

H2N

O

O

NH2 Cl

HN HN

O O

O NH

O O

NH

N O

H N

O

O 1424 R = X (mirabamide A) 1426 R = H (mirabamide C)

O

O O

NH

N OH

OR

Naturally Occurring Organohalogen Compounds …

175

O

X = HO HO OH

O N H

HO

OH

H N O HN

O O

O

NH2 Cl

HN HN

O

O O O

OH

O

N

NH

O

NH

O

H N

O

O NH

O

OR

N

O

OH

1425 R = X (mirabamide B)

OH R2

O

H N

N H

O HN

O

H2N

O

O

NH2 Cl

HN HN

O O

O NH

O O

NH

N O

H N

O

O

NH

OR1

N

O 1427 R1 = X, R2 = OH (mirabamide E) 1428 R1 = X, R2 = H (mirabamide F) 1429 R1 = R2 = OH (mirabamide G) 1430 R1 = OH, R2 = H (mirabamide H)

O

O

OH

O

X = HO HO

OH

The new miuraenamides C–F (1431–1434) are found in the halophilic myxobacterium Paraliomyxa miuraensis [1096] and join miuraenamides A and B described earlier [2]. Syntheses of miuraenamides A, D, and E are reported along with a biological evaluation in several cancer cell lines of the natural products and analogs [1097]. Miuraenamide A is the most active towards HCT-116, Hep G2, HL-60, and U-2 OS cells (IC 50 5.8, 13.7, 8.2 and 9.2 nM, respectively). A detailed synthesis and spectroscopic study has established the stereochemistry of the chlorinated residues in victorin C [1098]. As described earlier this toxic fungal metabolite is the major causal agent of a disease of oats [2].

176

G. W. Gribble Br

X HO

HO

O H N

H N 14

N

O

O

Ph

O H N

O

N

O O

O

O

Ph

H N

O

O

O

R 1431 X = Cl, R = H ((14E)-miuraenamide C) 1432 X = Br, R = H ((14Z)-miuraenamide D) 1433 X = Br, R = OH ((14E)-miuraenamide F)

1434 (miuraenamide E)

HO

O

OH O

HO

H N

O HN

Cl2HC

CO2H

O

NH

HN

O

H2N

O

NH O Cl

OH victorin C

The Chinese medicinal plant Aster tataricus (Plate 35), which is also a popular garden flower, is the source of a family of antitumor cyclic pentapeptides, the astins [1099]. Astins A–I were discussed previously [1, 2]. A later study has identified six new chlorinated astins K–P (1435–1440) [1100]. A study shows that astins originate from the fungal endophyte Cyanodermella asteris living within the Aster tataricus plant [1101]. A Streptomyces sp. bacterium within the conoidean mollusk Lienardia totopotens in the Philippines produces the novel polyketide totopotensamides A (1441) and aglycone B (1442) [1102]. Genome mining of a marine-derived Streptomyces pactum actinomycetes finds totopotensamides A and B along with a new analog totopotensamide C (1443) having a sulfonate group attached to the resorcinol ring [1103]. The legume-infesting fungus Diaporthe toxica has yielded a new phomopsin F (1444) [1104], which is the N-methyl derivative of phomopsin A, the major toxin in this fungus [1].

H N

Ph

R5 N

O R2 O

HN O R6

O

HN

N H

X Y R4

H N

Ph HN

R3 O

R1 1435 R1 = R2 = R6 = OH, R3 = R4 = Cl, R5 = H, X–Y = CH–CH (astin K) 1436 R1 = R2 = R6 = OH, R3 = R4 = H, R5 = Cl, X–Y = C=C (astin L) 1437 R1 = R2 = R3 = R5 = H, R4 = Cl, R6 = OH, X–Y = CH–CH (astin M) 1438 R1 = R2 = R3 = R5 = H, R4 = Cl, R6 = OH, X–Y = C=C (astin N) 1439 R1 = R2 = R5 = H, R3 = R4 = Cl, R6 = OAc, X–Y= CH–CH (astin O)

HO

O N

Cl

O O O O N H

NH

HO 1440 (astin P)

Cl

Naturally Occurring Organohalogen Compounds …

177

Plate 35 Aster tataricus (Photograph courtesy of KENPEI; GFDL, Creative Commons Attribution ShareAlike 2.1 Japan License)

178

G. W. Gribble OH Cl O R2O OR1 OH

O

OH

O

H N

N H

OH

O

NH

O

H N

N H

O

N H

O HN

O

OH 1441 R1 =

O

O HO

, R2 = H (totopotensamide A)

OH 1442 R1 = H, R2 = H (totopotensamide B) OH 1443

R1

=

O

O

, R2 = SO3H (totopotensamide C)

OH O N N H

O

HO

HN O Cl

OH

O

N O

N H

O

HO2C

NH CO2H

1444 (phomopsin F)

A Florida sample of the marine cyanobacterium Moorea confervoides contains the new cyclic peptide pompanopeptin A (1445) along with a non-halogen containing analog, which has a rare ureido linkage. Metabolite A selectively inhibits trypsin over both elastase and chymotrypsin (IC 50 2.4 μM) [1105]. Another collection of Moorea sp. from Florida yields kempopeptin B (1446), closely related to 1445. This new metabolite also selectively targets trypsin (IC 50 8.4 μM) [1106]. A Guam specimen of Moorea semiplena affords the bromine-containing lyngbyastatin 10 (1447), which inhibits porcine pancreatic elastase (IC 50 120 nM) [1107].

Naturally Occurring Organohalogen Compounds …

179

Br O O N

O

O

H N

N H

O H N

N

O

O

N H

HN

O

O S O

O

HO

NH2

HN

NH 1445 (pompanopeptin A) Br O O N

O

O

HN

O

O

O

HO

H N

N H

O H N

N

O

O

N H

NH2

1446 (kempopeptin B) Br O HO O

N O N

HO

O

O

N H H N

O HN

N H O

O

H N O

N H

O 1447 (lyngbyastatin 10)

The 7-chloroindole unit is embedded in pedein A (1448) a new antifungal cyclopeptide from Chondromyces pediculatus, a myxobacterium from a Key Largo, Florida, soil sample. Pedein A is also present in a soil sample from Costa Rica. This compound is inactive against both Gram-negative and Gram-positive bacteria, but broadly active against a range of yeasts and filamentous fungi (MIC 0.6–3.1 μg/cm3 ) [1108]. The Korean freshwater cyanobacterium Aphanocapsa sp. contains cyanopeptolin CB071 (1449), a trypsin inhibitor (IC 50 2.5 μM [1109]. Cultivation of Streptomyces sp. DSM14386 produces the new piperazic acid-containing cyclopeptides, the svetamycins A–G (1450–1456). Svetamycin G (1456) is the most active against the growth of Mycobacterium smegmatis (MIC 80 2 μg/cm3 ), and A (1450) and C (1452) are cytotoxic to HepG2 (IC 50 11.0 and 3.6 μg/cm3 , respectively) [1110].

180

G. W. Gribble

O

O O

OH

Ph O

HN

N OH H

O

H N

OH HN

N

N H

O

NH

H N

H N

N H O

O O

O

N

O

OH

O

HN N H

O

NH2 NH

O

O

HO

O

H N

CO2H

HO

N

O Cl

O

N H

Cl 1448 (pedein A)

1449 (cyanopeptolin CB071) OH O N

N

O O

HO OH HN

NH O O

O O N

HN

N

R1 N R3

R2

R4

1450 R1 = R2 = R3= H, R4 = Cl (svetamycin A) 1451 R1 = R3 = H, R2 = Me, R4 = Cl (svetamycin B) 1452 R1 = R2 = Me, R3 = H, R4 = Cl (svetamycin C) 1453 R1 = H, R2 = R3 = π bond, R4 = Cl (svetamycin D) 1455 R1 = R2 = R3 = H, R4 = Br (svetamycin F) 1456 R1 = R2 = Me, R3 = H, R4 = Br (svetamycin G)

Along with several known jaspamides and jasplakinolides, a Solomon Islands sponge Pipestela candelabra contains the new pipestelides A (1457) and B (1458), and a nonhalogenated analog. Pipestelide A is active towards the KB cancer cell line (IC 50 0.1 μM) [1111]. The two new didemnins 1459 and 1460 are found in the tunicate Trididemnum solidum living in Little Cayman Island along with the two known nonchlorinated didemnins A and B. All four didemnins strongly inhibit the cancer cell lines SK-MEL, KB, BT-549, and SK-OV-3 (IC 50 0.2–1.7 μM) [1112]. An investigation of several microsclerodermins, genera Chondromyces and Jahnella, from terrestrial myxobacteria reveals the new microsclerodermin L (1461). Pedein A (1448) is also identified in this study [1113]. A collection of the Fijian sponge Corticium sp. yields the new cyclocinamide B (1462) and corticiamide A (1463), the latter of which contains two (unactivated) bromophenyl rings and the former is the dichloropyrrole analog of cyclocinamide A [1114], as corrected by synthesis [1069]. While cyclocinamide A is highly cytotoxic in vitro, 1462 is inactive (against HCT-116 cells). The enduracidin and ramaplanin families of cyclodepsipeptide antibiotics are highly effective against Gram-positive bacteria [1115, 1116]. Three new enduracidins, 1464–1466, are found in a genetically engineered Streptomyces fungicidicus [1117].

Naturally Occurring Organohalogen Compounds …

181

OH

H N

Br

OH

H N

Br

Br O

O

H N

H N N

O

N

O

O

O O

O HN

HN

O

O

1457 (pipestelide A)

1458 (pipestelide B)

OH

O

O

O Cl

NH

O

O

NH

N H

O O

O

O

N

1459 R = i-Bu 1460 R = i-Pr

O

H N

O

HN i-Bu

Cl

O

R

HO

NH

O

O N

O NH

O N

HN

O

H N

OH

OH HN O

O OH

N H Ph

OH OH

1461 (microsclerodermin L)

The potent cytotoxin and selective chymotrypsin inhibitor symplocamide A (1467) is produced by the cyanobacterium Symploca sp. from Papua New Guinea. This metabolite is 200 times more inhibitory towards chymotrypsin than trypsin, and is highly cytotoxic against H-460 lung cancer cells (IC 50 40 nM) and neuro-2a neuroblastoma cells (IC 50 29 nM) [1118]. The cultured cyanobacterium Anabaena minutissima produces minutissamides A–D, one of which, B (1468), has a terminal chlorononane chain [1119]. The balticidins from a Baltic Sea Anabaena cylindrica Bio33 have a similar long-chain chloroalkane functionality in balticidins A (1469) and B (1470) [1120]. A slight revision was made later, and the corrected versions are shown. These metabolites are active towards Candida maltosa with inhibition zones of 12 and 15 mm, respectively, for A and B [1121]. A Red Sea cyanobacterium, Symploca sp., contains five bromine-containing jizanpeptins (1471–1475) that are very similar to symplocamide A (1467), the major difference being a side chain terminal glyceric acid sulfate unit occurring in each jizanpeptin. These micropeptin depsipeptides show specific inhibition of the serine protease trypsin (IC 50 72 nM– 1 μM) relative to chymotrypsin (IC 50 1.4– >10 μM) [1122]. The new vinyl-chloride tutuilamides A–C (1476–1478) are present in the marine cyanobacteria Schizothrix sp. and Coleofasciculus sp. and are similar to the known lyngbyastatin 7. These new cyclodepsipeptides are potent elastase inhibitors and moderately active towards H460 lung cancer cells [1123]. Further study of the cyanobacterium Moorea cf. confervoides that contains largamide D (1400) has now identified largamide D oxazolidine apparently resulting from intramolecular formal dehydration of largamide D (1479) [1124].

182

G. W. Gribble Cl

Cl N

HN

HN

O

Br

O

O

HN

N H NH

O

H2N

O

HN

O

H N

OH

O

1462 (cyclocinamide B) Br

H N O H

H N

N H

O

O N

N H

O

O

H N

N H

O

NH2

O SO3H

O

H N O

H2N

H N

N

O

O

O O

NH Br

O

H N

N H

O

O O HN

NH

H2 N

N C O

1463 (corticiamide A)

R O

OH

NH

O O

O

NH2

NH

HO2C

O

H N

N H

O

O

NH HO

O

HN HN

NH

O

O N H

OH O

H N O

N H

Y OH

NH

O O

N H

NH HN

H N

O NH

O N H

NH Cl

O

O OH

OH O

H N

N H

H2N HN

OH

O

H N

Z OH

1464 R = H, Y = Z = H (monodeschloroenduracidin A) 1465 R = CH3, Y = Z = H (monodeschloroenduracidin B) 1466 R= H, Y = Z = Cl (trichloroenduracidin)

NH

OH

NH OH

Naturally Occurring Organohalogen Compounds …

183

O Br

HN

O Cl

N

O

O

N O

NH O

N

O

O

O

HN

HN

O

CONH2

NH HO

NH2 O NH2

H N

O

HO

HN

O

H2NOC

H N

N H

O H N

N

O

O

N H

O OH

HN

O

HN

O

O O

N H

O

CONH2 1467 (symplocamide A)

1468

OH

OH

HO H N

HO HN

O

HO

O

H N

N H

O

O O

H2N

N H

O

HO

O

NH N H

N O

O HO HO

O

CO2H

OH

O

O

OH

HO

HO O

O

Cl

OH

CO2H NH2

N H

O

O

O

HO

OH

1469 (balticidin A) OH

OH HO O

O HO HO HN

O

H N O

NH

O

O N H

H N O

O

O

O N H

OH

O NH2

O

HN N

N H

H2N

HO

O

O

HO

HO

O O

O

O

HO

OH

1470 (balticidin B)

OH

HO O

OH CO2H Cl

184

G. W. Gribble O

O Br

Br

O

O N H

N

O

O

O N

NH3

OSO3–

O

O

NH3

1473 (jizanpeptin C)

O

O Br

Br

O

N

N

O O

O

N H O

HO

O

H N

HN

O

HO

1471 R = H (jizanpeptin A) 1472 R= Me (jizanpeptin B)

O

N H

O H N

O

O

O

N H

N

O

OSO3–

O

HN

O

HO

OR

H N

N H

O H N

N

O

O

N H

O H N

O

H N

O

N

OSO3–

O

HN

O N

O

NH3

N H

O H N

O

O

O

N H

HN

O

1475 (jizanpeptin E)

OH R

O

N O

Ph

N HO

O H N

HN

O

H N

O

N H

O

H N H2 N

1474 (jizanpeptin D)

O

O

O

HO

N H

O

O 1476 R = Me (tutuilamide A) 1477 R = H (tutuilamide B)

H N

Cl O

O

H N

NH2

OSO3–

Naturally Occurring Organohalogen Compounds …

185

OH

O

O

N O

Ph

O H N

N

HN

O

H N

O

N H

Cl

N H

O O

O

HO

1478 (tutuilamide C) HO O

O

OH

O

OH

N H

H N O

O N H

H N O

N

N H

HN O O O

O N

H N

O

O Br OH 1479 (largamide D oxazolidine)

An Australian soil sample containing Streptomyces sp. Gö-GS12 produces the novel chlorinated actinomycins Y1 (1480) and Y2 (1481) [1125]. The strain Streptomyces sp. KCB13F003 contains ulleungmycins A (1482) and B (1483) that feature the unusual 5-chlorotryptophan amino acid. Both exhibit moderate antibacterial activities against methicillin-resistant and quinolone-resistant Staphylococcus aureus [1126]. The 5-chlorotryptophan residue also resides in nicrophorusamides A (1484) and B (1485) from the gut of the carrion beetle (Nicrophorus concolor) that carries a rare Microbacterium sp. Metabolite A is eight times more active than B against several pathogenic bacteria (Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, and Salmonella enterica (MIC 8–16 μg/cm3 )) [1127]. The first two new natural analogs of hormaomycin [2] to be identified are hormaomycins B (1486) and C (1487) (not shown) from a Korean mudflat-derived Streptomyces sp. Both are decorated with two 3-(2-nitrocyclopropyl)alanines and a 2-chloro-N-hydroxypyrrole unit as is hormaomycin [1128].

186

G. W. Gribble O

O

HO

N N

NH

O

O

R

N

NH

N

O

Cl O

N

NH

O

O

O

N

O

O

O

O

O HN

O

NH

O

H N

NH

O

H2N

Cl

NH HO

NH2

O

N H

H N

HN HN

O

O

O

O

O

NH2

1482 (ulleungmycin A)

1480 R = O (actinomycin Y1) 1481 R = OH (actinomycin Y2)

Cl NH Cl HN

O

O

NH

O

H N

HN HN

H2N

NH HO

N H

O

O

H N

HN

O

O O

HN O NH2

NH O O

R NH2

O O

NH

O

N H NH2

1484 R = OH (nicrophorusamide A) 1485 R = H (nicrophorusamide B)

1483 (ulleungmycin B)

R1

Ph NO2

H N

NH O

O

NH

O N

R2

O O NH

O

Ph

O NH O HN O NO2 N OH Cl 1486 R1 = Me, R2 = H (hormaomycin B) 1487 R1 = H, R2 = Me (hormaomycin C)

Naturally Occurring Organohalogen Compounds …

187

A sediment sample from the Great Salt Lake, Utah, contains Streptomyces sp. GSL-6B that produces three linear heptapeptides, the bonnevillamides A–C (1488–1490). These novel natural products feature unprecedented non-proteinogenic amino acids, and each contains the bonnevillic acid unit (3-(3,5-dichloro-4methoxyphenyl)-2-hydroxyacrylic acid. Bonnevillamide A (1488) has the extremely rare 4-methylazetidine-2-carboxylic acid methyl ester moiety. These metabolites have no discernible antimicrobial activity but bonnevillamide B (1489) modulates heart growth and cardiac function in zebrafish embyros [1129]. A bloom of Moorea sp. cyanobacteria infesting the Kemp Channel in the Florida Keys generates kempopeptin C (1491), a novel depsipeptide exhibiting antiproteolytic activity against trypsin, plasmin, and matriptase (IC 50 0.19, 0.36, 0.28 μM, respectively) [1130]. Nannocystin A (1492) is a novel macrolactone isolated from the myxobacterium Nannocystis sp. ST201196, a compound with potent antifungal and antitumor properties. Against Candida albican, 1492 shows an IC 50 value of 73 nM, and towards cancer cell lines (HCT-116, PC3, HL60, MDA-MB231, MDA-A1, PBL) the antiproliferative activity is IC 50 1.0–12 nM [1131]. A large number of natural halogenated analogs are also present in this organism including nannocystins Ax, A1, B, B1 (1493–1496) and three brominated derivatives (1497–1499) [1131, 1132]. Total syntheses of the nannocystins and synthetic analogs have been intense [1133–1138]. MeO2C

AcO O

HO O Cl O

H N

N H

OH

N

O

HN

N

O N

O

OH

O

Cl

1488 (bonnevillamide A) HO2C

R O

HO O Cl

N H

OH

O

O

N

H N

HN

O N

O

OH

O

Cl

1489 R = OH (bonnevillamide B) 1490 R = OAc (bonnevillamide C) Cl O O N O

O N HO

O

O

N H

N H

O H N

HN

H N O

O NH2

O

1491 (kempopeptin C)

N

188

G. W. Gribble Ph

Ph

O

O O

O O

O

O O

NH

HO O

N

H N

O O

X

NH

HO

HO

R1

N

H N

O R3

O

HO Y

1493 X = Y = Cl (nannocystin Ax) 1499 X = H, Y = Br

R2 1492 R1 = R2 = Cl, R3 = Me (nannocystin A) 1494 R1 = H, R2 = Cl, R3 = Me (nannocystin A1) 1495 R1 = R2 = Cl, R3 = H (nannocystin B) 1496 R1 = H, R2 = Cl, R3 = H (nannocystin B1) 1497 R1 = Cl, R2 = Br, R3 = Me 1498 R1 = H, R2 = Br, R3 = Me

Three new diazonamides C–E (1500–1502) are found in the ascidian Diazona sp. (Plate 36) from Indonesia, along with the previously known diazonamides A and B [1, 2]. These new analogs are much less active than the very potent diazonamide A in these cancer cell lines: A549, HT-29, and MDA-MB-231 (GI 50 1.8–9.0 nM), with the most active being C (1500) and D (1501), but A shows GI 50 values of 0.006– 0.029 nM in these cell lines [1139]. The synthesis of diazonamide A continues to be of interest [1140, 1141]. The Red Sea sponge Theonella swinhoei contains the antifungal glycopeptide theonellamide G (1503), which is very similar to the known theonellamide A, lacking only a methyl group on the p-bromophenylalanine and a hydroxy group in the α-aminoadipic acid group [1142]. This new analog shows potent antifungal activity against both wild and amphotericin B-resistant strains of Candida albicans (IC 50 4.49 and 2.0 μM, respectively). The positive control amphotericin B shows an IC 50 value of 1.48 μM against the wild type. Another sample of this sponge from Japanese waters contains theonellamide I (1504) similar to the other theonellamides including G (1503). The difference between 1503 and 1504 is the presence of a β-l-arabinose moiety on the imidazole ring in 1504 [1143].

Naturally Occurring Organohalogen Compounds …

189

Plate 36 Diazona violacea (Global Biodiversity Information Facility)

N HN H N

H2N

N

O

HN

Cl

O

O

N

Cl

N

O

H2N

O

NH

O

O

O

1500 (diazonamide C)

O

HN HO

NH O

O C H N O

NH

1501 R = Cl (diazonamide D) 1502 R = H (diazonamide E)

OH O N H H2NOC

OH

O

H N

O N H X

NH2

O

Cl NH

NH

O2CH2

Cl

O R

H N

N H

O

OH N

N O

H N O

N H HO

O

NH

O

OH NH

HO OH

X=

Br

HO

OH

1503 (theonellamide G) 1504 X = β-L-arabinose (theonellamide I)

The novel taromycins A (1505) and B (1506) are the products of lipopeptide biosynthetic gene cluster engineering of marine bacteria (i.e., Saccharomonospora sp. CNQ-490 and Streptomyces coelicolor M1146), and both taromycins display potent activity against methicillin-resistant Staphylococcus aureus and vancomycinresistant Enterococcus faecium. Both metabolites are similar to daptomycin, which lacks the two chlorines and has R = (CH2 )9 (saturated) [1144, 1145]. A similar

190

G. W. Gribble

activation of a cryptic gene cluster leads to six novel polycyclic tetramate macrolactams, including the chlorohydrin pactamide F (1507), in a marine-derived Streptomyces pactum 2999PTMp1 [1146]. The closely related chlorohydrin capsimycin D (1508) is found in the mangrove-derived Streptomyces xiamenensis 318 [1147]. Other chlorohydrin-containing cyclodepsipeptides are trichomide D (1509) and a destruxin analog 1510 from the marine-derived fungus Trichothecium roseum [1148], and MBJ-0087 (1511) from Sphaerisporangium sp. 33226 [1149]. NH2 O

Cl NH CO2H

O

NH

R

H N

N H

O

O

O N H

H N

N H

NH

O

O HO2C O

O

CO2H

O

N H

O

NH O

HO2C

NH H N O

O Cl

O N H

N H

O

CO2H

NH2

1505 R =

(taromycin A)

1506 R =

(taromycin B) H N Cl

H N

OH

O

O HO

HO

HO NH

NH

Cl O 1507 (pactamide F)

O

O 1508 (capsimycin D)

O

Naturally Occurring Organohalogen Compounds … Cl

O

191 Cl

O

N

NH

HO

O

O

N

NH

HO

O

O

O

O

O

O

N

N

HN

HN

N O O 1509 (trichomide D)

N

O

O 1510

O O N O

N

N

O

NH O N

HN

O

O HO

O

O

O

HN

O

O

Ph

O N

NH

N OH

O

Cl 1511 (MBJ-0087)

The novel 11-membered heterocycle kauamide (1512) is found in the Hawaiian marine sponge Dactylospongia elegans, but demonstrated no significant biological activity [1150]. Two new bromine-containing halicylindramides G (1513) and H (1514) are present in the Korean Petrosia sp. marine sponge [1151]. O O N Cl

O 1512 (kauamide) H N O HO O H

N H

H N

O

O N

N H

O

H N O

O N H

CONH2 3 H N

SO3H

O

H N

N H

O

H2N

NH

1513 ((3S)-halicylindramide G) 1514 ((3R)-halicylindramide H)

H N

N

O

NH Br

O

O

O O

O N

O

Ph NH OH

O NH CONH2

192

G. W. Gribble

The linear anti-prostate linear peptides androprostamine A (1515) and B (1516) are found in a Streptomyces sp. MK932–CF8. These metabolites, which resemble the known resormycin [2], inhibit the androgen-dependent proliferation of human prostate cancer LNCaP and VCaP cells without cytotoxicity [1152]. Cl HO

OH

OH NH2 O

O

H N R CO2H

N H

N H

H N O

CO2H

1515 R = H (androprostamine A) 1516 R =

(androprostamine B) N H

O

Several noteworthy syntheses and structural revisions of halogenated peptides are cited here. Notably, the structure of cyclolithistide A [2] has been revised significantly [1153]. Total syntheses of NW-G01 (1407) [1154], sintokamides A (1280), B (1281), E (1284) [1155], C (1282) [1156], JBIR-34 (1297), -35 (1298), -126 (1299) [1157], bisebromoamide (1335) [1158], polydiscamides B (1338), C (1339), D (1340) [1159], chlorocatechelin A (1341) [1160], and androprostamine A (1515) [1161] are described, all of which confirm the proposed structures covered in the present survey. Total syntheses of previously known halogenated peptides that were covered in the earlier surveys [1, 2] include trichlorodermamides A and B (cf., 1351) [1162–1164], halicylindramide A (cf. 1513) [1165], (–)-dysithiazolamide [1166], neodysidenin [1167], dysideaproline [1168], dysidenin, dysidin, and barbamide [1169], (+)-lyngbyabellin M (cf., 1334) E [1170], chlorofusin [1171], aeruginosins 98A, 98C [1172], 98B, 298A [1173], halocyamine A [1174], and a synthesis of the simple amino acid analog acivicin [1175]. At least six total syntheses of the fungal metabolite (–)-kaitocephalin are described during this time period [1176–1181]. A total synthesis of the proposed keramamides A and L required slight structural revision involving the lysine units [1182]. Although no new natural cryptophycins were reported in the present survey, a review on their syntheses is available [1183]. A synthesis effort towards piperazimycin A (1404) is well underway [1184]. The final aspect of this Section concerns brominated tryptophans [1185], which are a small subset of the venomous Conus peptides. An extraordinary amount of new knowledge about these conotoxins has been gleaned since the last survey [2]. From some 700 living cone snail species throughout the tropical and subtropical waters it is estimated that more than 100,000 unique conopeptides may exist [1186–1189], and some 1,700 conotoxin sequences are identified [1189]. For a summary of the conopeptides containing one 6-bromotryptophan, see [2]. A new such conopeptide is found in the molluscivorous Conus bandanus (Plate 37) collected in Vietnam, which consists of 15 amino acids, one of which is 6-bromotryptophan [1190]. This is the first report of an “M-super family” conopeptide containing a 6-bromotryptophan.

Naturally Occurring Organohalogen Compounds …

193

Plate 37 Conus bandanus (Photograph courtesy of Cyndie Dupoux; https://www.gbif.org/occurr ence/1019708000; Creative Commons Attribution 4.0 International)

In light of their powerful toxicity, conopeptides are of intense interest for drug development [1191–1194]; for example, in the treatment of neuropathic pain [1195]. A concurrent goal of this research is the molecular engineering and the chemical synthesis of conopeptides [1196, 1197]. At least one conopeptide, “ziconotide,” is on the market for chronic pain, and several others are in preclinical or clinical trials [1186]. Two recent studies are illustrative of this research. The α-conotoxin (16 amino acids) from Conus victoria, which has potent analgesic activity and potential as a novel drug lead for the treatment of neuropathic pain, inhibits both voltage-gated calcium channels and the nicotinic acetylcholine receptor subtype α9α10 [1198]. Another study characterized a new α-conotoxin (15 amino acids) from Conus textile, which was synthesized using solid-phase methods and found to be a potent blocker of nicotinic acetylcholine receptor subtype α3β4 [1199]. Finally, it should be emphasized that the venom of the cone snail can be fatal to humans. This is especially true for Conus geographus and Conus tulipa, which are generally considered the two most deadly cone snails [1200, 1201]. Fatal injuries from the former snail are as high as 65%, and at least 36 deaths are documented from

194

G. W. Gribble

1670 to 1998 [1200, 1202, 1203]. From these data it is estimated that the human lethal dose is 0.038–0.029 mg/kg, from Conus geographus.

3.13 Alkaloids This section—as its predecessors [1, 2]—is deceptively short. Many “alkaloids” are either presented in the previous Sect. 3.12 or in the forthcoming Sect. 3.14 (Heterocycles). Moreover, the large number of new tyrosine-derived, brominated alkaloids are covered in Sect. 3.22.3 (Tyrosines), as was the case earlier [2]. Coverage in this Section follows that in the earlier surveys [1, 2]. The toxic plant “Tansy Ragwort” (Jacobaea vulgaris) is a menace to livestock [1204] due to the toxic pyrrolizidine alkaloid jaconine as cited earlier [1]. This alkaloid is thought to be the first halogenated alkaloid to be identified from any source [1]. Another “classic” alkaloid is epibatidine [1, 2], the much studied and synthesized biologically active compound from the skin of the Ecuadorian poison frog Epipedobates anthonyi (Plate 38) [1205, 1206]. Two of the subsequently identified alkaloids in this frog are N-methylepibatidine (1517) and phantasmidine (1518) [1207]. The latter has been synthesized [1208, 1209] and its absolute configuration established [1209, 1210]. Interestingly, phantasmidine is a 4:1 scalemic mixture enriched in the (2aR,4aS,9aS)-enantiomer (shown). It is about tenfold less potent than epibatidine in nicotinic receptors, but 100-fold more potent than nicotine in most receptors screened [1210]. An undescribed Panamanian cyanobacterium contains the novel chlorinated dragocins B (1519) and C (1520) that feature a β-ribofuranose tethered to a 2,3-dihydroxypyrrolidine. A dechlorinated analog dragocin A is more cytotoxic to human H-460 lung cancer cells than either B or C [1211].

O

R N

Cl

O

N

N

Cl

O

N HN

Cl

O

O

OH

HO OH 1517 (N-methyl-epibatidine)

1518 (phantasmidine)

1519 R = H (dragocin B) 1520 R = Me (dragocin C)

The fungus Aspergillus aegyptiacus growing on cotton textile produces the new pyrrolidine alkaloids aegyptolidines A (1521) and B (1522). Both compounds display moderate activity against murine lymphoma L5178Y cells (ED50 7.6 and 8.1 μg/cm3 , respectively [1212]. A Streptomyces HNA39 strain isolated from marine sediments of Hainan Island, China, revealed several novel cyclizidine chlorohydrin alkaloids, three of which contain chlorine, cyclizidines D (1523), H (1524), and I (1525).

Naturally Occurring Organohalogen Compounds …

195

Plate 38 Epipedobates anthonyi (Photograph courtesy of Nasser Halauch; Creative Commons Attribution-Share Alike 4.0 International)

The oxirane corresponding to 1523 is also found in this bacterium. Cyclizidines H and I exhibit moderate inhibition against the ROCK2 protein kinase (IC 50 39– 42 μM), and H is cytotoxic towards the PC-3 cell line (IC 50 17 μM) [1213]. The plant Ficus fistulosa var. tengerensis (Moraceae) from Malaysia contains the novel alkaloid tengechlorenine (1526) as a pair of phenanthroindolizidine enantiomers, which are strongly cytotoxic against three breast cancer cell lines, MDA-MB-468, MDA-MB231, and MCF-7 (IC 50 0.038–0.91 μM) [1214]. Tengechlorenine is the first naturally occurring halogenated phenanthroindolizidine alkaloid. The black marine sponge Halichondria okadai from Japan affords pinnarine (1527), a new member of the novel halichlorine family of macrocyclic alkaloids [1215]. The isolation of 1527 is suggestive of a biogenetic pathway from pinnaic acid to halichlorine, which are well-known marine alkaloids [2] and of intense synthesis interest [1216–1220].

196

G. W. Gribble

Plate 39 Menispermum dauricum (Photograph courtesy of Sten Porse; Botanical Garden of Aarhus, Denmark; Creative Commons Attribution-Share Alike 3.0 Unported)

OH HO

HO

OH

Cl N

Cl

OH

Cl

OH

OH

N

O O O

HO

N H

R

1521 R = Ac (aegyptolidine A) 1522 R = H (aegyptolidine B)

1523 (cyclizidine D)

1524 (cyclizidine H)

O

HO

O

HN

O

N

O Cl

OH

Cl

N

HO O

1526 ((±)-tengechlorenine)

Cl

OH

1527 (pinnarine)

1525 (cyclizidine I)

OH

Naturally Occurring Organohalogen Compounds …

197

Along with the known petrosamine [1], a Thai Petrosia marine sponge contains 2bromoamphinedine (1528) [1221]. The Taiwanese sea anemone Zoanthus kuroshio is home to the two novel zoanthamines, 5α-iodozoanthenamine (1529) and 11βchloro-11-deoxykuroshine A (1530), together with four nonhalogenated analogs. The aforementioned compounds are the first halogenated zoanthamines found in Nature. Compound 1529 displays the most anti-inflammatory activity for inhibiting superoxide anion generation and elastase release at 10 μM (24 and 43%, respectively) [1222]. The hexacyclic cytochalasan xylarichalasin A (1531) is a product of the endophytic fungus Xylaria cf. curta within Solanum tuberosum. This complex molecule is significantly cytotoxic towards the SMMC-7721 and MCF-7 cell lines, superior in potency to cisplatin [1223]. The unusual nitro morphine analog nitrotyrasacutuminine (1532) is found in the roots of the Chinese medicinal plant Menispermum dauricum DC. (Menispermaceae) (Plate 39), and is closely related to acutuminine [1, 1224]. A new alkaloid related to the acutumine family is hypserpanine A (1533), isolated from the folk medicine herb Hypserpa nitida, along with 11 known analogs. Some of these metabolites display anti-hepatitis B virus activity [1225]. Another traditional medicinal plant, Sinomenium acutum contains the new 2-O-demethylacutumine (1534) [1226]. Labeling studies determine that dechlorodauricumine is the principal precursor of chlorinated alkaloids produced by Menispermum dauricum [1227, 1228]. Thus, dechlorodauricumine and dechloroacutumine are converted to miharumine and dechloroacutumidine, respectively, by a cell-free preparation of Menispermum dauricum [1228]. Total syntheses of (–)-acutumine are described in Refs. [1229, 1230]. Three reports have appeared describing the isolation of new alkaloids bonded to a chloromethane moiety. These are undoubtedly artifacts from reaction with dichloromethane used in the isolation-purification process, as the authors recognize [1231–1233]. Syntheses of the ceratamine alkaloids have appeared [1234, 1235], as have additional syntheses of epibatidine, epiboxidine, and analogs [1236–1238]. A review on marine alkaloids in the treatment of neglected tropical diseases caused by protozoan parasites is available [1239].

198

G. W. Gribble O

O

O O

OH

Br

O

O

O

O Cl

N N

O

O

N

N O

I

N

O

O 1530 (11β-chloro-11-deoxykuroshine A)

1529 (5α -iodozoanthenamine)

1528 (2-bromoamphimedine)

O Cl Cl OAc

OH

NO2

O

O

N OH

NH

O

Cl

OH

O O O

1531 (xylarichalasin A)

1532 (nitrotyrasacutuminine)

N

OH OH Cl

O

OH Cl O

N O

O O

1533 (hypserpanine A)

N O

O O

1534 (2-O-demethylacutumine)

3.14 Heterocycles 3.14.1

Pyrroles

The enormous reactivity of pyrrole (and indole) in electrophilic biohalogenation leads to nearly 250 naturally occurring halogen-substituted pyrroles as disclosed earlier [1, 2]. Some new halopyrroles are tangentially attached to large peptides and are cited in Sect. 3.12. Most halogenated pyrroles are marine-derived, and coverage is generally chronological. Citations of total syntheses and revisions will appear as appropriately. An excellent review on the syntheses of natural products containing the pyrrole ring is available [1240]. The Australian soil ascomycete Gymnoascus reessii (Plate 40) contains the new (12E)-isorumbrin (1535), a methyl-containing analog of the known auxarconjugatin A and an isomer of the less stable known rumbrin ((Z)-isomer). Against a battery of human cancer cell lines, 1535 is highly potent and selective to ovarian (JAM) and prostate cells (DU145), with IC 50 values of 0.46 and 7.61 ng/cm3 , respectively [1241]. A companion study involving halide addition to the fermentation broths increased the

Naturally Occurring Organohalogen Compounds …

199

Plate 40 Gymnoascus reessii (Photograph courtesy of Adolf Engler; https://www.flickr.com/ photos/internetarchivebookimages/20910345116/in/photolist-8ZeeoA-ownSbW-ownSum-owp CPK-wNpG7v-xx7TtK-xS6ntE-y9Yy3g-xx4BKU-xRLZ6E-w5F81d-v9nh3U-w6NiS2-w9e7SX; Public Domain)

production of 1535 and the known analogs, as well as forming brominated derivatives (not shown) [1242]. A biosynthesis study of rumbrin, which is also produced by the fungus Auxarthron umbrinum, confirms the hypothesis that proline, methionine, and acetate are the precursors of the pyrrole ring, the methyl groups, and the backbone of rumbrin, respectively [1243]. Additional halogenated polyenes are formed via precursordirected biosynthesis with this fungus. These “forced” metabolites, 3-fluoro-, 3chloro-, and 3-bromoisorumbrin, are not counted as being natural, but they show improved cytotoxicity towards HeLa cancer cells compared with rumbrin [1244]. A Corsican sponge, Axinella damicornis, yields the new bromopyrrole alkaloids damipipecolin (1536) and damituricin (1537), which have a modulating effect of serotonin receptor activity in vitro and may be promising new serotonin antagonists [1245]. Another study of Axinella damicornis from Elba Island and the sponge Stylissa flabelliformis from Indonesia discovered the simple bromopyrroles 1538–1541, along with 13 known compounds. Compounds 1539–1542 are previously reported as synthetic compounds or as inseparable mixtures (i.e., 1542) but this is the first finding of them as genuine natural products [1246]. A Venezuelan sponge, Agelas dispar, contains the new dispyrin (1543) and dibromoagelaspongin methyl ether (1544). The former is unique in that it is the first marine natural product to feature a bromopyrrole tyramine motif [1247].

200

G. W. Gribble Br

Cl

Br

O N H

N H

O

O O

COOH

N H

NH

COO

O O

N

O 1536 (damipipecolin)

1535 ((12E)-isorumbrin)

1537 (damituricin) O

O Br

Br

Br

Br NH2 NH2

N H

N H

O

1538 (R = NH2) 1539 (R = OH)

1540

NH

R

N H

O

1541 R = Br (2,3-dibromoaldisin) 1542 R = H (3-bromoaldisin)

Br

H2N Br N H

H N

HN

Br

Br

NN

O O

O 1543 (dispyrin)

N

N

O

1544 (dibromoagelaspongin methyl ether)

A collection of the sponge Axinella cylindratus from Sedo Island, Japan, produced (+)-cylindradines A (1545) and B (1546), which show modest inhibition of murine leukemia P388 cells [1248]. Both metabolites have been synthesized [1249, 1250]. The Okinawan marine sponges, Agelas spp. are a fantastically rich source of bromopyrrole alkaloids [1251], and nagelamides A–H are depicted in the last survey [2]. In a series of studies with Okinawan Agelas species, Kobayashi et al. extended the list of the bromopyrrole nagelamides to include J (1547) [1252], K (1548), L (1549) [1253], M (1550), N (1551) [1254], O (1552), P (1553) [1255], Q (1554), R (1555) [1256], U (1556), V (1557), W (1558) [1257], X (1559, Y (1560), Z (1561) [1258], and I (1562) [1259]. Nagelamides S and T (not shown) were isolated by Al-Mourabit et al., from the Pacific sponge Agelas cf. mauritiana and do not contain bromine [1260]. The debrominated analogs, 2-debromonagelamide P (1563), 2-debromonagelamide U (1564), and 2-debromomukanadin G (1565) are present in Agelas sp. [1261], as is 2,2 -didebromonagelamide B (1566) [1259]. Baran has described a novel vinylcyclobutane rearrangement of sceptrin to ageliferin and nagelamide E, which encompasses total syntheses of all three bromopyrrole alkaloids [1262, 1263].

Naturally Occurring Organohalogen Compounds …

201 Br

Br

Br

Br

HN

HN H N

H N

Br

HN

Br

NH

H2N

H2N N

N

O

H N

O

N

N

HO

O

NH2

HO

O

H N

Br

N O N

N H

HN

Br 1546 (cylindradine B)

1545 (cylindradine A)

NH2

Br

HN

H N

Br

O

NH

Br Br

NH

O

SO3

–

Br N H

Br

NH2

Br

N H

1550 (nagelamide M)

O

Br

O H N N H

O

NH2

N

O 1553 (nagelamide P)

Br

OH HN O NH

O3S

Br 1552 (nagelamide O)

Br

N

HN

HN

N

O H N

NH

Br

Br NH2

NH

HN

HN

N Br

Br

SO3– H N

1554 (nagelamide Q)

NH N H

H N

N

Br H N

NH

H2N

N N H

N H

Br HN

1551 (nagelamide N)

H2N

O

Cl

N

O

Br

Br

NH2

OH

H2N

NH NH

HN

Br

SO3

H N

H N

O HO2C Br

O

HN

1549 (nagelamide L)

NH2

NH

N

HN

NH

N H

1548 (nagelamide K)

HO H N

N H

O

O

O

H N

Br

HN Br

H N

NH2

NH2

N

HN N H

Br

HN

NH HN

NH2

1547 (nagelamide J)

NH2

Br

O

NH

O

N H N H

NH N

Br

NH2 1555 (nagelamide R)

NH2

202

G. W. Gribble Br H N

Br N H

NH2 Br

NH

R H N

Br N H

N H

O N

HN

H N

Br

NH2

HN NH

NH R

HN NH

O

NH

NH

O

O3S

HN

O

NH2

SO3 1556 R = β-H (nagelamide U) 1557 R = α-H (nagelamide V)

H N

O H N

NH2

Br

H2N

Br HN Br

1558 (nagelamide W)

1559 R = OH (nagelamide X) 1560 R = H (nagelamide Y)

Br Br

NH H N

Br N H

NH2 O

N H

O

H N

NH

N H

Br

N H

HN

NH2 HN

H N

N O

NH

Br

H2 N

Br

1562 (nagelamide I)

1561 (nagelamide Z)

NH

Br

O

H2N NH

Br

N H

H N

N H

N

H2N

H N

O

H N

O H N

O

N

O

H N

N H

SO3 1563 (2-debromonagelamide U)

N H

HN

Br

O

Br

O

NH2 N H

1564 (2-debromomukanadin G)

NH N H NH

N H

O

NH

H N O

N H

NH2

1565 (2-debromonagelamide P) NH

Br

O

H N

OH

NH2

HN H N

Br

N

O N H

N HN NH2

1566 (2,2'-didebromonagelamide B)

Sponges of the Agelasidae family yield several new dimeric pyrrole-2aminoimidazole brominated alkaloids. Benzosceptrins B (1567) [1260] and C (1568) [1264, 1265] reside in Agelas cf. mauritiana (Guadalcanal), Phakellia sp. (New Caledonia), Agelas dendromorpha (New Caledonia), and Agelas sp. (Okinawa). The latter investigation also produces the new agelastatins E (1569) and F (1570), along with 10 known metabolites [1265]. Benzosceptrin C shows modest antimicrobial activity

Naturally Occurring Organohalogen Compounds …

203

against several bacterial strains, notably Micrococcus luteus and Trichophyton mentagrophytes (MIC 6.0 μg/cm3 ) [1264]. A biosynthesis of benzosceptrin C and nagelamide H from 7-15 N-oroidin using cell-free enzyme preparations from Agelas sceptrum was executed, and supports the hypothesis that oroidin is a precursor to more complex pyrrole-aminoimidazole alkaloids (i.e., sceptrins, benzosceptrins, nagelamides). In addition, the new didebromonagelamide A (1571) is found in the sponge Stylissa caribica, which is the first finding of a nagelamide in a Caribbean sponge [1266]. A sample of Agelas sceptrum from the Bahamas contains the new hybrid pyrrole-imidazole alkaloids 15 -oxoadenosceptrin (1572) and decarboxyagelamadin C (1573). Neither metabolite exhibits cytotoxicity or antibacterial activity [1267].

Br

N R

N H

HN

H N

NH NH

N

O

O

Br

O

N

NH

HN

N

Br

NH R1

R

R3

R2 O

NH2

O

NH2 1569 R1 = H, R2 = R3 = Me (agelastatin E) 1570 R1 = Br, R2 = R3 = H (agelastatin F)

1567 R = H (benzosceptrin B) 1568 R = Br (benzosceptrin C)

Br HN NH2

Br

H N

O N H

H N

N N H N

N

NH2

NH

O O HN

HN

Br

HN

Br NH2

HN

NH

O

H N

O N H

N

N

NH2

NH2

N N

1571 (didebromonagelamide A)

1572 (15'-oxoadenosceptrin)

H2N O HN Br

O

HN HN

Br

N H

N

O H2N

1573 (decarboxyagelamadin C)

A South China Sea Agelas sp. sponge contains the new hexazosceptrin (1574), agelestes A (1575) and B (1576), and (9S,10R,9 S,10 R)-nakamuric acid (1577), for which the absolute configuration was confirmed for the first time. Metabolites 1574 and 1577 display moderate antimicrobial activity [1268]. An examination of Agelas kosrae from Micronesia found the new sceptrins dioxysceptrin (1578) and ageleste C (1579), where the former exists as a mixture of α-amide epimers. These

204

G. W. Gribble

two compounds display modest anti-angiogenic and isocitrate lyase inhibitory activities, respectively [1269]. A deep-sea sediment containing Streptomyces sannurensis produces the six marinopyrroles A–F (1580–1585), which exist as optically active atropoenantiomers, except for 1585. These novel 1,3 -bipyrroles are highly active against methicillin-resistant Staphylococcus aureus [1270, 1271]. Synthesis efforts towards these metabolites are intense [1272–1276], and the halogenase enzymes responsible for the biosynthetic N,C-bipyrrole homocoupling are identified [1277]. A review of the marinopyrroles has appeared [1278]. New analogs of pyrrolnitrin, which was originally discovered in 1965 [1], are found in the bacterium Burkholderia cepacia K87, including 3-chloro-4-(3-chloro-2-nitrophenyl)-5-methoxy-3-pyrrolin2-one (1586) and 4-chloro-3-(3-chloro-2-nitrophenyl)-5-methoxy-3-pyrrolin-2-one (1587). The authors suggest that these compounds are oxidative degradation products [1279]. The proposed biosynthesis of pyrrolnitrin from tryptophan is supported by a chemical investigation [1280].

Br

Br

NH2

O N H

HN

H N

HN

N

N H

HN

O

H N

HN

NH2

O

H N

HN

CO2H

O

1577 ((9S,10R,9'S,10'R)-nakamuric acid)

Cl

N

O

HN

H N

HO

HN

O

O Cl

Cl Cl O

Cl

O O

OH

N

O

N

OH

N

O

Cl NH2

Br

OR2

N

X

HN

HN

HN

1575 R1 = Me, R2 = H (ageleste A) 1576 R1 = R2 = Me (ageleste B) 1579 R1 = R2 = H (ageleste C)

NH2

H N

N H

Br

O HN

C OR1

O

Br

1574 (hexazosceptrin)

N H

HN

O

NH

Br

O

O

HN Br

NH2

Br

O

HN

1578 (dioxysceptrin)

Cl

Z Y

1585 (marinopyrrole F)

1580 X = H, Y = H, Z = H (marinopyrrole A) 1581 X = H, Y = H, Z = Br (marinopyrrole B) 1582 X = Cl, Y = H, Z = H (marinopyrrole C) 1583 X = H, Y = Cl, Z = H (marinopyrrole D) 1584 X = H, Y = Br, Z = H (marinopyrrole E) Cl

Cl

NO2

NO2

Cl

Cl

O

N H

1586

O

O

N H

O

1587

Three chlorinated malbranpyrroles C–F (1588–1591) are found in the thermophilic fungus Malbranchea sulfurea from fumarole soil in a Taiwanese hot spring.

Naturally Occurring Organohalogen Compounds …

205

These 3-chloropyrrole polyketides are active against PANC-1, Hep G2, and MCF7 cancer cell lines (IC 50 3–11 μM) [1281]. Three new neopyrrolomycins, from an Arizona watershed Streptomyces sp. AMR1-33844, are B–D (1592–1594), which have potent activity against Gram-positive pathogens including resistant strains (MIC < 1 μg/cm3 ). Pyrrole 1592 is isolated in optically active form, but 1593 and 1594 exhibit no optical activity, illustrative of an interesting example of a “buttressing effect” that hinders or prevents biaryl rotation in 1592. Pyrrole 1592 is 100 times more active than vancomycin and ciprofloxacin in many instances [1282]. The Indonesian sponge Acanthostylotella sp. contains the four new bromopyrroles acanthamides A– D (1595–1598) and 1599, 1600 [1283]. The novel pigments keronopsamides A–C (1601–1603) are found in the marine ciliate Pseudokeronopsis riccii [1284]. Cl

Cl

Cl

N H

N H

N H O

O

O

Br

N

N H

R2

1592 R1 = Cl, R2 = Cl (neopyrrolomycin B) 1593 R1 = Cl, R2 = H (neopyrrolomycin C) 1594 R1 = H, R2 = Cl (neopyrrolomycin D)

R2

R1

OR1 N H

O R2

1599 = Me, = H, R3 = Br 1600 R1 = H, R2 = Br, R3 = H

Br

Br H N

CO2R

N H

O

CO2R

O

1597 R = Me (acanthamide B) 1598 R = Et (acanthamide C)

1595 R = Me (acanthamide A) 1596 R = Et (acanthamide D)

Br

RO

Br

1591 (malbranpyrrole F)

Br

Br H N

O

O

1590 (malbranpyrrole E)

Cl

Cl R1

O

O

O

1589 (malbranpyrrole D)

HO

R3

O

O

Cl

Cl

N H

O

O

1588 (malbranpyrrole C)

Cl

O

H N

N H

Br Br

1601 R = H (keronopsamide A) 1602 R = SO3H (keronopsamide B)

HN

HO3SO

Br

O

Br

N H 1603 (keronopsamide C)

Of five new nitropyrrolines A–C, two are chlorinated, C (1604) and E (1605), all of which are found in a marine-derived Streptomyces sp. The epoxide corresponding to 1604 is nitropyrrolin B [1285]. A review on nitropyrrole natural products is available [1286]. The Indonesian sponges Stylissa massa and Stylissa flabelliformis contain the new dispacamide E (1606) and the simple dibromopyrrole ester 1607, along with 23 known bromopyrroles. The former compound displays significant protein kinase inhibitory activity against GSK-3, DYRK1A, and CK-1 (IC 50 2.1–6.2 μM) [1287]. Another study of different Indonesian sponges uncovered eleven new bromopyrrole alkaloids 1608–1619 from Agelas linnaei and one, longamide C (1619), from Agelas nakamurai [1288].

206

G. W. Gribble Cl

Cl

O2N

O2N OH

HN

OH

HN

1604 (nitropyrrolin C) Br

Br

1605 (nitropyrrolin E)

O

Br

N

H N N H

OH

NH2

N H

O

Br

1607

NH2

Br

Br

O

N

Br

N

O

N

O

HO

OH N

CO2Et

N H

1606 (dispacamide E)

HN

Br

Br

O

HN

H N

N Br

Br

O

O

OH

O

N R

S OH O

HN NH 1608

1610 R = H (mauritamide B) 1611 R = CH2CH3 (mauritamide C)

1609 (agelanin B)

NH2 Br

Br

N

Br

O HN

O

N

O

O

Br

N

OH

S OH

OH

Br

O

O 1612 (mauritamide D)

N

N

Br

N H 1613

1614 (agelanin A) O

R1

Br

H N

O O R N H

2

N Br

N N

O O

1615 R1 = H, R2 = Br (agelanesin A) 1616 R1 = H, R2 = I (agelanesin B) 1617 R1 = Br, R2 = Br (agelanesin C) 1618 R1 = Br, R2 = I (agelanesin D)

N

1619 (longamide C)

Naturally Occurring Organohalogen Compounds …

207

A marine Pseudoalteromonas sp. (CMMED 290) isolated from the surface of an undescribed nudibranch living in Kaneohe Bay, Oahu, contains the novel 2,3,5,7tetrabromobenzofuro[3,2-b]pyrrole (1620) and a tribromo-2,2 -biphenol cited later. Metabolite 1620 shows activity against methicillin-resistant Staphylococcus aureus with IC 50 1.93 μM, where vancomycin has an IC 50 of 0.91 μM [1289]. The three stylissazoles A–C (1621–1623) are found in the marine sponge Stylissa carteri living in the Solomon Islands (shown as a neutral species) [1290]. Along with several known bromopyrroles found in the Cuban sponge Agelas cerebrum, 5-bromopyrrole2-carboxylic acid (1624) is also present and reported to be the first finding as a natural product [1291]. The New Caledonian sponge Cymbastela cantarella yields the new epimeric dihydrohymenialdisines 1625 and 1626 [1292], but they lack the kinase inhibitory activity of the known hymenialdisin having a (conjugated) double bond connecting the two rings [1]. An Indonesian specimen of Stylissa sp. from the Derawan Islands contains the four new alkaloids 1627–1630, along with eight known analogs, several of which show excellent cytotoxicity against L5187Y lymphoma cells (EC 50 3.5 μg/cm3 for 1627) [1293]. An investigation of the coralline alga Neogoniolithon fosliei containing the Pseudoalteromonas strain J010 contains the new tribromopyrrole 1631 and three new chlorine-containing korormicins 1632– 1634. Pyrrole 1631 has broad-spectrum activity against all bacteria tested, the protozoan Tetrahymena pyriformis, and the fungus Candida albicans [1294]. A marine Streptomyces sp. from California produces the novel 5H-pyrrolo[2,1-a]isoindol-5one (chlorizidine A) (1635), which is strongly cytotoxic to the HCT-116 human colon cancer cell line (IC 50 3.2–4.9 μM) [1295]. Given the known reactivity of Nacylpyrroles to nucleophilic attack, it is not surprising that chlorizidine A undergoes facile nucleophilic substitution at the carbonyl group.

208

G. W. Gribble O H N

Br

N

Br

H2 N Br

N

NH

N

HN

O NH

N

NH N

H2N

Br

O

O

H2N

Br

O

N H

H N

Br

HN

H N

O

O

N

H2 N

NH

NH 1620

1622 (stylissazole B)

1621 (stylissazole A)

Br NH2 NH

N

NH N H

HN

Br O

O

N

CO2H

N H

N

NH

Br

N H

NH

N H

H N

H2 N O

N N

H N

H2N

O

NH

Br

N H

O

O

O 1623 (stylissazole C)

1625 ((+)-dihydrohymenialdisine)

1624

NH2 HN

NH2

N R1

N N

R1

Br

R2

Br R2

NH

NH N H

Br

O

N H

Br O

1629 R1 = CO2Me, R2 = H 1630 R1 = R2 = H

1627 R1 = Me, R2 = Br 1628 R1 = Me, R2 = H

N H

OH

Br

1631

Cl

Cl N

O

O

N H

OH

R1

O

1626 ((–)-dihydrohymenialdisine)

N

OH

R2

1632 R1 = OH, R2 = Br (korormicin F) 1633 R1 = Cl, R2 = OH (korormicin H) 1634 R1 = OH, R2 = Cl (korormicin I)

Cl O

OH

1635 (chlorizidine A)

Cl

Naturally Occurring Organohalogen Compounds …

209

Along with three known phorbazoles, A, B, D [1], the new 9-chlorophorbazole D (1636), and N-1-methylphorbazole A (1637) are present in the Indian Ocean nudibranch Aldisa andersoni (Plate 41) and express modest growth inhibition against the human cell lines A-549, MCF-7, SKMEL-28, Hs683, and U373 (IC 50 18–29 and 19–34 μM for 1636 and 1637, respectively). These data are comparable or even superior to the IC 50 value levels observed with carboplatin and temozolomide [1296]. The Streptomyces armeniacus strain DSM 19369 produces the three novel armeniaspirols A–C (1638–1640) and their putative precursors, 1641–1643 [1297]. The armeniaspirols show activity against Gram-positive pathogens, and 1639 is active in vivo and shows no development of resistance. The known streptopyrrole [2] is also present in this culture. The pyrronazols 1644–1648 are novel chlorinated pyroneoxazole-pyrroles (1644–1646) and together with related diastereomers (1647 (E, Z)) are present in the myxobacteria Nannocystis pusilla and Nannocystis exedens, respectively [1298]. These two strains are found in soil samples from Germany and Greece, respectively. The biosynthesis of pyrronazol B has been explored and a total synthesis confirms the structure [1299].

Plate 41 Aldisa andersoni (Photograph courtesy of Bernard Picton; a mating pair of the nudibranchs, Mirissa, Sri Lanka; Creative Commons Attribution-Share Alike 4.0 International)

210

G. W. Gribble R2 R1 Cl

Cl

Cl

Cl

OH

OH

HO

O

O

Cl

O

N

N H

N

N

N

Cl

Cl

1638 R1 = H, R2 = Me (armeniaspirol A) 1639 R1 = Me, R2 = H (armeniaspirol B) 1640 R1 = R2 = Me (armeniaspirol C)

1637 (N-1-methylphorbazole A)

1636 (9-chlorophorbazole D)

O

O

R2 O

O R1

HO

N

O

O

Cl

OH

R

O

O

O

O

O

N H

Cl

OH

N

N H

Cl

HN Cl

1641 R1 = H, R2 = Me 1642 R1 = Me, R2 = H 1643 R1 = R2 = Me

1644 R = OH (pyrronazol A) 1645 R = H (pyrronazol B)

1646 (pyrronazol A2) OH

OH N

OH

OH O

N

HN

O N H 1647 ((E)-pyrronazol C1)

Cl

Cl 1647 ((Z)-pyrronazol C2)

The South China Sea sponge Agelas mauritiana contains the simple 2bromopyrrole amide 1648 [1300], and an Okinawan Agelas sp. affords five new bromopyrrole alkaloids, agelamadins A (1649) and B (1650) [1301], and C–E (1651– 1653) [1302]. Both 1649 and 1650 are active against Bacillus subtilis (MIC 16 μg/ cm3 ) and Micrococcus luteus (MIC 4.0 and 8.0 μg/cm3 , respectively) [1301]. In contrast, 1651–1653 display only antifungal activity towards Cryptococcus neoformans (IC 50 32 μg/cm3 ) [1302]. Agelamadins A and B are racemates and either a biogenesis from two molecules of oroidin or an intramolecular cyclization of nagelamide J (1547) is suggested [1301]. Agelamadins C–E could arise by a condensation between oroidin and 3-hydroxykynurenine [1302]. The Mauritius Island sponge Axinella donnani contains the new (–)-donnazoles A (1654) and B (1655), which are closely related to the postulated intermediate “pre-axinellamine” for the dimeric pyrrole-aminoimidazole alkaloids (i.e., palau’amine, massadines, kombuacidines, and styloguanidines). The absolute configurations of 1654 and 1655 are established [1303]. A deep-sea Axinella sp. sponge from the Great Australian Bight yields the three new brominated massadines, 1656–1658, along with 15 known compounds. Metabolite 1658 displays activity against two Staphylococcus aureus strains (IC 50 3.7, 4.2 μM), two Bacillus subtilis strains (IC 50 2.2, 2.6 μM), Escherichia coli (IC 50 4.4 μM), and Pseudomonas aeruginosa (IC 50 4.9 μM). Compounds 1656 and 1657 are inactive in all assays [1304].

Naturally Occurring Organohalogen Compounds …

211 H N

Br NH

N H

N

HN

O H2N

N H

O

N H

Br O

Br

HN

NH

HN

9

HO2C

O

HN

NH2

N H

10

N H

NH Br

NH

R

O NH

H2N

O

1649 R = OMe (agelamadin A) 1650 R = OH (agelamadin B)

1648

Br

Br

R O

H N

Br

NH Br

NH

Br

NH2

O

NH OH NH NH O

N H

NH

NH

O

Br 1651 ((9R,10S)-agelamadin C) 1652 ((9S,10R)-agelamadin D) 1653 ((9R,10R)-agelamadin E)

Br

1654 R = OH (donnazole A) 1655 R = Cl (donnazole B) NH2

Br

H N

HN

Br

HN N H

NH

R2O N H

Br

Br

O

O

O HN R1

NH NH2

1656 R1 = OSO3–, R2 = H (14-O-sulfate massadine) 1657 R1 = OMe, R2 = H (14-O-methyl massadine) 1658 R1 = Cl, R2 = Me (3-O-methyl massadine chloride)

A Callyspongia sp. sponge also from the Great Australian Bight contains the four novel callyspongisines A–D along with the known hymenialdisine and 2bromoaldisine. The authors consider that only A (1659) is a natural product and that B–D are storage and handling artifacts. The observed kinase inhibitory activity is attributed to hymenialdisine [1305]. Despite their nondescript appearance, bryozoans (“moss animals”) can be the repository of incredible complex natural products, many of which are heavily brominated. An example is the Patagonian bryozoan Aspidostoma giganteum that contains nine new aspidostomides A–H (1660–1667) and aspidazide A (1668). The only cytotoxic member of this collection is aspidostomide E (1664) (IC 50 7.8 μM, towards the human renal carcinoma cell line 786-O) [1306]. A study of the Indonesian Stylissa massa and Stylissa flabelliformis sponges found two new metabolites, dispacamide E (1669) and 1670, together with 23 known bromopyrroles. The latter compound is a known synthetic product, and 1669 shows significant activity in six kinase assays (IC 50 2.1–18.8 μM) [1307].

212

G. W. Gribble SO3– H2N

SO3– O

N

N

NH

NH

O

O NH

Br

N H

NH

Br

N H

O

OR1 Br

R2

RO

N H

O

N Br

Br

1660 R1 = R2 = H, R3 = Br (aspidostomide A) 1661 R1 = R3 = H, R2 = Br (aspidostomide B) 1662 R1 = H, R2 = R3 = Br (aspidostomide C) Br

1663 R = H (aspidostomide D) 1664 R = Me (aspidostomide E)

1665 (aspidostomide F)

O

H N O

N H

Br

Br

N

O

Br

1667 (aspidostomide H)

O

Br

Br

Br

N

Br

N

Br

O

N

Br

N

H N N H

Br

O

O

N H

Br

OH

Br O

1666 (aspidostomide G) Br

Br

Br Br

Br

Br Br

Br

N H

O

OH

N Br

N H

NH HN

Br

HN Br

Br

O

HO

O

R = Et (callyspongisine C) R = Me (callyspongisine D)

Br

HN

H N

N H

O

Br

R3

NH

Br

O

callyspongiasine B

1659 (callyspongisine A)

CO2R

RO

N H

1669 (dispacamide E)

NH2

N H

CO2Et

Br

Br OH

1670

1668 (aspidazide A)

An Okinawan Agelas sp. sponge contains the five new 2,3-dibromopyrrole alkaloids 1671–1675. Particularly novel is mukanadin G (1675) having a fused tricyclic ring, and this compound shows moderate antifungal activity towards Candida albicans and Cryptococcus neoformans (IC 50 16 and 8 μg/cm3 , respectively) [1288]. Another study of Agelas sp. from Okinawa found agelamadin F (1676) and tauroacidin E (1677), which is a racemate [1308]. A collection of Agelas citrina from the Bahamas contains the new citrinamines A–D (1678–1681) and Nmethylagelongine (1682). The former are recognized as dimers of hymenidin, which is a major metabolite in this sponge. The citriamines A and B are closely related to mauritiamine [2], and are racemates (counted as one each). Biological activities of 1678–1682 are low (antimicrobial) or nonexistent (cytotoxicity) [1309].

Naturally Occurring Organohalogen Compounds …

213

Br

H N

Br H N

Br

N H

N

Br

NH2 O

N H

N

O

NH

1671 (2-bromokeramadine)

NH2

H N

1672 (2-bromo-9,10-dihydrokeramadine) NH

NH Br

Br O HN

H N

Br

N H

NH SO3

N H

O

O HN

H N

Br

N H

NH SO3

N H

O

1674 (tauroacidin D)

1673 (tauroacidin C) O HN Br Br

N H

NH2

H N

O H N

Br NH2

N H

N H

O

1675 (mukanadin G) Br

Br H N

Br

N H

H N

O3S

O

H N H N

H N

N H

1678 (citrinamine A)

O

H N

H N

NH2 N H

N

O

O

O

N

1679 (citrinamine B)

H N O

O

H N

N H

HN

O N H

Br

Br

H N

Br

H N

N H

NH2 N

O

N

Br

N H

N

Br

NH2

H N N H

N H

H N NH2

H N

SO3

N H

1677 (auroacidin E) Br

O

NH

OH

O

N O

1676 (agelamadin F)

NH2 HN

NH

N

H N

Br

NH2 N H

O

NH

1680 (citrinamine C)

O

Br

Br H N N H

O 1681 (citrinamine D)

N N H

O NH2

N

N

CO2

O 1682 (N-methylagelongine)

A South China Sea Agelas sp. sponge affords six new bromopyrrole alkaloids, longamides D–F (1683–1688), and 1689–1691. The former were resolved into their respective enantiomers, which were individually tested for antifungal activity. Compounds 1689 and 1690 were not resolved, and 9-oxoethylmukanadin F (1691) is optically active [1310]. The new 5-bromophakelline (1692) is present in the Indonesian sponge Agelas sp. along with a dozen known congeners [1311]. A Chinese

214

G. W. Gribble

marine sponge, Axinella sp., contains the new pyrrolactam alkaloids axinellines A and B (1693), where the latter contains bromine [1312]. A collection of Agelas oroides near Marseille, France, yields the novel monobromoagelaspongin (1694) [1313]. The new pyrrolo-2-aminoimidazole clathriole A (1695) is found in the Myanmarese marine sponge Clathria prolifera. Interestingly, 1695 seems to be the enantiomer of the known antifungal N-methylmanzacidin C from Axinella brevistyla, but unlike the latter, clathrirole A lacks antifungal activity against Saccharomyces cerevisiae [1314]. Br

Br O

Br O

NH

N NH

2

2

R O

R O

R1

R1

1684 R1 = OEt, R2 = Et ((–)-longamide D) 1688 R1 = H, R2 = n-Pr ((–)-longamide F)

1683 R1 = OEt, R2 = Et ((+)-longamide D) 1687 R1 = H, R2 = n-Pr ((+)-longamide F) Br

Br O

Br

O

Br O

N

Br

O

Br

N NH

Br

NH

EtO

H N

N N H

EtO O

OEt CO2Et

O

O 1686 ((–)-longamide E)

1685 ((+)-longamide E) Br

1689 Br

H N

Br

N H

O

OEt Br

CO2Et

OEt HN

H N N H

O 1690

NH

O

O 1691 Br

NH2

HO

N

Br

NH NH

Br

N

N H

N HN

O

HO

O 1692 (5-bromophakelline)

O

NN

H2N

N

1694 (monobromoagelaspongin)

1693 (axinelline B) Br N N H

N OH

O O

O

1695

A collection of Dictyonella sp. sponge from the mouth of the Amazon River has furnished four new bromopyrroles, 4-debromooroidin (1696), 4-debromougibohlin (1697), 5-debromougibohlin (1698), and 5-bromopalau’amine (1699), where the bromine is attached to C-2 of the pyrrole ring (not shown). This latter metabolite

Naturally Occurring Organohalogen Compounds …

215

is the most active of this group in the 20S proteasome inhibition assay [1315]. A Tedania brasiliensis sponge from Cabo Frio, Rio de Janeiro, contains the new pseudoceratidines 1700–1704 and tedamides A–D (1705–1708). Compounds 1700 + 1701, 1702 + 1703, 1705 + 1707, and 1706 + 1708 are isolated as pairs of inseparable structural isomers differing in the sites of bromination or oxidation. Several of these metabolites exhibit antifouling and antiparasitic activity [1316]. A Hainan Island Stylissa massa sponge contains the five new stylisines A–E (1709–1713), together with 27 known bromopyrroles [1317]. NH R2

N Br

N H

HN

NH2

NH2

H N

N H

R1

N

N H

O

O 1696 (4-debromooroidin)

1697 R1 = Br, R2 = H (4-debromougibohlin) 1698 R1 = H, R2 = Br (5-debromougibohlin) R4

R3

R7

O

NH

H N

N

N H

R2

O

HN

O

R R5

N H

Br R6

O

NH

R1

HN

H N

H N

Br O

O

Br 1705 R = H (tedamide A) 1706 R = Br (tedamide B)

1700 R1 = R4 = R5 = Br, R2 = R3 = R6 = R7 = H 1701 R1 = R2 = R4 = Br, R3 = R5 = R6 = R7 = H 1702 R1 = R2 = R3 = R4 = R5 = Br, R6 = R7 = H 1703 R1 = R2 = R4 = R5 = R6 = Br, R3 = R7 = H 1704 R1 = R2 = R3 = R4 = R5 = R6 = Br, R7 = H

Br O O NH

Br

N H

O

Br H N

HN NH2

R

O

Br

NH2

N

HN

Br O

Br N

HN

H N

1707 R = H (tedamide C) 1708 R = Br (tedamide D)

O H N

Br

H N

N

H N

HN

O

O

O

NH 1709 (stylisine A)

1711 (stylisine C)

1710 (stylisine B)

Br Br

Br N

O

Br

N

NH O

NH2

1712 (stylisine D)

NH2

N Br

O NH

O

NH2

1713 (stylisine E)

N

216

G. W. Gribble

An Indonesian sample of Agelas sp. affords the new agesamines A (1714) and B (1715), along with the well-known oroidin and manzacidin C. The agesamines are present as an inseparable mixture of epimers and the absolute configuration was determined. The authors suggest a cyclization of bis-oroidin to form the two agesamines after oxidation [1318]. The Agelas nemoechinata from the South China Sea contains the new 9-N-methylcylindradine A (1716), 1-N-methylugibohlin (1717), and nemoechine H (1718). The latter metabolite is cytotoxic against K562 and L-O2 cells (IC 50 6.1 and 12.3 μM, respectively) [1319]. This sponge also affords the dimeric bromopyrrole agelanemoechine (1719), which embodies the unique imidazo[1,5-a]azepine nucleus. The absolute configuration was determined and this novel metabolite shows potent angiogenesis activity in a zebrafish (Danio rerio) model [1320]. O

Br N

Br

Br

NH

Br

NH

H

1714 H 1715 H

N

H 2N

N

NH2

(agesamine A) (agesamine B)

H N

H 2N

HN O

Br

Br

HN

O

N

NH

1716 (9-N-methylcylindraline)

N

N

O

1717 (1-N-methylugibohlin)

O O H N H N

Br

O

O N H

O

NH2

N N

N H

NH HN

Br

1718 (nemoechine H)

O

Br

O

NH

OH

HN Br 1719 (agelanemoechine)

An Okinawan Agelas sp. sponge contains the new agesasines A (1720), B (1721), and 1722–1724. The authors admit that the two agesasines could be artifacts formed during isolation, since they are rare bromopyrrole alkaloids lacking an aminoimidazole moiety [1321]. The sponge Agelas oroides from the Israeli Mediterranean coastline yields eight new bromopyrroles: agesamine C (1725), dioroidamide A (1726), slagenin D (1727), (–)-monobromoagelaspongin (1728), (–)-11deoxymonobromoagelaspongin (1729), (–)-11-O-methylmonobromoagelaspongin (1730), dispacamide E (1731), and pyrrolosine (1732). In a biofilm assay the known oroidin is the most active [1322]. The sponge Stylissa aff. carteri in the Futuna Islands in the Southwestern Pacific ocean produces futunamine (1733), debromokonbu’acidin (1734), and didebromocarteramine (1735). Futunamine features the unprecedented pyrrolo[1,2-c]imidazole core, and the latter two metabolites are palau’amine analogs. The authors suggest that the condensation between clathrodin and oroidin would lead to futunamine [1323].

Naturally Occurring Organohalogen Compounds … Br

217

Br H N

Br N H

Br

OH Br

O

O

N H

O

Br

N H

O

H N

O

N

NH2

H N

N H

N

O 1724 ((9E)-keramadine)

1723 (9-hydroxydihydrooroidin)

Br

O

Br NH2

Br

O NH

NH2 HN

H N

Br N H

NH

NH

NH2 N H 1725 (agesamine C)

O

O

O

Br O

N H

N HN

NH HO

Br

N H

O

O

N H R 1728 R = OH 1729 R = H 1730 R = OMe

NH2

Br

N H

Br

NH

O

O

O

H N

N H

N

H2 N

1727 (slagenin D)

NH

N H

1726 (dioroidamide A)

O

Br

N

HN

O

NH

Br

Br

O

NH

Br

NH2 N

1722

N H

Br

H N

O OH

H N

Br O

H N

OH

H N

N H

O

1721 (agesamine B)

1720 (agesamine A)

Br

H N

OH

NH

N H

Br HN

Br 1731 (E-dispacamide)

Br 1732 (pyrrolosine) Br

H N

Br

H2N HN

NH2 NH

N

HN

H N

H N Br

O HN

2CF3COO–

HN N H H N

O N

HN

1733 (futunamine)

2CF3COO– O

X O

Br

Cl

H2 N H2N

HN

HN

OH

Y 1734 X = N, Y = CH 1735 X = C, Y = NH

The three mindapyrroles A–C (1736–1738), analogs of pyoluteorins, are present in the giant shipworm Kuphus polythalamius and isolated from the associated bacterium Pseudomonas aeruginosa. Mindapyrrole B exhibits the most potent antimicrobial activity (MIC 2–4 μg/cm3 ) and widest selectivity index over mammalian cells in a range of strains, such as methicillin-resistant Staphylococcus aureus, Bacillus

218

G. W. Gribble

subtilis, and Staphylococcus epidermidis [1324]. The pyonitrins A–D, three of which are chlorinated A, B, D (1738–1741), are found in Pseudomonas protegens, an insectassociated bacterium. Like the mindapyrroles, the pyonitrins are “tethered” via a thiazole ring [1325]. The hypothesis that the pyonitrins arise via the condensation between the pyochelin and pyrrolnitrin biosynthetic intermediates [1325] has been demonstrated [1326]. A Micromonospora sp. bacterium living with the Florida Keys tunicate Phallusia nigra contains the novel phallusialides A–E, four of which, A, B, D, E (1742–1745) are halogenated. The former two are antibacterial against methicillin-resistant Staphylococcus aureus and E. coli (MIC 32 and 64 μg/cm3 , respectively) [1327]. O

H N

OH

OH

O

H N

OH

Cl

Cl S

OH

HO Cl

N

Cl H N

1736 (mindaspyrrole A)

O

OH

OH

O

H N

Cl

Cl

OH

OH

HO Cl

Cl

S N OH

O

H N

OH

HO

O

H N

NH

OH

HO

Cl

Cl

Cl

1738 (mindaspyrrole C)

1737 (mindaspyrrole B) O

OH

HO

HO

R2

NH2

O N

O NH2

O

O

O

O

HO

O

S N

HN

O

NH

R1

O

Cl

Cl

Cl

OH

O NH2

O

O

O

OH O

O

R

O

O

O NH

O

Cl

O

NH

O NH Cl 1739 R1 = Cl, R2 = H (pyonitrin A) 1742 R = Cl (phallusialide A) 1740 R1 = H, R2 = Cl (pyonitrin B) 1743 R = Br (phallusialide B) 1741 R1 = Cl, R2 = Cl (pyonitrin D)

1744 (phallusialide D)

1745 (phallusialide E)

An Amycolatopis sp. MK575-fF5 produces amycolamicin (1746), which is active against both methicillin-resistant Staphylococcus aureus (MIC 90 0.39 μg/cm3 ) and

Naturally Occurring Organohalogen Compounds …

219

vancomycin-resistant enterococci (MIC 90 0.2–0.78 μg/cm3 ) [1328, 1329]. A related compound, kibdelomycin from Kibdelosporangium sp., was initially proposed to have the structure of a diastereomer of 1746 [1330]. Subsequently, syntheses of amycolamicin established the identity of amycolamicin (1746) with kibdelomycin [1331–1333] and the kibdelomycin A (1747) [1334]. This confusion arose from the fact that the isolated kibdelomycin was “a salt form” of amycolamicin, which have different NMR spectra. A strain of Actinoallomurus 145414 produces the new spirotetronate analogs nai 414-A (1748) and nai 414-B (1749). These novel metabolites are active against a battery of Gram-positive bacteria (MIC 0.25–4 μg/cm3 ) and the human microvascular endothelial cells HMEC-1 (IC 50 2–9 μM). The corresponding brominated pyrroles form when bromide is added to the culture medium [1335]. OAc HO H N

R Cl

O

O

O CONH2

N

O HO N H

O

O O

O

OH

Cl 1746 R = Me (amycolamicin; kibdelomycin) 1747 R = H (kibdelomycin A)

HO2C

O

O O

Cl O

HN

H N

O OH

R O

Cl

1748 R = H (nai 414-A) 1749 R = Cl (nai 414-B)

Although tetrabromopyrrole and hexabromo-2,2 -bipyrrole were identified in the marine bacterium Chromobacterium sp. nearly 50 years ago [1], mixtures of bromochloro-2,2 -bipyrroles and heptahalogenated-1-methyl-1,2 -bipyrroles since 1999 are ubiquitous in the marine environment [2]. These polyhalogenated bipyrroles are pervasive in the environment and in food derived from marine life. An excellent review by the pioneer in this field, Walter Vetter, is available [1336]. For example, heptachloro-1 -methyl-1,2 -bipyrrole (“Q1”) and both chlorinated, brominated, and mixed analogs of Q1, and halogenated 2,2 -bipyrroles are found in the common dolphin (Delphinus delphis) [1337], 15 species of deep-sea squid [1338], the tiger shark (Galeocerlo cuvier) [1339], killer whales (Orcinus orca) [1340],

220

G. W. Gribble

dugongs (Dugong dugon) [1341], seagrass from Queensland, Australia [1342], bluefin tuna (Thunnus thynnus), two species of ray (Gymnura altavela, Zapteryx brevirostris) [1343], sea cucumber (Holothuria sp.) [1344], humpback dolphin (Sousa chinensis), Australian venus tuskfish (Choerodon venustus), white whale (Delphinapterus leucus), sperm whale (Physeter macrocephalus) [1345], blue mussels (Mytilus edulis) [462, 1346], oysters (Crassostrea gigas) [462], choka squid (Loligo reynaudii) [463], sardine (Sardinops sagax) [465], swordfish (Xiphias gladius), yellow fin tuna (Thunnus albacares), bigeye tuna (Thunnus obesus), skipjack tuna (Katsuwonus pelamis), silky shark (Carcharhinus falciformis), Indian mackerel (Rastrelliger kanagurtá) [1347], and California sea lion (Zalophus californianus) [466]. The concentrations of the polyhalogenated bipyrroles vary between species and nearly all of these investigations also report the presence of anthropogenic-persistent organic pollutants (POPs). One new halogenated bipyrrole is described, heptachloro1,2 -bipyrrole (Q1), which was found in several marine mammals stranded on the French Atlantic coasts [466]. Some of these studies find that the natural halogenated organic compounds (bipyrroles, diphenyl ethers) are predominant over the POPs (e.g., [1346]). The halogenated bipyrroles are also found in seabirds [1348]. In fact, the 1999 discovery of all but one of the halogenated bipyrroles was from seabird eggs [2]. Heptachloro-1 -methyl-1,2 -bipyrrole (Q1) is also detectable in air samples from the Arctic, the Antarctic, and Southern Norway [1349], and is present in ocean waters from the Great Barrier Reef, Australia, at an estimated mean concentration of 25 pg/dm3 of heptachloro-1 -methyl-1,2 -bipyrrole [460], which is comparable to the concentration of dichlorodiphenyltrichloroethane in a polluted lake in the U.S. Dichlorodiphenyltrichloroethane and polybrominated diphenyl ethers were not detected in waters off the Great Barrier Reef [460]. Several studies demonstrate that these polyhalogenated bipyrroles concentrate in marine food webs [1336, 1350– 1352]. Although the general premise is that halogenated bipyrroles are biosynthesized [1352], there is a study showing that ozone can affect the halogenation of bipyrroles in seawater (mainly bromination) [1353]. Interestingly, photolytic dehalogenation of heptachloro-1 -methyl-1,2 -bipyrrole (Q1) occurs rapidly under ultraviolet irradiation to produce two hexachloro isomers and, subsequently, two pentachloro isomers [1354]. At least some of these photo dehalogenated heptachloro-1 -methyl-1,2 -bipyrrole analogs are also present in environmental samples [2]. Moreover, the photolysis of heptachloro-1 -methyl-1,2 bipyrrole in the presence of bromine leads to four isomeric BrCl6 -MBPs (MBP = 1 -methyl-1,2 -bipyrroles), seven Br2 Cl5 -MBPs, and traces of Br3 Cl4 -MBPs and Br4 Cl3 -MBPs [1355], many of which are present in environmental samples [2]. It has been shown that enzymatic reductive dehalogenation of marine bromopyrroles can control their biosynthesis activities. For example, gene clusters from Marinomonas mediterranea MMB-1 and Pseudoalteromonas sp. PS5 transform l-proline to 2,3,4,5-tetrabromopyrrole, then to 2,3,4-tribromopyrrole, which can couple to 2,4-dibromophenol and provide the known metabolite pentabromopseudilin [1356].

Naturally Occurring Organohalogen Compounds …

221

The most frequently encountered naturally occurring polyhalogenated 2,2 bipyrrole is 5,5 -dichloro-1,1 -dimethyl-3,3 ,4,4 -tetrabromo-2,2 -bipyrrole (DBPBr4 Cl2 ; “BC-10”) [2]. This metabolite is axially chiral due to restricted biaryl rotation, and it has been resolved. Both atropisomers are present in the natural sample with enrichment of the levo (–)-enantiomer. No racemization is observed up to 150°C [1357]. A new synthesis of Q1 and the first synthesis of the naturally occurring 2,3,3 ,4,4 ,5,5 -heptabromo-1 -methyl-1,2 -bipyrrole are reported [1358]. A new synthesis route to hexahalogenated 2,2 -bipyrroles is described [1359]. Cl Cl

Cl

Br

Cl Cl

N

N Cl Q1

Cl

Br

Br

Br

Br Br

N

N Br

Br

2,3,3',4,4',5,5'-heptabromo-1'-methyl-1,2'-bipyrrole

Br

Br N

Br

N Br

Br

BC-10

Several notable syntheses and biosynthesis studies of pyrrole natural products are recorded, including that of dispyrin (1543) [1360], (–)-agelastatins E (1569) and F (1570) [1361], chlorizidine A (1635) [1362] and its biosynthesis [1363], and the biosyntheses of armeniaspirols (1638–1640) [1364]. Several syntheses have led to structural revisions or incorrect assignments including those of mukanadin F [1365], nagelamide D [1366], and celastramycin A [1367]. The large ensemble of pyrrole2-aminoimidazole marine alkaloids continues to be of great interest [1368, 1369]. At the top of this list is palau’amine, which succumbed to total synthesis by Baran in 2010 [1370, 1371], followed by a second total synthesis [1372]. These successful syntheses were guided by the revision of palau’amine [1373–1378]. Thereafter, extensive synthesis work continues of these complex pyrrole-imidazole alkaloids (i.e., axinellamines, massadines, stylissadines, benzosceptrins) [1379–1386].

3.14.2

Indoles

Like pyrrole, indole is enormously reactive in electrophilic halogenation. The indole molecule at once is an enamine and an aniline, imparting reactivity at both the indole double-bond and the benzene ring. A very large number of mono- and polyhalogenated (mainly brominated) indoles are found in Nature [1, 2]. The new 2,3,4,6tetrabromo-1-methylindole (1750) is present in the red alga Laurencia decumbens from Weizhou Island in the South China Sea [576], and a collection of Laurencia similis from Hainan Province, China, yields 3,5-dibromo-1-methylindole (1751) and the new bis-indole 1752 [1387]. A New Zealand red alga Rhodophyllis membranacea contains eleven novel tetrahydrogenated indoles 1753–1763 [1388]. This extensive investigation uncovered four unprecedented bromochloroiodoindoles (1754–1757).

222

G. W. Gribble H N

Br

Br Br

Br

Br

Br

Br

Br Br

Br

N

Br

N

1750

1751 Br

1752 Cl

Cl Br

Br

Cl

N H

Br

N H

Br

N H

I

Br

N H

I Br

Br

1753

1754 Cl

Br

1755 Cl

Cl

Cl

Br Br

Cl

Cl N H

N H

N H

I

I

Br 1756

1758

1757 R2

Cl R

R3 R4

Cl

1

Cl

N H

1759 R1 = Cl; R2 = R3 = R4 = Br 1760 R1 = R3 = R4 = Br; R2 = Cl 1761 R1 = R2 = Cl; R2 = R4 = Br 1762 R1 = R2 = R4 = Cl; R3 = I

N H I 1763

A number of new simple halogenated indoles that are functionalized, typically at C-3, are now known, including the 6-bromoindoles 1764 and 1765 from the sponge Spongosorites sp. [1389], 1766 from the sponge Iotrochoto birotulata [1390], 1767 from the Kuril Islands ascidian Syncarpa oviformis [1391], and 1768 from the sponge Mycale fibrexilis [1392]. An examination of the Thai sponge Smenospongia sp. gathered in the Andaman Sea uncovered the bromoindoles 1769–1773, which are found from a natural source for the first time, along with the new natural products 1774–1777. The compounds were screened SmallCapsagainst a battery of human cell lines for cytotoxicity but only the known 5,6-dibromotryptamine shows good activity against MOLT-3 (human leukemia) and HeLa cells [555]. The Fijian sponge Hyrtios sp. contains the new 5,6-dibromo-l-hypaphorine, which displays significant antioxidant activity in the ORAC assay, only four-fold less active than Trolox, the water-soluble Vitamin E analog. Four other known tryptamines are also present in this sponge [1393]. Three new polybrominated tryptamines, terminoflustrindoles A–C (1779–1781), are found in the bryozoan Terminoflustra membranaceatruncata collected in the White Sea [1394, 1395].

Naturally Occurring Organohalogen Compounds … R1

O

R

N H

N H

Br

1764 R1 = OMe, R2 = H 1765 R1 = NH2, R2 = H 1766 R1 = OEt, R2 = H 1767 R1 = OEt, R2 = OH

R1

N H

1769 R1= R2 = Br, R3 = OMe 1770 R1= Br, R2 = H, R3 = OMe 1771 R1= Br, R2 = R3 = H 1772 R1= R2 = Br, R3 = H 1773 R1= Br, R2 = H, R3 = OH O CO2–

N N H

Br N H

R3

1

R2

1768

2 N R

Br Br

O

NH2

O

R2 Br

O

223

O

N H

Br

1774 R1 = H, R2 = CHO 1775 R1 = H, R2 = COMe 1776 R1 = Me, R2 = COMe

Br

N H

1778 (5,6-dibromo-L-hypaphorine)

1777 R1

R2

N

Br

NH2

N H

Br

1779 R1 = R2 = Br (terminoflustrindole A) 1780 R1 = Br, R2 = H (terminoflustrindole B) 1781 R1 = H, R2 = Br (terminoflustrindole C)

A series of structurally unique indole alkaloids is found in the Okinawan sponge Suberites sp. that include nakijinamines A (1782), B (1783), F (1784), G (1785), H (1786), I (1787), and 6-bromoconicamin (1788) [1396]. An earlier study of this sponge identified C (1789), D (1790), and E (1791) [1397]. Of these alkaloids only nakijinamine A (1782) is active against Staphylococcus aureus (MIC 16 μg/ cm3 ), Bacillis subtilis (MIC 16 μg/cm3 ), and Micrococcus luteus (MIC 2 μg/cm3 ). Nakijinamine I (1787) is the first aaptamine-type alkaloid to have a 1,4-dioxane unit. A sample of the sponge Geodia barretti from the Norwegian coast contains 6-bromoconicamin (1788) and the novel 1792 [1398]. Along with 1788 there is found in the Indonesian sponge Oceanapia sp. CO 11,027 the new 6-bromo-8-ketoconicamin A (1793), which is active towards the pancreatic cancer cell line PANC-1 (IC 50 1.5 μM) [1399].

224

G. W. Gribble Br HN

N

OH

R

O

N

OH

R

HO

N

HN NH

HN

O

Br

O

N H

HN

N H

HN

N H

N H

1784 R = iso-Bu (nakijinamine F) 1785 R = sec-Bu (nakijinamine G) 1786 R = CH2Ph (nakijinamine H)

1782 R = Br (nakijinamine A) 1783 R = H (nakijinamine B)

1787 (nakijinamine I)

SO3 N

Br

N NH

HN N H

Br

R

O

N

O

Br

HN N H

HN N H

N H

1788 (6-bromoconicamin)

N

OH

1789 (nakijinamine C)

1790 R = CH2SO3– (nakijinamine D)

N N O

N

HO

O

N

N O

Br

N NH

HN

N H

Br

Br

N H

N H

1791 (nakijinamine E)

1792

1793

Several collections of the bryozoan Amathia verticillata from Brazil, Italy, and Florida revealed the new 2,6-dibromo-N-methylgramine (1794), together with the known 2,5,6-tribromo-N-methylgramine [1400]. The Great Barrier Reef sponge Jaspis splendens contains the new imidazole jaspnin A (1795) and a novel bisindole alkaloid splendamide (1796) [1401]. A Red Sea collection of the sponge Hyrtios erectus presents the new bromoindole 1797, which shows antiproliferative activity against several cancer cell lines (HCT-116, MCF-7, Hep G2) and has some antibacterial activity [1402]. The Southwestern Pacific sponge Narrabeena nigra from the Futuna Islands led to the new bromotryptamines 1798–1802 along with three new non-indolic analogs presented later in the appropriate sections. No significant cytotoxicity is observed [1403]. The Australian bryozoan Amathia lamouroux from New South Wales affords the new 2,5-dibromo-1-methylindole-3-carbaldehyde (1802), along with five new convolutamines (K and L) and volutamides (F–H) presented later [1404]. An earlier study found 2,5-dibromo-1-methylindole (1803) in the red alga Laurencia similis from China [1405].

Naturally Occurring Organohalogen Compounds …

225

Plate 42 Salinispora arenicola (Photograph courtesy of Xanthippi P. Louka et al.; isolated from the soft coral Scleronephtya lewinsohni; https://www.mdpi.com/cimb/cimb-44-00002/article_deploy/ html/images/cimb-44-00002-ag.png Creative Commons Attribution-Share Alike 4.0 International)

HN

N

NH2

O

Br N

N H

Br

HN

NH

1796 (splendamide)

1795 (jaspnin A)

1794

Br

N H

Br Br

O

Cl O

O

N

N N N H Br

N H

O

Br

Br N H

Br

Br

1798

1797

N H 1799

HN Br

Br

Br

N

O Br

R

HO

HO

N H 1800

Br

N H 1801

Br N 1802 R = CHO 1803 R = H

226

G. W. Gribble

A collection of Formosan Laurencia brongniarii yields the new polybrominated indole 1804, in addition to eleven known analogs [1406]. The unique indiacen B (1805) is produced by the myxobacterium Sandaracinus amylolyticus NOSO-4 T, which is the inaugural representative of this new genus of gliding bacteria. This metabolite is active against both Gram-positive and Gram-negative bacteria as well as the fungus Mucor hiemalis, as is the dechlorinated indiacen A. Indiacen B is more active than indiacen A against Arthobacter rubellus (MIC 0.8 vs. 16.6 μg/ cm3 ) and Nocardioides simplex (MIC 3.3 vs. 8.3 μg/cm3 ) [1407]. The new 6-bromo oxindoles 1806–1808 are found in the two actinomyceles, Saccharomonospora sp. UR22 and Dietzia sp. UR66, living in the Red Sea sponge Callyspongia siphonella. Compounds 1806 and 1808 are potent Pim-1 kinase inhibitors (IC 50 0.3 and 0.95 μM, respectively) [1408]. The 6-bromoindole enone 1809 is found in the marine sponge Iotrochoto birotulata [1390]. The novel 5-chloro oxindole 1810 is found in the marine Salinispora arenicola (Plate 42) strain from Brazilian sediments [1409]. The rare sponge Lamellomorpha strongylata found in deep New Zealand waters (200 m) produces the new isomeric (Z)- and (E)-coscinamide D (1811), and the brominated lamellomorphamides B–D (1812–1814), which are known synthetic compounds but not as natural products. Another 15 known related natural products are present in this sponge [1410]. A sample of the sponge Fascaplysinopsis reticulata from the Island of Mayotte in the Mozambique Channel delivered the new brominated isoplysins 1815 and 1816, which display antibacterial activity against Vibrio natrigens (MIC 0.01 and 1 μg/cm3 , respectively) [1411]. The sea anemone Heteractis aurora from Bali, Indonesia, contains the new 6bromoindole imidazolone 1817, an aplysinopin-type alkaloid, which was confirmed by synthesis [1412]. Kororamide A (1818) and B (1819) are found in the Australian bryozoan Amathia tortuosa [1413, 1414]. The simple 2-bromotryptamine 1820 is present in the Mediterranean gorgonian Paramuricea clavata (Plates 43 and 44) along with the isomeric 1821, which is a known synthetic product but is a new natural product. Both compounds exhibit antifouling properties against three marine biofilm bacteria [1415]. Purpuroine J (1822) along with nine halogenated non-indoles, to be described separately, are found in the China sponge Iotrochota purpurea [1416]. The new aplysinopsin 1823 is found in the Mediterranean coral Astroides calycularis near Gibraltar, together with several known aplysinopsin analogs [1417]. Both enantiomers of bromoanaindolone (1824) are produced by the cyanobacterium Anabaena constricta, with a slight excess of the (3R) isomer [1418].

Naturally Occurring Organohalogen Compounds …

227 O

Cl

O

Br

O

HN

OH

Br S N H

Br

O

O O

N H

1805 (indiacen B)

1804

N H

Br

N H

Br

1807 (convolutamydine F)

1806 (saccharomonosporine A) O

HN

HO

O

Cl

OH

O

O N H

Br

1810

O

H N

HN NH

N

MeO

1809

O N H

N H

Br

1808

O O

NH

HN

HN

NH

O

O

O

R1 Br

Br (Z)-1811

O N N H

R Br

N H 1815 R = H 1816 R = Br

N H 1812 R1 = Br, R2 = H 1813 R1 = H, R2 = Br 1814 R1 = R2 = Br

(E)-1811

N

R2

228

G. W. Gribble

Plate 43 Paramuricea clavata (Photograph courtest of Parent Géry; Banyuls-sur-Mer, Sec de Rédéris; Creative Commons CCO 1.0 Universal Public Domain Dedication)

Plate 44 Paramuricea clavata (Photograph courtesy of Waielbi; Open polyps; Creative Commons Attribution-Share Alike 3.0 Unported)

Naturally Occurring Organohalogen Compounds …

229 O

O

N

N

N

NH2

N

H

O

N

N

Br N H

Br

Br

N

Br Br

Br

1818 (kororamide A)

1817

N

Br

1819 (kororamide B) N N

N

NH

N CO2Me

O

R1 R

2

N H

1820 R1 = Br, R2 = H 1821 R1 = H, R2 = Br

N H

Br

Br

1822 (purpuroine J)

N H 1823

HO O Br

N H

1824 (bromoanaindolone)

The novel streptochlorin (1825) is produced by the marine-derived Streptomyces sp. 04DH110 [1419], and earlier from Streptomyces sp. SF2583A and known as SF2583A but unavailable to this author until now [1420]. Streptochlorin has excellent activity against the K-562 leukemia cell line (IC 50 1.05 μg/cm3 ), only slightly weaker than doxorubicin [1419]. The Australian marine sponge Trachycladus laevispirulifer contains trachycladindoles A–F (1826–1831), alkaloids similar to discodermindole [1]. The relative and absolute configurations are unknown. These metabolites show a range of cytotoxicity against the cancer cell lines A-549, HT29, and MDA-MB-231, with the most active compounds favoring N-10 and N-12 dimethylation, and C-9 hydroxylation [1421]. Bunodosine 391 (1832) is a toxic ingredient of the venom of the sea anemone Bunodosoma cangicum (Plate 45). This novel metabolite verified by synthesis displays potent analgesic activity as mediated by serotonin receptors [1422]. The dried roots of Zanthoxylum nitidum, which have been used for more than 1000 years in Chinese traditional medicine, yield the novel indolium chloride (no number). The authors presume that the trichloromethyl group is derived from chloroform used in the extraction process from an unknown precursor [1423].

230

G. W. Gribble

Plate 45 Bunodosoma cangicum (Photograph courtesy of Pablo Balduvino; NaturalistaUY)

N Cl

Y

Br

O

NR

N

N

N H 1825 (streptochlorin)

H N

NH2 X N H

Br

CO2

1826 X = H, Y = H, R = H (trachycladindole A) 1827 X = H, Y = H, R = Me (trachycladindole B) 1828 X = OH, Y = H, R = H (trachycladindole C) 1829 X = OH, Y = H, R = Me (trachycladindole D) 1830 X = H, Y = OH, R = Me (trachycladindole E) 1831 X = OH, Y = OH, R = Me (trachycladindole F) OH

N H

O

CO2H

N H

1832 (bunodosine 391)

O

HO CCl3 N Cl indolium chloride

A fungus from a Chinese salt field, Aspergillus variecolor, produces variecolorins A (1833), B (1834), and F (1835), which are essentially non-cytotoxic against several standard cancer cell lines (IC 50 70–200 μM) [1424]. The novel iodinated hicksoanes A–C (1836–1838) are found in the Gulf of Aqaba gorgonian Subergorgia hicksoni. These metabolites show antifeeding activity against goldfish at 10 μg/cm3 [1425]. The Great Barrier Reef ascidian Eusynstyela latericius contains eusynstyelamides A–C (1839–1842, 1843) [1426]. An earlier report identified “eusynstyelamide” (most likely = ent-eusynstyelamide A (1842), the antipode of 1839) from Eusynstyela misakiensis [1427], and eusynstyelamides D–F (1844–1846) along with ent-eusynstyelamide B (1843), which is the antipode of 1841, have been discovered in the Arctic bryozoan Tegella cf. spitzbergensis [1428]. The reassignment of “eusynstyelamide” (1842) to the antipode of 1839 is based on their opposite optical rotations.

Naturally Occurring Organohalogen Compounds …

231 O

O

NH

NH

R2

O

HN O

O

N H

R2

HO

O

1835 (variecolorin F)

H N

N OH NH

HN

1836 R1 = H, R2 = I (hicksoane A) 1837 R1 = I, R2 = H (hicksoane B) 1838 R1 = I, R2 = I (hicksoane C)

Cl

1833 R1 = OH, R2 = Cl (variecolorin A) 1834 R1 = Cl, R2 = OH (variecolorin B)

HO

O

N H

N H

Br

NH2

Br

HO

O

H N

N

NH

OH NH

HN

O NH

NH

N H

Br

HN

NH HN

NH2

NH2

1839 (eusynstyelamide A) 1842 (ent-eusynstyelamide A)

Br

HO

1840 (eusynstyelamide B) 1843 (ent-eusynstyelamide B)

Br

O

H N

N OH NH

HN

NH

N H

R1

O HO

NH2

N OH

HN

NH O

O Br

NH2

O

N H

Br

NH

R1

HN

HN R1

H N

NH HN

Br

N H

R2

NH2 1841 (eusynstyelamide C)

1844 R1 = R2 = NH2 (eusynstyelamide D) 1845 R1 = NH(C=NH)NH2, R2 = NH2 (eusynstyelamide E) 1846 R1 = NH2, R2 = NH(C=NH)NH2 (eusynstyelamide F)

The new bis-indole pyrroles, lynamicins A–E (1847–1851) are present in a marine Marinispora sp. actinomycete from Mission Bay in San Diego. These alkaloids are active against a battery of drug-resistant pathogens, especially Staphylococci and Enterococci [1429], and 1850 and 1851 are related to lycogalic acid dimethyl ester. The Panamanian sponge Smenospongia cerebriformis contains the complex alkaloids dictazolines A–D (1852–1855) and dictazoles A (1856) and B (1857). A vinyl cyclobutane rearrangement would appear to convert the dictazoles to the dictazolines [1430, 1431]. Structurally related to the dictazolines are the new tubastrindoles D (1858) and F (1859) present in the stony coral Tubastraea aurea [1432]. Leptoclinidamine C (1860) is present in the Australian ascidian Leptoclinides durus, and this novel bromoindole contains the rare 5-(methylthio)histidine moiety. Two related metabolites are devoid of bromine. This new compound is inactive in the bioassays screened (antimalarial, cytotoxicity, and antitrypanosomal) [1433]. The Southern Australian sponge Ianthella sp. contains several new dictyodendrins, two of which H (1861) and I (1862) are halogenated. Both compounds show Gram-positive antibacterial activity against Bacillus subtilis (ATCC 6051 and 6633): 1861 (IC 50 1.2 and 3.1 μM), and 1862 (IC 50 2.5 and 2.8 μM) [1434].

232

G. W. Gribble R4 H N

R2 X

Cl

Y

NH N R3

R1

Z N H

R2

N

O

R1

N H

N H

1847 R1 = CO2Me, R2 = H; X = Cl, Y = Z = H (lynamicin A) 1848 R1 = CO2Me, R2 = H; X = Y = Cl, Z = H (lynamicin B) 1849 R1 = R2 = H; X = Y = Z = Cl (lynamicin C) 1850 R1 = R2 = CO2Me; X = Cl, Y = Z = H (lynamicin D) 1851 R1 = R2 = CO2Me; X = Y = Z = H (lynamicin E)

NH

N O

N

NH

1852 R1 = Br, R2 = Br, R3 = Me, R4 = Me (dictazoline A) 1853 R1 = Br, R2 = Br, R3 = H, R4 = H (dictazoline B) 1854 R1 = Br, R2 = H, R3 = H, R4 = H (dictazoline C) 1855 R1 = Br, R2 = H, R3 = H, R4 = Me (dictazoline D) Br

NH2 N

NH2

NH

Br

NH

HN

N

Br

O

Br

N

O

N

NH N

NH

O N

O N

N

O

HN

N

NH2

1856 (dictazole A)

N H NH2

NH

N O

N

O

1858 (tubastrindole D)

1857 (dictazole B) O HO O

Br

N

O

O

NH

N N H

N O

N

S

Br

NH

N CF3COO N

N H NH

1860 (leptoclinidamine C)

1859 (tubastrindole F)

HO OH NH O N

O

X OH HO

1861 X = Br (dictyodendrin H) 1862 X = I (dictyodendrin I)

The Chinese medicinal plant Alstonia yunnanensis contains eight new monoterpenoid indole alkaloids, including the chlorohydrin alstoyunine H (1863). The authors admit that 1863 could be an artifact formed from the corresponding epoxide (lochnerinine), which was also isolated, and HCl was used in the extraction procedure [1435]. Three new chlorinated ambiguine isonitriles, K, M, and O (1864–1866) are found in cultures of the cyanobacterium Fischerella ambigua [1436], and, in a later study, fischambiguine B (1867) [1437]. Both 1864 and 1865 show potent activity against Mycobacterium tuberculosis (MIC 6.6 and 7.5 μM, respectively), and 1867 is even more potent (MIC 2 μM). The famous Madagascar periwinkle plant,

Naturally Occurring Organohalogen Compounds …

233

Plate 46 Flustra foliacea (Photograph courtesy of Hans Hillewaert; from the Belgian coastal waters; Creative Commons Attribution-Share Alike 4.0 International)

Catharanthus roseus, which produces the life-saving anticancer drugs vincristine and vinblastine, also contains the chlorinated tabersonine alkaloids 1868–1872 (absolute configuration shown). An HPLC examination of the crude plant extract reveals the presence of these four alkaloids [1438]. The prolific bryozoan Flustra foliacea (Plate 46), collected from Scandinavia and Canada, delivers nine new brominated flustramine alkaloids 1873–1881. Not shown are two dimers that the authors caution are isolation artifacts [1439]. Synthesis activity in this area has been intense and a review is available covering work prior to 2008 [1440]. Syntheses include those of deformylflustrabromine [1441, 1442], flustramine A [1443, 1444], flustramine B [1445, 1446], flustramine C [1443], flustramide A [1443], debromoflustramine A [1443], and debromoflustramine B [1447]. Cl

Cl OH

N

OH

Cl NC

OH

Cl NC

OH

OH OH

O

NC

COOCH3

N H

1863 (alstoyunine H)

NH

O

NH

NH

1864 (ambiguine K isonitrile) 1865 (ambiguine M isonitrile) 1866 (ambiguine O isonitrile)

Cl O

O N

NC O

NH 1867 (fischambiguine B)

N H

N

Cl

Cl

19

19

CH3

CH3

COOCH3

1868 ((19S)-chlorotabersonine) 1869 ((19R)-chlorotabersonine)

N H

COOCH3

1870 ((19S)-chloro-3-oxotabersonine) 1871 ((19R)-chloro-3-oxotabersonine)

234

G. W. Gribble

OH

OH

R1 N

N

N

R

N

Br

R

OH N

R2

N H

N H

N H

Br

Br

Br 1873 R1 = H, R2 = Ac (flustramine F) 1875 R = H (flustramine H) 1877 R = H (flustramine I) 1874 R1 = Br, R2 = H (flustramine G) 1876 R = Br (flustramine J) 1878 R = Br (flustramine K) HO

HO2C

H 2N HO

Br

O

1879 (flustramine L)

O

NH

N N

O

O

N H

O

N H

Br 1880 (flustramine M) H2N

1882 (kingamide A)

1881 (flustramine N)

O

CONH2

CONH2

N

N

HN

N

H2N

H2N

CO2H

O

H2N

Cl

S N

Cl

N

Cl

NH2

NH2

1883 X = S (ammosamide A) 1884 X = O (ammosamide B)

1885 (ammosamide C)

HN O

Cl O

1886 (ammosamide D)

N

N O

1887 (citharoxazole)

The Australian ascidian Leptoclinides kingi contains the bromoindole kingamide A (1882), which represents the first natural product to be identified in this animal [1448]. A marine Streptomyces sp. CNR-698 from a Bahamas sediment has provided ammosamides A (1883) and B (1884), which are significantly cytotoxic towards HCT-116 colon carcinoma cells (IC 50 0.32 μM) [1449], and target the motor protein myosin [1450]. Following the first syntheses of ammosamides A and B [1451], there followed a flurry of syntheses of B (1884) [1452–1455], and a summary of the initial discovery [1456]. Subsequently, ammosamides C (1885 [1451] and D (1886) were isolated from this marine bacterium [1457]. Ammosamide C (1885) can undergo a hydrolysis-oxidation sequence to give ammosamide B (1884), raising the question of ammosamide artifacts [1457]. A new batzelline analog, citharoxazole (1887), is present in the Mediterranean deep-water (103 m) sponge Latrunculia citharistae [1458]. The unique 1,2,4-oxadiazole-containing phidianidine A (1888) is found in the mollusk Phidiana militaris living along the coast of Hainan Island together with the debromo-analog, phidianidine B. Both A and B are highly cytotoxic towards C6 (rat glioma), HeLa (human cervical), and 3T3-L1 (murine embryonic) cells (IC 50 0.64, 1.52, 0.14 μM, respectively, for phididianidine A) [1459]. Later studies find

Naturally Occurring Organohalogen Compounds …

235

Plate 47 Didemnum molle (Photograph courtesy of University of Guelph students; http://lifg. australianmuseum.net.au/HotShot.html?resourceld=IhJXEimf; Creative Commons Attribution 3.0 Unported)

that 1888 and some analogs show nontoxic inhibition of barnacle cyprid metamorphosis [1460], and show immunosuppressive properties [1461]. A synthesis of 1888 is described [1462]. The New Zealand ascidian Didemnum sp. (Plate 47) contains didemnidine B (1889), along with the debrominated A, with both structures confirmed by synthesis. Didemnidine B and a synthetic precursor show some growth inhibition of Plasmodium falciparum (IC 50 15 and 8.4 μM, respectively) [1463]. The Vanuatin sponge Clathria (Thalysias) araiosa delivers the four extraordinarily complex tris-bromoindole cyclic guanidine alkaloids, araiosamines A–D (1890–1893) [1464], the structures of which are validated by total synthesis [1465]. The new herdmanine D (1894) is found in the Korean ascidian Herdmania momus [1466], which also provides herdmaines E (1336) and F (1337) [1039]. Herbmanine D inhibits the mRNA expression of iNOS and the resulting production of nitric oxide (IC 50 9 μM) [1466].

236

G. W. Gribble O

O H N

N

H N

O N

Br

N H

NH2 NH

NH2 2CF3COO

N H

Br

N H

NH3 1889 (didemnidine B)

1888 (phidianidine A) R

R

R

R

R

O

HO NH

NH HN

HN

HN

NH

NH

NH HN

NH

R= N H

NH

NH

Br

1891 (araiosamine B)

1890 (araiosamine A) Br R

NH

HN HN

HN

R

N

HN

R

R

R HN

NH

O CO2H

Br N H

NH NH

O

HO

HN

H2N

NH NH

1892 (araiosamine C)

1893 (araiosamine D)

1894 (herdmanine D)

A collection of the fungus Aspergillus sp. living on the mussel Mytilus edulis galloprovincialis in the Sea of Japan affords two halogenated notoamides N (1895) and P (1896) [1467, 1468]. Notoamide P is the first brominated prenylated indole alkaloid to be isolated, and notoamide N is related to the malbrancheamides, such as the new 1897 from the fungus Malbranchea aurantiaca from Mexican bat guano [1469, 1470], and, subsequently, isomalbrancheamide B (1898) from this organism [1471]. This metabolite is also found in Malbranchea graminicola isolated from an invertebrate-derived fungus in Kona, Hawaii, a study that produced the new (–)spiromalbramide (1899) and two brominated analogs when bromide salts were added to the culture medium (not shown) [1472]. The synthesis and biological activity of the malbrancheamides and synthetic analogs has been intense [1471, 1473–1478], as has been the study of their biosynthesis [1479, 1480]. The pyrroloiminoquinone family of alkaloids is very large [1, 2], including the discorhabdins [1481–1483]; new examples are numerous. The Southern Australian Higginsia sp. sponge contains (+)dihydrodiscorhabin A (1900), along with three other new non-halogenated analogs [1484]. The structure of 1900 was revised as shown [1485, 1486]. This latter study also found both enantiomers of 16a,17a-dehydrodiscorhabdin W (1901, 1902) in New Zealand-sourced Latrunculia spp. sponges [1486]. A deep-water (230 m) Latrunculia sp. sponge from the Aleutian Islands, Alaska, contains dihydrodiscorhabdin B (1903) and discorhabdin Y (1904), together with six known pyrroloiminoquinone alkaloids [1487]. An investigation of the many discorhabdins in the New Zealand sponge Latrunculia spp. uncovered some new non-halogenated examples and established the absolute configurations of the known discorhabdins H, D, 2-hydroxy-D, N, Q, S, T,

Naturally Occurring Organohalogen Compounds …

237

and U [1488]. Although the mechanisms of action of the cytotoxic discorhabdins are unknown, it is known that discorhabdin B is electrophilic towards nucleophilic thiol species leading to debrominated adducts [1489]. An examination of the discorhabdins (B, L, G, and 3-dihydro-7,8-dehydrodiscorhabdin C) found in Antarctic Latrunculia spp. sponges shows that they are reversible competitive inhibitors of cholinesterases [1490]. O

HO

ON N H

Cl

N

Br N

O

N H

O

N H

O

N H

O

Br N S O

1898 (isomalbrancheamide B) O

1899 ((–)-spiromalbramide)

O Br 17a

N

N S

16a

S

O

1900 (dihydrodiscorhabdin A) O

OH

Br

N H

N H

N H

Cl

N H

OH

N

Cl

N H

O

1897 (malbrancheamide B)

HN

O N

O N

O

Cl

N H

H N Cl

1896 (notoamide P)

1895 (notoamide N)

H N

O

HO

Br

Br

N

N

S N H

N H O

1901 (discorhabdin W) 1902 (16a,17a-dehydrodiscorhabdin W)

N H

N H O

1903 (dihydrodiscorhabdin B)

N H

O

N H

1904 (discorhabdin Y)

The Antarctic deep-sea (290 m) sponge Latrunculia biformis contains the novel (–)-2-bromodiscorhabdin D (1905) along three known and two new non-halogenated analogs. Modeling studies revealed plausible binding opportunities for 1905 (and others) to active sites of two anticancer targets (e.g., topoisomerase I–II and indoleamine 2,3-dioxygenase) [1491]. Two subsequent studies of this sponge identified tridiscorhabdin (1906) and didiscorhabdin (1907) [1492] and dimers 1908–1910 [1493]. Dimer 1908 was previously synthesized but not isolated as a natural product until now. The diversity and electrophilic reactivity of the pyrroloiminoquinones produced by Latrunculid sponges is discussed [1483, 1494].

238

G. W. Gribble O HN

H N

H N

N

H N

HN

N

O O

S

NH

S

S O

O

H N

N

O

S

N N Br

Br

O

O 1906 (tridiscorhabdin)

1905 (bromodiscorhabdin D) O

H N

HN

O HN

S N

O O

N

H N S

H N

H N

N S

O

N Br

Br O

O 1907 (didiscorhabdin)

HN

1908 O

H N

HN S H N

N O

H N S

O H N

S

1909

H N

S

N

O

O

H N

N O

O H N

S

N

N

Br

Br O

O 1910

The new pyrroloiminoquinone atkamine (1911) is found in the deep-water Alaskan sponge Latrunculia sp. collected from the Aleutian Islands. The position of the double bond was determined elegantly by olefin metathesis [1495]. Another examination of an Aleutian Islands sponge, Latrunculia (Latrunculia) austini, identifies aleutianamine (1912), which is highly potent towards the pancreatic cancer cell line PANC-1 (IC 50 25 nM) and the colon cancer cell line HCT-116 (IC 50 1 μM) [1496]. The Tongan sponge Strongylodesma tongaensis contains 6-bromodamirone B (1913) [1497], and the new makaluvamine Q (1914) is present in the sponge Tsitsikamma favus from Algoa Bay in South Africa, together with six known analogs [1498]. Syntheses of pyrroloiminoquinone alkaloids related to the discorhabdins are noted: prianosin B [1499], batzelline C and isobatzelline C [1500, 1501], batzelline A and isobatzelline A/B [1502], makaluvamine A/D, damirone B, and makaluvone [1501]. An evaluation of the antioxidant activity of these known makaluvamines A, F, G, H, J, K, and P concludes that the most active molecules should possess an

Naturally Occurring Organohalogen Compounds …

239

unsubstituted nitrogen in the pyrrole ring, plus a para-hydroxystyryl group without a double bond, leading to a substantial antioxidant effect in neuronal cells [1503]. A deep-water (630 m) collection of the sponge Spongosorites sp. from the Bahamas finds dragmacidin G (1915) [1504], and both dragmacidin G and H (1916) are present in the sponge Lipastrotethya sp. from Japan also in deep waters (185–213 m) [1505]. Dragmacidin G shows a range of biological activity, both cytotoxicity to cancer cells and antimicrobial activity against resistant bacteria [1504]. New analogs, dragmacidins I (1917) and J (1918) are found in the sponge Dragmacidon sp. from Tanzania at 80 m [1506]. These two compounds exhibit low micromolar cytostatic activity by inhibiting PP1 and/or PP2A phosphatases. Syntheses of both dragmacidin D [1507–1509] and E [1510] are recorded. A revision of the stereochemistry has been determined [1509], and this study reveals that natural dragmacidin D is isolated as either a racemate or a scalemic mixture 39% ee. O HN

H N

Br

O

O OH

S

NH

HN

O

H N S

O

HN

Br N

N Br

1913 (6-bromodamirone B)

1912 (aleutianamine)

1911 (atkamine)

H N

Br

NH

O N

NH2

N

N

R N

Br N 1914 (makaluvamine Q)

S

H N

HN 1915 R = Br (dragmacidin G) 1916 R = H (dragmacidin H)

NH2 NH

Br N HN

R

1917 R = H (dragmacidin I) 1918 R = Me (dragmacidin J)

240

G. W. Gribble

Plate 48 Caulerpa racemosa (Photograph courtesy of Nick Hobgood; Creative Commons Attribution-Share Alike 3.0 Unported)

The novel caulerchlorin (1919) is found in the Chinese green alga Caulerpa racemosa (Plate 48), and it has weak activity against Cryptococcus neoformans (MIC 16 μg/cm3 ) [1511]. Iotrochamide B (1920) was isolated from the Australian sponge Iotrochota sp., and this metabolite inhibits Trypanosoma brucei brucei (IC 50 4.7 μM) [1512]. The deep-sea (3412 m) Streptomyces sp. SCS 10 03032 sediment sample from the Bay of Bengal provides the remarkably complex spiroindimicins A–D (1921– 1924). Spiroindimicin B (1922) is moderately active against B16 (murine melanoma), H460 (human lung), and CCRF-CEM (human leukemia) cells (IC 50 5, 12, 4 μg/ cm3 , respectively). Spiroindimicin C (1923) is active towards the HepG2 (human hepatocellular liver) and H460 cell lines (IC 50 6 and 15 μg/cm3 , respectively). The other two metabolites are less active (1923) or inactive (1924) [1513]. In addition to several known 6-bromoindoles, the sub-Arctic sponge Geodia barretti contains the new geobarretins A–C (1925–1927), which display anti-inflammatory activity (inhibition of human dendritic cell secretion of IL-12p40) [1514]. A synthesis of barettin is described [1515]. The cyanobacterium Fischerella sp. SAG 46.79 houses the new fischerindoles 1928 and 1929, along with the corresponding two dechloro analogs. Compound 1929 is the first carbazole-type fischerindole to be discovered [1516]. A review of the syntheses of the related welwitindolinones also includes a section on fischerindoles [1517].

Naturally Occurring Organohalogen Compounds …

MeO2C

HO2C

CO2Me H N

241 H N

CO2Me

O

N N H

N H

O

NH Cl Cl

NH

Cl

Br 1920 (iotrochamide B)

1919 (cauterchlorin)

H N

MeO2C R1

1921 (spiroindimicin A)

R2

NH

Cl HN

O

OH

Br

N

H N

HN O

N H

O

NH2

HN

Cl 1925 (geobarrettin A)

1922 R1 = Me, R2 = H (spiroindimicin B) 1923 R1 = R2 = H (spiroindimicin C) 1924 R1 = Me, R2 = CO2Me (spiroindimicin D)

O Br

N NH

N H

O

HN H N

O 1926 (geobarrettin B)

NH2 NH

N H

Br

1927 (geobarrettin C)

Cl NC

N H

Cl

NC

N H

1928

1929

The solitary tunicate Herdmania momus contains the four novel epimeric methylsulfinyladenosines, 1930–1933, which are interconvertible transesterification isomers at room temperature and/or sulfinyl epimers [1518]. The colonial ascidian Leptoclinides durus living in Australia yields the novel leptoclinidines A (1934) and B (1935), durabetaine B (1936), and leptoclinidamine D (1937). The two leptoclinidines are the first indole-3-carboxylic acid esters of thymidine [1519]. Leptoclinidamine C (1860) was featured earlier [1433].

242

G. W. Gribble O NH

NH2 N

N

O S

N

N

O

O

N

O

O

OH R1 O

OR2

A=

1930 R1 = A, R2 = H 1931 R1 = H, R2 = A 1932 R1 = A, R2 = H (epimer of 1930 at S) 1933 R1 = H, R2 = A (epimer of 1931 at S)

O

O

OH

HO

N H

Br N H

Br

1934 (leptoclinidine A)

O NH N

O O

O O HO Br

O

O

O

CO2H O

O

O

N

OH

OH

N H

Br

O N H 1935 (leptoclinidine B)

1936 (durabetaine B) MeO2C O

N NH S

N

N H 1937 (leptoclinidamine D)

The unprecedented polybrominated spiro-trisindole enantiomers, similisines A (1938) and B (1939) are found in the South China Sea red alga Laurencia similis [1520], and confirmed by total synthesis from 5,6-dibromoindole [1521]. Also isolated is the new oxindole 1940. A subsequent study of the red alga Laurencia similis uncovered the new minor indoles 1941–1942, degradation product 1943, and a carbazole presented in Sect. 3.14.3 [1522]. The new indole alkaloids rauvoloids B (1944) and C (1945) are present in the leaves of Rauvolfia yunnanensis from China together with five nonchlorinated indole alkaloids [1523]. Another Chinese plant of the Rauvolfia genus, Rauvolfia vomitoria, contains the chlorinated rauvomine A (1946) [1524]. The fungus Talaromyces wortmannii found on Brazilian apples (Malus domestica) produces the new halogenated ergot alkaloids 2,8-dichlororugulovasine A (1947) and B (1948), 7-bromorugulovasine A (1949) and B (1950) [1525].

Naturally Occurring Organohalogen Compounds … Br

Br

Br Br

243 Br

HN

NH HN

NH

Br Br

Br O

O

Br Br

Br

N H

N H

Br

Br

Br

1939 (similisine B)

1938 (similisine A) Br OH O N

Br

Br

CO2Me

Br

NH

Br

Br

O

Br N H

Br

1940

N

Br

CO2Me

OH 1943

1942

1941

O

O

N

O

O

OAc N

N R

1944 R = α-Cl (rauvoloid B) 1945 R = β-Cl (rauvoloid C)

N H

1946 (rauvomine A)

R1

R1 Cl

NH

NH

CHO

HN

HN R2 1947 R1 = R2 = Cl 1949 R1 = H, R2 = Br

R2 1948 R1 = R2 = Cl 1950 R1 = H, R2 = Br

A mutant strain of Streptomyces sp. produces inducamides A–C (1951–1953), generated when cultivated in the presence of tryptophan and 6-methylsalicylic acid [1526]. The tunicate Diazona cf. formosa living off the coast of Timor Island, near Indonesia, affords the novel tanjungides A (1954) and B (1955). The former is strongly active against the cancer cell lines A-549, HT-29, and MDA-MB-231 (IC 50 0.33, 0.19, and 0.23 μM, respectively) [1527]. These two structures are confirmed by total synthesis [1527]. A Korean colonial tunicate Didemnum sp. reveals the new 16-epi-18-acetyl herdmanine D (1956) [1528]. Herdmanine D (1894) was found in a different ascidian and is listed above [1466].

244

G. W. Gribble OH Cl

CO2H O

O O

OH

N H R

HN

Br

HN O

N H

O

Cl

O

N H N H

Br

Cl

NH2

S S

1954 (tanjungide A)

1953 (inducamide C)

1951 R = Cl (inducamide A) 1952 R = H (inducamide B)

H N

CO2H NHAc O HN

H N

O O

Br NH2

S

Br

O HO

N H

S

1955 (tanjungide B)

Br

N H

1956 (16-epi-18-acetyl herdmanine)

A Palauan deep-water (140 m) Topsentia sp. sponge contains the new tulongicin A (1957) and dihydrospongotine C (1958), together with two known analogs, spongotine C and dibromodeoxytopsentin [2]. All four compounds are strongly active towards Staphylococcus aureus, especially 1957, 1958, and spongotine C (MIC 1.1– 3.7 μg/cm3 ) [1529]. An Antarctic marine-derived Aspergillus sp. SF-5976 produces the dioxopiperazine alkaloid 5-prenyl-dihydrovariecolorin F (1959), together with four new and 23 known compounds. Indole 1959 shows some activity in the BV2 cell-antiinflammatory assay (IC 50 18.0 μM) but not in RAW 264.7 cells [1530]. An Arctic bryozoan Securiflustra securifrons living off the coast of Hjelmsøya, Norway, yields the three new securamines H–J (1960–1962), together with the known C and E [2]. Securamines H (1960) and I (1961) are cytotoxic against three human cancer cell lines, A2058 (melanoma), HT-29 (colon), and MCF-7 (breast), with IC 50 1.4–2.7, 1.9–2.5, and 2.1–2.4 μM, respectively. Securamine J is inactive in all three cell lines [1531].

Naturally Occurring Organohalogen Compounds … Br

245 Br

NH H N

NH

NH

NH

H N

Br

HO N

N

Br

N H 1957 (tulongicin A)

O

H N

Br

1958 (dihydrospongotine C)

Br

R

Br

Br O

O

N H

O

Br

Br

N

N

N

N H HO

N

O

HO Cl

HN O

Cl

HN N

N O

Cl 1959 (5-prenyl-dihydrovariecolorin F)

1960 R = Br (securamine H) 1961 R = H (securamine I)

1962 (securamine J)

A sponge-derived fungus, Aspergillus sp. SCS1041018, produces the novel chlorohydrin asterriquinone J (1963), claimed to be the first chlorine-containing bis-indolylquinone, along with ten non-chlorinated analogs. Quinone 1963 is active towards the cancer cell lines K562, BEL-7042, and SGC-7901 (IC 50 8.5, 11.1, 18.7 μM, respectively) [1532]. The new indole-diterpenoid 19-hydroxypenitrem (1964) is found in cultures of Aspergillus nidulans EN-330, which is associated with the marine red alga Polysiphonia scopulorum var. villum. The related known penitrem A is also found in this culture [1]. Alkaloid 1964 is more active in antimicrobial assays than the dechlorinated analog (19-hydroxypenitrem E), which is also found in this study [1533]. The related asperindoles A (1965) and C (1966) are present in the unidentified marine ascidian-derived fungus Aspergillus sp. KMM 4676, along with two complementary dechloro analogs. Asperindole A is highly active against human prostrate cells (22Rv1) that are resistant to androgen receptor-targeted therapies. The 2-hydroxyisobutyric acid unit in 1966 is quite rare in natural products [1534]. A mangrove-derived fungus, Mucor irregularis QEN-189, affords rhizovarins A (1967) and B (1968) along with four non-chlorinated analogs. The acetal/ketal linkages are unique in indole-diterpene alkaloids. Rhizovarin B is the most cytotoxic towards A-549 and HL-60 cancer cell lines (IC 50 6.3 and 5.0 μM, respectively) among the other rhizovarins [1535]. Four related indole diterpenoids, ascandinines A–D, are found in a sponge-derived fungus, Aspergillus candidus HDNIS-152, collected from Prydz Bay, Antarctica. Three of the ascandinines, A (1969), B (1970), and D (1971) are 6-chloroindoles. Ascandinine D is cytotoxic towards HL-60 cells (IC 50 7.8 μM), and C (the dechloro-analog of B) displays anti-influenza virus A (H1N1) activity (IC 50 26 μM) [1536].

246

G. W. Gribble

O

NH

O

O

HO

O

Cl

OH

OH

N H

Cl

O

HN

OH

OH

O

O

1964 (19-hydroxypenitrem A)

1963 (asterriquinone J)

OH

OH

O

O N H

Cl

N H

Cl O

O

O

O

O

O O

O

O

1966 (asperindole C)

1965 (asperindole A)

O

OH O

O

O

OR

OH

O

O NH

OH

OH

O O

O

NH

OH

Cl Cl 1967 R = H (rhizovarin A) 1968 R = Me (rhizovarin B)

1969 (ascandinine A) O OH

OH

O

O Cl

N H

Cl O

O O

O O 1970 (ascandinine B)

N H

OH

OH O

1971 (ascandinine D)

The Arctic marine hydrozoan Thuiaria breitfussi contains breitfussins A–H (1972–1979), novel pyrrole-indole metabolites tethered via an oxazole ring [1537, 1538]. These compounds inhibit several cancer cell lines, such as the drug-resistant breast cancer MDA-MB-468 (IC 50 0.34 μM). Synthesis activity vis-á-vis the breitfussins has been vigorous [1538–1541]. A mudflat-sediment-derived fungus Chaetomium cristatum at Suncheon Bay, Korea, gave rise to the new dioxopiperazine alkaloid cristazine (1980), which is active against human cervical cells (HeLa; IC 50 0.5 μM) [1542]. Noteworthy is a review on natural products having the hexahydropyrrole[2,3-b]indole framework [1543]. A fermentation of Streptomyces sp. SANK 60101 contains the new chlorinated indoline A-503451 A (1981), related to the known antibiotic virantmycin, which has a tetrahydroquinoline skeleton [1], and is also found in the present work. Both 1981 and virantmycin are potent activators of hypoxia-inducible factor (HIF) (EC 50 8 and 17 ng/cm3 , respectively). The activation of HIF promotes cell survival under hypoxic (low oxygen) conditions such

Naturally Occurring Organohalogen Compounds …

247

as ischemia and protects the brain [1544]. An investigation of the green biofluorescence in sharks led to several new compounds (1982–1986) derived from bromokynurenine metabolism. Although not all indole structures, it is useful to show them all here. 6-Bromotryptophan and two other metabolites are known compounds. The proposed bromo-kynurenine pathway to generate the biofluorescent shark metabolites is shown (Scheme 4). In addition to 1982–1985 shown in the pathway, bis-indole 1986, which is not shown, is also formed [1545]. Scheme 4 Formation of 8-bromo-kynurenine (1985)

CO2H

O

NH2 Br

CO2H

?

N H

N H

Br

CO2H NH2 O Br

NHCHO

1982 (8-bromo-N-formyl-kynurenine)

CO2H NH2 CO2H

O Br

NH2

Br

NH2

1983 (8-bromo-kynurenine) OH

CO2H

Br

N

CO2H

? O O Br

NH2

1984 (8-bromo-CKa) Br

N H

CO2H

1985 (8-bromo-kynurenine yellow)

248

G. W. Gribble R2 Br NH N

O

O

N

O R1

O

O

NH

N

N

O

O

O

N H

Br

NH

NH

Br

1972 R1 = I, R2 = H (breitfussin A) 1973 R1 = H, R2 = Br (breitfussin B)

N H

N H

Br

1974 (breitfussin C)

N H

Br

1975 (breitfussin D)

1976 (breitfussin E)

Br Br

O

O

O

NH

NH N

O

NH

N

O

H N

N

N N

O

N

N H

Br

N H

1978 (breitfussin G)

1977 (breitfussin F)

N H

N H

Br

1979 (breitfussin H)

Ac O

1980 (cristazine) H N

O

Cl

O O S N

O

I Br

N N H

Br

NH HO2C

N Cl H

HN O

O Br

1981 (A-503451 A)

N H 1986

The Red Sea sponge Callyspongia siphonella contains two novel oxindoles, 5(1987) and 6-bromotrisindoline (1988), which display potent antibacterial activity against Gram-positive bacteria and modest biofilm inhibition [1546, 1547]. A specimen of the sponge Spongosorites caliciola from the Celtic Sea at Rathlin Island, Northern Ireland, led to the new calcicamides A (1989) and B (1990), isolated as trifluoroacetates. The authors suggest that these compounds may be important biosynthetic intermediates for other known bis-indoles such as hamacanthin, dragmacidin, coscinamide, and topsentin derivatives [1548]. Another Spongosorites sp. sponge from Jeju Island, Korea, produces the new spongosoritins C (1991) and D (1992) and spongocarbamide B (1993), along with non-brominated counterparts. The only significant biological activity is towards transpeptidase sortase A [1549]. A deep-water Southern Australian Bight Geodia sp. sponge contains the novel trachycladindoles H (1994), J (1995), and K (1996), in addition to non-brominated analogs and seven known examples [1550]. Trachyladindoles A–F (1826–1831) found in the sponge Trachycladus laevispirulifer are depicted earlier in this Section [1421]. The simple amakusamine (1997) is found in the sponge Psammocinia sp. from Japan. This compound inhibits the receptor activator of nuclear factor-κB ligand (RANKL)induced formation of multinuclear osteoclasts (IC 50 10.5 μM) in RAW264 cells [1551].

Naturally Occurring Organohalogen Compounds …

HN

249

HN

NH

NH

Br O

O N H

N H

Br

1988 (6-bromotrisindoline)

1987 (5-bromotrisindoline) HN

NH2

Br O

N H

Br

N H 1989 (calciamide A)

N H NH

NH2

N

N

O

Br

NH2

N N Br

COO– NH

R

NH

N

OH

O

O

1991 R = H (spongosoritin C) 1992 R = OH (spongosoritin D)

1990 (calciamide B)

NH

H N

N H

O O

O

NH N H

O

HN

Br

O

H2N

O

N H

R

Br

COO– N H

HO Cl

1993 (spongocarbamide B)

1994 R = OH (trachycladindole H) 1995 R = H (trachycladindole J)

1996 (trachycladindole K)

Br O N H

O Br

1997 (amakusamine)

The prolific bryozoan Flustra foliacea continues to impress with novel halogenated metabolites. A collection of this animal from Iceland reveals 13 new examples, flustramines R, T, U, V, W (1998–2002), flustraminols C–H (2003–2008) along with 12 previously isolated brominated alkaloids [1552]. Several of these compounds decrease dendritic cell secretion of the pro-inflammatory cytokine IL12p40. Two additional flustramines, Q and S, are presented in Sect. 3.14.6. The two new spiroindimicins E (2009) and F (2010) are produced by Streptomyces sp. MP131-18 from a Norway marine sediment [1553], which complement A–D (1921– 1924) shown earlier [1513]. Total syntheses of (±)-spiroindimicins B (1922) and C (1923) have been achieved [1554]. A South China Sea marine sediment containing Streptomyces sp. SCS10 11791 contains the new bis-indoles dionemycin (2011), 6O-methyl-7 ,7 -dichlorochromopyrrolic acid (2012), together with 2013 and 2014, previously known from two patents. The known lynamicins A, B, and D are also present [1555]. Compound 2015 was unearthed separately [1556].

250

G. W. Gribble O N

N N

HO

HN

NH N H

Br

S O O

N NH

N H

Br

O N H

Br

N H

Br

Br 1999 (flustramine T)

1998 (flustramine R)

2000 (flustramine U)

H N

HO

N

O N

Br

2001 (flustramine V)

N

Br

N

R

HO

MeO2C

N

O

N

HO

OH

2005 R = H (flustraminol E) 2006 R = OH (flustraminol F) 2007 R = OCH3 (flustraminol G)

NH

Me

R

HO

OH

2003 R = H (flustraminol C) 2004 R = OH (flustraminol D)

2002 (flustramine W)

N

Br

H N

O

Cl

Cl

OH N H

Br

H N

N H

R2

R1

2009 R1 = Cl, R2 = H (spiroindimicin E) 2010 R1 = H, R2 = Cl (spiroindimicin F)

2008 (flustraminol H)

HO2C

R

HN

O

H N

CO2Me

N H

2011 R = Cl (dionemycin) 2013 R = H (dionemycin)

HO2C

CO2H

H N

CO2H

Cl Cl

Cl

Cl

Cl Cl

N H

N H

Cl

2012 (6-O-methyl-7’,7“-dichlorochromopyrrolic acid)

N H

N H 2014

N H

N H

2015 (dichlorochromopyrrolic acid)

The eagle-killing toxin, aetokthonotoxin (2016), produced by the cyanobacterium Aetokthonos hydrillicola living on the invasive aquatic plant Hydrilla verticillata has finally been characterized [1557]. This toxin causes a neurological disease particularly deadly to bald eagles. It is biosynthesized from two molecules of tryptophan culminating in the condensation of 2,3,5-tribromoindole with 5,7-dibromo-3cyanoindole [1558]. The structure of psammopemmin A [2] is reassigned to that of meridianin A via synthesis [1559]. Similarly, the structure of echinosulfone A and the related echinosulfonic acids [2] have all been reassigned by a combination of synthesis, spectral data, and DFT calculations [1560–1562]. The revised structures are shown, A–E.

Naturally Occurring Organohalogen Compounds …

251 R

CN Br Br

Br N

CO2Me

Br Br

N H Br Br 2016

O

Br

N HO3S

NH A

Br N HO3S

N H

B R = OEt C R = OMe D R = OH ER=H

Several noteworthy syntheses of the aforementioned metabolites have been achieved, including those of indiacen B (1805) [1563], (±)-eusynstyelamide A (1839 [1564], (±)-dictazole B (1857) [1565], and inducamides A (1951) and B (1952) [1566]. Some indole compounds are also amino acids and are depicted in Sect. 3.12. Syntheses of JBIR-126 (aka tambromycin) (1299) [1567, 1568] and (±)-aspidostomide B (1661) and C (1662) [1159] are recorded. A number of syntheses of halogenated natural products reported earlier [1, 2] have been achieved in recent years. These include (+)- and (±)-perophoramidine [1569, 1570], (±)-aplicyamins A, B, E [1571], (+)- and (±)-hinckdentine A [1572, 1573], dendridine A [1574], kottamide E [1575], coscinamides A and B, and igzamide [1576], alternatamide D [1577], polybrominated 3,3 -bis-indoles [1578], meridianins and meriolins [1579], 6-bromo-2-mercaptotryptamine dimer [1580], topsentin C (revision) [1581], hapalindoles K, A, G [1582], (+)-ambiguine G [1583], and 6,6 -dibromoindigo [1584]. The family of welwitindolinones from blue-green algae has been a particular target of the synthesis community [1585–1597]. In addition, several syntheses have encompassed multiple related alkaloids, such as the hapalindoles, fischerindoles, ambiguines, and the welwitindolinones, each of which have chlorinated derivatives [1598–1602]; for reviews, see [1517, 1603].

3.14.3

Carbazoles

The carbazole ring is particularly unreactive towards biohalogenation compared to pyrroles and indoles. Indeed, only two examples of naturally occurring halogenated carbazoles are described in the first volume [1] and none in the second [2]. The encrusting cyanobacterium Kyrtuthrix maculans from the Hong Kong shores contains the three brominated-iodinated carbazoles 2017–2019, which are the first such examples of bromine- and iodine-containing natural carbazoles to be discovered [1604]. A Lake Michigan sediment core uncovered the presence of 1,3,6,8tetrabromocarbazole (2020), which may or may not be natural. Evidence in favor of a natural origin is that sediment layers containing 2020 date from before 1900 [1605]. In contrast to 2020, 1,3,6,8-tetrachlorocarbazole is suggested to be an anthropogenic contaminant (in the Buffalo River, New York) [1606]. Both 3-chloro- (2021) and 3,6-dichlorocarbazole (2022) are found in Bavarian soils [1607]. Theory (DFT) and experiment predict these isomers for both mono-chlorination (para to the nitrogen) and di-chlorination (more active benzene ring). Enzymatic syntheses of 2020–2022,

252

G. W. Gribble

and other polyhalogenated carbazoles, have been executed using Caldariomyces fumago in water [1608]. A recent study finds 15 novel polyhalogenated carbazoles in Lake Michigan, seven of which are mixed halogenated carbazoles (chlorine, bromine, and/or iodine) [1609]. However, it is reported that anthropogenic halogenated indigo dyes may be the source of 2020 and other halogenated carbazoles in the environment [1610–1613]. A new investigation of Lake Michigan and Arctic Ocean sediments has employed untargeted screening to detect particularly organoiodine compounds (~4000 in Lake Michigan and ~3000 in Arctic Ocean) [1614]. A study of the endocrine-disrupting effects of polyhalogenated carbazoles shows that these compounds are antagonists of the estrogen receptor α in vitro and in vivo in young female rats [1615]. The Brazilian ascidian Didemnum granulatum contains the carbazole 6-bromogranulatimide (2023) together with granulatimide [1616]. Br Br

Br

2017

I

N H

N H

2018

2019

Br

N H

I

H N

O Br

Br

O

R

Cl

NH Br

N H

N H

Br

2020

Br

2021 R = H 2022 R = Cl

N H

N

2023 (6-bromogranulatimide)

The marine sponge Penares sp. from Vietnam contains the two novel brominated indolocarbazole 2024 and indolo[3,2-k]phenanthridine 2025. The latter ring system is a new naturally occurring skeleton, and 2024 has modest cytotoxicity towards the HL-60 and HeLa cancer cell lines (IC 50 16.1 and 33.2 μM, respectively) [1617]. The South China Sea marine-derived actinomycete Streptomyces sp. SCSIO 02999 collected at 880 m produces chloroxiamycin (2026) [1618]. This metabolite is also found in Streptomyces sp. HK18 from a Korean solar saltern [1619]. OH CO2H

Br Br

N H NH

N H

N Br N H

Br 2024

Br 2025

Cl

2026 (chloroxiamycin)

Naturally Occurring Organohalogen Compounds …

3.14.4

253

Indolocarbazoles

In contrast to the relatively few known natural halogenated carbazoles, there are several well documented halogenated indolo[2,3-a]carbazoles in Nature, including the antitumor rebeccamycin and 13 tjipanazoles from the blue-green alga Tolypothrix tjipanasensis [1]. Reviews of indolocarbazole natural products are available [1620–1622]. The novel chlorinated cladoniamides A, B, D-G (2027–2033) are isolated from cultures of Streptomyces uncialis collected from the lichen Cladonia uncialis living near the Pitt River, British Columbia. Cladoniamide G is cytotoxic against MCF7 cancer cells (IC 50 10 μg/cm3 ). Cladoniamide C is devoid of chlorine [1623]. Cladoniamide G has been synthesized [1624–1626], as has F [1626]. The synthesis and assignment of the absolute configuration of the natural BE-54017 (2033) are reported. This new indenotryptoline bis-indole alkaloid was previously described in a Japanese patent from Streptomyces sp. A54017 [1627].

N

O X

HN

O OH

HO

O

X

N H

O

2027 X = Cl, Y = H (cladoniamide A) 2028 X = Y = Cl (cladoniamide B)

O

2029 X = H (cladoniamide D) 2030 X = Cl (cladoniamide E)

N

O Cl

Cl

N

Y

NH

O

OH

Cl

N N H

O

O

HO N N H

X O

2031 X = H (cladoniamide F) 2032 X = Cl (cladoniamide G)

O OH

HO N N O

2033 (BE-54017)

The new indolo[3,2-a]carbazoles 2034 and 2035 are found in the deep-water (131 m) sponge Asteropus sp. from the Bahamas [1628]. A series of borregomycins (2036–2040) is produced by homology-guided screening for indolotryptoline gene clusters using Streptomyces albus AB1091. The closely related dichlorochromopyrrolic acid (2041) is also produced [1629].

254

G. W. Gribble HO

OR

N

O

O

O

H N

O N

Cl

NH

Br

Cl

R1 O

N

O

2036 R = H (borregomycin A) 2037 R = Me

2034 R = H 2035 R = SO3Na

O

N RO H

HO2C

O

H N

CO2H

OR2 Cl

Cl N N H H 2038 R1 = R2 = Me (borregomycin B) 2039 R1 = Me, R2 = H (borregomycin C) 2040 R1 = R2 = H (borregomycin D) Cl

Cl N H

N H

2041 (dichlorochromopyrrolic acid)

A deep-sea derived Streptomyces sp. SCSIO 03032 produces the new indimicins A–E (2042–2046) and the related novel lynamicins F (2047) and G (2048). Indimicin B exhibits moderate cytotoxicity toward the MCF-7 cancer cell line (IC 50 10.0 μM) [1630]. A synthesis of the earlier described lynamicin D is known [1631]. A soil sample from Bristol Cove, California, contains Actinomadura melliaura ATCC 39691, which produces the new indolocarbazoles 2049–2053 [1632]. Genome mining of an indolocarbazole-type gene cluster from a marine-derived Nocardiopsis flavescens NA 01583 from a Chinese marine sediment produces the new loonamycin alkaloids 2054–2056. Loonamycin A is highly potent against several cancer cell lines (5H-SY5Y, Sum 1315, HT-29, HCT-116, HeLa, SW872, HCC78) with IC 50 41–283 nM [1633].

3.14.5

Carbolines

Given their origin from tryptophan and/or tryptamine, nearly all naturally occurring carbolines are β-carbolines, and more than 50 halogenated β-carbolines are cited earlier [1, 2]. An undescribed thorectid sponge from Saipan contains 7-bromoreticulatine (2057) and 10-bromohomofascaplysate (2058), along with the known 10bromofascaplysin. The latter metabolite has potent activity against two clones of Plasmodium falciparum (IC 50 0.26, 0.3 nM) [1634]. The cancer-related activity of 3- and 10-bromofascaplysin is mediated by caspase-8, -9, -3-dependent apoptosis [1635]. An Eudistoma sp. Korean tunicate yields the six new brominated β-carbolines, eudistomins Y2 –Y7 (2059–2064). Eudistomicin Y6 (2063) displays modest antibacterial activity against the Gram-positive Staphylococcus epidermis and Bacillus subtillis [1636]. The New Zealand bryozoan Pterocella vesiculosa produces the β-carboline 2065 [1637], and a Eudistoma glaucus tunicate from Okinawa contains eudistomidin G (2066), and the revised stereochemistry of the known eudistomidin B at the α-carbon was confirmed by asymmetric synthesis

Naturally Occurring Organohalogen Compounds …

255

[1638]. This Okinawan sponge also contains the new eudistomidins H–K (2067– 2070). Eudistomidin J (2069) is cytotoxic against P388 and L1210 murine leukemia cells (IC 50 0.04 and 0.047 μg/cm3 , respectively) and human epidermoid carcinoma KB cells (IC 50 0.063 μg/cm3 ). The other three new eudistomidins were inactive in these assays (IC 50 > 10 μg/cm3 ) [1639]. R1 N

N

N

R2 Cl

Cl

Cl

R

Cl

Cl

Cl

2047 R = H (lynamicin F) 2048 R = CO2Me (lynamicin G)

2046 (indimicin E)

2042 R1 = Me, R2 = H (indimicin A) 2043 R1 = R2 = Me (indimicin B) 2044 R1 = H, R2 = Me (indimicin C) 2045 R1 = R2 = H (indimicin D)

N H

N H

N H

N

N H

N

R1 O

N

O

O I=

R5 = H or Me

O

O OH

HO

R4

N H

OH

N R3

OH

O R5HN

R2

O

R6O

II =

HO

2049 R1 = R4 = H, R2 = Cl, R4 = I, R5 = Me (AT2433-A3) 2050 R1 = R6 = Me, R4 = H, R2 = Cl, R3 = II (AT2433-A4) 2051 R1 = R3 = R4 = H, R2 = Cl (AT2433-A5) 2052 R1 = R6 = Me, R2 = R4 = H, R3 = II (AT2433-B3) 2053 R1 = R5 = Me, R2 = R4 = H, R3 = I (AT2433-B1)

OH

R1 N

O

O

OH O

N R2

O

HO O

N H OH

O

N

OH R2

OH 2054 R1 = Me, R2 = Cl (loonamycin A) 2055 R1 = H, R2 = Cl (loonamycin B) 2056 R1 = Me, R2 = Br (loonamycin C)

R6 = H or Me

256

G. W. Gribble R1

MeOOC

N H

Br

2057 (7-bromoreticulatine)

N H

Br

N

R2

N

N

N H

OH COOH

O

R3

2058 (10-bromohomofascaplysate)

R4

HO R1

R2

R3

R4

2059 = Br, = H, = H, = H (eudistomin Y2) 2060 R1 = H, R2 = H, R3 = Br, R4 = H (eudistomin Y3) 2061 R1 = Br, R2 = H, R3 = Br, R4 = H (eudistomin Y4) 2062 R1 = H, R2 = H, R3 = Br, R4 = Br (eudistomin Y5) 2063 R1 = Br, R2 = H, R3 = Br, R4 = Br (eudistomin Y6) 2064 R1 = H, R2 = Br, R3 = Br, R4 = Br (eudistomin Y7) Br

Br

N H

O

N

N H

N

N

Br N N

HN

2065

2066 (eudistomidin G)

2067 (eudistomidin H)

Br N

HO

Br

HO

Br

N N N

N H

N S O

HN 2068 (eudistomidin I)

2069 (eudistomidin J)

N H O 2070 (eudistomidin K)

The Australian Ancorina sp. marine sponge produces the antimalarial (+)-7bromotrypargine (2071), which inhibits the growth of two Plasmodium falciparum strains (Dd2 and 3D7) (IC 50 5.4 and 3.5 μM, respectively). 6-Bromotryptamine is active against both malarial strains at concentrations up to 80 μM [1640]. Related to 2071 is its homolog (–)-7-bromohomotrypargine (2072), which is present in the New Zealand ascidian Pseudodistoma opacum, along with the new opacalines A–C (2073–2075). The absolute configuration of 2072 is shown. Opacalines A and B, and some synthetic analogs, display antimalarial activity (IC 50 2.5– 14 μM) against a chloroquine-resistant strain of Plasmodium falciparum [1641]. A Fijian Didemnum sp. ascidian contains 3-bromohomofascaplysin (2076) along with fascaplysin and homofascaplysin. The latter metabolite is particularly potent towards Plasmodium falciparum ring-stage parasites (IC 50 0.55 nM) [1642]. The New Zealand bryozoan Pterocella vesiculosa affords the new alkaloid 2077 [1643]. A sample of Streptomyces coelicolor M1146 yields the novel xenocladoniamide F (2078) [1644].

Naturally Occurring Organohalogen Compounds …

NH

Br

257

NH

Br

N H

N

Br

N H

N R

NH HN

HN

NH2

n NH

NH2

2071 ((+)-7-bromotrypargine)

2072 ((–)-7-bromohomotrypargine)

2073 R = H, n = 2 (opacaline A) 2074 R = OH, n = 2 (opacaline B) 2075 R = H, n = 1 (opacaline C) O

O Cl N

N

N

Br

Br

N H

NH2

HN

NH

N H

N H

O

OH O 2076 (3-bromohomofascaplysin)

2077

2078 (xenocladoniamide F)

The New Zealand ascidian Pseudodistoma opacum contains the N-hydroxy derivative of 7-bromohomotrypargine (2079), which exhibits modest antimalarial activity against a chloroquine-resistant strain (FcB1) of Plasmodium falciparum (IC 50 3.82 μM) [1645]. The new irenecarbolines A (2080) and B (2081) are found in the solitary ascidian Cnemidocarpa irene, and both compounds inhibit acetylcholinesterase [1646]. Two new eudistomins, Z1 (2082) and Z2 (2083), are produced by a group of Fijian marine sponges [1647].

Br

NH

Br N

N

Br

OH

N H HN

NH2

N

Br N H

R

N

NH 2079 (7-bromohomotrypargine)

2080 R = H (irenecarboline A) 2081 R = Me (irenecarboline B)

2082 (eudistomin Z1)

Br N

Br N H

N

2083 (eudistomin Z2)

Total syntheses of the β-carboline bauerines [1648, 1649], brominated fascaplysins [1650], eudistomins [1650–1658], and eudistomidins are documented [1659–1661].

258

G. W. Gribble

3.14.6

Quinolines and Other Nitrogen Heterocycles

As revealed in the previous surveys [1, 2], very few natural halogenated quinolines per se exist. Nevertheless, a number of examples of naturally occurring halogencontaining nitrogen heterocycles that are not appropriate for other sections are presented here. A review of marine pyridoacridine alkaloids is available [1661]. O

O

O

HN

HN

O

2084

2085

O

N

O Cl

O

OH O

Cl

O

Cl

Cl

OH

N

O

2087

2086

I Cl

O

OH

OH

O

N OH O

Cl N

O

O

N

NH2

Cl

O O

O

O

N

N

OH

O

OH 2090

2089 (NBRI23477 A)

2088 (chlorodesoxyevoxine) O S HO

H N

O

Cl N N

N O

S 2091 (lodopyridone)

The fungus Geotrichum sp. AL4 living on the leaves of the “neem” tree (Azadirachta indica), which is widely employed as a medicinal plant in Asia, Africa, and other tropical areas, contains the two chlorinated 1,3-oxazinanes 2084 and 2085, which show nematocidal activity against two nematodes [1662]. The Surinamese rainforest plant Ertela (Monnieria) trifolia affords the related furoquinoline alkaloids 2086 and 2087. Both alkaloids display some cytotoxicity towards the A2780 human ovarian cancer cell line (IC 50 13 and 9 μg/cm3 , respectively) [1663]. The related furoquinoline alkaloid chlorodesoxyevoxine (2088) is found in the ornamental shrub Choisya ternata (Mexican Orange) (Plate 49), and its absolute configuration is shown [1664]. A new atpenin, NBRI23477 A (2089), is produced in the fermentation of Penicillium atramentosum PF1420 from a Japanese soil sample in

Naturally Occurring Organohalogen Compounds …

259

Plate 49 Choisya inflorescence (Photograph courtesy of JLPC; Creative Commons AttributionShare Alike 3.0 Unported)

addition to the known atpenins A4, A5, and B. This novel gem-dichloro metabolite inhibits the growth of the prostate cancer cell line DU-145 [1665]. Syntheses of atpenins A5 [1666], A4, B, and NBRI23477 B [1667], and 4-epi-atpenin A5 [1668] are recorded. The Okinawan ascidian Diplosoma sp. contains the novel iodinated pyrrolo[2,3-d]pyrimidine 2090. Interestingly, this metabolite is also found in the red alga Hypnea valendiae, supporting the possibility of a microbial and/ or a dietary connection [1669]. A La Jolla, California, marine sediment containing Saccharomonospora sp. delivereds lodopyridone (2091), which is cytotoxic against HCT-116 human colon cancer cells (IC 50 3.6 μM) [1670]. This novel compound has been synthesized [1671]. Another marine-derived sediment Streptomyces sp. Mei 37 from the North Coast of Germany, produces the novel mansouramycins A–D, one of which, B (2092), contains chlorine [1672]. A Madagascan tunicate contains the first marine proaporphine alkaloids saldedines A (2093) and B (2094). The former is isolated as a racemate while the latter is optically active [1673]. The Australian ascidian Aplidium caelestis is found to have the novel brominated quinoline carboxylic acids, caelestines A–D (2095–2098), a previously unknown class of natural organohalogens. Activity against MCF-7 (breast) and MM96L (melanoma) cancer cell lines is only minor [1674]. The two iodinated ascidines B (2099) and C (2100) are isolated from the tunicate Ascidia virginea found in Norwegian fjords near Bergen. Three related brominated analogs are also in this animal but the structures are unidentified [1675]. The endophytic microfungus Pestalotiopsis sp., grown on damp white rice, yields the novel caprolactams pestalactams A–C, two of which A (2101) and C (2102) are chlorinated. Pestalactam A shows modest activity against Plasmodium falciparum (3D7 and Dd2) and the cancer cell lines MCF-7 and NFF (IC 50 58.5 and 12.8 μM,

260

G. W. Gribble

respectively) [1676]. Pestalactams D–F are found in Australian fungi, and pestalactam D (2103) contains chlorine [1677]. The marine bacterium Streptomyces sp. CNS284 produces the phenazine 2104, which has activity in the NF-κB-luciferase assay (IC 50 73 μM) [1678]. This organism also produces phenazines 2105 and 2106, which also inhibit TNFα-induced NF-κB activity and LPS-induced NO production [1679].

O

O O Cl

N

HO

N

HO

N

N

Br

Br

H

O O

2093 (saldedine A)

2092 (mansouramycin B)

Br

HO

Br

2094 (saldedine B)

OH R1

O

O

R2 HO

R1 R2 R3

N H

OH O

2

3

2095 R = H, R = Br, R = H (caelestine A) 2096 R1 = Br, R2 = Br, R3 = H (caelestine B) 2097 R1 = Br, R2 = H, R3 = OMe (caelestine C) 2098 R1 = Br, R2 = Br, R3 = OMe (caelestine D)

OH

1

2099 R = I, R2 = H (ascidine B) 2100 R1 = R2 = I (ascidine C)

2101 (pestalactam A)

O

O

OH

HO

HO

N

NH

Cl

NH

Cl

OH

O

N HO

1

NH

Cl

O O

N

O

O

2104

2103 (pestalactam D)

2102 (pestalactam C)

O

O N

Br

N

N

N

2105

2106

Br

Br

Naturally Occurring Organohalogen Compounds …

261

A Palau sediment sample yields a new Streptomycete strain that produces marinocyanins A–F (2107–2112), which are novel brominated phenazinone meroterpenoids. Of the six, marinocyanin A is the most active potent antifungal agent against amphotericin-resistant Candida albicans (MIC 0.95 μM). Both A (2107) and B (2108) display potent cytotoxicity towards HCT-116 human colon carcinoma cells (IC 50 0.049 and 0.029 μM, respectively) [1680]. The related chlorinecontaining WS-9659 B (2113) is found in cultures of Streptomyces sp. 9659. Both 2113 and the dechloro analog inhibit testosterone 5α-reductase, particularly the latter compound [1681]. The novel caulamidines A (2114) and B (2115) from the bryozoan Caulibugula intermis, which also produces the caulibugulones [2], have had their structures confirmed [1682]. The Chinese bryozoan Cryptosula pallasiana contains several aromatic metabolites, including the new 7-bromoquinolin-4-1H-one (2116) [1683]. This metabolite is also found in an unidentified sponge from the Gulf of Aqaba in the Red Sea [1684]. A marine-derived Streptomyces variabilis produces ammosamide D (2117), related to (and derived from) the ammosamides presented in Sect. 3.14.2. This new quinolone is modestly cytotoxic to the MIA PaCa-2 pancreatic cell line (IC 50 3.2 μM) [1685]. A cyanobacterial collection from Belize yields the simple chloromethyl pyridine, carriebowlinol (2118), which inhibits the growth of pathogenic and saprophytic marine fungi and marine bacteria [1686]. Geloline A (2119) is a new antioxidant quinoline found in the fermentation broth of Streptomyces sp. SBT345, which was cultured from the Mediterranean sponge Agelas oroides. This new compound also inhibits the growth of Chlamydia trachomatis (IC 50 9.54 μM) [1687]. The two new lodopyridones B (2120) and C (2121) are found in the sediment-derived bacterium Saccharomonospora sp. CNQ-490 [1688]. Two Streptomycetes, a soil-derived Streptomyces sp. FXJ1.235 and a deep-sea Streptomyces olivaceus FXJ8.0121741, produce mycemycins A–E, of which four are chlorinated, the dibenzoxazepinones B–E (2122–2125) [1689, 1690], and F–H (2126–2128) [1691].

262

G. W. Gribble O O N

O Br

O Br

N

N

N

N N

Br

Br N

N O O

2108 (marinocyanin B)

2107 (marinocyanin A) O N

OH

2110 (marinocyanin D)

2109 (marinocyanin C) O

Br

N

N

N

O Br

N

Cl

N

OH

OH

2111 (marinocyanin E)

2112 (marinocyanin F)

2113 (WS-9659 B) Br

Cl N

N N

N

N

N Cl

Cl

N

N

Cl Br 2114 (caulamidine A)

2115 (caulamidine B)

The bark of Codiaeum peltatum from New Caledonia contains the novel chloroaustralasines A–C (2129–2131), and isochloroaustralasine A (2132) [1692]. The marine algicidal bacterium Alteromonas sp. D produces questiomycin E (2133) along with three related non-brominated analogs, all of which have potent algicidal activity [1693]. The cyanobacterium Leptolyngbya sp. affords the novel leptazolines A–D, two of which, A (2134) and B (2135), are chlorinated along with the degradation (hydrolysis) products 2136 and 2137. This seems to be the first report of the oxazoline ring system from the genus Leptolyngbya. Leptazoline B (2135) inhibits growth of the PANC-1 cancer cell line (GI 50 10 μM) [1694].

Naturally Occurring Organohalogen Compounds …

O

O

263

NH

O

Cl

OH

O

O Br

N

Cl

N H

CONH2

N

2116 O

O O

H N

N

N O

S

HO N

2120 (lodopyridone B) R1

O

O O

S Cl

H N

Cl N

N O

S

N

2121 (lodopyridone C) R3O

O

O

O HN

HN

R1

R4 R2

CO2H

2119 (ageloline A)

2118 (carriebowlinol)

2117 (ammosamide D)

S AcO

N H

Cl

NH2

O R3

2122 R1 = OMe, R2 = R3 = H, R4 = Cl 2123 R1 = OMe, R2 = Cl, R3 = CH3, R4 = Cl 2124 R1 = NH2, R2 = Cl, R3 = CH3. R4 = H 2125 R1 = NH2, R2 = Cl, R3 = CH3, R4 = Cl

R2

O

2126 R1 = R2 = Cl, R3 = H 2127 R1 = Cl, R2 = H, R3 = Me 2128 R1 = H, R2 = Cl, R3 = Me

A sample of the sponge Verongula rigida from the Florida Keys yields veranamine (2138), which displays good in vivo antidepressant activity for 5HT2B and sigma-1 receptors, and is confirmed by synthesis [1695]. The earlier cited solitary tunicate Cnemidocarpa irene also contains irenecytidine (2139) and ireneguanine (2140), where the latter is the first report of a naturally occurring 8-halogenated guanine [1696]. The soil bacterium Streptomyces calvus T-3018, which produces the wellknown antibiotic nucleocidin [1], also contains the two 3 -O-β-glucosylated nucleoside fluoro metabolites, F-Met I (2141) and F-Met II (2142) [1697]. Along with the ammosamides A–D (1883–1886) presented in Sect. 3.14.2, two additional ammosamides, the amidine analogs E (2143) and F (2144), are found in the marinederived Streptomyces variabilis. When aryl and alkyl amines are added to the fermentation broth, the corresponding amidine analogs are produced via a non-enzymatic addition to ammosamide C (1885) [1698].

264

G. W. Gribble O

O OH N

O

Br

N

Cl

Cl

O

N

NH2

O

O

OH

R 2129 R = Me (chloroaustralasine A) 2130 R = H (chloroaustralasine B) 2131 R = CH2OAc (chloroaustralasine C)

2132 (isochloroaustralasine A)

2133 (questiomycin E)

HO HO O

O

HO

HN

HO

HO

OH

OH

OH

O

OH

OH

OH N

O

N

HO

OH

OH

N H

HO Cl

Cl

Cl 2137

2136

2135 (leptazoline B)

2134 (leptazoline A)

NH

O

HO

HO Cl

NH

O

O

OH

O

NH2 Cl

N

N O Br

N

H2N

N

NH2

O Cl

N

H2N

N

NH2 N

N OH

Cl

NH2

O F Glu–O

N

2140 (ireneguanine)

NH2

O

Cl N

O

2139 (irenecytidine)

NH2 N

N

N H2 N

HO

2138 (veranamine)

N

O O

HO

N H

RO

N

HN

N CO2H

2141 R = H (F-Met I) 2142 R = -OS(O)2NH2 (F-Met II)

2143 (ammosamide E)

2144 (ammosamide F)

Additional research supports the natural origin of at least some of the chlorinated benzodiazepines discussed in the first survey [1]. Thus, the drug diazepam was discovered in three human brains that were preserved prior to the industrial synthesis of this minor tranquilizer and antidepressant [1699, 1700]. This and other benzodiazepines, chlorinated or not, are found in plants (corn, lentil, potato, soy, rice, mushrooms) at levels of 0.005–0.05 ng/g and in animals (rat, mice, deer, dog, bovine, chicken, fish, frog, human) [1701–1704].

Naturally Occurring Organohalogen Compounds …

265

Benzodiazepine-like molecules are present in samples of human cerebella stored in paraffin since 1940, strongly suggestive of a biosynthetic and/or dietary origin [1705, 1706]. These benzodiazepines are elevated (4–6 fold) in rats with hepatic encephalopathy [1707]. For discussions on the origin and/or biosynthesis of these benzodiazepines see [1708, 1709]. Several syntheses of relevant halogenated nitrogen heterocycles are described: mansouramycin B (2092) [1710], atpenin A5 analogs [1711], the three halogenated 5 -deoxytubercidins [1712], caulibugulones A–D [1713], and trachycladine A [1714].

3.14.7

Benzofurans and Related Compounds

The simple 3-bromofuran (40) is described earlier [338], and 3-chlorofuran (2145) is a newly-described natural product found in sediments and water samples from the Dead Sea and Western Australia salt lakes, along with 3-bromofuran found in water samples [1715, 1716]. Dibenzofurans are covered in Sect. 3.25 with dibenzodioxins. The three new iantherans, iso-iantheran A (2146), 8-carboxy-iso-iantheran A (2147), and iso-iantheran B (2148) are found in the Australian sponge Ianthella quadrangulata, together with two brominated tyrosines presented later. Metabolites 2146 and 2147 display potent agonist activity at P2Y11 receptors (EC 50 1.29 and 0.48 μM, respectively) [1717]. The marine fungus Pseudallescheria boydii living in the starfish Acanthaster planci produces the two novel isomeric chlorinated dihydrobenzofurans 2149 and 2150 [1718]. The similar dihydrobenzofuran, colletochlorins E (2151) and F (2152) are found in the fungus Colletotrichum higginsianum, together with the known colletochlorin A and 4-chloroorcinol. All four of these metabolites display herbicidal activity, especially 2152 and 4-chloroorcinol [1719].

266

G. W. Gribble Br

Br O

OSO3Na

HO

Cl

R

OH

NaSO3O

O

O

Br 2146 R = H (iantheran A) 2147 R = CO2H (8-carboxy-iso-iantheran A)

2145

Br

OH Br O Br O

Br Br NaO3SO

HO

HO

OH

OH Cl

HO

O

O Cl

OSO3Na

2148 (iso-iantheran B)

2149

OH

O

2150

OH

OH

O

OH

OH O

O Cl

Cl 2151 (colletochlorin E)

2152 (colletochlorin F)

The Penicillium sp. F37 isolated from the marine Brazilian sponge Axinella corrugata produces arvoredol (2153), which is active against colorectal carcinoma HCT116 (MIC 7.9 μg/cm3 ), and prevents biofilm formation of the human pathogen Staphylococcus epidermidis by 80% at 1 mg/cm3 , without acting as an antibiotic [1720]. The marine fungus Zopfiella marina contains the isobenzofuran 5chloro-3-deoxyisoochracinic acid (2154) along with several non-chlorinated analogs [1721]. O

OH

Cl

Cl

OH

O O

OH

2153 (arvoredol)

3.14.8

OAc

CO2H

OH

2154

Pyrones

The next three sections cover new examples of halogenated oxygen heterocycles that are variations of aromatic cyclic lactones (or vinylogous cyclic lactones). In some cases the distinction between these compounds is marginal.

Naturally Occurring Organohalogen Compounds …

267

The two chlorohydroaspyrones A (2155) and B (2156) are found in the marinederived fungus Exophiala sp. living on the surface of the Korean sponge Halichondria panicea. Both metabolites display mild antibacterial activity against Staphylococcus aureus (MIC 62.5 and 125 μg/cm3 , respectively), and two resistant strains thereof [1722]. The myxomycete Fuligo septica f. flava from Japan contains the new yellow pigment fuligoic acid (2157) [1723]. Dehydrofuligoic acid (2158) is also present in this slime mold [1724]. Fusarium tricinctum, which is found on the edible brown alga Sargassum ringgoldium in Korea, produces bromomethylchlamydosporols A (2159) and B (2160). Both compounds are active towards Staphylococcus aureus and two resistant strains (IC 50 15.6 μg/cm3 for both compounds and for all three strains) [1725]. The new polyporapyranone D (2161) is generated from the fungi Polyporales PSU-ES44 and PSU-ES83 derived from the seagrass Thalassia hemprichii [1726]. The halogenated halomadurones A–D (2162–2165) are found in the marine bacterium Actinomadura sp. living within the ascidian Ecteinascidia turbinata. Halomadurones C and D show potent Nrf2-ARE activation [1727].

Cl

O

OH

HO

HO O

O

Cl

OH

O

O

2155 (chlorohydraspyrone A)

Cl

O

COOH

O

2156 (chlorohydraspyrone B)

2157 (fuligoic acid) O

O

O

O

O

COOH

R R

O

Cl

O

HO O

O

O

O

O

Br Cl

2159 R = H 2160 R = Br

2158 (dehydrofuligoic acid)

2162 R = CCl3 (halomadurone A) 2163 R = CHCl2 (halomadurone B) 2164 R = CHBrCl (halomadurone C) 2161 (polyporapyranone D) 2165 R = CHBr2 (halomadurone D)

Parvistone A (2166) is found in the Asian tree leaves of Polyalthia parviflora [1728], and ptilone C (2167) is produced by the Australian red alga Ptilonia australasica [363]. A gene cluster in Streptomyces sp. S006 yields the new 2-chlorovenemycin (2168) [1729]. O O

O Cl

OH

Br O OH

2166 (parvistone A)

O

Br

HO

Cl OH

O Br 2167 (ptilone C)

OH 2168 (2-Cl-venemycin)

The biosynthesis of α-pyrones is reviewed [1730], and syntheses of parvistone A (2166) [1731], 8-chlorogoniodiol [1731, 1732], and (–)-bitungolides B and E [1733] are reported.

268

3.14.9

G. W. Gribble

Coumarins and Isocoumarins

The well-known fungal metabolite isocoumarin ochratoxin A [1, 2] continues to be of intense interest. Studies include the origin of ochratoxin A in coffee [1734–1738], in grapes and wine [1739–1741], in red paprika [1742], in sea bass [1743], and in rice [1744]. Syntheses of ochratoxin A and labeled derivatives are reported [1745, 1746], as are all ochratoxin A stereoisomers to assess their cytotoxicity [1747]. A fluorescence immunoassay is available for sensitive detection of ochratoxin A [1748], and the nephrotoxicity and immunotoxicity of this toxin is reported [1749, 1750]. A synthesis of (R)-ochratoxin alpha is described [1751]. Two new ochratoxins have been discovered: the n-butyl and methyl esters 2169 and 2170 from the marinederived fungus Aspergillus sp. SCSGAF0093 [1752], and ochratoxin A1 (2171) from a sponge-derived fungus Aspergillus ochraceopetaliformis [1753]. HO HO OH O

OR O

Ph

OH

N H

O

O

O

Ph

O

O

OH

O

N H

O

Cl

Cl

2169 R = n-Bu 2170 R = Me

2171 (ochratoxin A2)

The ascomycete Lachnum papyraceum (Karst.) Karst. produces the new chlorinated isocoumarins 2172–2174. The brominated analog of 2172 is obtained in the presence of CaBr2 [1754]. Three new clorobiocin-related antibiotics are found in Streptomyces coelicolor M512 strain, ferulobiocin (2175), 3-chlorocoumarobiocin (2176), and 8 -dechloro-3-chlorocoumarobiocin (2177) [1755].

OH OH

O

OH H N

R2

O O

O

O

O

R1O

O R2

OH

O

O

O

R1

Cl NH

2172 R1 = R2 = H (4-chloro-6-hydroxymellein) 2173 R1 = Me, R2 = H (4-chloro-6-methoxymellein) 2174 R1 = H, R2 = OH (4-chloro-6,7-dihydroxymellein)

2175 R1 = Cl, R2 = OMe (ferulobiocin) 2176 R1 = Cl, R2 = Cl (3-chlorocoumarobiocin) 2177 R1 = H, R2 = Cl (8'-dechloro-3-chlorocoumarobiocin)

Bark extracts of the Tanzania tree Tessmannia densiflora yield the isocoumarin 7chloro-8-hydroxy-6-methoxy-3-pentylisocoumarin (2178), along with several other compounds [1756]. The new palmariols A (2179) and B (2180) are found in the

Naturally Occurring Organohalogen Compounds …

269

discomycete Lachnum palmae (NRBC-106495), and display weak antimicrobial activity against Mucor racemosus and Bacillus subtilis [1757]. A subsequent study of this organism reveals palmaerin A (2181), together with three brominated analogs when KBr is added to the culture (palmaerins B–D) (not counted). Palmaerins A–C show plant growth-regulating activity against Lepidium sativum [1758]. A Northern Thailand rain forest containing the basidiomycete Gymnopus sp. produces gymnopalynes A (2182) and B (2183), which are cytotoxic to the mouse fibroblast cell line L-929 (IC 50 3.7 and 14 μM, respectively). Antimicrobial activities are weaker [1759]. The polypore mushroom Fomitopsis officinalis yields the two new chlorinated coumarins 2184 and 2185, and the latter has activity towards Mycobacterium tuberculosis (IC 50 36.7 μg/cm3 ) [1760]. O OH

O

Cl

R2

O

OH

HO

O

O

O R1

2179 R1 = Cl, R2 = H (palmariol A) 2180 R1 = H, R2 = Cl (palmariol B)

2178

O Cl

OR1 O

O R2

O

O O

O

HO

HO

R3

Cl R1

2181 (palmaerin A)

R2

= H, = Br (palmaerin B) R1 = Me, R2 = R3 = Br (palmaerin C) 1 2 3 R = R = H, R = Br (palmaerin D)

2182 (gymnopalyne A)

O

O

O O Ph

O Ph

Cl Cl

2183 (gymnopalyne B)

O

O

O

Cl

Cl

Cl

R3=

Cl 2184

2185

The new isocoumarins 2186–2188 are produced by a mutant strain of G-444 of Tubercularia sp. TF5, along with a tetralone shown in Sect. 3.21.1, and several other metabolites. No antifungal activity is observed against Candida albicans at 30 μg/disk [1761]. A marine fungus Phoma sp. 135 living on the sponge Ectyplasia perox collected in Dominica affords the new dihydroisocoumarin 2189 along with a known analog, (3R)-6-methoxy-7-chloromellein [1762]. The fungus Peyronellaea glomerata associated with the sponge Amphimedon sp. in the South China Sea produces the five new isocoumarins, two of which, peyroisocoumarins A (2190) and B (2191), are unusual in having chlorine atoms in a pentane chain. Both compounds are effective at inducing ARE (Antioxidant Response Element) luciferase [1763]. The three new tricyclic isocoumarins 2192–2194 are found in a mangrove-endophytic

270

G. W. Gribble

fungus Pencillium chermesinum. The previously known related TMC-264 [2] reacts with glutathione and thio-peptides under physiological conditions, but 2192–2194 do not [1764]. A total synthesis of TMC-264 was accomplished [1765]. OH

OH

O

Cl

OH

O

Cl

O

OH

OH Cl

OH 2188 (7-chloromellein-5-ol)

2187 (cis-7-chloro-4-hydroxymellein)

O

OH O

O O

O

Cl

R2

OH

OH

O

Cl O

O

O

R1

Cl HO

O

O

OH

OH

2190 R1 = Cl, R2 = H (peyroisocoumarin A) 2191 R1 = R2 = Cl (peyroisocoumarin B)

2189 ((3R,4S)-4-hydroxy-6-methoxy-7-chloromellein)

O

OH

O OH

HO

O

OH

2186 (trans-7-chloro-4-hydroxymellein)

O

Cl

O

O O

OH

O O

2192 (penicilliumolide A)

OH

O

2193 (penicilliumolide C)

O OH

O

2194 (penicilliumolide D)

The earlier study of cyclopericodiol (56) from the marine fungus Periconia macrospinosa KT3863 also found the two new melleins 2195 and 2196 [359]. A deep-sea derived Spiromastix fungus (MCCC 3A 00308) produces the two new isocoumarins, spiromastimelleins A (2197) and B (2198), together with three depsidones presented in Sect. 3.22.5. Both melleins show antibacterial activity against Staphylococcus aureus, Bacillus thuringiensis, and Bacillus subtilis, but 2198 is most effective, having IC 50 values of 16, 4, and 4 μg/cm3 , respectively [1766]. The snow flea Ceratophysella sigillata produces an array of polychlorinated octahydroisocoumarins 2199–2207 as allomones to repel predators. The major metabolite is sigillin A (2199) and sigillins B–I (2200–2207) are also present in this defensive secretion [1767]. The total synthesis of (–)-sigillin A is described [1768]. Sigillin A shows high repellent activity against the predatory ant Myrmica rubra [1767].

Naturally Occurring Organohalogen Compounds … OH

271 O

O

O

O

O Cl

OH

2195 ((3R,4S)-5-chloro-4-hydroxy-6-methoxymellein)

OH

O

Cl

O

O

O

R

2196 ((R)-7-chloro-6-methoxy-8-O-methylmellein)

OH

O

O

O

Cl

OH

Cl Cl

O

Cl Cl

Cl3C

HO

HO

Cl 2197 R = H (spiromastimellein A) 2198 R = Cl (spiromastimellein B) O O Cl3C

O CCl3

HO

2203 R = Ac (sigillin E) 2204 R = H (sigillin F)

3.14.10

Cl

O Cl

O Cl3C

OR

OH

OR

2201 R = Ac (sigillin C) 2202 R = H (sigillin D)

2199 R = Ac (sigillin A) 2200 R = H (sigillin B)

OH

HO

Cl

OR

OH

O

Cl Cl

Cl HO

OR

2205 R = Ac (sigillin G) 2206 R = H (sigillin H)

Cl

HO

OAc

2207 (sigillin I)

Flavones, Isoflavones, and Chromones

A rotenone analog 2208 is present in the root extract of the Peruvian plant Lonchocarpus utilis is 7 -chloro-5 -hydroxy-4 ,5-dihydrodeguelin (2208) [1769]. The novel antibiotic, coniothyrione (2209) is isolated from Coniothyrium cerealis MF7209 and has good antibacterial activity against several strains (MIC 16–32 μg/ cm3 ) [1770]. The two novel chroman derivatives, ammonificins A (2210) and B (2211), are found in the marine hydrothermal vent bacterium Thermovibrio ammonificans on the East Pacific Rise, the first report of secondary metabolites from this bacterium [1771]. Subsequently, ammonificins C (2212) and D (2213) were found in this bacterium. The ortho-dibromophenyl ring is unique amongst natural organohalogens. Both C and D induce apoptosis at 2 and 3 μM, respectively, in a standard assay with W2 and D3 cells [1772]. The three new chromones, pestalochromones A–C (2214–2216), are present in the mangrove (Rhizophora apiculata)-derived fungus Pestalotiopsis sp. PSU-MA69, along with additional chlorinated metabolites discussed in the appropriate sections [1773]. The new 5 -hydroxychlorflavonin (2217) is found in the marine strain Aspergillus sp. AF119 obtained from beach soil at Xiamen, China [1774]. The novel trichlorinated flavonoid 2218 is found in the plant Bidens bipinnata (Plate 50), which is used widely in Chinese traditional medicine to treat diabetes and other diseases [1775].

272

G. W. Gribble NH2 OH

O O

OH

O

O

HO O Cl

O

O

Br

Cl

HO

R

2208

H2 N

O OH

O

O

2210 R = OH (ammonificin A) 2211 R = Br (ammonificin B)

2209 (coniothyrione)

OH

OH

O

O

OH

O

O

O

O HO

HO

O OH

HO

O

O Cl

R

Br R

2214 R = β-Cl (pestalochromone A) 2215 R = α-Cl (pestalochromone B)

2212 R = OH (ammonificin C) 2213 R = Br (ammonificin D)

2216 (pestalochromone C)

OH

O

O

Cl OH O

OH

OH

Cl

O

O

2217 (5'-hydroxychlorflavonin)

O

HO Cl

OH Cl

OH

O 2218

Plate 50 Bidens bipinnata (Photograph courtesy of Dalgial; Creative Commons Attribution 3.0 Unported)

Naturally Occurring Organohalogen Compounds …

273

Together with eight new and eight known chromones, the chlorinated 2219 and 2220 are isolated from an extract of Aquilaria malaccensis agarwood from Laos [1776]. Chinese “Eaglewood”, Aquilaria sinensis (Plate 51), which is used in traditional medicine for a variety of ailments, contains the two chloro chromones 2212 and 2222 [1777]. Two other investigations of Aquilaria sinensis found the new 2223 along with 14 related 2-(2-phenylethyl)chromones [1778], and the three new tetrahydrochromones 2224–2226 [1779]. Of the 15 novel dimers isolated from Aquilaria sinensis, one contains chlorine, aquisinenone (2227) [1780]. O

Cl O

HO

R1

Cl O

R

HO

R2

HO O

OH

O 2221 R1 = R2 = H 2222 R1 = OMe, R2 = H 2223 R1 = OMe, R2 = OH

2219 R = H 2220 R = OH

Cl Cl HO 7 8 HO 6

HO

R O

O

O

HO O

5 OH

O

2224 R = OMe (5R,6R,7R,8S) 2225 R = H (5S,6S,7S,8S) 2226 R = OMe (5R,6R,7R,8R)

Ph

Ph

O

O 2227 (aquisinenone)

Plate 51 Aquilaria sinensis (Photograph courtesy of Chong Fat; Creative Commons AttributionShare Alke 3.0 Unported)

274

G. W. Gribble

Along with several known flavonoids and related compounds, the traditional herbal medicine tree Pongamia pinnata (L.) Pierre contains the chlorinated furanoflavone 2228, which is inactive in an anti-inflammation assay [1781]. A novel flavone, aspergivone A (2229), is found in the marine fungus Aspergillus candidus derived from the gorgonian Anthogorgia ochracea living in the South China Sea [1782]. Aspergivone A is a methoxy derivative of the well-known chlorflavonin [1]. The fungal pathogen Cochliobolus australiensis isolated from infected leaves of the weed “buffelgrass” (Pennisetum ciliare aka Cenchrus ciliaris), produces the two new chloromonilinic acids C (2230) and D (2231) together with the known chloromonilinic acid B. All three of these chloromonilinic acids are toxic to the invasive buffelgrass, reducing germination and radicle growth at a concentration of 0.005 M [1783]. An Iranian oak tree (Quercus brantii)-associated fungus Fimetariella rabenhorstii affords the unusual rabenchromenone (2232) along with a related benzophenone rabenzophenone (2233), and two known non-chlorinated analogs. All four metabolites display strong phytotoxicity against oak and tomato leaves [1784]. O

Cl

Cl O

HO

O

O

O Cl

O

OH

OH CO2Me

OH

O

O

Cl

HO2C

2229 (aspergivone A)

O

O

O O

2228

OH

O

O

O HO CO2Me

2230 (chloromonilinic acid C) OH

O

CO2Me

CO2Me O

Cl O Cl CO2H

2231 (chloromonilinic acid D)

2232 (rabenchromenone)

HO OH Cl 2233 (rabenzophenone)

In the presence of the plant isoflavonoids daidzein and genistein, the termite (Macrotermes natalensis)-associated fungus Actinomadura sp. RB99 effects polyhalogenation (chlorination and bromination) to produce an array of polychlorinated and polybrominated isoflavones. These fermentations are conducted in the presence of NaCl and KBr to give the 15 maduraktermols A–N shown. As “forced” metabolites, these halogenated isoflavanoids are not “counted”, as the growth medium contains both daidzein and genistein. Maduraktermols G and G1 are known metabolites, and H and L display antimicrobial activity against Helicobacter pylori (MIC 50 6.9 and 14.5 μg/cm3 , respectively) [1785].

Naturally Occurring Organohalogen Compounds …

275 Cl

Cl R1O

O

HO Cl

R2 O

Cl

R1 R

OH

2

R1 = OMe, R2 = H (maduraktermol D) R1 = Cl, R2 = H (maduraktermol E) R1 = Cl, R2 = OH (maduraktermol F)

OH

R1 = OH, R2 = Cl (maduraktermol G) R1 = Cl, R2 = OH (maduraktermol G-1)

Br

R1 R1

O Br O

O

OH Cl

R1 = R2 = H (maduraktermol A) R1 = H, R2 = OMe (maduraktermol B) R1 = Me, R2 = OMe (maduraktermol C)

HO

R1 R2

O

Cl

O

HO

O

OR2 Br

Br O Br

R2 R3

O

HO

O

Br

Br

OH

OH

O

OH

Br

R1 = OMe, R2 = OH, R3 = H (maduraktermol K) R1 = Br, R2 = H (maduraktermol H) R1 = OMe, R2 = Me (maduraktermol I) R1 = OH, R2 = Br, R3 = OH (maduraktermol L) R1 = OH, R2 = OMe, R3 = OH (maduraktermol M) R1 = Br, R2 = Me (maduraktermol J)

maduraktermol N

3.15 Polyacetylenes 3.15.1

Terrestrial Polyacetylenes and Derived Thiophenes

A review covering approved and potential acetylenic anticancer agents includes polyacetylenes of all types [1786]. The chlorinated thiophene xanthopappin B (2234) (a racemate) is found in the Chinese plant Xanthopappus subacaulis C. Winkl. along with two non-chlorinated analogs and three known related thiophene acetylenes. These compounds exhibit significant photoactivated insecticidal activity against the Asian tiger mosquito larvae (Aedes albopictus) [1787]. The new spiroketal enol ether flosculin A (2235) is found in leaves of Plagius flosculosus from Sardinia, Italy, along with seven non-chlorinated new and known spiroketal analogs. Flosculin A has modest cytotoxicity against Jurkat T and HL-60 leukemia cells (IC 50 13.2 and 18.9 μM, respectively) [1788]. The related artemiselenol A (2236) resides in the plant Artemisia selengensis [1789], and the four new chlorinated lactiflodiynes A, B, C, F (2237–2240) are found in Artemisia lactiflora (Plate 52) from China, along with new non-chlorinated lactiflodiynes, known spiroacetals, and the previously reported enantiomer of 2240 [1790]. Two new thiophene acetylenes from Rhaponticum uniflorum (L.) DC. are 7-chloroarctinone-b (2241) and rhapontiynethiophene A (2242), along with three related compounds [1791]. The “Formosan thistle” (Cirsium japonicum DC. var. australe Kitam.) (Plate 53) contains the three chlorinated polyacetylenes, cirsiumyne D (2243) and ciryneols C (2244) and H (2245) along with non-chlorinated analogs [1792]. The latter two metabolites were omitted from the earlier surveys [1, 2].

276

G. W. Gribble

Cl

Cl

OH

OH O

O

Cl S

O

O

HO

O

O

AcO 2234 (xanthopappin B)

2236 (artemiselenol A)

2235 (flosculin A)

R2

Cl

O

O

S

S

R1

R

O 2237 R1 = OAc, R2 = OH (lactiflodiyne A) 2238 R1 = OH, R2 = OH (lactiflodiyne B) 2239 R1 = O-i-val, R2 = OH (lactiflodiyne C) 2240 R1 = H, R2 = OH (lactiflodiyne F)

2241 R = C–CH2Cl (7-chloroarctinone-b) 2242 R = Cl (rhapontiynethiophene A)

OH

OH

Cl

Cl

OH

2243 (cirsiumyne D)

OH

2244 (ciryneol C)

OH

Cl

OH

2245 (ciryneol H)

Plate 52 Artemisia lactiflora (Photograph courtesy of Dominics Johannes Bergsma; Creative Commons Attribution-Share Alike 3.0 Unported)

Naturally Occurring Organohalogen Compounds …

277

Plate 53 Cirsium japonicum (Photograph courtesy of Qwert1234; Creative Commons AttributionShare Alike 4.0 International)

An enantioselective synthesis of the known scorodonin is reported, but there is some discrepancy in two of the 13C NMR chemical shifts that remain unresolved [1793]. A biosynthesis study of acetylenic thiophenes in Tagetes patula confirms the previously suggested pathway via long-chain fatty acids and polyacetylenes. However, the data do not exclude a route in which a thiophene precursor is obtained by ring-opening of a cyclic polyketide intermediate [328]. Fatty acid acetylenases are found in polyacetylene-containing plant species, such as those in the families Asteraceae, Apiaceae, and Araliaceae. A proposed biosynthesis pathway is shown (Scheme 5) [1794].

3.15.2

Marine Polyacetylenes

Examples of marine polyacetylenes are covered in the section on Lipids and Fatty Acids (3.8).

278

G. W. Gribble

Scheme 5 Formation of falcarinol and falcarindiol from linoleic acid

CO2H linoleic acid O2 H2O

Divergent FAD2 acetylenase

CO2H crepenynic acid O2 Denaturase H 2O

CO2H dehydrocrepenynic acid O2 Acetylenase H 2O

CO2H

CO2H

X2

X1 X1 = H, X2 = OH (falcarinol) X1 = X2 = OH (falcarindiol)

3.16 Enediynes No new enediyne natural products are reported since the last survey [2]. However, a few presumed enediyne-derived halogenated natural products are described herein. Four new cyanosporasides C–F (2246–2249) are found in the marine actinomycetes Salinispora pacifica CNS 143 and Streptomyces sp. CNT-179 [1795]. The two previous cyanosporasides A and B are shown in the Aromatics Sect. 3.20 [2]. The proposed enediyne precursor is shown.

Naturally Occurring Organohalogen Compounds … Cl

279

Cl

O NC HO

OH

OH O

OH OR NC

NC

O O

Cl

S

OH

NHAc

OAc 2247 R = Ac (cyanosporaside D) 2248 R = H (cyanosporaside E)

2246 (cyanosporaside C)

O

O

2249 (cyanosporaside F)

O

NC enediyne precursor?

A locust-associated Amycolatopsis sp. HCa4 yields the two new amycolamycins A (2250) and B (2251). Interestingly, only 2250 is cytotoxic to the M231 cell line (IC 50 7.9 μM), but neither compound shows activity against the HL-60, A-549, MCF-7, and BL6-F10 cell lines [1796]. In the biosynthesis of dynemicin A, the novel iodoanthracene 2252 is found as a mid-pathway intermediate, in a process that requires some iodide (at only 0.5 mg/dm3 ) [1797]. O

O

O

R2

HO

R1

Cl O

O

O

HO O

O

O

H N

S O

OH

OH

2250 R1 = OH, R2 = H (amycolamycin A) 2251 R1 = H, R2 = OH (amycolamycin B)

I 2252

The predominant research in this Section involves the biosynthesis of the enediyne natural products—halogenated or not. Two important reviews on this subject have appeared [1798, 1799]. The biosynthesis of the enediyne C-1027 in Streptomyces globisporus has been manipulated so as to improve production of this antitumor antibiotic [1800, 1801]. The importance of enediynes in anticancer therapy is reviewed [1802, 1803]. Several synthesis studies of these halogenated enediyne natural products are reported: (–)-maduropeptin chromophore [1804, 1805], C-1027 chromophore [1806], and hedarcidin chromophore [1807–1809].

280

G. W. Gribble

3.17 Macrolides and Polyethers The very large group of macrolides and polyethers includes many new halogencontaining examples, as more than 120 are documented in the prior surveys [1, 2]. The soil bacterium Serratia plymuthica A 153 furnishes a new member of the haterumalide family [2], haterumalide X (2253) [1810]. Total syntheses of the known haterumalides NA, NC, and B are reported [1811, 1812]. Three new chlorinated spirastrellolides D (2254), F (2255), and G (2256) are found in the sponge Spirastrella coccinea from Dominica along with two new non-halogenated analogs [1813]. Total syntheses of the methyl esters of spirastrellolides A [1814–1816] and F [1817, 1818] are reported. OR1 O

RO2C O

X

Cl

O OH

O HO

O

Y

HO

Z O O

O HO

OH O

15 2253 (haterumalide X)

O

O

CO2H OAc

O O

16

2254 R = R1 = Z = H, X = Y = Cl, 15,16 (spirastellolide D) 2255 R = R1 = X = Z = H, Y = Cl (spirastellolide F) 2256 R = X = Z = H, R1 = Me, Y = Cl 15,16 (spirastellolide G)

The family of phorbasides from a Western Australian Phorbas sp. sponge is enriched by the discovery of phorbasides C–E (2257–2259) [1819] and G–I (2260– 2262) [1820], each of which contains a chlorocyclopropane unit. A total synthesis of (+)-phorbaside A [1] verifies the structure [1820].

Naturally Occurring Organohalogen Compounds …

281 O O

OH O

OX

O

NH

O

O

OH OH

O

O

OH

X= O O

O O

O

O

Cl

2257 (phorbaside C) HO

O

OH

OH O

O

2258 (phorbaside D)

Cl

O

HO

OX

OH O

O

OH

OH

O O

O

O

O

OH

O

O

X= O O

O

O

OH O

O

O

Cl

2259 (phorbaside E)

Cl

OH O

OH O

O

O

O

2260 (phorbaside G)

OX O

OH

OH

O

NHCHO

O

OH

O

X= O O O

O

OH O

O

O

2261 (phorbaside H)

Cl

OH O

O

2262 (phorbaside I)

Cl

The myxobacterium Sorangium cellulosum, So ce1525 produces chlorotonil A (2263) [1822], which contains a novel gem-dichloro-1,3-dione moiety (and confirmed by a total syntheses [1823]). Lactone 2264 is found in the marine-derived fungus Curvularia sp. from a red alga. The corresponding epoxide is also found and the authors raise the possibility of 2264 being an artifact from CH2 Cl2 used in the workup [1824]. Another new macrocyclic lactone, oxacyclododecindione (2265) is found in the fungus Exserohilum rostratum and is a novel inhibitor of IL-4 mediated signal transduction [1825]. Three new chlorinated radicicol analogs, pochonins G–I (2266–2268) and K–P (2269–2274) are found in the fungus Pochonia chlamydosporia var. chlamydosporia. Some of these lactones are inhibitors of the secretory glycoprotein WNT-5A related to the proliferation of dermal papilla cells [1826, 1827]. When NaBr is added to this fungal culture medium 13-bromomonocillin I

282

G. W. Gribble

is produced (not shown), which is very potent in the WNT-5A assay [1828]. Total syntheses of (+)-pochonin D and (+)-monocillin II [1829], and pochonins E and F [1830] are reported.

O

O

Cl OH

OH 2264

OH

O

HO

O

O

Cl

O

O

2268 (pochonin I)

O

OH O

Cl

2267 (pochonin H)

2266 (pochonin G)

OH

O O

O

O

RO

HO

HO

HO

O O

HO

HO

Cl

OH O

O

OH

O

2265 (oxacyclododecindione)

O

O

Cl

OH

O

2263 (chlorotonil A)

OH

O

O

HO

HO

O

Cl

O

Cl

O

Cl

HO

Cl

O

HO Cl

O

O R

O (pochorin K)

2269 R =

2270 (pochonin L)

2271 R = H (pochonin M) 2272 R = OH (pochonin N)

HO OH OH

O

OH O

O

O

HO

O O

HO Cl

Cl HO

O OH

2273 (pochonin O)

OH 2274 (pochonin P)

Seven new chlorinated resorcylic acid lactones, greensporones 2275–2281, are produced by the freshwater aquatic fungus Halenospora sp. from North Carolina. Seven non-chlorinated analogs are also present [1831]. Total syntheses of greensporone F and dechlorogreensporone F led to the revision of the tetrahydrofuran ring stereochemistry. The corrected versions are shown [1832]. Two brominated resorcylic acid lactones 2282–2283 are produced naturally by the marine-derived fungus Cochliobolus lunatus induced by histone deacetylase inhibitors [1833].

Naturally Occurring Organohalogen Compounds …

O

O

O

O

O

Cl

O

O

O

O O

O

O

Cl

O

O

O

OH

Br

O HO

O Cl

Cl O

2279 (greensporone E)

2278 (greensporone D)

OH

HO

HO Cl

O

OH

OH

HO

O

2277 (8,9-dihydrogreensporone A)

2276 (greensporone B)

O

O

HO Cl

2275 (greensporone A)

O O

HO

O

O

O O

O

O HO Cl

283

O

O

2280 (8,9-dihydrogreensporone D) O O

O

OH R

OH OH

2281 (greensporone F)

2282 R = H (5-bromozeaenol) 2283 R = Br (3,5-dibromozeaenol)

The marine-derived fungus Humicola fuscoatra contains three new radicicols B–D (2284–2286) in addition to several known analogs. Radicicol B (2284) is moderately active in the latent HIV-1 reactivation assay [1834]. The new dichlorinated dehydrocurvularin 2287 is found in Alternaria sp. AST0039, which is a fungal endophyte of Astragalus lentiginosus (“spotted locoweed”) collected in central Arizona [1835]. A South China Sea gorgonian, Dichotella gemmacea houses the fungus Cochliobolus lunatus, which produces the new cochliomycin C (2288) [1836, 1837]. Cochliomycin F (2289) is also found in this fungus [1838]. A total synthesis of cochliomycin C [1839] and other syntheses of these lactones are known [1840, 1841].

284

G. W. Gribble OH

OH

O

O

OH

HO Cl

O

HO

HO Cl

O

O

O Cl

O

O

2286 (radicicol D) OH

O

OH

HO

O

OH

2285 (radicicol C)

2284 (radicicol B)

O O

O O

Cl

O

OH

2287 ((–)-(10E,15S)-4,6-dichloro10(11)-dehydrocurvularin)

OH

Cl

Cl

O

OH

OH

HO

HO

Cl

O

O

O HO

OH

O

OH OH

OH

2288 (cochliomycin C)

2289 (cochliomycin F)

Nine novel resorcylic acid lactone ilyoresorcys 2290–2298 are present in a Chinese soil fungus Ilyonectria sp. sb65 growing near the fibrous roots of Schisandra bicolor var. tuberculata [1842]. OH

O

OH

O

O O

HO

OH O

O

O

HO

Cl

O

HO

Cl

Cl

OH

OH

OH

2290 (ilyoresoray A) OH

O

2291 (atrop-ilyoresoray A) OH

O

O

OH

O

O

O

HO

O

OH

O HO

Cl

Cl

O

OH

O

O HO

2292 (ilyoresoray B)

O Cl

O 2294 (ilyoresoray E)

2293 (ilyoresoray C)

OH

OH

O

2296 (ilyoresoray G)

O O

OH

OH

O Cl

OH

O O

O HO

2295 (ilyoresoray F)

O

HO O

Cl

O

2297 (ilyoresoray J)

HO Cl 2298 (ilyoresoray K)

Halichondrin B-1140 (2299) is the first chlorinated halichondrin to be isolated, in this case from the New Zealand deep-water (>100 m) sponge Lissodendoryx sp. [1843]. The tetrachloro polyketide muironolide A (2300) resides in the well-known marine sponge Phorbas sp. [1844]. This compound was synthesized and revised at one chiral center (corrected structure shown) [1845]. The soil bacterium Sorangium cellulosum So0157-2 produces the new epothilone N (2301) [1846].

Naturally Occurring Organohalogen Compounds … O

O

O HO

285

O

O

O

O Cl

O

O

O

O

O

O

O

O O

O

O 2299 (halichrondrin B-1140) O S

Cl

HN N

HO

OH

OH O

CCl3

O

O

Cl

O

O

O

OH

O

2301 (epothilone N)

2300 ((+)-muironolide A)

An investigation of the Guam cyanobacterium Moorea bouillonii produces the six new macrolides 2302–2307 [1847].

O

O

O

O

O

O

O

O

O O

O

O

O OH

O OH O HO

R2

O

R2

O O O

O O

N

O

S O

N

O

O

O

O

Cl

2305 (27-deoxylyngbyabellin A)

HN

S

O

N

S

O

2303 = Br, = H ((18E)-lyngbyaloside C) 2304 R1 = H, R2 = Br ((18Z)-lyngbyaloside C)

O

N

OH

R1

2302 (2-epi-lyngbyaloside)

S O

O

R1

Br

HO

HN

HN

O

N O

Cl

Cl

Cl

O

2306 (lyngbyabellin J)

2307 (laingolide B)

Cl

286

G. W. Gribble

Of 13 new isobiscembranoids, lobophytones A–G [1848] and O–T [1849], isolated from the Chinese soft coral Lobophytum pauciflorum (Plate 54), two contain chlorine D (2308) and Q (2309), and are the only two lobophytones to show potent inhibition against LPS-induced NO release in mouse macrophages (IC 50 4.70 and 2.8 μM, respectively) [1848, 1849]. A Vietnamese marine cyanobacterium Lyngbya majuscula (Moorea producens) produces nhatrangin B (2310) along with the nonbromo analog (A) and the known anhydroaplysiatoxin, which nhatrangin B resembles [1850]. A marine-derived sediment bacterium from Fiji, Nocardiopsis sp. affords fijiolides A (2311) and B (2312), which inhibit TNFα-induced NF-κB activation [1851]. A synthesis of fijiolide A is described [1852].

O O

HO O

O CO2Me

O Cl

MeO2C

O

Cl

O

HO

OH

O

HO

O

HO

2308 (lobophytone D)

OH 2310 (nhatrangin B)

2309 (lobophytone Q) Cl

OH

O O N

OH OH

Br

HO2C

O

HO

O

O O

O

Cl NHR 2311 R = COCH3 (fijiolide A) 2312 R = H (fijiolide B)

The Fijian red alga Callophycus serratus is a treasure trove of brominated diterpene-benzoate macrolides. Four new bromophycolides R–U (2313–2316) are found in this alga [1853], and previous bromophycolides are described in Marine Diterpenes Sect. 3.4.3.2 [2]. The Madagascar sponge Fascaplysinopsis sp. contains seven salarins, two of which, F (2317) and G (2318) are chlorinated [1854].

Naturally Occurring Organohalogen Compounds …

287

Plate 54 Lobophytum pauciflorum (Photograph courtesy of David Witherall; https://www.gaiagu ide.info/HotShot.html?resourceld=8uwc9KFn; Creative Commons Attribution 3.0 Unported)

Br O

O

O O

HO

HO

HO

O

2

O

Br

Br

Br

2313 (bromophycolide R)

2315 (bromophycolide T)

2314 (bromophycolide S) O

O O

Cl O HO

HO O

O

O

N H

Br

Br

O O

O O

2316 (bromophycolide U) O O

HO O N H

N

2317 (salarin F)

Cl O

O O

Br

O

O

O

O O

O

N O

2318 (salarin G)

O

O

288

G. W. Gribble

The marine-derived Streptomyces sp. MA2-12 furnishes chlokamycin (2319), a novel macrolactam, which displays modest cytotoxicity towards Jurkat and HCT-116 cells (IC 50 24.7 and 33.5 μM, respectively) [1855]. The new polyketide cryptosporiopsin A (2320) is found in the fungus Cryptosporiopsis sp. living on the plant Zanthoxylum leprieurii [1856]. A collection of Moorea bouillonii from the Palmya Atoll in the Central Pacific Ocean affords the five novel lyngbyabellins 2321–2325. In the HCT-116 colon cell line, lyngbyabellin N (2325) is very potent (IC 50 40.9 nM) [1857]. H N OH

O

O

O

OH

Cl

O

HO

O

NH

O

HO Cl

O O

2320 (cryptosporiopsin A)

2319 (chlokamycin) OH O

S

OH O

S O

N

O

O

O

N O

S O

N

O

O

N

S Cl

OH O

Cl

O

O

O

2321 (lyngbyabellin K)

N

O

O

N

S

Cl

S O

2322 (lyngbyabellin L)

2323 (7-epi-lyngbyabellin L) OAc

O N

OH O O

N

O S

OH

Cl

Cl S

H N

N O

O O

S

Cl

O

O

EtO2C

O

S O

N

O

O

N O

Cl

Cl

O

2324 (lyngbyabellin M)

2325 (lyngbyabellin N)

The Indonesian sponge Callyspongia sp. contains the novel cytotoxic callyspongiolide 2326, which is potent towards L5178Y mouse lymphoma, human Jurkat J16T, and Ramos B lymphocytes (IC 50 320, 70, and 60 nM, respectively) [1858]. Two new ansamitocins, ACGP-2 (2327) and ACGP-1 (2328) are present in Actinosynnema pretiosum ssp. auranticum ATCC 31565 [1859]. Another cultivation of Actinosynnema pretiosum produces the new ansamitocin analogs 2329 and 2330 [1860].

Naturally Occurring Organohalogen Compounds …

289 O

O O

OH Br H2 N

O

O

HO

O O

O H

O

OH

O

HO

H2N

O

O

O O

N

HO Cl

2326 (callyspongiolide)

O 2327 (ACGP-2')

O

O H2N

HO HO

O HO

O

R

O

NH

O

O

O

O

O

Cl

O

N

O

O O O

N

OH O

Cl O

O

2328 (ACGP-1)

N O H

O

2329 R = Et 2330 R = i-Bu

The extraordinarily complex forazoline A (2331), from Actinomadura sp. cultivated from the ascidian Ecteinascidia turbinata, is active towards Candida albicans (MIC 16 μg/cm3 ). It is also active in vivo in a disseminated model in mice with no toxicity [1861]. Candidiasis affects 400,000 people annually with a mortality rate of 46–75% [1862]. The marine cyanobacterium Trichodesmium erythraeum from Singapore produces the new 3-methoxyaplysiatoxin (2332) [1863]. A marine sponge of the Petrosiidae family yields phormidolides B (2333) and C (2334), related to the known phormidolide A and oscillariolide [1864]. O

S N O HN

O Cl

N

SO OH

O

O

O

O

O

O

O O

O

OH

O O

O

O

Br

OH

N

2331 (forazoline A)

2332 (3-methoxyaplysiatoxin)

290

G. W. Gribble HO O

OH

O O O Br

O

OH

OH

OH

OH

OH

O

49 R Cl 2333 R = Cl, Δ49 (phomidolide B) 2334 R = Br (phomidolide C)

The new C-1027 chromophore-V (2335) is found in cultures of the Arctic marine sediment actinomycete Streptomyces sp. ART 5, along with C-1027 chromophoreIII (2336), shown with the parent C-1027 chromophore (2337). The earlier cited fijiolides A (2311) and B (2312) are also identified. Chromophore-V is significantly cytotoxic against breast carcinoma and colorectal carcinoma cells (IC 50 0.9 and 2.7 μM, respectively) [1865]. The incorporation of chlorine in 2335 has been explained via a para-benzyne intermediate from 2337 [1866]. The new 14-deoxyoxacyclododecindione (2338), an analog of the congener 2265, is found in the fungus Exserohilum rostratum and inhibits TGF-β-induced CTGF promoter activity [IC 50 336 nM) [1867]. The structure of 2338 is confirmed by total synthesis and X-ray crystallography as (14S)/(15R). The natural (+)-2338 enantiomer is 17–27 times more active than the synthetic (–)-enantiomer in two anti-inflammatory assays [1868]. Prymnesin-B1 (2339) is found in a Danish strain of Prymnesium parvum that is highly toxic to rainbow trout. This new prymnesin contains the usual chloroethene terminus and generally resembles the known prymnesins [2] but with a different linkage between rings G and J [1869]. The reader is referred to this paper for the full structure, and for those of prymnesins-1 and -2 [2]. Moreover, this paper describes 13 additional prymnesin analogs tentatively detected by LC/MS/HRMS [1869]. The marine cyanobacterium Moorea producens living in the Okinawan coastal area provides the new oscillatoxin I (2340), which shows cytotoxicity against L-1210 cells and diatom growth inhibition (IC 50 4.6 and 1.2 μg/cm3 , respectively) [1870].

Naturally Occurring Organohalogen Compounds … O

O

O N H

R

291

O

N H

O O

O O

O

Me2N OH

O

H2N

O

OH

OH

O

O

O

O O

OH

OH

OH

O

O

O Cl

Cl NH2

NH2

2335 R = Cl (C-1027 chromophore-V) 2336 R = H (C-1027 chromophore-III)

Cl

2337 (C-1027 chromophore)

OH

O

O

Br

O

O

14

HO

O

O

O OH

OH

O O C91H132ClNO34

2338 ((+)-14-deoxy-oxacyclododecindione)

O 2340 (oscillatoxin I)

2339 (prymnesin-B1)

Several new brominated aplysiatoxins, 2341–2347, are present in the Okinawan cyanobacterium Moorea producens. Oscillatoxin 2344 shows the highest diatom growth inhibition towards Nitzschia amabilis [1871]. Another study of this cyanobacterium produces the new neo-aplysiatoxin A (2348) [1872]. R HO

O

O

O

O

O

O

Br

O

O

O

O

O

Br

O O

O OH

OH

OH

2341 (2-hydroxyanhydroaplysiatoxin)

OH

2342 R = OH (17-bromooscillatoxin B2) 2343 R = OOH (17-bromo-4-hydroperoxyoscillatoxin B2)

O O O

O O

O

O

Br

O

O

O O

O

O

Br

O O

OH

OH

2344 (17-bromo-4,26-epoxyoscillatoxin B2)

OH 2345 (oscillatoxin E)

292

G. W. Gribble O O

O O

O

Br

O

O

O

O

O

O

Br

O O

OH

O

OH

O 2346 (oscillatoxin F)

2347 (17-bromo-30-methyloscillatoxin D) HO O

O O O

O

Br

O O

OH

OH 2348 (neo-aplysiatoxin A)

The Indonesian sponge Callyspongia sp. contains the novel macrolide callyspongiolide (2349), which is strongly cytotoxic towards Jurkat J16T and L5178Y cells [1873]. It is also a potent inhibitor of vacuolar ATPase [1859]. Several syntheses of 2349 were described ([1874, 1875] and references therein). A culture extract from Actinomadura sp. K4S16 yields nonthmicin (2350), which is a chloro analog of the known ecteinamycin. The former polyether shows potent antimicrobial activity (IC 50 0.0013–0.005 μg/cm3 ) against Kocuria rhizophia, Bacillus cereus, Staphylococcus aureus, and Enterococcus faecalis. Ecteinamycin is much less active against all four bacterial strains [1876]. The new phocoenamicin (2351) is found in a culture of Micromonospora auratinigra strain from the Harbor porpoise microbiota. This metabolite has excellent antimicrobial activity towards several bacterial strains [1877]. A subsequent examination of Micromonospora sp. from a Canary Islands marine sediment affords the new phocoenamicins B (2352) and C (2353) [1878]. All three phocoenamicins have strong antimicrobial activities, especially C (2353), which features a mid-structure ester rather than a ketone functionality.

Naturally Occurring Organohalogen Compounds …

293 OH Br

O

O

O

O

OH

NH2 2349 (callyspongiolide) OH

O

OH

O

O

O Cl

O

O

OH

OH

O

O

2350 (nonthmicin) R

HO HO OH OH

HO

O

HO

O

O

O

O

O

O

O O

O

O OH

O

OH

O O

HO

O OH

O

HO

OH

O

OH O

OH

O

O

HO

O

HO Cl

2351 R = H (phocoenamicin) 2352 R = OH (phocoenamicin B)

Cl 2353 (phocoenamicin C)

The family of tiacumicins (= fidaxomicins, lipiarmycins, and clostomicins) [2] isolated from several Actinoplanaeae strains, such as Actinoplanes deccanensis, has been extended in recent years to include the new tiacumins 2354–2368 [1879–1881]. For an excellent summary and review of these antibiotics, see [1882], which includes the seven unpublished tiacumins 2369–2375. As often is the case, the addition of bromide salts to the culture medium gives brominated analogs. It is noted that tiacumicin 2367 is the C18 epimer of lipiarmycin A4 [1882]. The chemistry and biology of fidaxomicin (tiacumicin B) is reviewed [1883], as are the syntheses and biological evaluation of iodinated analogs [1884]. The biosynthesis of tiacumicin B utilizes two P450 enzymes, wherein both the first and last steps involving hydroxylation are determined [1885]. Total syntheses of the aglycone of tiacumicin B are described by three groups [1886–1888], and one of tiacumicin B itself [1889].

294

G. W. Gribble OH

HO

RO

OH Cl

O

O OH

O O

O HO

O

Cl

2354 R = H 2355 R = Me OH

O

HO

O

OH Cl

O

HO

O

O

OH

O O

O

O O

HO

O HO

2356 R1 Z Z X Y Z Z H Z X Y Z Z

OH

HO

R3 O

O O

O

Cl

O OH

O R1O

2357 2358 2359 2360 2361 2362 2363 2364 2365 2366 2367 2368

OH R4

HO

O

O 18

HO

O

Cl

Cl

R2

R2 H OH H H OH Me H H H H OH Me

R3 H H H H H H Me Me Me Me Me Me

R4 Et Et Et Et Me Et Et Et Et Et Me Et

O X= O Y= O Z=

OH

O W=

HO

O

O

OH Cl

HO

O

O

O OH

O R1O

O

O HO

O R2

Cl

2369 2370 2371 2372 2373 2374

R1 H W X Z Y Z

R2 H OH OH OH OH H

R3 H H H Me H H

O X= O Y= O Z=

R3

O

O

HO

O

OH Cl

HO

O

O

O

OH

O O

O

O O

O HO

HO

Cl

2375

Total syntheses of previously described macrolides and polyethers include laingolide B [1890], biselide E [1891], (+)-oocydin A [1892], sporolide B [1893], (+)spongistatin 1 [1894, 1895], (+)-phorboxazole A [1896], and callipeltosides A, B, and C [1897, 1898]. Other purported syntheses of phormidolide A [1899], leidolide

Naturally Occurring Organohalogen Compounds …

295

B [1900], chagosensine [1901], and lytophilippine [1902] have been frustrated by the reports of incorrect structures. Syntheses of (–)-lyngbyalside B [1903, 1904] and lyngbyaside C [1905] were successful following reassignment of the reported structure. Reviews of import to this Section include marine polyether biotoxins [1906], tetrahydrofuran macrolides [1907], benzenediol lactones [1908], radicicol inhibitors of Hsp90 [1909], polyketide-derived polycyclic ether biosynthesis [1910], and recent advances in polyketide natural product total synthesis [1911].

3.18 Naphthoquinones and Higher Quinones A member of the palmarumycin family of fungal metabolites that was omitted earlier [2] is Sch 53,825 (2376), which shows inhibitory activity in the fMLP-stimulated phospholipase assay (IC 50 19 μM) [1912]. The Chinese mangrove plant Bruguiera gymnorrhiza (Plate 55) contains seven new palmarumycins, three of which, BG5– BG7 (2377–2379) contain chlorine [1913]. Guignardin E (2380) is found in the fungus Guignardia sp. KcF8 isolated from the fruits of the mangrove plant Kandelia candei together with five non-chlorinated analogs. All of these guignardins display cytotoxicity against a battery of ten cancer cell lines (for 2380: IC 50 1.24–11.3 μM) [1914]. The first chlorinated preussomerins, A (2381) and B (2382), are found in the mangrove-derived fungus Lasiodiplodia theobromae ZJ-HQ1, living on Acanthus ilicifolius (Plate 56), together with nine known analogs. Compounds 2381 and 2382 are cytotoxic towards the A-549 and MCF-7 cell lines (IC 50 5.9–9.8 μM), and show antibacterial activity against Staphylococcus aureus (MIC 6.2 and 3.2 μg/ cm3 , respectively) [1915]. The new perylenequinone 2383 is present in the marinederived fungus Alternaria sp. NH-F6, and is moderately inhibitory against the BRD4 protein [1916]. The Okinawan plant Achyranthes aspera var. rubrofusca-associated fungus Cladosporium sp. TMPU1621 contains 2-chlorocladosporol D (2384), but shows no anti-MRSA activity [1917]. The structure of palmarumycin B6 is revised by synthesis to that of 6-chloropalmarumycin CP17 [1918]. An extensive review of structures, bioactivities, biosynthesis, and synthesis of the spirodioxynaphthalenes is available [1919].

296

G. W. Gribble

Plate 55 Bruguiera gymnorrhiza (Photograph courtesy of Dinesh Valke; Source Bruguiera gymnorrhiza (L.) Savigny; Creative Commons Attribution-Share Alike 2.0 Generic)

Plate 56 Acanthus ilicifolius (Photograph courtesy of Vengolis; Creative Commons AttributionShare Alike 3.0 Unported)

Naturally Occurring Organohalogen Compounds … OH

OH

OR

297 OH

OH

Cl

OH Cl

Cl O O

2378 (palmarumycin BG6)

2377 R = H (palmarumycin BG5) 2379 R = SO3H (palmarumycin BG7) O

O Cl

Cl

OH

RO O

O

O

O

O

O

2376 (Sch 53825)

OH

OH

OH

O

OH

OH

O

O

OH OH

O O

Cl OH

OH O 2380 (guignardin E)

2383

2381 R = H (chloropreussomerin A) 2382 R = Me (chloropreussomerin B) OH

OH

HO Cl O

O

OH

2384 (2-chlorocladosporol D)

Nine new napyradiomycins (2385–2393) are present in a culture of Streptomyces antimycoticus NT17, and two of which, 2391 and 2392, show antibacterial activity against six strains [1920]. Napyradiomycin A1 (2389) is an inhibitor of the mitochondrial electron transport complexes I and II [1921]. The biosynthesis of the known napyradiomycin azamerone [2] involves a novel rearrangement of SF2415A3 [1922]. A review of the rare diazo group-containing natural products, such as 2391 and 2392, is available [1923].

Cl

Cl

O

OH

Cl

Cl

O

O O

O

O

OH

OH O

OH 2385 (napyradiomycin SR)

2386 (16-dechloro-16-hydroxynapyradiomycin C2)

298

G. W. Gribble Cl

Cl

O

OH

Cl

Cl

O

OH

O

OH

O

O

OH O

O R 2390 (16-oxonapyradiomycin A2)

2387 R = CH2OH (18-hydroxynapyradiomycin A1) 2388 R = CHO (18-oxonapyradiomycin A1) 2389 R = Me (napyradiomycin A1) Cl

Cl

O

OH

Cl

Cl O

O O

N

O

OH

O

OH

Cl

O

O O

N

O

O O

N

N Cl

2391 (7-demethyl SF2415A3)

2392 (7-demethyl A80915B)

2393 ((R)-3-chloro-6-hydroxy-8methoxy-α-lapachone)

Three new halogenated napyradiomycins, 2394–2396, are produced by the marine-derived Streptomyces sp. SCSIO 10428, along with six known related analogs. Metabolite 2395 is the most active of the three against the cancer cell lines SF-268, MCF-7, NCI-H460, and HepG2 (IC 50 < 20 μM) [1924]. A Californian marine sediment contains Streptomyces CNQ-329 and CNH-070, which produce six new napyradiomycins 2397–2402 and the three known napyradiomycins B2–B4. Of these metabolites, 2397 and B3 are the most active against MRSA (MIC 16 and 2 μg/ cm3 , respectively) [1925]. A La Jolla, California, coastal sediment affords the actinomycete strain CNQ525 that yields the four novel napyradiomycins 2403–2406, and CNQ525.538 (2404) is the most cytotoxic of the four towards the HCT-116 human colon carcinoma cell line (IC 50 6 μM) [1926]. Napyradiomycins 2403 and 2404 target the heat-shock protein hGrp94 within the endoplasmic reticulum of the HCT-116 cells [1927]. A Spanish ascidian-derived Streptomyces sp.

Naturally Occurring Organohalogen Compounds … O

OH

Cl

Br

Cl

O

OH

O

OH

OH

O

O

O

O

2394

2395

2396

O

OH

OH

Cl OH

Cl

R OH

O

OH

O

O

2397 R = α-Cl (napyradiomycin A) 2398 R = β-OH (napyradiomycin B) O

OH

O O

2399 (napyradiomycin C)

2400 (napyradiomycin D)

OH

O

Cl

O

Cl

OH

O

O

OH

Cl

O

OH

O

O

299

OH

Cl OH

O O

Br

2401 (napyradiomycin E)

O HO

OH O

Cl

2402 (napyradiomycin F)

CA-271078 affords the new napyradiomycin MDN-0170 (2407), and three known analogs. MDN-0170 has no antibacterial or antifungal activity in the assays chosen [1928]. Another examination of this Streptomyces strain finds an additional four new napyradiomycins A3 (2408), which are not halogenated, B7a (2409), B7b (2410), and D1 (2411). In addition, SC (2412) is characterized fully for the first time. Of these napyradiomycins, D1 (2411) exhibits significant growth-inhibitory activity against MRSA, Mycobacterium tuberculosis, and the HepG2 hepatoma cell line [1929].

300

G. W. Gribble OH

O

HO

OH

Cl

O

R HO

O

OH

Cl

Br HO

O

O

OH

O

O

O

O

Br

O

Br

2403 R = Cl (napyradiomycin CNQ525.510B) 2405 (napyradiomycin CNQ525.538) 2406 (napyradiomycin CNQ525.600) 2404 R = Br (napyradiomycin CNQ525.554)

OH

OH

O

OH

O

HO

O

HO

R1 R2

HO

O

OH

O

O

OH

OH

O

OH

O

O

OH Cl

Cl

2407 (napyradiomycin MDN-0170)

O

2408 (napyradiomycin A3)

O

HO

2409 R1 = Cl, R2 = H (napyradiomycin B7a) 2410 R1 = H, R2 = Cl (napyradiomycin B7b)

OH

Cl

O

Cl O

O

OH

HO

Cl

O O

OH

Cl 2411 (napyradiomycin D1)

2412 (napyradiomycin SC)

Napyradiomycin A1 (2389) is an antiangiogenic compound that inhibits human umbilical vein endothelial cell tube formation [1930]. The antifouling potential of 12 known napyradiomycins against the settlement of Mytilus galloprovincialis larvae reveals several candidates for the development of marine antifouling paints and coatings. The authors suggest that napyradiomycin B3 and 4-dehydro-4adechloronapyradiomycin B3 possess the ideal features of bioactivity and low toxicity to be preferred candidates [1931]. Total syntheses of napyradiomycins A1 [1932, 1933] and B1 [1933] are described. The new fasamycins A (2413) and B (2414) are produced in a DNA-encoded Streptomyces albus gene cluster [1934], and fasamycin A is particularly active against both MRSA and vancomycin-resistant Enterococcus faecalis (VREF). Cultivation of Streptomyces formicae reveals the new fasamycins C–E, of which two are chlorinated, 2415 and 2416, along with a new scaffold in formicamycins A–M (2417– 2429). Both sets of naphthacenes are active against the MRSA and VREF assays conducted [1935]. The biosynthesis of the formicamycins involves a unique two-step ring expansion-ring contraction of the prevursor fasamycins [1936].

Naturally Occurring Organohalogen Compounds … R2

R3

OH

HO R4 OH

O

301

2413 2414 2415 2416

R1 H H H Cl

R2 H H Cl Cl

R3 Cl Cl H H

R4 H Cl H H

R5 – – H H

R6 H H Me Me

2417 2418 2419 2420 2421 2422 2423 2424 2425 2426 2427 2428 2429

R1 H Cl H Cl Cl Cl H Cl Cl Cl H Cl H

R2 Cl Cl Cl Cl Cl Cl Cl H Cl Cl Cl Cl Br

R3 H H Cl Cl Cl H Cl Cl Cl Cl Br Br H

R4 H H H H H Cl Cl Cl Cl Cl Cl Cl H

R5 Me H Me H Me Me Me Me H Me Me Me Me

(formicamycin A) (formicamycin B) (formicamycin C) (formicamycin D) (formicamycin E) (formicamycin F) (formicamycin G) (formicamycin H (formicamycin I) (formicamycin J) (formicamycin K) (formicamycin L) (formicamycin M)

OR5

OH

(fasamycin A) (fasamycin B) (fasamycin D) (fasamycin E)

R1 OR6 R2

R3

O

HO R4 OH

O

OH

OR5

O R1 O

Fermentation extracts of Streptomyces sp. KB-3346-5 reveal the 17 new naphthacemycins, most of which are chlorinated (2430–2441) [1937]. O

R2

HO

OH

O

OR1

2430 2431 2432 2433 2434 2435 2436 2437

R1 H Me H Me Me Me Me Me

R2 H Cl H H Cl Cl Cl H

OH

2438 2439

R1 H Cl

R2 Cl (naphthacemycin B3) H (naphthacemycin B4)

O

2440 2441

R1 Cl H

R2 H Cl

O R3 OR4

R1 HO

OH

O

R3 Cl H Cl Cl Cl H Cl Cl

R4 H H Me H H Me Me Me

(naphthacemycin A2) (naphthacemycin A4) (naphthacemycin A5) (naphthacemycin A6) (naphthacemycin A7) (naphthacemycin A8) (naphthacemycin A10) (naphthacemycin A11)

OH O R2 OH O O

R1

HO

OH

O

OH O R2 OR3

R3 (naphthacemycin C1) H Me (naphthacemycin C2)

302

G. W. Gribble

An additional set of 1-phenylnaphthacene antibiotics is found in a culture of Streptomyces sp. N12W1565, naphthacemycins B5 –B13 (2442–2450), which each exhibit activity against protein tyrosine phosphatase 1B (IC 50 < 10 μM). Naphthacemycin B13 (2450) is the most active at IC 50 0.34 μM [1938]. R1

R3 2442 2443 2444 2445 2446 2447 2448 2449 2450

OH

HO R2 OH

O

OH O R4

R5 OH

R1 H H H H H Cl H Cl Cl

R2 H Cl H H Cl Cl Cl Cl Cl

R3 H H Cl Br H H Cl Cl Cl

R4 H H H H H H H H Cl

R5 Cl H Cl Cl Cl Cl Cl Cl Cl

(naphthacemycin B5) (naphthacemycin B6) (naphthacemycin B7) (naphthacemycin B8) (naphthacemycin B9) (naphthacemycin B10) (naphthacemycin B11) (naphthacemycin B12) (naphthacemycin B13)

The rhizospheric soil of Polyalthia cerasoides in China contains Streptomyces sp. K1B-1414 that yields the new chlorinated fasamycins G, I–K (2451–2454) and formicamycins N–Q (2455–2458). Taken together, these new polyketides are active against MRSA, Bacillus subtilis, and Escherichia coli strains (MIC 0.20–50 μg/cm3 ) [1939]. R3 OR4

HO

OH

O

2451 2452 2453 2454

R1 H Cl Cl H

R2 Me H H Me

R3 Cl H H Cl

R4 Me Me H H

(fasamycin G) (fasamycin I) (fasamycin J) (fasamycin K)

2455 2456 2457 2458

R1 H Cl H Cl

R2 H H H Me

R3 Cl H Cl Cl

R4 Me Me H Me

(formicamycin N) (formicamycin O) (formicamycin P) (formicamycin Q)

OR2

OH R1 O R3

OR4

HO

OH

O

HO

OR2

O R1 O

The new formicapyridines D–I (2459–2464) are found in cultures of Streptomyces formicae sp. KY5, along with three non-halogenated analogs, and several known fasamycins and formicamycins shown previously. No antibacterial acidity towards Bacillus subtilis is observed [1940].

Naturally Occurring Organohalogen Compounds … HO R

OH

O

OR2

OH

R1 H Me Me H Me Me

2459 2460 2461 2462 2463 2464

N

3

303 R2 H H Me H H Me

R3 Cl Cl Cl Br Br Br

(formicapyridine D) (formicapyridine E) (formicapyridine F) (formicapyridine G) (formicapyridine H) (formicapyridine I)

OR1

The novel bacterial metabolites merochlorins A–D (2465–2468) are produced by the marine bacterium Streptomyces sp. CNH-189. These unique structural metabolites are active against MRSA and Clostridium difficile but not against Gram-negative bacteria [1941–1943]. A subsequent study furnishes merochlorins E (2469) and F (2470). Both merochlorins E and F display strong antibacterial activity against Bacillus subtilis, Kocuria rhizophila, and Staphylococcus aureus (MIC 1–2 μg/cm3 ) [1944]. A biosynthetic connection between the napyradiomycin and merochlorin classes of antibiotics was discovered [1945]. Several total syntheses of merochlorins A and B are reported [1946–1950].

OH O

OH

Cl

O

OH

O

Cl O HO

OH

O

Cl

OH

OH HO

HO

O

O

Cl

O

O

Cl

2465 (merochlorin A)

2466 (merochlorin B)

OH

2467 (merochlorin C)

O

HO O

2468 (merochlorin D)

Cl

OH 14

2469 ((14S)-merochlorin E) 2470 ((14R)-merochlorin F)

Total syntheses of kibdelones C [1951–1953] and A [1954] are described, and the absolute stereochemistry of C was determined [1951].

3.19 Tetracyclines No new examples of halogen-containing tetracyclines are reported during the period in question.

304

G. W. Gribble

3.20 Aromatics The previous two surveys featured the extraordinary blue-green alga Nostoc linckia nostocyclophanes [1] and the Nostoc sp. carbamidocyclophanes [2]. Subsequent work uncovered new examples of these novel natural products. A collection of Nostoc sp. UIC 10022A alga from a parkway soil in Chicago contains nine new chlorinated cylindrocyclophanes (2471–2479) together with three non-chlorinated known analogs. A bromo analog of 2471 is formed when the culture is enriched with KBr. Several metabolites are active in both the HT-29 cancer cell (EC 50 0.5–2.8 μM) and the 20S proteasome assay (IC 50 2.55–44.8 μM) [1955]. A related study finds the non-chlorinated merocyclophanes that are characterized by α-branched methyl groups in the alkyl chains [1956].

R1

R4 HO

HO

OH

OH R3

R2

2471 2472 2473 2474 2475 2476 2477 2478 2479

R1 OH OH OH OH OH OH OH OH H

R2 CHCl2 CH2Cl Me Me CHCl2 CH2Cl Me Me CHCl2

R3 OH OH OH OH H H H H H

R4 CHCl2 CHCl2 CHCl2 CH2Cl CHCl2 CHCl2 CHCl2 CH2Cl CHCl2

(cylindrocyclophane A4) (cylindrocyclophane A3) (cylindrocyclophane A2) (cylindrocyclophane A1) (cylindrocyclophane C4) (cylindrocyclophane C3) (cylindrocyclophane C2) (cylindrocyclophane C1) (cylindrocyclophane F4)

An extract from the cultured freshwater Nostoc sp. UIC 10274 reveals the two new carbamidocyclophanes F (2480) and G (2481) along with known analogs A–C. Both F and G exhibit antiproliferative activity against MDA-MB-435 and HT-29 cancer cell lines (IC 50 0.5–0.7 μM) [1957]. An additional five new derivatives, H–L (2482–2486) are generated by the Vietnamese cyanobacterium Nostoc sp. CAVN2, and are very active against MRSA (MIC 0.1–1.0 μM). The carbamoyl residue is important for biological activity. Eleven known paracyclophanes are also present [1958].

R1 HO HO R2

OH

OH R3

R4 2480 2481 2482 2483 2484 2485 2486

R1 OCONH2 OCOMe OCONH2 OCONH2 OCONH2 OCONH2 OCONH2

R2 CHCl2 CHCl2 Me Me CH2Cl Me CH2Cl

R3 OH OCONH2 OH OH OCONH2 OH OH

R4 CHCl2 CHCl2 Me CH2Cl CH2Cl CHCl2 CHCl2

(carbamidocyclophane F) (carbamidocyclophane G) (carbamidocyclophane H) (carbamidocyclophane I) (carbamidocyclophane J) (carbamidocyclophane K) (carbamidocyclophane L)

The cyanobacterium Cylindrospermum stagnale PCC 747 produces the novel cylindrofridins A–C (2487–2489). Metabolite A shows moderate activity against MRSA and Streptococcus pneumoniae (MIC 9 and 17 μM, respectively) [1959]. The biosynthesis of these cylindrocyclophanes has been of intense interest [1960–1964], as are syntheses of the natural (dechloro) paracyclophanes [1965–1968]. The Hainan,

Naturally Occurring Organohalogen Compounds …

305

China, red alga Laurencia similis contains the three polybrominated aminonaphthalenes 2490–2492 and benzophenone 2493. Two of these novel metabolites inhibit protein tyrosine phosphatase 1B (for example, 2493: IC 50 2.66 μg/cm3 ) [1969].

AcO

R Cl

HO

Cl

OH

OH

HO

OAc OH

OH 2487 (cylindrocyclophane A)

Br

R3

2488 R = OH (cylindrocyclophane B) 2489 R = OAc (cylindrocyclophane C)

R1

Br Br

R2

N H

Br

O

Br Br

O Br

Br

HO Br

2490 R1 = Br, R2 = R3 = H 2491 R1 = R2 = H, R3 = Br 2492 R1 = R3 = H, R2 = Br

O O

2493

The serine carboxypeptidase inhibitors, belactins A (2494) and B (2495) are produced by Saccharopolyspora sp. MK19-42F6 [1970], and the absolute configuration is as shown [1971, 1972]. Cyanosporasides A and B are presented in the earlier survey [2], and the new cyanosporasides C–F (2496–2499) are found in the marine actinomycetes Salinispora pacifica CNS-143 and Streptomyces sp. CNT-179. It is self-evident that these three metabolites are enediyne polyketide biosynthesis products [1796].

NHR O N H

Cl O O

OH O

Cl

O

OAc

HO

Cl

O

NC

2494 R = H (belactin A)

NC 2497 R = Ac (cyanosporaside D) 2498 R = H (cyanosporaside E)

2496 (cyanosporaside C) OH

O 2495 R =

OH (belactin B) HO

OH OR

O

OH OH O

O S

Cl NHAc NC 2499 (cyanosporaside F)

OH

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Two brominated phthalate esters, 2500 and 2501, are found in the marine macro brown alga Dictyopteris hoytii collected along the Oman coast. Diester 2501 has some inhibitory activity against α-glucosidase (IC 50 234 μM) [1973]. Six halogenated anilines, 2502–2507, are found in the biofilm-forming microalga Nitzschia cf. pellucida, the first report of these halogenated anilines as natural products. Stable isotope labeling and time-course experiments confirm the microalgal biosynthetic origin of these compounds [1973]. A Red Sea sponge contains the 3-bromoaniline derivative 2508 along with quinolone 2116 cited earlier [1684]. The myxobacterium Enhygromxya salina yields the novel tetracycle salmabromide (2509), which has antibiotic activity towards Arthrobacter cristallopoietes (MIC 16 μg/cm3 ) [1974]. This unique structure has succumbed to total syntheses [1975–1977]. Bromo ester 2510 is found in a culture of the saprophytic fungus Aspergillus parasiticus MOR3 after the addition of the insect Tribolium castaneum Herbst as an elicitor of this novel compound to the fungus [1978]. The known naturally occurring chlorobenzene [1] along with chloroaniline (2511), which is a new natural product, are found in 4.5-billion-year old halite crystals embedded in the Zag and Monahans meteorites [1979]. Chlorobenzene is also present in 3-billion-year old mudstones at the Gale Crater on Mars [1980]. CO2Et

Br

Cl

Br

Cl

NH2

NH2

NH2

NH2

NH2 Br

Cl

Br

Br

Br

Cl

Br CO2R

Br

Cl

Br

Cl

Cl

2500 R = Me 2501 R = Et

2502

2503

2504

2505

2506

NH2 Cl

Br O

2507

O

Br O 2508

O

Ph

O

NH2 Br

Br

NH2

O

NH2 O Cl

Cl

Br

2509 ((+)-salimabromide)

2510

2511

3.21 Simple Phenols Like pyrrole and indole, phenol is exceptionally reactive towards electrophilic halogenation and new examples abound in the biosphere subsequent to the two previous surveys, in which over 200 simple halogenated phenols are tabulated [1, 2].

Naturally Occurring Organohalogen Compounds …

3.21.1

307

Terrestrial

A large number of chloroanisoles [9], bromoanisoles [5], and bromochloroanisoles [2] are detected in air over the North Atlantic Ocean, with the highest concentrations of 2,4,6-trichloroanisole and 2,3,4,5-tetrachloroanisole [1981]. The sex pheromone of the female tick, Ixodes ricinus, is methyl 3-chloro-4-methoxybenzoate (2512) [1982], a new derivative of the known natural 3-chloro-4-methoxybenzoic acid [2]. The 2,3,4,5-tetramethoxybenzoylchloride (2513) is found in the parasitic fungus Antrodia camphorata living on the heartwood of Cinnamomum kanehirai, a Taiwanese medicinal plant [1983]. If correct, this compound is a rare example of a naturally occurring acid chloride. Following the discovery of the differentiationinducing factor-1 (DIF-1) [1], the related DIF-2 (2514) and DIF-3 (2515) are found in the cellular slime mold Dictyostelium discoideum [1984]. For recent studies of the function of these DIFs, see [1985, 1986]. The Chilean liverwort Riccardia polyclada contains the four new polychlorinated bibenzyls 2516–2519. Compounds 2517 and 2519 display modest antifeedant activity against Spodoptera littoralis larvae and growth inhibition towards Cladosporium herbarum [1987]. The Chinese plant Viburnum foetidum var. foetidum contains the new lignan 2520, which is detected in the crude plant extract and is not believed to be an artifact [1988]. Moreover, the lignan epoxide in the plant has the wrong configuration to form 2520 by ring opening. The novel acetylenic chlorophenol 2521 from a culture of the plant Helichrysum aureonitens is proposed to be an intermediate for other acetylenic compounds in Helichrysum species [1989]. COCl

CO2Me

OH

O O

Cl

O

OH

Cl O

O

OH

O

O 2512

O

Cl O

OH

Cl

2513

2514 (DIF-2)

2515 (DIF-3)

HO R1

Cl

OH

Cl

OH

Cl

R3 1

2516 2517 2518 2519

R H H Cl Cl

2

R H Cl Cl Cl

OH

O O

R2

OH

R OMe OMe OMe OH

Cl

O

3

2520

2521

The Arctic sea ice bacterium Salegentibacter sp. T436 contains three novel aromatic nitro compounds, 2522–2524. A biogenesis from nitrotyrosines is proposed [1990, 1991]. The fungus Leptoxyphium sp., also known as the genus Caldariomyces, isolated from the green fruit of Gustavia superba, yields the new dichlorodiketopiperazine 2525, which is 10–20 times more active than the nonchlorinated analog in the inhibition of CCL2-induced chemotaxis [1992]. The cytotoxic and antiviral

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ascochlorin precursor LL-Z1272α epoxide (2526) is produced by a mutant of Ascochyta viciae, but this new metabolite has no growth inhibitory activity against Candida albicans [1993]. Fruiting bodies of the slime mold Polysphondylium tenuissimum contain several new aromatics, including one chlorinated compound, Pt-5 (2527), which is related to DIF-1. Compound Pt-5 shows activity on 3T3-L1 cells in a glucose consumption-promotive assay [1994]. The well-known terrestrial fungal metabolite 2,3,5,6-tetrachloro-4-methoxyphenol (drosophilin A) [1] is found in the meat of wild boar (Sus scrofa) in Southern Germany, in higher concentrations than the anthropogenic polychlorinated biphenyls and DDT [1995]. The fungus Geniculosporum sp. produces the two novel o-dimethoxy chlorobenzenes 2528 and 2529, for which the structures are confirmed by synthesis. This study also finds methyl 2-iodobenzoate (2530) from headspace extracts of Streptomyces chartreusis [1996]. R1 O

Cl R2

Cl NO2

OH

N

O

O

HN

HO

OH O

Cl

OH 2522 R1 = H, R2 = NO2 2523 R1 = CO2Me, R2 = NO2 2524 R1 = CO2Me, R2 = H

OH OHC

Cl 2526 (LL-Z1272 α-epoxide)

2525

Cl

Cl

CO2Me

Cl HO

O

O O 2527 (Pt-5)

2528

O

Cl

I

O 2529

2530

The Chinese traditional medicine plant “Xian-Mao” (Curculigo orchioides) contains five new chlorinated phenolic glycosides, curculigines E–I (2531–2535) along with eight known analogs. Four of the curculigines (E, F, G, H) show moderate antiosteoporotic activity against the cell line MC3T3-EI with the proliferation rates of 10–14% [1997]. A subsequent investigation of “Xian-Mao” produces the new curculigines J–N (2536–2540) [1998]. Three related glycosides, przewatangosides A–C (2541–2543), are found in Tibet. Only A (2541) shows (weak) activity towards SMMC-7721 liver carcinoma cells (IC 50 38 μM) [1999]. Also isolated are globosumosides A (2544) and B (2545a), which are found in the fungus Chaetomium elatum [2000]. The mutant strain G-444 of Tubercularia sp. TF5 produces the new tetralone 7-chloroscytalone (2545), along with three new isocoumarins cited earlier [1761].

Naturally Occurring Organohalogen Compounds …

309

R2 1 OH R

O

HO HO

R

OH

5

O

2531 R1 = R3 = Cl, R2 = OMe, R4 = Me, R5 = H (curculigine E) 2532 R1 = R3 = Cl, R2 = Me, R4 = OMe, R5 = H (curculigine F) 2533 R1 = R5 = H, R2 = Me, R3 = Cl, R4 = OMe (curculigine G) 2534 R1 = R3 = Cl, R2 = R4 = OMe, R5 = H (curculigine H) 2535 R1 = R5 = Cl, R2 = R4 = OMe, R3 = H (curculigine I) 2536 R1 = R3 = H, R2 = Me, R4 = OH, R5 = Cl (curculigine J) OH HO HO

O

HO HO

R4

O

Cl

OH

R3

O

HO HO OH

2537 (curculigine K)

OH O

R1

Cl

O

R2

HO O

HO HO

O

HO HO

OH O

HO HO

O

HO O

OH

O

Cl

2538 R1 = R3 = H, R2 = OH (curculigine L) 2539 R1 = H, R2 = OMe, R3 = Cl (curculigine M) 2540 R1 = R2 = OMe, R3 = Cl (curculigine N)

O

HO HO

OH Cl

2541 (przewatangoside A)

OH

Cl

O

HO

R3

HO

OH

O

2542 (przewatangoside B)

OR O

Cl

HO

O

HO HO

O

Cl

HO

HO

O

Cl

OH

HO O

O Cl

2543 (przewatangoside C)

OH 2544 R = H (globosumside A) 2545a R = Ac (globosumside B)

O

2545 (7-chloroscytalone)

The new 3,3 -neolignan 2546 is found in Pithecellobium clypearia Benth along with several non-chlorinated analogs, both new and old [400]. This compound resembles manneoinsigins A (2547) and B (2548) from Manglietia insignis [2001]. The novel cosmochlorins A–C (2549–2551) are found in the endophytic fungus Cosmospora vilior IM2-155 living with the mangrove plant Sonneratia alba (Plate 57) in Indonesia. These metabolites are apparently the first natural products to possess the 3(1,5-dihydroxy-2,4-dichloro)phenyl ring structure. Cosmochlorine A and B display glycogen synthase kinase (GSK)-3β inhibition activity (IC 50 62.5 and 60.6 μM, respectively) and A and C exhibit moderate antibacterial and antifungal activity towards a few standard strains [2002]. A subsequent study of Phomopsis sp. N-125 produces cosmochlorins D (2552) and E (2553) [2003].

310

G. W. Gribble HO

Cl

HO

HO

OH

OH

OH Cl

Cl

OH OH

OH

OH

OH

HO 2547 (manneoinsigin A)

2546 (clypearianin)

2548 (manneoinsigin B) OH

OH

Cl

Cl HO

HO

CO2H

Cl

Cl

O

2550 (cosmochlorin B)

2549 (cosmochlorin A)

O

CO2H OH

O

O Cl

HO

Cl

Cl O

O Cl 2551 (cosmochlorin C)

Cl

O

2552 (cosmochlorin D)

Cl

O

2553 (cosmochlorin E)

Plate 57 Sonneratia alba (Photograph courtesy of Ton Rulkens; Creative Commons AttributionShare Alike 2.0 Generic)

Naturally Occurring Organohalogen Compounds …

311

Studies of the fungus Collectotrichum higginsianum IMI 349063 reveal the four novel colletochlorins E–H (2554–2557) together with known analogs. These compounds display some phytotoxicity, but the known 4-chloroorcinol [2] is the most active in this assay [1720, 2004]. A culture of Malbranchea flavorosea from grain results in the formation of 8-chloroxylarinol A (2558) [2005]. The plant Seidlitzia rosmarinus (Plate 58) from the Sinai desert shoreline of the Gulf of Aqaba contains the two isomeric α-chloroferuloylamides 2559 and 2560. Interestingly, this study finds the registered drug metformin in this plant [2006]. The bacteria-eating slime mold Dictyostelium monochasioides yields eight new chlorinated alkylresorcinols, monochasiols A–H (2561–2568), which are confirmed by synthesis. Monochasiol A (2561) inhibits the concanavalin A-induced interleukin-2 production in Jurkat cells (a human T lymphocyte cell line) [2007]. Ethyl chlorohaematommate (2569) is present in oakmoss [2008]. A large source of natural drosophilin A methyl ether, which is produced by the lignicolous basidiomycete Phellinus badius [1], is in the heartwood of mesquite trees (Prosopis juliflora), to the extent of 30 g per kilogram of decayed heartwood, with 24 g per kilogram of dried fruiting body [2009].

Plate 58 Seidlitzia rosmarinus (Photograph courtesy of Alex Sergeev; Creative Commons Attribution-Share Alike 2.0)

312

G. W. Gribble Cl O Cl

OH

Cl

Cl

HO

O

O

OH

OH

O

OH

OH

Cl

HO

OH

N H

O

HO O

2560 (2-chloro-N-(E)-feruloyltyramine)

2559 (2-chloro-N-(Z)-feruloyltyramine) 13

HO

OH

Cl

N H

O

2558 (8-chloroxylarinol A)

2557 (colletochlorin H)

2556 (colletochlorin G)

O

O O

OH

OH

2555 (colletochlorin F)

2554 (colletochlorin E)

Cl

O

OH

OH O

HO

n

6

13

7

Cl

Cl

OH

OH 2561 n = 11 (monochasiol A) 2562 n = 12 (monochasiol B) 2563 n = 13 (monochasiol C)

2564 (monochasiol D)

HO

HO

8

6 7

15

9

13

Cl

Cl OH

OH

2565(monochasiol E) HO

2566 (monochasiol F)

8 9

8

HO

15

4

Cl

9

15

5

Cl OH

OH

2567 (monochasiol G)

2568 (monochasiol H) Cl HO O O

OH

O

2569 (ethyl chlorohaematommate)

Several papers discuss the effect of 2,4,6-trichloroanisole, 2,4,6-tribromoanisole, 2,6-dibromophenol, and related microbial compounds on wine cork taint [2010, 2011], in off-flavors from apple [2012, 2013] and orange juice [2014], and in foods in general [2015].

Naturally Occurring Organohalogen Compounds …

3.21.2

313

Marine

Whereas most natural terrestrial halogenated phenols contain chlorine, the vast majority of marine phenols are brominated. The ease with which bromide is oxidized to active bromine (e.g., with bromoperoxidase) and the relative abundance of bromide in the oceans, accounts for the large number of organobromines in the marine environment. A Chinese collection of the red alga Polysiphonia ureolata (Plate 59) finds the new bromophenols 2570–2572, and 2571 is particularly effective as a DPPH radical scavenger (IC 50 9.67 μM), and is 8–9 times more potent than BHT [2016]. Our earlier survey [1] omitted the structure of 2,3-dibromobenzyl alcohol 4,5-disulfate dipotassium salt (2573) that is found in the red algae Polysiphonia lanosa [2017] and Odonthalia corymbifera [2018]. An examination of the red alga Symphyocladia latiuscula (Plate 60) from the same location as above provides three new bromophenols, 2574–2576, and diphenylmethane 2577. Bromophenol 2575 exhibits DPPH radicalscavenging ability (IC 50 10.2 μM) [2019]. In addition to the iantherans shown earlier (2146–2148), this Australian sponge contains the simple dibromoanisoles 2578 and 2579 that are likely tyrosine-derived [1717]. The marine-derived fungus Penicillium terrestre from a Chinese sediment yields the two chlorinated terrestrols B (2580) and D (2581), along with two diphenyl ethers depicted later. Both terrestrols are radical scavengers against DPPH (IC 50 4.3 and 4.4 μM, respectively), with ascorbic acid having an IC 50 of 17.4 μM [2020].

Plate 59 Polysiphonia urceolata (Photography courtesy of Gabriel Kothe-Heinrich; Creative Commons Attribution-Share Alike 3.0 Unported)

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G. W. Gribble

Plate 60 Symphyocladia gracilis (Photograph courtesy of Kintaro Okamura; https://www.flickr. com/photos/biodivlibrarv/60499282074; Biodiversitv Heritage Library)

Br

OH O

O

Br

OH

O Br

CO2H Br Br HO

Br

OH

Br

2570

Br

OH

OH

OH

2572

2571

OSO3K OSO3K 2573

Br Br

O

Br

N Br

HO

Br Br

S Br

HO

O

OH Br

HO

O

Br

Br

HO OH

2576

OH

O Br

Br

Br

Br

O

Br

OH

2575

2574

OH

Br

OH

OH

Br

O

Br

Br

Br Br

OH OH

2577

OH O

Cl

OH Cl

O

OH OH

OSO3Na

CO2H

OH

OH

OH

CO2H 2578

2579

2580 (terrestrol B)

2581 (terrestrol D)

Naturally Occurring Organohalogen Compounds …

315

The marine-derived fungus Acremonium sp., an endophyte of marine algae, furnishes the new acremonisol A (2582) [2021]. The Queensland Great Barrier Reef produces clavatadines A (2583) and B (2584) courtesy of the sponge Suberea clavata. Clavatadine A inhibits the human blood coagulation Factor XIa (IC 50 1.3 μM), a trypsin-like serine protease [2022]. The structure of 2583 is confirmed by total synthesis [2023]. The tribromocatechol 2585 is found in the red alga Symphyocladia latiuscula and it, along with the corresponding known benzyl alcohol [1], inhibits Taq DNA polymerase [2024, 2025]. The Red Sea sponge Pseudoceratina arabica produces the novel ceratinophenol A (2586) together with two new bromotyrosines shown later [2026]. The novel bromophenol metabolite 2587, later named urceolatol, is found in the red alga Polysiphonia urceolata from China, having the unusual chromeno[4,4,3-cde]chromene ring system [2027]. The marine fungus Acremonium sp., found living with a Stelletta sp. sponge on the Korean coast, produces the sesquiterpenoids acremofuranones A (2588) and B (2589) along with the merosesquiterpenoid chlorocylindrocarpol (2590), and several known analogs [2028]. The ethyl ether corresponding to 2585 is found in the alga Symphyocladia latiuscula, but it may be an artifact as ethanol is used in the extraction process, and 2585 is also isolated (as a precursor?) [2029]. The first total synthesis of 2585 is documented [2030]. CO2H

Cl

Br

HO

O OH O

O

H N

N H

O Br

O

2582 (acremonisol A)

CONH2

Br HO NH2

O

Br

O

NH

H N

N H

NH2 NH

2584 (clavatadine B)

2583 (clavatadine A)

O CH2O Br

O

Br

HO

OH O

Br

OH

O

OH 2586 (ceratinophenol A)

2585

2587

O

O

O O

Br

O OH

Br

Br

HO

O

O

OH

O

OH

OH

OH

HO

OH OH

OH Cl 2588 (acremofuranone A)

OH

Cl

Cl 2589 (acremofuranone B)

2590 (chlorocylindrocarpol)

In addition to several known bromophenols, the New Zealand red alga Osmundaria colensoi produces the new colensolide A (2591) [2031]. The marine chrysophyte alga Chrysophaeum taylori from St. John, U.S. Virgin Islands, contains

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G. W. Gribble

the eight new antimicrobial chrysophaentins A–H (2592–2599), which are vaguely related to the liverwort bazzanins. Chrysophaentin A (2592) is the most active in several bacterial assays (Staphylococcus aureus, MRSA, VREF, Enterococcus faecium) (MIC 50 1.8, 1.5, 3.8, 2.9 μg/cm3 , respectively) [2032]. Together with a bromopyrrole cited earlier, the marine Pseudoaltermonas sp. from an Oahu nudibranch yields the biphenyl 2600, which is active against MRSA (IC 50 2.19 μM) [1289]. The red alga Rhodomela confervoides from China affords 19 bromophenols, including six new metabolites, 2601–2605. Most of these 19 compounds are active in the DPPH radical-scavenging assay, with 2602 being the most active (IC 50 7.43 μM) [2033]. HO

OH R2 O

Br

OH

Cl

Br

N O

HO

HN

Cl

NH

HO

HO

OH O

O R1

HO

OH

2592 R1 = Cl, R2 = Cl (chrysophaentin A) 2593 R1 = Br, R2 = Cl (chrysophaentin B) 2594 R1 = Cl, R2 = Br (chrysophaentin C) 2595 R1 = Br, R2 = Br (chrysophaentin D)

2591 (colensolide A)

R2

OH Cl

OH

OH

Cl

OH Cl

Cl

Cl

HO

HO HO

HO

R

OH

Cl

Br

Br

OH

Br

Br

S O

Br

Br

OH

HO OH

HO

OH

Br Br

HO OH

2605

R

HO

2603 R = NH2 2604 R = CO2H O

OH

O

Br

OH

2602

2601

2600

OH

O

O

HO

Br

1

2597 R1 = Cl, R2 = Cl, R3 = H (chrysophaentin F) 2598 R1 = Cl, R2 = Br, R3 = H (chrysophaentin G) 2599 R1 = Cl, R2 = Cl, R3 = Br (chrysophaentin H)

2596 (chrysophaentin E)

OH

R3

O

O

Br

OH

O

HO

OH

2606

Naturally Occurring Organohalogen Compounds …

317

The simple 4-bromo-3-pentylphenol (2607) is found in a tunicate Diplosoma sp. from Okinawa, a compound that inhibits the division of fertilized sea urchin eggs [2034]. A selective kynurenine-3-hydroxylase inhibitor, ianthellamide A (2608), occurs in the Australian marine sponge Ianthella quadrangulata, and shows a value of IC 50 1.5 μM in a rat brain assay protocol [2035]. The novel chlorinated polyketides, chloctanspirones A (2609) and B (2610), and their quasi-precursors, terrestrols K (2611) and L (2612), are found in the marine-derived fungus Penicillium terrestre. Compound 2609 is active against HL-60 and A-549 cancer cells (IC 50 9.2 and 39.7 μM, respectively) [2036]. Five new nitrogen-containing bromophenols are present in the Chinese red alga Rhodomela confervoides, 2613–2617, in addition to nine known analogs. Metabolite 2613 is the most active in the DPPH radicalscavenging assay (IC 50 5.22 μM) [388]. The venerable marine red alga Symphyocladia latiuscula has furnished symphyocladins A–G (2618–2624). Metabolite G (2624) exhibits modest antifungal activity towards Candida albicans (MIC 10 μg/ cm3 ) [2037]. O

H N

O

H2N

HO

Br

O

O

HO

Br

Br OSO3H

2607

O

HO

Cl

O

Br

N H

NH

Cl

HO

Br

CO2R

HO OH

OH

2614 R = Me 2615 R = H

2613

2611 ((5S,6R)-terrestrol K) 2612 ((5R,6S)-terrestrol L)

R

MeO

O

OH

OH

2609 ((19R)-chloctanspirone A) 2610 ((19S)-chloctanspirone B)

Br

O

Br

5 HO

O

2608 (ianthellamide A)

Br

6

HO

HO 19

2616 R = CONH2 2617 R = CH2CONH2 HO2C

Br

Br

CO2H

HO

HO

CO2H

CO2H Br

HO

Br

HO

CO2R

Br

Br

CO2H

Br

2623 (symphyocladin F)

Br

HO Br

Br

O N H

O

Br

2622 (symphyocladin E)

HO

Br

HO

CO2H

Br

2618 R = H ((E)-symphyocladin A) 2619 R = H ((Z)-symphyocladin B) 2620 R = Me ((E)-symphyocladin C) 2621 R = Me ((Z)-symphyocladin D)

N

HO

OH

N H Br

OH Br

2624 (symphyocladin G)

318

G. W. Gribble

Subsequent investigations of Symphyocladia latiuscula uncovered diketopiperazine-coupled bromophenol 2625 [2038], and 2626 and 2627. The latter two compounds are active in the DPPH anti-oxidant assay (IC 50 14.5 and 20.5 μg/cm3 , respectively) [2038]. An additional study of this alga identified sulfoxide 2628, which has some antifungal activity against Candida albicans (MIC 37.5 μg/cm3 ); cf., ketoconazole (MIC 0.8 μg/cm3 ) [2040].

O

N N

O

Br

Br Br OH Br

OH

O

Br

Br

N H

N H

CO2Me

Br

HO

CO2H CO2H

HO CO2Me

HO

OH

Br

2625

2627

2626

Br Br

S Br

HO

O

OH

2628

Further studies of this Chinese marine red alga yield new symphyocladins H–Q (2629–2638) [2041], and R–Y (2639–2646) [2042]. A solvent-derived metabolite of S (2640, R2 = Et) is likely an artifact. A biosynthesis pathway involving a cascade of quinone methide generation and additions is proposed [2042]. CO2Me

CO2H

CO2Me

HO

MeO2C Br

HO

CO2Me Br

HO

Br

HO

HO

2629 ((Z)-symphyocladin H) 2630 ((E)-symphyocladin I)

2631 ((Z)-symphyocladin J) 2632 ((E)-symphyocladin K)

2633 R = H (symphyocladin L) 2634 R = Et (symphyocladin M)

CO2Me

CO2R MeO2C Br

Br

Br CO2Me Br Br

2635 (symphocladin N)

Br Br

CO2H

HO

CO2Me

HO

Br

Br

HO

CO2R

HO2C Br

HO2C Br

HO

O

CO2Me

Br

HO Br

2636 (symphocladin O)

HO Br

HO Br

2637 R = H (symphocladin P) 2638 R = Me (symphocladin Q)

Naturally Occurring Organohalogen Compounds …

319

OH Br

OH

X

Br CO2R1

HO2C Br

CO2R2

HO

2639 2640 2641 2642 2643

R1 H Me Me Me H

R2 H H H H H

X Br Br H Br H

Y Br Br Br H Br

(symphocladin R) (symphocladin S) (symphocladin T) (symphocladin U) (symphocladin V)

Y

HO Br OH Br

OH

Br

CO2H

Br

Br

CO2Me

HO2C Br

CO2H

HO

CO2H

HO

Br

HO Br

2644 (symphocladin W)

O

HO Br Br

HO

O Br

Br Br

HO

Br

HO Br

OH 2645 (symphocladin X)

2646 (symphocladin Y)

The new histamine derivatives, leptoclinidiamines E (2647) and F (2648), are found in the Australian ascidian Leptoclinides durus, the producer of several bromoindoles cited earlier [1519]. The soft-coral associated actinomycetes strain, Streptomyces sp. OUCMDZ-1703 produces two novel strepchloritides A (2649) and B (2650), which display modest antibacterial activity [2043]. The known and commercially available antibacterial agent, 2-benzyl-4-chlorophenol (2651), is found to be a natural product in the marine bacterium Shewanella halifaxensis, and confirmed by synthesis [2044]. The new bromophenol 2652 occurs in the red alga Odonthalia corymbifera from Japan along with several known analogs. 1-Butanol was not used in the isolation process [2045]. The Norwegian marine bryozoan Securiflustra securifrons contains the new alkaloid securidine A (2653) [2046]. The two related metabolites, pulmonarin (2654) [2048] and synoxazolinone (2655) [2047] are found in the sub-Arctic ascidian Synoicum pulmonaria. A culture of Streptomyces sp. SBT345 from the sponge Agelas oroides yields the new strepthonium A (2656) [2049]. This metabolite inhibits the production of shiga toxin (Stx) without influencing bacterial growth [2049].

320

G. W. Gribble Cl O

H N

O

S

Cl

HO

N

Br

R

OH

N

Ph

R

HO

OH

OH

Cl

2647 R = Br (leptoclinidiamine E) 2648 R = H (leptoclinidiamine F)

2651

2649 R = H (streptochloritide A) 2650 R = Cl (streptochloritide B)

Br Br

O

O

O

Br

HO OH

NH

Br

Br

Br

NH2

2653 (securidine A)

2652

O

H N

N H

O

O N H

N

NH O NH

Br

N H

NH2

O

2654 (pulmonarin)

2655 (synoxazolidinone)

N

O

O Cl

2656 (strepthonium A)

The new bromophenol odonthadione (2657), found in the alga Odonthalia corymbifera, contains the unprecedented cyclopentenedione unit and is a racemate. A related diphenyl ether is shown in Sect. 3.22.2 [2050]. Of 11 new depsides from the marine-derived fungus Thielavia sp. UST 030 930-004, only one is chlorinated, thielavin Z6 (2658). This compound (and the others) is active against cyprids of the barnacle Balanus (= Amphibalanus) amphitrite [2051]. The simple chlorobenzoic acid engyodontiumin A (2659) is found in a deep-sea-derived fungus Engyodontium album collected from a sediment at 3542 m in the Atlantic Ocean [2052]. The fungus Hansfordia pinuosae found living with the South China Sea sponge Niphates sp. affords the three chlorinated resorcinols, hansfordiols H–J (2660–2662). Metabolites H and I show good antioxidant activity comparable to Trolox [2053]. A culture of Cylindrocarpon sp. SY-39 from a sample of driftwood from Japan led to 10 hydroxyilicicolinic acid D (2663), which is active against Staphylococcus aureus (MIC 5.0 μg/cm3 ) [2054]. The Cyanobium sp. LEGE 06,113 produces hierridin C (2664), which was confirmed by synthesis [2055].

Naturally Occurring Organohalogen Compounds …

321 OH

Br Br

OH OH

HO

Cl O

O

O O

O OH

CO2H

O

O

O

O

CO2H

HO Cl

2657 (odonthadione)

HO

2658 (thielavin Z6)

CO2Me

HO

CO2H

R

2659 (engyodontiumin A)

Cl

Cl

Cl OH

OH

2660 R = H (hansfordiol H) 2661 R = Cl (hansfordiol J)

2662 (hansfordiol K)

OH

OH

OH

HO2C

O OH

OH

Cl

Cl

O 2663

2664 (hierridin C)

The Vietnam marine-derived Streptomyces sp. G212 produces the novel ester 2665, confirmed by synthesis [2056]. The resemblance of this compound to the Vietnam warfare defoliant “Agent Orange”, one-half of which is “2,4-D” (2,4dichlorophenol or 2,4-dichlorophenoxyacetic acid) is noteworthy. The new chlorinated polyketide graphostrin A (2666) is found in a deep-sea-derived fungus Graphostroma sp. MCCC 3A00421, collected from hydrothermal sulfide deposits at a depth of 2721 m, along with 27 other nonchlorinated polyketides, both known and new [2057]. An examination of the red alga Vertebrata lanosa finds one new metabolite, dibromocatechol 2667 [2058]. Three new chlorinated phenylpropanoic acids (2668–2670) are found in Streptomyces coelicolor LY001 associated with the Red Sea sponge Callyspongia siphonella. Of these metabolites, 2668 displays the highest activity against Escherichia coli and Staphylococcus aureus (MIC 16 and 32 μg/cm3 , respectively) [2059]. A new set of seven bartolosides E–K (2671–2677) is found in Synechocystis salina LEGE 06099 [2060], a strain closely related to the cyanobacterium that generates bartolosides B–D (1171–1173) shown earlier [907]. A new group of chrysophaentin analogs (2678–2681) is found in the marine microalga Chrysophaeum taylorii [2061], following the earlier discovery of A–H (2592–2599) [2032].

322

G. W. Gribble OH OH Cl

O

Cl

N O

O HO

O Cl

Cl

HO HO

CO2R2

Cl

Br

OH 2666 (graphostrin A)

2665

Cl

2667

O R3

HO O

R4 R1

HO R1

4

NH2

Br

HO

Cl

CO2H

N H

N H

R2

3 OH 2671 R1 = H, R2 = H, R3 = Cl, R4 = Me (bartoloside E) 2672 R1 = Cl, R2 = H, R3 = H, R4 = n-Bu (bartoloside F) 2673 R1 = H, R2 = H, R3 = H, R4 = n-Pr (bartoloside G) 2674 R1 = Cl, R2 = H, R3 = H, R4 = n-Pen (bartoloside H) 2675 R1 = Cl, R2 = Cl, R3 = H, R4 = n-Pr (bartoloside I) 2676 R1 = H, R2 = H, R3 = H, R4 = Me (bartoloside J) 2677 R1 = Cl, R2 = H, R3 = H, R4 = Et (bartoloside K)

2668 R1 = Cl, R2 = H 2669 R1 = H, R2 = H 2670 R1 = Cl, R2 = Me

Cl HO

OH

HO

OH

Br

Br

HO OH

R1

Cl OH OH Cl

HO

HO

HO

OH R2

2678 (chrysophaentin 1)

2679 R1 = H, R2 = Br (hemichrysophaentin B) 2680 R1 = Cl, R2 = Cl (hemichrysophaentin C) 2681 R1 = H, R2 = Cl (hemichrysophaentin D)

The mutant strain G-444 of Tubercularia sp. TF5 produces the new tetralone 7chloroscytalone (2682), along with three new isocoumarins cited earlier [1761]. The Red Sea sponge Suberea mollis contains the new subereaphenols B (2683), C (2684) [2062], and K (2685) [2062] (revised structures shown [2063]). Subereaphenol A (2686) was reported separately [2064]. The sub-Arctic colonial ascidian Synoicum pulmonaria contains the two pulmonarins A (2687) and B (2688). Both pulmonarins are reversible, non-competitive acetylcholinesterase inhibitors; for example, pulmonarin B shows K i = 20 μM towards vertebrate acetylcholinesterase [2065]. The marine-derived fungus Chrysosporium synchronum produces the new glycosidic metabolite, 1-O-(α-d-mannopyranosyl)chlorogentisyl alcohol 2689, a derivative of chlorogentisyl alcohol (2690), which was isolated earlier from an Aspergillus marine algicolous fungus [2049].

Naturally Occurring Organohalogen Compounds …

323 OH

OH HO

OH

Br

Br

Br CO2R

Cl OH

O

HO

OH

2682 (7-chloroscytalone)

Br

CONH2 2686 (subereaphenol A)

2683 R = Me (subereaphenol B) 2684 R = Et (subereaphenol C) 2685 R = H (subereaphenol K) Br

Br O

O O

Br

N

O N H

Br

O

N

2688 (pulmonarin B)

2687 (pulmonarin A) OH HO HO

OH O

HO

O Cl 2689

OH

OH

OH

Cl

OH

2690 (chlorogentisyl alcohol)

The biosynthesis of polybrominated aromatic organic compounds by marine bacteria is discussed [2066]. Several total syntheses of marine halogenated phenols are described, including those of Odonthalia corymbifera [2067], (±)-polysiphenol [2068], Rhodomela confervoides [2069], and others [2070–2075]. The biological activity of marine halogenated phenols has been extensively studied, and a recent review on cancer-related activities is available [2076], as are summaries of bromophenols from marine algae [2077, 2078]. The well-documented “iodoform taint” or “halogen odor” in seafood, for example, from 2,6-dibromophenol and 2,4,6-tribromoanisole, is reviewed [2079–2083], and the quantification of bromophenols in Islay whiskies is determined [2084]. Of great interest is the flow and distribution of bromophenols, such as the ubiquitous halogenated anisoles, in atmospheric transport and sea-air exchange [1981, 2085–2087]. For example, the natural halogenated bipyrrole Q1 is detected in air samples from both the Antarctic and southern Norway, and tribromoanisole is found in the Arctic, Antarctic, and southern Norway [1349]. As noted in earlier Sections, 2,4,6-tribromoanisole is present in myriad marine organisms [459, 460, 463, 1342–1344] and a new study finds this compound in blue mussels (Mytilus edulis), brown algae (Dictyosiphon foenicolaceus) and cyanobacteria (Nodularia spumigena) from the Baltic Sea and the west coast of Sweden [2088]. An important discovery, applicable to all naturally occurring organobromines vis-à-vis their anthropogenic counterparts, is that these two categories can be distinguished using bromine isotope compositions [2089]. Thus, given that heavier bromine isotopes (81 Br) react slower than lighter bromine isotopes (79 Br), one may expect to see isotope fractionation effects and a variation of δ 81 Br in the two origins

324

G. W. Gribble

of organobromines. The study in question shows that for industrial organobromines the δ 81 Br is –4.3 to –0.4%, but for natural 2,4-dibromophenol the δ 81 Br is + 0.2 ± 1.6%. The δ 81 Br for industrial 2,4-dibromophenol is –1.1 ± 0.9%, with a statistical difference of ~1.4 (P < 0.05) [2089]. δ 81 Br is defined as: d 81 Br   = 81 Br/79 Br (sample)/81 Br/79 Br (standard mean ocean bromide)−1 × 1000%.

3.22 Complex Phenols 3.22.1

Diphenylmethanes and Related Compounds

As discussed in the prior survey [2], brominated diphenylmethanes may arise via a reaction path similar to the acid-catalyzed dimerization of benzyl alcohols, which has been shown to give, for example, [1.1.1.1.1.1]paracyclophane, shown in Eq. 2 [2090, 2091].

OH

H+

(2)

[1.1.1.1.1.1]paracyclophane

A collection of the marine red alga Rhodomela confervoides yields the three new brominated diphenylmethanes 2691 [2092], and dibenzylphenol 2692 [2093]. The ethyl ether of 2691 is also isolated but is likely to be an artifact, because the alga extraction was performed in hot 95% ethanol (60°C 72 h) [2092]. The red alga Polysiphonia urceolata contains the three novel bromophenols 2693–2695 together with the known urceolatol (2587). Compounds 2693–2695 display potent radicalscavenging activity in the DPPH assay (IC 50 6.1–8.1 μM) [2094]. The marinederived fungus Penicillium terrestre, which contains terrestrols B (2580) and D (2581) shown earlier, also produces the diphenylmethanes 2696 and 2697, and the simple chlorohydroquinone 2698 [2020]. The new polybrominated biphenyls 2699–2701 are found in the blubber of several Australian marine mammals, and these compounds are related to the known natural product 2,2 -dimethoxy-3,3 ,5,5 -tetrabromobiphenyl [2095].

Naturally Occurring Organohalogen Compounds …

325

Br Br OH

Br

Br

Br

OH

Br Br

HO OH

OH

Br Br

HO

OH

OH

OH

OH

OH

OH

OH

Br O HO

HO

Br

OH O

Br

HO 2695

2693 R = H 2694 R = Br

OH

Cl

Cl

HO

OH

Cl HO

HO

OH

OH

OH

OH

OH

HO

R

2692

2691

OH

Br OH

R

Br

Br O

O

O

O OH

Br

Br 2696

2697

2698

2699 R = H 2700 R = Br

2701

The Norwegian marine red alga Vertebrata lanosa yields the new complex bromophenol 2702 [2096], and the productive Chinese red alga Symphyocladia latiuscula contains bromodiphenylmethane 2703 along with bromophenolic ureas 2704 and 2705 [2097]. The South Korean red alga Polysiphonia morrowii affords the new bromophenol 2706, which inhibits LPS-induced inflammation in RAW 264.7 macrophage cells [2098]. A collection of the red alga Polysiphonia decipiens from Australia gives the new polysiphonol (2707). In addition to the procerolides 1257–1260 shown in Sect. 3.11, the Australian ascidian Polycarpa procera also contains procerones A (2708) and B (2709) [990]. Rabenzophenone (2710) is found in the fungus Fimetariella rabenhorstii, which earlier was shown to contain rabenchromenone (2232) [1784]. The Chinese tree Melia azedarach L. is associated with the fungus Pestalotiopsis sp., which affords pestalachloride G (2711) as a racemate. Both enantiomers show appreciable activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis (MIC 50 4.1, 15.0, 13.5, and 16.5 μg/cm3 , respectively) [2100].

326

G. W. Gribble OH Br

HO

CO2Me Br

O HO

O

Br

HO

Br

Br

Br

OH

HO

O N

Br

Br

HO OH

Br Br

Br

Br

OH

HO

HN

N

R Br

Br

Br

OH

OH

OH OH

Br

HO OH

2703

2702

2704 R = H 2705 R = Br

O

O

HO

O

OH

Br HO

O

HO Br

OH

Br

OH

HO

Br

HO

Br OH

2706

Br

HO

O

R

OH

O

OH Br

OH

Br

2707 (polysiphonol)

2708 R = H (procerone A) 2709 R = Br (procerone B) OH

OH

O

CO2Me OH HO OHC

OH OH

Cl

HO

Cl

O Cl

2710 (rabenzophenone)

2711 (pestalachloride G)

The biological activity of natural bromophenols is widely studied with regard to cytotoxic effects [2101, 2102], antimicrobial activity [2103–2105], hyperglycemia [2106–2107], antioxidants [2109], and others [2110, 2111]. Total syntheses of avrainvilleol [2112] and other bromophenols [2113] are documented.

3.22.2

Diphenyl Ethers and Related Compounds

Given that the two phenyl rings in diphenyl ethers are activated towards halogenation by the tethering oxygen, natural brominated diphenyl ethers are far more abundant than brominated diphenylmethanes [1, 2]. The Xestospongia sp.-associated sponge bacterium Micrococcus luteus from New Caledonia yields the trichlorodiphenyl ether 2712 [2114], which was found previously in grapefruit seeds [2115], and also known as a commonly used antimicrobial compound [2116]. A widely studied tropical sponge Dysidea spp., provides the new polybrominated diphenyl ether 2713 [2117]. The novel pestheic acid (2714) resides in the fungus Pestalotiopsis theae, which is a causal fungus for gray blight disease. The suggested biosynthetic precursor, chloroisosulochrin (2715), is also present in this fungus [2118]. A related xanthone is depicted in Sect. 3.22.6. The marine sponge

Naturally Occurring Organohalogen Compounds …

327

Plate 61 Dysidea herbacea (Photograph courtesy of Jason Biggs)

Dysidea herbacea (Plate 61) contains the new 2716 along with five known analogs [2119]. The red alga Rhodomela confervoides produces the two new brominated diphenylmethanes 2717 and 2718 (which belong in the previous section). Ethanol was not employed in this isolation [2120].

Cl

Br

OH

O

Cl

Cl

CO2Me Br

O

O Br

O Br

2712 MeO2C

O

OH

Cl

OH OH

2715 (chloroisosulochrin)

Br

OH

2714 (pestheic acid) OR

Br

Br Br

HO Br

2716 (R = H) 2716a (R = Me)

OR

Br Br

O O

OH

Cl

2713 OH

CO2H

O

OH

OH OH

2717 R = H 2718 R= Et

The unique chlorophellins A–C (2719–2721) are found in the fungus Phellinus ribis. Metabolite C (2721) is highly potent as a PPAR-γ agonist, comparable to rosiglitazone [2121]. A collection of the sponge Dysidea sp. from Micronesia contains one new polybrominated diphenyl ether, 2722, along with eight known analogs, all of which display some activity against the MCF-7 cancer cell line (for 2722, IC 50 8.69 μM) [2122]. The unique urceolatin (2723) is a novel benzylphenanthro[4,5bcd]furan metabolite found in the red alga Polysiphonia urecolata. It shows radical-scavenging activity in the DPPH assay (IC 50 7.9 μM) [2123].

328

G. W. Gribble O

Cl

O Cl Cl

O Cl

Cl Cl

O Cl

Cl Cl

Cl O

Cl

Cl

O

O OH

Cl

O

Cl Cl Cl

OH Cl O O Cl Cl

Cl

Cl

Cl

O

O

Cl Cl O O

O

Cl HO Cl

Cl

Cl Cl

2721 (chlorophellin C)

2720 (chlorophellin B)

2719 (chlorophellin A)

Cl

Br HO Br

OH O

O Br

Br

Br Br

2722

Br

O

OH

HO

OH OH 2723 (urceolatin)

Four new polybrominated diphenyl ethers 2724–2747 are found in a collection of the sponges Dysidea granulosa (Plate 62) and Dysidea (Lamellodysidea) herbacea [2124]. The terrestrial lichen Diploicia canescens found on rocks of the French seacoast produces buellin (2728), which is active against B16 melanoma cells (IC 50 0.25 μM) [2125]. The deep-sea-derived fungus Penicillium chrysogenum SCSIO 41001 produces the four novel chrysines A–D (2729–2732) and dichloroorcinol (2733), along with a new xanthone in Sect. 3.22.6, and 14 known analogs. Chrysines B and C inhibit α-glucosidase (IC 50 0.35 and 0.20 mM, respectively) [2126].

Plate 62 Dysidea granulosa (Photograph courtesy of Julien Bidet; Maldives; Creative Commons Attribution-Share Alike 4.0 International)

Naturally Occurring Organohalogen Compounds … OH

OH

Br

OH Br

O

329

Br

OH

OH

O

Br

Br

Cl O

O

O Cl

Br

CO2R Cl

HO

O

Cl

CO2R2

1

O Cl

O

OR3

2729 R1 = R3 = Me, R2 = H (chrysine A) 2730 R1 = Et, R2 = Me, R3 = H (chrysine B)

CO2R2

CO2R1 HO

Cl

Cl

2728 (buellin)

2727

Br

2726

2725 CO2Me

O

O

Br

2724

Br

Br

Br Br

OH

Br

Br Br

Br

Br

OH O

Br

O

OR3

2731 R1 = R2 = R3 = Me (chrysine C) 2732 R1 = R3 = Me, R2 = H (chrysine D)

HO

OH

Cl

Cl

2733 (dichloroorcinol)

The Hawaiian bloom-forming cyanobacterium Leptolyngbya crossbyana yields the toxic crossbyanols A–D (2734–2737), and B (2735) is active towards methicillinresistant Staphylococcus aureus (MRSA) (MIC 2.0–3.9 μg/cm3 ). The large mats of this organism can smother and kill the subtending corals [2127]. A new methoxysubstituted brominated diphenyl ether, 2738, occurs in the blubber of a dead northern bottlenose whale (Hyperoodon ampullatus) found in the North Sea. The amount of 2738 in this organism is 100 ng/g, which is 2.5 times higher than the most abundant methoxypolybrominated diphenyl ether congeners. The authors interpret this high amount as being indicative of a natural origin [2128]. Two new linear chrysophaentins E2 (2739) and E3 (2740) are found in the alga Chrysophaeum taylori from St. John, U.S. Virgin Islands, and partial syntheses are described [2129]. The new aryl ether 2741 is produced by a Steganospora sp., related to the known dihydromaldoxin [2130], and Penicillium griseofulvum cib-119 yields 2742, along with a griseofulvin described in Sect. 3.22.8 [2131].

330

G. W. Gribble Br

Br

Br

O

O

OR2

O Br

Br

Br

O O

Br

Br

Br Br

O OR1

Br R1

R2

2738 (6-MeO-5-Me-BDE42)

2734 = = H (crossbyanol A) 2735 R1 = R2 = SO3H (crossbyanol B) 1 2736 R = SO3H, R2 = H (crossbyanol C) 2737 R1 = H, R2 = SO3H (crossbyanol D) HO

2 OH R

HO

OH CO2Me

CO2H Cl

HO Cl HO

O

O

OH

HO Cl

HO

O

Cl O

OH HO

CO2Me

O R1

OH

2739 R1 = Cl, R2 = Br (chrysophaentin E2) 2740 R1 = R2 = Br (chrysophaentin E3)

2741

2742

The soil fungus Penicillium sp. PSU-RSP699 from Thailand produces the new penicillither (2743) together with a new xanthone (Sect. 3.22.6), and 12 known analogs [2132]. A Japanese sample of the red alga Odonthalia corymbifera affords odonthalol (2744) in addition to the previous odonthadione (2657). Both metabolites show antioxidant and tyrosinase inhibitory activity [2050]. Along with seven nonchlorinated analogs, spiromastols A–C, F (2745–2748) are found in the deepsea-derived fungus Spiromastix MCCC 3A00308 collected from a sediment in the South Atlantic Ocean at 2859 m. Spiromastols A (2745) and C (2747) display potent antibacterial activity against seven bacterial strains (MIC 0.25–0.5 μg/ cm3 ), for which chloroamphenicol has a MIC value of 1–2 μg/cm3 [2133]. The novel triphenyl diether microsphaerol (2749) is found in the marine endophytic fungus Microsphaeropsis sp. [2134]. A mixed collection of the Papua New Guinea sponges Lamellodysidea sp. and Dysidea granulosa resulted in finding 14 polybrominated diphenyl ethers, including one new metabolite, 2750 [2135]. The new oxy-polybrominated diphenyl ether 2751 is present in the Australian nudibranch Miamira magnifica along with six known analogs [2136].

Naturally Occurring Organohalogen Compounds …

331

O

OH

Br

Cl Br

HO

CO2Me

CO2Me O HO

O

O

O

OH

Br

HO

OH

Cl OH

2745 R1 = R2 = H (spiromastol A) 2746 R1 = Cl, R2 = H (spiromastol B) 2747 R1 = Cl, R2 = Me (spiromastol C)

O

2748 (spiromastol F)

Br

Cl

OH 2749 (microsphaerol) Br

Br

O Br

OH

O OH

OH

OH

Cl O

O CO2H

Cl OH

OH

2744 (odonthalol)

2743 (penicillither)

R1

OH

OH

Cl

O R2 O

Br

Cl

Cl

Br

Br O

2750

OH O

Br

Br Br 2751

The ubiquitous fungus Aspergillus unguis contains the two new aspergillusethers C (2752) and D (2753). The dichloro derivative 2753 is four to eight times more active than 2752 as an antifungal agent against Candida albicans, Cryptococcus neoformans, and Penicillium marnefeii (MIC 16, 8, 16 μg/cm3 , respectively) [2137]. The new iodine-containing polybrominated diphenyl ether 2754 is present in the Vietnamese sponge Arenosclera sp. with eight known analogs [2138]. The new tribromodiphenyl ether 2755 is found in a mixed collection of ten Dysidea sp. and Phyllospongia sp. sponges from the Seto Inland Sea and the Mindanao Sea, along with nine known analogs [2139]. The new ambigols D (2756) and E (2757) occur in cultures of the cyanobacterium Fischerella ambigua (Näg) Gomont 108b [2140]. The characterization of 3-chloro-4-hydroxybenzoic acid [2] as a building block for the biosynthesis of the ambigols is presented [2141].

332

G. W. Gribble Cl

CO2Me

Cl

CO2Me

HO

O

HO

Br

OH

OH O

Br

OH

OH

2754

OH O Br

Br

Cl

Cl

Cl

OH

O

Cl

Cl HO

Cl

Cl

HO Cl

Br

I

Br

Cl 2753 (aspergillusether D)

2752 (aspergillusether C)

OH O

Cl

O

Cl Cl

Cl OH

2755

2756 (ambigol D)

2757 (ambigol E)

Given the widespread occurrence and biomagnification of polybrominated diphenyl ethers—natural and anthropogenic—there has been intense study of the biological properties of these compounds, including antibacterial [2142–2145], cancer-related [2146], oxidative phosphorylation [2147], and miscellaneous efffects [2148]. Of equal importance is the question of the origin of polybrominated diphenyl ethers—natural or man-made? Some recent investigations have addressed this [2149– 2151], and others discuss bioaccumulation and biomagnification of polybrominated diphenyl ethers [2152, 2153]. Two reports that may be highly significant in the area of brominated phenols and diphenyl ethers are (1) the UV-induced formation of bromophenols from polybrominated diphenyl ethers [2154], and (2) the production of hydroxy-substituted polybromination diphenyl ethers from bromophenols via bromoperoxidase-catalyzed dimerization [2155].

3.22.3

Tyrosines

Simple Tyrosines, Thyroxine, and Related Compounds Derived from Tyrosine This Section now encompasses the old Sects. 3.22.2 and 3.22.3 from the previous two surveys [1, 2], since the overlap is marginal. The ascidian Didemnum rubeum contains the new iodo-tyramines 2758–2763 [2156]. Iodocionin (2764), a cytotoxic metabolite, is found in the ascidian Ciona edwardsii living in the Bay of Naples. It shows potent activity towards mouse lymphoma (L51784) cells (IC 50 7.75 μg/cm3 ). The corresponding known bromo analog is also in this animal [2157]. A Mediterranean gorgonian, Paramuricea clavata produces 3-bromo-N-methyltyramine (2765), in addition to the two tryptamines 1820 and 1821 cited earlier [1415]. In addition to one indole, purpuroine J (1822), cited earlier, nine purpuroines A–L (2766–2774) are found in the marine sponge Iotrochota purpurea from Hainan Island, China. Purpuroine I (2774) shows

Naturally Occurring Organohalogen Compounds …

333

selective inhibition of the human pathogen Streptococcus pneumonia (IC 50 18 μg/ cm3 ), and A and D are selective inhibitors of the kinase LCK (IC 50 2.35 and 0.94 μg/ cm3 , respectively) [1416]. I

O

I NH2

O

NH2

O

I

I

2758

2759

O

O

N H

N H

I

I R

O

I

Br N

HO

NH

HO 2765

2764 (iodocionin) OR R1

2

R3

R3 N

O

CO2 R1

2762

I

2

R1

NH2

HO

I

O

2763

NHR

2760 R = CHO 2761 R = COPh

I

O

I

I

R2

R3

2766 = = = Br (purpuroine A) 2767 R1 = R2 = Br, R3 = H (purpuroine B) 2768 R1 = R3 = Cl, R2 = Br (purpuroine C) 2769 R1 = R2 = Br, R3 = I (purpuroine D) 2770 R1 = R2 = Br, R3 = Cl (purpuroine E)

N

CO2 2771 R1 = R3 = I, R2 = Mr (purpuroine F) 2772 R1 = R3 = I, R2 = H (purpuroine G) 2773 R1 = Br, R2 = Me, R3 = I (purpuroine H) 2774 R1 = Br, R2 = H, R3 = I (purpuroine I)

A collection of the Australian marine sponge Callyspongia sp. uncovered three new bromotyrosines (2775–2777), together with ten known analogs. Metabolite 2776 possesses the rare enol form of a phenylpyruvic acid, and it displays an ability to increase ApoE from human astrocytoma cells at a concentration of 40 μM [2158]. The new bromotyrosines, anomoian B (2778) and aplyzanzine B (2779), are found in a mixed Indonesian sponge collection (Hexadella cf. indica Dendy, Jaspis sp., and Bubaris sp.). The latter compound (2779) is the first bromotyrosine to bear a ketone functionality adjacent to a dibromophenyl ring. Both compounds are moderately active against several cancer cell lines (A549, HT-29, MDA-MB-231) [2159]. A South African collection from Algoa Bay of the ascidian Aplidium monile affords the new 2780, and 2781 is present in a Didemnum sp. These compounds represent the first occurrence of iodinated metabolites in South African marine invertebrates [2160]. The tropical sponge Narrabeena nigra, which produces indoles 1798–1801, also contains tyramine 2782 and kynuramines 2783–2784 [1403]. An examination of the Eastern Pacific zoantharians Antipathozoanthus hickmani and Parazoanthus darwini revealed the new valdiviamides A–D (2785–2788) and iodo tyramines 2789 and 2790, respectively, from these separate organisms (isolated as trifluoroacetate salts). Valdiviamide B shows moderate cytotoxicity towards HepG2 cells (IC 50 7.8 μM) [2161].

334

G. W. Gribble Br O

OH Br

Br

HO2C Br

NH

HO N

O

Br HO

O

O

HO NH

CO2H Br 2775 (callyspongic acid) O Br

2777

2776 O

Br

Br

Br Br

O

N

Br

N H

O

N

Br

N

O

N

O

N

Br

O 2779 (aplyzanzine B)

2778 (anomoian B)

O I

I NH2

O

CO2H N

O

Br

Br NH

O

Br

Br

Br

OH Br

Br

H N HO2C

2783 R = H (5,6-dibromokynuramine) 2784 R = OMe OH

OH R

O

2785 R = Br (valdiviamide A) 2786 R = I (valdiviamide B)

I

R

H N

N HO2C

NH2 R

2782

2781

2780

NH2

R

N N O

2787 R = Br (valdiviamide C) 2788 R = I (valdiviamide D)

2789 R = I 2790 R = Br

The Australian bryozoan Amathia lamourouxi contains the new convolutamines K (2791) and L (2792), and volutamides F–H (2793–2795), the former isolated as trifluoroacetate salts. An indole 1802 from this bryozoan is cited in Sect. 3.14.2. Volutamides F and G show potent antiplasmodial activity against both the chloroquinesensitive (3D7) and chloroquine-resistant (Dd2) parasite strains of Plasmodium falciparum (IC 50 0.57–0.85 μM) [1404]. The two new halogenated tyramines 2796 and 2797 are found in the solitary tunicate Cnemidocarpa irene, which displayed metabolites 2139 and 2140 earlier in Sect. 3.14.2 [1696]. The natural hormone 3iodothyronamine (2798) is a rapid-acting derivative of thyroid hormone [2162, 2163]. The chemistry of thyroxine and thyroid hormones is reviewed [2164, 2165].

Naturally Occurring Organohalogen Compounds …

N

O Br

335

Br

Br

Br

O N

O Br

R2

Br

N

N N

Br

2792 (convolutamine L)

2791 (convolutamine K)

Br

NH

O

N

O

R1

2793 R1 = R2 = Me (volutamide F) 2794 R1 = Me, R2 = H (volutamide G) 2795 R1 = H, R2 = Me (volutamide H) O

R2 NH2

R1O R1

I

HO

NH2

2798 (3-iodothyronamine)

R2

2796 = H, = Cl (3-chlorotyramine) 2797 R1 = SO3H, R2 = Br (3-bromotyramine-O-sulfate)

Halogenated amino acids are found in the sponge skeletons of Aplysina cavernicola [2166, 2167] and Ianthella basta [2167]. These amino acids include 3-chlorotyrosine, 3-bromotyrosine, 3,5-dichlorotyrosine, 3-iodotyrosine, 3bromo-5-chlorotyrosine, 3,5-dibromotyrosine, 3-chloro-5-iodotyrosine, 3-bromo-5iodotyrosine, 3,5-diiodotyrosine, and bromohistidine, which are found to varying degrees in both sponges, except for bromohistidine, which is not present in Ianthella basta. The major halogenated amino acids in both sponges are 3-bromo-5chlorotyrosine and 3,5-dibromotyrosine [2167]. A collection of the marine sponge Aplysina caissara from Brazil affords the new agelocaissarines A1, A2, B1, B2 (2799–2802), isolated as diastereomeric pairs, and caissarine C (2803), along with the known fistularin-3 and 11-hydroxyaerothionin [2168]. The similar aplysinones A–D (2804–2807) are present in Aplysina gerardogreeni, a sponge from the Gulf of California. Aplysinones A, B, and D display significant growth inhibitory activity towards the MDA-MB-231, A-549, and HT-29 cancer cell lines (GI 50 1.6–3.5, 2.0– 5.7, 1.5–4.1 μM, respectively) [2169]. An earlier review of marine bromotyrosines is noted [2170]. O Br

O Br

HO O

H N

N O

Br HO

O

OH

Br

O N

N H

H N

N

O

O

O

OH

N

N H

O

OH Br 2799 (agelocaissarine A1)

Br O

OH Br 2800 (agelocaissarine A2)

Br O

336

G. W. Gribble O

Br

O

O Br

HO O

H N

N

Br

Br

OH

HO

Br

OH

O

H N

O

O

N

N

O

H N

N

OH

OH

O

H N

O

O

Br

O

O

Br HO

N H

O N

O

n

N H

N O OH

Br

2804 n = 3 (aplysinone A) 2805 n = 2 (aplysinone D)

Br

Br O

N H

O N

O

O

O

HO

O

O

N

2803 (caissarine C)

Br

N

Br Br

Br

HO

O

H N

2802 (agelocaissarine B2) O

Br

Br OH

OH

O

O

O

Br

H N

2801 (agelocaissarine B1)

Br

O Br

N H

N

O

Br OH

2806 (aplysinone B) Br

Br O Br HO

O N

O

O

O N H

N H

N

O

O

2807 (aplysinone C)

New subereamollines A (2808) and B (2809) are present in the Red Sea sponge Suberea mollis, along with the new resorcinols, subereaphenols B (2810) and C (2811), which have significant antioxidant activity [2171]. A Florida Keys Aplysina fulva sponge contains araplysillin N 9 -sulfamate (2812) and spiroisoxazoline carboxylic acid 2813 [2063]. The hydroxy analog, 2814, of 2813 is present in the Queensland, Australia, sponge Ianthella flabelliformis [2172]. The isolation of ianthesine E from the Great Barrier Reef sponge Pseudoceratina sp. appears to be identical with araplysillin N 9 -sulfamate (2812) [2173]. A South China Sea Pseudoceratina sp. sponge contains the new purealidins T (2815) and U (2816) together with five known analogs. The former is a rare Noxide to be found in marine life [2174]. Spermatinamine (2817) [2175] and pseudoceramines A–D (2818–2821) [2176] occur in a collection of Pseudoceratina sp. sponges from Australia. Spermatinamine (2817) is the first natural product inhibitor of isoprenylcysteine carboxy methyltransferase, a novel cancer target [2175], and pseudoceramine B and spermatinamine inhibit secretion of the Yersina outer protein YopE (IC 50 19 and 6 μM, respectively) and the enzyme activity of YopH (IC 50 33 and 6 μM, respectively) [2176].

Naturally Occurring Organohalogen Compounds …

337

O Br

O

OH

Br Br

Br

Br

Br

HO O

H N

N

H N

HO

HO

O

O

n O

O

2808 n = 2 (subereamolline A) 2809 n = 3 (subereamolline B)

O

H N

N

CO2R

OH

O

2810 R = Me (subereaphenol B) 2811 R = Et (subereaphenol C)

2812

O Br

Br

HO O

Br

H N

N

O

O

19

Br

SO3Na

N H

R 2813 R = H 2814 R = OH

O

O Br

Br

Br

Br

HO

HO O

O

H N

N O

O

O

N

O Br

Br

H N

N

Br

N

Br

O 2816 (purealidin U)

2815 (purealidin T)

Br O Br HO

O

H N

N

N

N H

N

N

OR

OH

Br O

Br 2817 R = Me (spermatinamine) 2818 R = H (pseudoceramine A) O Br HO

O

N

2819 (pseudoceramine B) O

HO

O

N

Br O

Br

Br

O

HN

H N

N

N

N H

Br

N H

N

Br

H N

O Br HO

O

N

N H

Br 2820 (pseudoceramine C)

2821 (pseudoceramine D)

N H

338

G. W. Gribble

Two new psammaplysenes C (2822) and D (2823) are found in an Australian sponge Psammoclemma sp. [2177], close analogs of A and B found earlier in an Indian Ocean species [2]. An Australian sponge, Pseudoceratina sp., produces aplysamine 6 (2824), another inhibitor of isoprenylcysteine carboxy methyltransferase [2178]. The total synthesis of 2824 is described [2179]. An Okinawan sponge, Pseudoceratina purpurea, has furnished 20-N-methylpurpuramine E (2825) [2180], the methylated analog of the known purpuramine E [1]. The two-sponge association of Jaspis sp. and Poecillastra sp. provides the new psammaplin M (2826) and cyclobispsammaplin A (2827), a cyclic derivative of bis-psammaplin A [2181], which is cytotoxic to five standard cancer cell lines (ED50 1.14–3.82 μg/cm3 ). Br N

O

O Br O

Br

H N

N R

Br

O

Br

O

N

O

Br 2824 (aplysamine 6)

2822 R = H (psammaplysene C) 2823 R = Br (psammaplysene D)

OH HO

Br

N

H N

Br

O

O CO2Me

N

O

N HO 2826 (psammaplin M)

Br 2825 (20-N-methylpurpuramine E) HO

N

H N

S S

O Br

N

H N O

OH

Br

OH

Br

O

N

Br

O

O

HO

OH

O N H

S S

N H

2827 (cyclobispsammaplin A)

N

OH

NH2

Naturally Occurring Organohalogen Compounds …

339

Plate 63 Parazoanthus axinellae (Photograph courtesy of Parent Géry; Banyuls-sur-Mer; Public Domain)

The three clavatadines, C–E (2828–2830), are found in the Australian sponge Suberea clavata, with the known aerophobin 1, purealdin L, and aplysinamisine II [2182]. Several collections of Aplysina fulva find the new aplysinafulvin (2831) from Brazil and the Southern USA coast [2183]. The novel imidazolyl-quinolone tyrokeradines A (2832) and B (2833) are found in an Okinawan Verongid sponge [2184]. Another Okinawan sponge, Psammaplysilla purpurea, contains JBIR-44 (2834) [2185]. The sea anemone Parazoanthus axinellae (Plate 63) is home to the hydantoin alkaloids parazoanthines D (2835) and E (2836) along with three non-brominated analogs [2186]. The Australian ascidian Aplidium altarium contains the new botryllamide K (2837), which is weakly cytotoxic towards the H460, MCF-7, and SF268 cancer cell lines (IC 50 74–87 μM) [2187]. A brief review of the botryllamides has appeared [2188]. The unique adenine-substituted dibromotyrosine metabolite aphrocallistin (2838) is found in the deep-water (725 m) Florida Hexactinellida sponge Aphrocallistes beatrix.

340

G. W. Gribble O

O

Br

Br

O

Br

NH2

H N

N

N H

O

Br

O

H N

H N

N

NH

O 2829 (clavatadine D)

2828 (clavatadine C) OH

Br

O

HO

H N

N H

Br

O

NH2

HO CONH2

NH

2831

2830 (clavatadine E) HO

HN

O

OH Br

Br R

O

NH

O

Br

N

NH2

HO

Br

Br

O

N

H N

Br

OH

O

HN

OH

O

NH HO

NH2

N

N H

Br

2834 (JBIR-44)

2832 R = Me3N (tyrokeradine A) 2833 R = H3N (tyrokeradine B)

Br

O

O N

5

6

NH O 2835 (parazoanthine D) 2836 Δ5,6 (parazoanthine E)

NH N H

NH2

It inhibits the growth of several cancer cell lines; for example, G1 cell cycle arrest in the PANC-1 pancreatic carcinoma cell line (IC 50 22.8 μM) [2189]. The originally proposed structure of “zamamistatin” [2190] has been revised to that of the well-known aeroplysinin-1, as shown [2191]. An Okinawan Verongida sp. sponge produces sunabedine (2839), which shows cytotoxicity towards B16 mouse melanoma cells (IC 50 39 μM) [2192]. The closely related metabolite to 2839 (a diastereomer?) is pseudoceratinazole A (2840) from the Australian sponge Pseudoceratina sp. [2193].

Naturally Occurring Organohalogen Compounds …

341

Br HO N H

Br

N

O O O

Br

OH

Br O Br

Br CN OH

O

OH Br

Br O

"zamamistatin"

O

N N

Br

O NH OH

Br

N

2838 (aphrocallistin)

2837 (botryllamide K) HO HN O

N N H

O

aeroplysinin-1

OH O N

Br

O

H N

N N

O

N H

Br

N O HO

O Br

2839 (sunabedine) Br O Br

OH O N

O

H N O

N N

N H

Br

N O HO

O Br

2840 (pseudoceratinazole A)

The Okinawan sponge Pseudoceratina sp. contains the new ceratinadins A–C (2841–2843). The former two metabolites show antifungal activity against Cryptococcus neoformans and Candida albicans (MIC 2–8 and 2–4 μg/cm3 , respectively) [2194]. In addition to the known psammaplysin F, the new G (2844) [2195] and H (2845) [2196] have been isolated from the Australian sponges Hyattella sp. and Pseudoceratina sp., respectively. Psammaplysin H displays the most potent in vitro antimalarial activity (IC 50 0.41 μM), whereas F and G are more active in the cancer cell lines HEK293 and HepG2 (IC 50 3.7–18.7 μM) [2196]. The new psammaplin N (2846) that contains a sulfoxide group is found in Queensland sponge Aplysinella rhax [2197]. The Red Sea sponge Suberea mollis affords the new subereaphenol D (2847) and subereamines A (2848) and B (2849) [2198].

342

G. W. Gribble O Br

Br O

HO

Br O N

H N

Br

NH2

N OH

O N

OH

OH

HN

HO

O

N

O

NH

OH

O

H N

OH

O

N H

N H

OH

2841 (ceratinadin A)

2842 (ceratinadin B) R

O Br

Br

HO

Br O N

H N

H N

NH2

H N

O

NH

O

O O N

Br

2843 (ceratinadin C)

HO

Br

Br O

O

2844 R = N(Me)CONH2 (psammaplysin G) 2845 R = NMe3 (psammaplysin H)

OH CONH2

Br Br

H 2N

O

N

O

CO2H

N H

HN

R

O

S HO

Br

NH

OH

O

O

2846 (psammaplin N)

2848 R = H (subereamine A) 2849 R = Br (subereamine B)

2847 (subereaphenol D)

The new convolutamines I (2850) and J (2851) are found in the bryozoan Amathia tortusa. The former metabolite is particularly active against the parasite Trypanosoma brucei brucei (IC 50 1.1 μM) and also in the kidney HEK293 cell line (IC 50 22 μM) [2199]. The Balinese sponge Aplysinella strongylata is home to 21 new psammaplysins (2852–2872), along with six known analogs. Of these, 19hydroxypsammaplysin E (2852) displays the best antimalarial activity (IC 50 6.4 μM) [2200]. O HN HO O

O Br

O Br

Br O

Br

Br

Br

N H

2850 (convolutamine I)

N

Br

O N

N

H N

O N

2851 (convolutamine J)

Br

Br

Br O

HO O

2852 (19-hydroxypsammaplysin E)

Naturally Occurring Organohalogen Compounds …

343 O NH

R

O

Br

O N

Br

Br

H N

O

O

O

Br

Br

O N

O

HO

H N

O O

Br

2853 R = CHO (psammaplysin K) 2854 R = CH(OMe)2 (psammaplysin K dimethoxy acetal)

Br

Br O

HO O

2855 (psammaplysin L) O

NHCOCH2OH HN

O

Br

O N

Br

Br

H N

O

Br

O

Br

O

O N

HO

H N

O

O

Br

2856 (psammaplysin M)

O

n

R

O

Br

O N

H N

O Br

Br

Br O

HO

O HN

Br

9

Br O

HO O

2858 R = H, n = 10 (psammaplysin O) 2859 R = H, n = 12 (psammaplysin P) 2860 R = OH, n = 12 (19-hydroxypsammaplysin P) 2861 R = H, n = 8 (psammaplysin Q) 2862 R = OH, n = 8 (19-hydroxypsammaplysin Q)

2857 (psammaplysin N)

344

G. W. Gribble O HN

n

R

O

Br

O N

H N

O

Br

Br O

HO

Br

O

2863 R = OH, n = 8 (psammaplysin R) 2864 R = H, n = 9 (psammaplysin S) 2865 R = OH, n = 9 (19-hydroxypsammaplysin S) 2866 R = H, n = 11 (psammaplysin T) 2867 R = OH, n = 11 (19-hydroxypsammaplysin T) O HN

n

O

Br

O N

H N

O

m R2

R1

Br

Br O

HO

Br

O 1

R2

= Me, n = 5, m = 1 (psammaplysin U) 2868 R = H, 2869 R1 = OH, R2 = Me n = 5, m = 1 (19-hydroxypsammaplysin U) 1 2 2670 R = H, R = H, n = 5, m = 1 (psammaplysin V) 2871 R1 = H, R2 = H, n = 8, m = 1 (psammaplysin W) 2872 R1 = OH, R2 = H, n = 8, m = 11 (19-hydroxypsammaplysin W)

The Guam “twilight zone” sponge Suberea sp. collected at 90 m contains the two new psmmaplysins I (2873) and J (2874), along with six known analogs [2201]. A Micronesian sponge Suberea sp. affords four new psammaplysin analogs (2875– 2878) and four new ceratinamine derivatives (2879–2882) [2202]. Two wilsoniamines, A (2883) and B (2884), are found in the Australian bryozoan Amathia wilsoni. These novel metabolites possess a hexahydropyrrolo[1,2c]imidazole-1-one ring system that is new to Nature. The new amathamide H (2885) is also present in this animal. The authors suggest that the known amathamides C–F should be revised to each possess a 2,4,6-tribromo-3-methoxyphenyl moiety [2203]. A study of two southern Australian Pseudoceratina spp.

Naturally Occurring Organohalogen Compounds … Br

Br

O O

O O

Br

R

N

HO

345

O

Br

NH2

Cl

O O N

R Br

HO

H N O

O

N H

N H

O

O

O Br

Br

2873 R = H (psammaplysin I) 2874 R = OH (psammaplysin J)

2875 R = H (psammaplysin X) 2876 R = OH (19-hydroxypsammplysin X)

Br

Br

O

O

O O N

Br

OH Br

HO O

N H

H N

O

CHO

O O N

Br

H N

Br

HO

O

O

O Br

2877 (19-hydroxyceratinamide A)

N H

O Br

2878 (psammaplysin Y) O

O

CN

H N

Br

O

O O

N H

N H

O

O Br 2879 (subereamide A)

O Br

2880 (subereamide B) R Br

CN O

H N

Br

CN

Cl

N H

H N O

O

9

Br

2881 R = H (subereamide C) 2882 R = OH (12-hydroxysubereamide C)

sponges reveals seven new bromotyrosine metabolites, aplysamine-7 (2886), (–)purealin B (2887), purealin C (2888), purealin D (2889), (–)-purealidin R (2890), (–)-aerophobin-2 (2891), and (±)-purealin (2892), the latter of which is the first recorded example of a racemic bromotyrosine-derived spiroisoxazole. Both 2888 and 2892 display broad-spectrum activity against several Gram-positive bacteria [2204].

346

G. W. Gribble Br

Br O

Br

Br HO

O

Br

Br

Br N

8

H N

N

O

O

N

HO

N

N

Br

O

O Br

2885 (amathamide H)

2883 (wilsoniamine A) 2884 (wilsoniamine B) (C-8 epimer)

2886 (aplysamine-7)

O Br

Br

HO O

Br

H N

N

O

O

HO

N

H N

Br

NH2

O

2887 ((–)-purealin B)

Br HO

HO

Br

H N

N

O

O

HO

N

H N

Br

2888 R = H (purealin C) 2889 R = OH (purealin D) O

R NH2

O

O Br

Br

Br

HO

Br

HO

O

NH

O

N

NH2

H N

N

O

N

O

2890 ((–)-purealidin R)

2891 ((–)-aerophobin-2)

O Br

Br

HO O

H N

N O

Br O

HO

N

H N

Br

NH2 O

2892 ((±)-purealin)

H N N

NH2

N

Naturally Occurring Organohalogen Compounds …

347

The Red Sea sponge Pseudoceratina arabica contains the five novel ceratinines A–E (2893–2897), along with seven known analogs. Ceratinine B (2894) possesses an unprecedented 5,8-dibromoindoline moiety with an amino-oxirane ring on the side chain. The known subereamolline A, which is present in Suberea mollis, is a potent inhibitor of the migration and invasion of the metastatic breast cancer cell line MDAMB-231 at about IC 50 0.4 μM [2205]. The Australian sponge Suberea ianthelliformis contains three new ianthelliformisamines A–C (2898–2900). Metabolite A (2898) is particularly active against Pseudomonas aeruginosa (IC 50 6.8 μM). This is the first report of chemistry from this sponge [2206]. Br

Br

CONH2

Br

H2N

NH

O

2895 (ceratinine C)

2894 (ceratinine B)

2893 (ceratinine A) Br

CONH2

H N

O

O

Br

N H

Br

H N

O OHC

H N

O

NH2

Br

Br

H2 N

Br

O O

NH2

O

OHC

CO2Et

Br

N H

2897 (ceratinine E)

2896 (ceratinine D) Br O H N

Br

H N

NH2

N H

O 2898 (ianthelliformisamine A) Br O H N

Br

H N

NH2

O 2899 (ianthelliformisamine B) Br O H N

Br O

H N

O N H

Br

N H

O 2900 (ianthelliformisamine C)

Br

Another investigation of Suberea ianthelliformis (four sample sites) from the Solomon Islands finds five new compounds, araplysillin N20-formamide (2901), araplysillin N20-hydroxyformamide (2902), and araplysillins IV–VI (2903–2905), and 13 known analogs, but not the aforementioned ianthelliformisamines A–C (2898–2900). Metabolite 2898 shows good activity against MCF-7 and Vero cells (IC 50 3.8 and 5.0 μM, respectively), and both 2898 and 2899 are active against two Plasmodium falciparum malaria strains (FcB-1 and 3D7) (IC 50 3.6–7.0 μM)

348

G. W. Gribble

[2207]. The Australian sponge Pseudoceratina verrucosa contains the new pseudoceralidinone A (2906) and aplysamine 7 (2907). The latter metabolite is cytotoxic to HeLa and PC3 cancer cells (IC 50 19 and 4.9 μM, respectively) [2208]. The new (+)-ceratinadin D (2908) and aplysamine 8 (2909) are found in the sponge Pseudoceratina purpurea from Australia. A predator of this sponge, the mollusk Tylodina corticalis, contains a few of the sponge metabolites [2209].

O Br

Br

HO O

Br

H N

N

O

O

Br

N

R2

R1

2901 R1 = H, R2 = CHO (araplysillin N20 formamide) 2902 R1 = OH, R2 = CHO (araplysillin N20 hydroxyformamide) 2903 R1 = H, R2 = CO(CH2)8CH(Me)(CH2)5Me (araplysillin IV) 2904 R1 = H, R2 = CO(CH2)10CH(Me)(CH2)5Me (araplysillin V) Br OH

O Br

Br

H N

N OH

O

O

O

Br

N H

(CH2)11CHMe2

2905 (araplysillin VI) Br N

Br N

O Br

O

O

Br

NH O

OH

N H

Br N

OH

O

O

2906 (pseudoceralidinone)

2907 (aplysamine 7)

Br

O Br

Br

O NH2

HO O

H N

N

N

NH OH

OH

HO

H N

N O

O OH 2908 (ceratinadin D)

Br

O

N H

Br O Br

NH2

2909 (aplysamine 8)

The Australian sponge Aplysinella sp. contains the new aplysinellamides A– C (2910–2912) and aplysamine-1-N-oxide (2913), and several related known compounds [2210]. A Mediterranean zoanthid Parazoanthus axinellae produces the four brominated parazoanthins G–J (2914–2917), in addition to a new nonbrominated analog [2211]. The novel 14-debromo-11-deoxyfistularin-3 (2918),

Naturally Occurring Organohalogen Compounds …

349

aplysinin A (2919), and aplysinin B (2920) are found in the Caribbean sponge Aplysina lacunosa together with 15 known analogs. Metabolite 2919 shows some cytotoxicity towards KB-31 and MCF-7 cells (IC 50 25.8 and 77.5 μM, respectively) [2212]. NH2

O

O

HO

Br

N H

O

O Br

N H

HO

O

O R 2910 R = H (aplysinellamide A) 2911 R = Br (aplysinellamide B)

2912 (aplysinellamide C) Br R1O

N

O

Br

HO

N

N

O

NH

6

5

R2

N H

NH

Br

NH2

O 2914 R1 = H, R2 = H (parazoanthine G) 2915 R1 = H, R2 = H 5,6 (parazoanthine H) 2916 R1 = Me, R2 = Br (parazoanthine I) 2917 R1 = Me, R2 = Br 5,6 (parazoanthine J)

2913 (aplysamine-1-N-oxide)

O

Br

Br OH

Br O Br

N H

O N HO

H N

Br

O

O

OH

N O

O

2918 (14-debromo-11-deoxyfistularin-3) O

Br

Br OH Br

O N H

H N

O N O

O Br 2919 (aplysinin A)

Br

OH

NH2

O H N

Br O

2920 (aplysinin B)

HN N

350

G. W. Gribble

Three more ceratinines, F–H (2921–2923), are found in the Red Sea Verongid sponge Pseudoceratina arabica, to complement the earlier members of this group, 2893–2897 (A–E). Ceratinine H shows potent antiproliferative activity against HeLa cells (IC 50 2.56 μM) [2213]. A Thai sponge, Acanthodendrilla sp., contains 20 bromotyrosines including the one new 13-oxosubereamolline D (2924). This is the first report of bromotyrosines in a sponge of the order Dendroceratia [2214]. Br

Br NH2

O O

N H

NH2 O

Br

N H

Br O

H N

O

O

2922 (ceratinine G)

2921 (ceratinine F) O H N

O

NH2

O

HO O

O

Br

N H

Br

Br

Br

O

O

H N

N

H N

O 2923 (ceratinine H)

O O

2924 (13-oxosubereamolline D)

The Red Sea Verongid sponge Suberea sp. contains the two new subereamollines C (2925) and D (2926), and this study results in a revision of the known subereaphenol C (2811). The new subereamollines are similar to the known A (2808) and B (2809), which are the corresponding ethyl esters [2215]. An Indonesian sponge in the family Aplysinellidae (Order Verongiida) produces seven new bromotyrosines, purpuramines M and N (2927, 2928), and araplysillins VII–XI (2929–2933), along with six known analogs. Screening in a BACE1 Alzheimer’s disease assay (aspartic protease inhibition) and against several cancer cell lines provides only modest results [2216]. O Br

O Br

Br

Br

Br HO

HO

HO

O

H N

N O

O N H

2925 (subereamolline C)

CO2Me

H N

N

H N

Br CO2Me

OH CO2Et

O 2926 (subereamolline D)

2811 (subereaphenol C (revised))

Naturally Occurring Organohalogen Compounds …

351 Br

OH

Br O

O HO

N

O N

Br

H N

Br

O

O

Br

Br HN

OH

O

Br

O

R Br

R

NH 2929 R =

2927 R = NH2 (purpuramine M)

N H

NH 2928 R =

N H

NH2

NH2

(araplysillin VII)

Br

(purpuramine N)

O

O

(araplysillin VIII)

2930 R = Br

N H Br

OH

OH O N

O

O

Br

Br HN

O Br

CO2H

2931 (araplysillin IX) Br

OH O N

O

O

Br

Br HN

O Br

NHR

2932 R = CO(CH2)7CH(CH3)(CH2)5CH3 (araplysillin X) O (Z) 2933 R = (CH2)6CH=CH(CH2)3CH(CH3)(CH2)3CH3 (araplysillin XI)

352

G. W. Gribble

The Thai sponge Acanthodendrilla sp. contains acanthodendrilline (2934), confirmed by total synthesis and confirmation of the absolute configuration. The natural (S)-configured enantiomer is three times more cytotoxic than the (R)-isomer using the H292 non-small cell cancer cell line (IC 50 58.5 μM) [2217]. Seven novel bromo- and iodo-containing tyrosine analogs are present in the Indonesian sponge Iotrochota cf. iota, named enisorines A–E (2935–2939) and hemibastadinols 2940 and 2941. All of these new metabolites inhibit T35S-dependent YopE secretion, which is a virulence factor employed by many Gram-negative pathogens that inject bacterial effector proteins into host cells to negate host cell defenses [2218]. O

R

Br

O HN

X

N

O Br

N H

CO2Me

O

O

HO

Y

O N

2935 R = H, X = Br, Y = H (enisorine A) 2936 R = H, X = I, Y = H (enisorine B) 2937 R = Me, X = Br, Y = H (enisorine C) 2938 R = H, X = Br, Y = Br (enisorine D) 2939 R = H, X = I, Y = Br (enisorine E)

2934 (acanthodendrilline)

Br O

OH

Br O

H N

X OH

2940 X = Br ((+)-1-O-methylhemibastadinol 2) 2941 X = I ((+)-1-O-methylhemibastadinol 4)

An Okinawan sponge Pseudoceratina sp. contains the new ceratinadins E (2942) and F (2943), and the former is antimalarial against both drug-resistant (K1) and drugsensitive (FCR3) strains of Plasmodium falciparum (IC 50 1.03 and 0.77 μg/cm3 , respectively) [2219]. The Madagascan sponge Amphimedon sp. produces amphimedonoic acid (2944) and psammaplysene E (2945), which are inactive towards KB cancer cells. The known 3,5-dibromo-4-methoxybenzoic acid is also found in this sponge [2220].

Naturally Occurring Organohalogen Compounds …

353

Br O O Br

R1

O HO O

N

Br

N H

O

N

R2

Br

H N

Br O

2942 (ceratinadin E) R1 = Me, R2 = O

N H

Br

H N 1

Br

O

2943 (ceratinadin F) R = Me, R = O

Br

N

H N

Br

O

2

N H

O Br

Br

CO2H

O O Br O

N

Br

Br

N H

O

N Br

2944 (amphimedonoic acid)

2945 (psammaplysene E)

The sponge Pseudoceratina sp. from the South China Sea possesses two new metabolites, 2946 and 2947 [2221]. The Red Sea sponge Suberea mollis produces the simple subereaphenol A (2948) together with several known analogs [2222]. Note that the related subereaphenol C has been revised structurally (2684). The South China Sea sponge Dysidea frondosa contains the unprecedented terpenepsammaplysin bioconjugates, frondoplysins A (2949) and B (2950), and both metabolites are potent inhibitors of protein-tyrosine phosphatase 1B (IC 50 0.39 and 0.65 μM, respectively) [2223].

354

G. W. Gribble O Br

OH

O

O

Br

Br

Br

Br

Br

HO

HO HO

CN

HO

CONH2

CONH2 2948 (subereaphenol A)

2947

2946

Br

O

O

OH

O

Br

N H

N O O

H N

O

Br O Br

OH 2949 (frondoplysin A)

Br

O

O

O

N H

Br

N O O

H N O

OH

Br O Br

OH 2950 (frondoplysin B)

The new psammaplysin Z (2951) and 19-hydroxypsammaplysin Z (2952) are found in the Red Sea sponge Aplysinella sp. living off the coast of Jizan [2224]. The Okinawan sponge Suberea sp. yields an additional pair of ma’edamines C (2953) and D (2954). These novel metabolites are the first natural compounds to possess a tetrasubstituted pyridinium moiety [2225]. The Caribbean sponge Aplysina lacunosa from the Bahamas yields lacunosins A (2955), B (2956), and desaminopurealin (2957). Noteworthy is the rare amino acid (±)-isoserine found in 2956 [2226]. The new aplyzanzines C–F (2958–2961) are present in the French Polynesian sponge Pseudoceratina n. sp. All four compounds exhibit quorum-sensing inhibition and antifouling activities, but especially C and E [2227].

Naturally Occurring Organohalogen Compounds …

355

O HN

NH2

R

O N

O

Br O

HO Br

N

Br

H N

Br O

Br

O

Br

Br

Br

O

O

N O

Br

H N

N

N

O

HO

O

HN

O

HN

O

N

2954 (ma'edamine D)

HO

HO O

Br O

O

Br

HO

Br N

2953 (ma'edamine C)

O Br

Br O

O

2951 R = H (psammaplysin Z) 2952 R = OH (19-hydroxypsammaplysin Z)

Br

N

N

H N

Br

N

O

HO O

NH

O O

2955 (lacunosin A)

2956 (lacunosin B)

2957 (desaminopurealin)

Br R1O

Br O

N N

Br

Br

O

OR2 Br

2958 R1 = Me, R2 = (CH2)3NH2 (aplyzanzine C) 2959 R1 = H, R2 = Me (aplyzanzine D)

N

Br

Br

O

OR Br

2960 R = (CH2)3NH2 (aplyzanzine E) 2961 R = H (aplyzanzine F)

The first dimer to be identified among the family of psammaplysins is psammaceratin A (2962) living in the Red Sea sponge Pseudoceratina arabica. This molecule exhibits growth inhibition of the cancer cell lines MDA-MB-231, HeLa, and HCT 116 (IC 50 3.90, 8.50, 5.10 μM, respectively) [2228]. A Solomon Islands Suberea clavata sponge contains eight new fistularin analogs, subereins 1–8 (2963– 2970). In this study, the absolute configurations were determined for the known 11-epi-fistularin-3,17-deoxyfistularin-3, and subereins 1–8 [2229].

356

G. W. Gribble Br O

Br O

Br

O N

HO O

H N

Br

N H

CONH2 N H CONH2

O

O

H N

Br

N

O OH

O

Br O

Br

O 2962 (psammaceratin A) O

Br

O N OH

Br

Br

OH Br

NH

O

Br

N HN

O Br

OH

O

OH

Br O

OH

2963 (suberein 1) OH

O

Br

OH NH

O

HO

N

O O

Br

OH

Br

HN

O

Br

HO N O

Br

Br

2964 (suberein 2)

OH

O

Br

NH

O Br

O N OH

HO N O

Br

O

HN

O Br

OH

R

O

Br

2965 R = α-Br (suberein 3) 2967 R = β-Br (suberein 5) O

Br

OH NH

O Br

O N OH

HO N O

Br

O

HN

O OH

Br

Br

2966 (suberein 4)

O

Br

Naturally Occurring Organohalogen Compounds …

357 OH

O

Br

NH

O O N OH

Br

HO N O

Br

Br O

HN

O

O

Br

OH

Br

2968 (suberein 6) O

O

Br

NH

O O N OH

Br

HO N O

Br

Br OH

HN

O

O

Br

OH

Br

2969 (suberein 7) OH

HO N O

Br N

Br O

HN

O Br

O

Br

2970 (suberein 8)

The Polynesian sponge Suberea ianthelliformis contains eight new tyrosine alkaloids, psammaplysenes F–I (2971–2974) and anomoians C–F (2975–2978), along with the previously found psammaplysene D (2823) [2230]. OH Br Br N

Br

O Br

N

O Br

Br

OH

Br O

O N

O

Br

2971 (psammaplysene F)

N

N

2972 (psammaplysene G) Br

O Br

N

Br

N

N

OH

2975 R = Me (anomian C) 2976 R = H (anomian D)

Br O

R Br

R

Br

Br

N

O

N

2973 R = Me (psammaplysene H) 2974 R = H (psammaplysene I)

N

O

Br

O Br

Br

O Br

N N

R

O Br

N

2977 R = H (anomian E) 2978 R = Me (anomian F)

The new tyrokeradines C–H (2979–2984) are found in an Okinawan sponge of the order Verongidae, related to analogs A (2832) and B (2833) presented earlier [2184]. Tyrokeradines E and F possess a cyano group [2231], while G is the first

358

G. W. Gribble

bromotyrosine alkaloid with a β-alanine unit, and H has the rare N-substituted pyridinium ring. The latter two tyrokeradines are antifungal against Aspergillus niger (IC 50 32 μg/cm3 for both) and G is active towards Cryptococcus neoformans (IC 50 16 μg/cm3 ) [2232]. Br O R

N

HO

N

R

H N

Br

Br

H N

O

O

CN

Br

NH HN

O

NH2 2979 R = H (tyrokeradine C) 2980 R = Me (tyrokeradine D)

2981 R = H (tyrokeradine E) 2982 R = Me (tyrokeradine F) Br

Br O NH2

HO

N

N

O

H N

Br

HO

N

Br

O

CO2H

CO2H

2983 (tyrokeradine G)

2984 (tyrokeradine H)

A Western Australian sponge Pseudoceratina cf. verrucosa contains the two new pseudoceratinamides A (2985) and B (2986) along with the enantiomer (2987) of a known bromotyrosine [2233]. A new member of the synoxazolidinone family is synoxazolidinone C (2988) found in the sub-Arctic ascidian Synoicum pulmonaria [2234]. This organism also contains synoxazolidinones A (2989) and B (2655) (previously shown as “synoxazolidinone” [2047]), and pulmonarins A (2990) and B (2654) (previously shown as “pulmonarin” [2048]). A summary of the anti-fouling properties of these compounds has appeared [2235], and the absolute configurations of synoxazolidinones A and C are (tentatively) assigned [2236].

O

O

Br

Br

Br

HO

Br

HO

O

O

H N

N

R

O

H N

N

CO2H

O

OH Br

2985 R = Br (pseudoceratinamide A) 2986 R = H (pseudoceratinamide B)

2987

Cl Br O

NH O

N

Br

N H

O

2988 (synoxazolidinone C)

O

NH2

NH

Cl

Br O

NH

N H

Br

NH2

Br O O

Br O

2989 (synoxazolidinone A)

O

2990 (pulmonarin A)

N

Naturally Occurring Organohalogen Compounds …

359

Several studies of the biological properties (antiparasitic, antibacterial, anticancer, antiviral, etc.) for this compound class are reported [2237–2240]. Reviews of aeroplysinin-1 enantiomers [2241], the oxepane motif in marine drugs [2242], and Aplysina sp. dibromotyrosine derivatives and base-catalyzed transformations [2243, 2244] are available. The absolute configurations of the well-known psammaplysin A [2245] and the fistularin-3 stereoisomer [2246] are now established. A study shows that the marine sponge bromotyrosine metabolites fistularin3,11-hydroxyaerothionin, verongidoic acid, and others can be biosynthesized by the marine bacterium Pseudovibrio denitrificans Ab134, isolated from the marine sponge Arenosclera brasiliensis [2247]. Total syntheses of natural bromotyrosines not cited earlier and within the current time frame are those of racemic hydroxymoloka’iamine [2248], moloka’iakitamide [2249], psammaplin F [2250], psammaplin library [2251], psammaplin C [2252], oximinotyrosines (review) [2253], ianthelline, JBIR-44, and 5-bromoverongamine [2254], spermatinamine [2255, 2256], subereamollines A and B [2256, 2257], subereamollines A and B [2257, 2258], pseudoceramines A–D [2256], amathaspiramides A–F [2259], (±)-amathaspiramide F [2260], (–)-amathaspiramide E [2261], amathaspiramide C [2262], amathaspiramide B, D, F [2263], amathamide F [2264], amathamide A (revision) [2265], aplysamine-2 [2258], aplyzanzine A [2258], wilsoniamines A and B [2266], (+)-hemifistularin 3 [2267], lutamides A and C [2265], convolutamines F and H [2265], psammaplysene A [2268], purpurealidin E [2258], purpurealidin I [2269], purpuroine A [2270], pulmonarin B [2271], iso-anomoian A [2258], clavatadine B [2272] and C [2273], parazoanthine F [2274], ianthelliformisamines A–C [2275, 2276], ma’edamines A and B [2277], ma’edamine analogs [2278], and synoxazolidinones A and B [2279].

Bastadins The new cytotoxic bastadin 24 (2991), along with the known bastadins 4, 5, 6, 7, 12, and 21 are found in the Australian sponge Ianthella quadrangulata. This new metabolite is the 25-hydroxy derivative of bastadin 6, and is selectively cytotoxic towards five of 36 tested cancer cell lines, SF268 (glioblastoma), 629L (lung), 401NL (mammary), 276L (melanoma), and 22RV1 (prostate) (IC 50 0.37–0.59 μg/ cm3 ) [2280]. Three new bastadins 25 (2992), 15-O-sulfonatobastadin 11 (2993), and bastadin 26 (2994) are present in the Australian Ianthella flabelliformis. Only bastadin 26 exhibits potent affinity for the guinea pig δ-opioid receptors (K i 100 nM), and the new bastadins show no or weak affinity for the μ- and κ-opioid receptors [2281].

360

G. W. Gribble

Br

OH

N

H N

Br

OH

O

O O

Br

O

N

H N

O

Br

Br

HO

OH Br

Br

O3SO

O

Br

Br

O

OH Br

O OH

N H

N

R

N H

OH

N

OH

2992 R = OH (bastadin-25) 2993 R = H (15-O-sulfonatobastadin 11)

2991 (bastadin-24)

OH Br

N

H N

OH

O O Br

O OSO3 Br

Br

HO

O N H

OH N

OH

2994 (bastadin-26)

Two new bastadins, (E,Z)-bastadin 19 (2995) and dioxepine bastadin 3 (2996), are found in the Papua New Guines sponge Ianthella cf. reticulata, together with ten known related compounds [2282]. This is the first report of secondary metabolites from this sponge. A synthesis of dioxepine bastadin 3 is reported [2283].

N

H N

OH

Br

(E)

NH N OH

HO O

O

Br

HO O

Br

Br

Br

O

O

OH Br

Br

O

O O N H HO

(Z) N

2995 ((E,Z)-bastadin 19)

Br

HO NH

N OH

Br 2996 (dioxepine bastadin 3)

The Palau red alga Lithothamnion fragilissimum contains the bastadin-like metabolite lithothamnin A (2997), with the novel meta–meta linkage between two of the aromatic rings to distinguish it in part from the bastadin structure. This compound

Naturally Occurring Organohalogen Compounds …

361

shows modest antiproliferative activity towards five cancer cell lines (IC 50 7.6– 19.0 μM), including LOX, SNB-19, OVCAR-3, COLO-205, and MOLT-4 [2284]. A study of numerous known bastadins and analogs demonstrates their inhibition of foam cell formation due to the suppression of acyl-coenzyme A: cholesterol acyltransferase [2285]. The first trimeric hemibastadin, sesquibastadin 1 (2998), is present in an Indonesian version of the sponge Ianthella basta, along with five known bastadins. Metabolite 2998 and bastadin 3 show the most potent inhibition of 22 protein kinases (IC 50 0.1–6.5 μM), and the known bastadins 6, 7, 11, and 16 exhibit a strong cytotoxic effect against the murine lymphoma cell line L5178Y (IC 50 1.5–5.3 μM) [2286]. A collection of Ianthella basta from Guam reveals the new bastadin-6-34-O-sulfate ester (2999) [2287]. Br HO

O

N

H N

Br Br

HO

Br

N

H N

O

OH

OH

OH

OH Br

Br Br

O

N

OH

OH

O

Br

N H

Br

O

O O

OH N OH

N H

HO

HO

OH

N

H N

Br O

OH

2998 (sesquibastadin 1)

2997 (lithothamnin A)

N

H N

OH

O

Br O HO

Br

O Br

Br

Br

Br OSO3Na Br

O N H

N

OH

2999 (bastadin-6-34-O-sulfate ester)

Total syntheses of bastadins 2, 3, and 6 are achieved [2288], and model studies explore the conformational effects on the biological activity of the bastadins [2289, 2290]. Dibromohemibastadin-1 is found to be an important antifouling coating compound [2291].

362

G. W. Gribble

3.22.4

Depsides

The new depside 3-chloro-4-O-demethylmicrophyllinic acid (3000) is produced by the lichen Hypotrachyna leiophylla along with known metabolites [2292]. The plant endophytic fungus Pestalotiopsis adusta contains the three pestachlorides A–C (3001–3005). Pestachlorides A and B show significant antifungal activity toward three plant pathogens, and the former exists as two inseparable atropisomers. Pestachloride C is a racemate [2293]. Crassifoside H (3006) is found in the rhizomes of Curculigo glabrescens, along with seven known compounds [2294]. OH

O

OH

OH

O

CO2H

O

Cl

HN OH

O O

HO

OH

OH

Cl

Cl

O

OH

O

OH

O

Cl

Cl 3000 (3-chloro-4-O-demethylmicrophyllinic acid)

3003 (pestachloride B)

3001 (pestachloride A) 3002 (pestachloride A') OH HO

Cl Cl

O

OH

O

O

CH2OH O

O

HO

O

OH HO Cl

OH HO 3004 (pestachloride C) 3005 (pestachloride C')

3.22.5

3006 (crassifoside H)

Depsidones

The new depsidone, parellin (3007), is present in the lichen Ochrolechia parella encrusted on rocks along the coast of France, along with five known analogs [2295]. The fungus Chaetomium brasiliense contains the new chlorinated depsidone, mollicellin J (3008) [2296]. Another collection of this fungus, from Thailand, provides the new chlorine-containing mollicellin M (3009), along with three new non-chlorinated and six known mollicellins. All of these mollicellins are cytotoxic towards several cholangiocarcinoma cell lines [2297].

Naturally Occurring Organohalogen Compounds …

363

O

O Cl

O

O Cl

O

O O

HO

O

O O

HO O

Cl 3007 (parellin)

HO

O

O O

OH 3008 (mollicellin J)

O

3009 (mollicellin M)

A marine fungus, Aspergillus unguis, found on an unidentified sponge contains the three new chlorinated depsidones, aspergillusidone B (3010) and C (3011), and diaryl ether aspergillusether A (3012), together with several known analogs. Only 3011 shows (weak) activity against several cancer cell lines (Hep G2, A549, MOLT3, and HuCCA-1). Metabolites 3011 and 3012 are aromatase inhibitors (IC 50 4.1 and 0.7 μM, respectively) [2298]. O R1

O

Cl

CO2Me

HO

O

OH

OH

R3O R2

O

Cl

Cl O Cl

3010 R1 = H, R2 = Cl, R3 = Me (aspergillusidone B) 3011 R1 = Cl, R2 = H, R3 = H (aspergillusidone C)

3012 (aspergillusether A)

Of 15 new depsidones from the deep-sea (2869 m) fungus Spiromastix sp., 14 are chlorinated, spiromastixones B–O (3013–3026). All exhibit significant inhibition of Gram-positive bacteria (MIC 0.125–8.0 μg/cm3 ), and several inhibit MRSA and MRSE. Spiromastixone J inhibits the growth of two vancomycin-resistant strains [2299]. A subsequent study of this fungus found the additional spiromastixones P– R (3027–3029) and spiromastimelleins A (3030) and B (3031). Metabolite 3029 shows strong activity against Gram-positive pathogenic bacteria (MIC 0.5–1.0 μg/ cm3 ) [1766].

O

R3

O R2

R4 O

HO

R5

R1

O O R1

R5 O

HO

R2

R3

R4

3013 R1 = R3 = R5 = H, R2 = Cl, R4 = OH (spiromastixone B) 3014 R1 = Cl, R2 = R3 = R5 = H, R4 = OH (spiromastixone C) 3015 R1 = R5 = Cl, R2 = R3 = H, R4 = OH (spiromastixone D) 3016 R1 = R2 = Cl, R3 = R5 = H, R4 = OH (spiromastixone E) 3017 R1 = R2 = R5 = Cl, R3 = H, R4 = OH (spiromastixone F) 3018 R1 = R2 = R5 = Cl, R3 = H, R4 = OMe (spiromastixone G) 3019 R1 = R2 = R3 = Cl, R4 = OH, R5 = H (spiromastixone H) 3020 R1 = R2 = R3 = R5 = Cl, R4 = OH (spiromastixone I) 3021 R1 = R2 = R3 = R5 = Cl, R4 = OMe (spiromastixone J) 3022 R1 = R2 = R5 = Cl, R3 = H, R4 = OMe (spiromastixone K) 3023 R1 = R2 = R3 = R5 = Cl, R4 = OMe (spiromastixone L) 3024 R1 = R2 = Cl, R3 = R5 = H, R4 = OH (spiromastixone M) 3025 R1 = R2 = R5 = Cl, R3 = H, R4 = OH (spiromastixone N) 3026 R1 = R2 = R3 = R5 = Cl, R4 = OH (spiromastixone O)

364

G. W. Gribble O O

R2

OH

1

R

R

OH O

O

HO

R3

HO

O

Cl

3027 R1 = R2 = H, R3 = Cl (spiromastixone P) 3028 R1 = R2 = Cl, R3 = H (spiromastixone Q) 3029 R1 = R2 = R3 = Cl (spiromastixone R)

3030 R = H (spiromastimellein A) 3031 R = Cl (spiromastimellein B)

The soil-derived fungus Aspergillus unguis PSU-RSPG199 contains the new depsidone, aspersidone (3032) [2300]. A novel inhibitor of sterol O-acyltransferase, 7-chlorofolipastatin (3033), is found in the marine-derived Aspergillus unguis NKH-007, along with five related depsidones [2301].

O Cl

O O

O O

HO O

OH

HO O

Cl

Cl

3033 (7-chlorofolipastatin)

3032 (aspersidone)

Three novel chartarolides A–C (3034–3036) are found in the sponge (Niphates recondita)-associated fungus Stachybotrys chartarum WGC-25C-6. These compounds are significantly cytotoxic in a panel of tumor cell lines; especially 3034 (IC 50 1.3–5.5 μM), towards HCT-116, HepG2, BGC-823, NC1-H1650, A2780, and MCF-7 cells. The chartarolides also inhibit several protein kinases [2302].

HO

HO

HO O

O O

O

O

O

HO

HO

O

N O

HO

Cl

HO

HO

3034 (chartarolide A)

Cl

HO

O

O

O

O O

O HO

O O

HO O

HO

3035 (chartarolide B)

3036 (chartarolide C)

Cl

Naturally Occurring Organohalogen Compounds …

365

Of the four cytorhizins found in the endophytic fungus Cytospora rhizophorae, one is chlorinated, cytorhizin B (3037). This compound shows modest cytotoxicity against HepG-2, MCF-7, SF-268, and NC1-H460 cells [2303]. An excellent review of the chemistry, biosynthesis, and bioactivities of fungal depsidones is available [2304].

HO HO

HO

O

O O Cl

3037 (cytorhizin B)

3.22.6

Xanthones

A new xanthone, chloroisosulochrin dehydrate (3038), is found in the fungus Pestalotiopsis theae, which earlier afforded chloroisosulochrin (2715) and pestheic acid (2714) [2118]. The new xanthone 3039 is present in the endophytic fungus Chalara sp., along with four novel non-chlorinated chromone-3-oxepines. The fungus is found on Artemisia vulgaris [2305]. A Madagascar rain forest plant, Psorospermum molluscum, contains the new dihydrofuranoxanthone 3040, along with the corresponding epoxide, psoroxanthin. The authors do not rule out the possibility that 3040 is an artifact. Xanthone 3040 shows selective cytotoxicity against bovine endothelial cells (IC 50 0.004 μM); and is also active against the A2780 and HCT-116 cell lines (IC 50 0.042 and 0.068 μM, respectively) [2306]. The marine-derived fungus Chaetomium sp. produces three chaetoxanthones A–C, one of which, C (3041), is chlorinated and is active towards Trypanosoma cruzi (IC 50 1.5 μg/cm3 ) [2307]. Blumeaxanthene II (3042) is found in the Chinese medicinal herb Blumea riparia DC., which is the main ingredient of the traditional medicine “Fu Xue Kang Ke Li”. This compound is the first example of a natural halogenated xanthene [2308].

366

G. W. Gribble HO O

MeO2C

OH

O

MeO2C

OH

OH

OH Cl

O O

O

O

O

O

Cl

Cl

3038 (chloroisosulochrin dehydrate)

O

O

3040

3039

O

OH

O

O

OH O

OH

O

O

Cl

Cl 3041 (chaetoxanthone C)

3042 (blumeaxanthene II)

The deep-sea (3258 m)-derived fungus Emericella sp. SCSIO 05240 contains the new prenylxanthone, emerixanthone A (3043) together with three non-chlorinated analogs [2309]. The new chromone engyodontiumone B (3044) is the only chlorinated example found among 19 other chromones and related compounds occurring in the deep-sea fungus Engyodontium album DFFSCS02 collected from a sediment in the South China Sea. Compound 3044 has little or no antibacterial activity and only weak cytotoxicity activity towards the cancer cell lines U937, HeLa, MCF-7, and HepG2 (IC 50 55.5, 96.1, 172.3, 73.8 μM, respectively) [2310]. Along with known xanthones, the sponge-derived fungus Stachybotrys sp. HH1 ZDDS1F1-2 produces the new stachybogrisephenone B (3045) [2311].

OH

HO O

OH

O

O

O

OH

Cl O

O

Cl

OH

CO2Me

OH

O

OH

O

Cl

OH 3043 (emerixanthone A)

3044 (engyodontiumone B)

3045 (stachybogrisephenone B)

A strain of Alternaria sp. collected from the root of the marine semi-mangrove plant Myoporum bontioides A. Gray yields the new chloroxanthone 3046, which is active against Calletotrichum musae (MIC 214 μM) and Fusarium graminearum (MIC 107 μM) (more potent than triadimefon) [2312]. The new xanthone 3047 is found in the mangrove-derived fungus Penicillium citrinum HL-5126 from the South China Sea along with a new anthraquinone in the next Section [2313]. The simple xanthone 3048 is present in a Virginia liverwort (Trichocolea tomentella)-derived fungus Penicillium concentricun [370]. A deep-sea-derived fungus, Penicillium chrysogenum SCSIO 41001, which produces the chrysines 2729–2732 described earlier, also contains chrysoxanthone (3049). This compound is the most potent (IC 50 0.04 mM) of nine compounds tested in an α-glucosidase assay [2126]. The

Naturally Occurring Organohalogen Compounds …

367

phylopathogenic fungus Bipolaris sorokiniana strain 11134 contains the new chlorinated xanthones 3050 and 3051 along with ten known analogs [2314]. A review of xanthone natural products, their biological activity, and syntheses has appeared [2315]. OH

O

MeO2C

MeO2C

O

OH

OH

OH

O

O

OH

Cl

O

Cl

O

OH

Cl

3046

3047 OH

O

3048 OH

CO2Me

Cl

CO2Me

O

OH R

O

OH

O

Cl

Cl

3050 R = H 3051 R = OH

3049 (chrysoxanthone)

3.22.7

O

Anthraquinones

A Streptomyces sp. DSM 17045 furnishes the new chlorocyclinones A–D (3052– 3055), for which C (3054) is the most potent PPAR-γ antagonist (IC 50 0.60 μM, in the rosiglitazone assay). These four chlorocyclinones are the first PPAR-γ antagonists of natural origin [2316]. A total synthesis of chlorocyclinone A (3052) is achieved [2317]. Cl

Cl O

O

O

O

MeO2C

MeO2C

AcO OH

O

OH

OH

O

OH

3053 (chlorocyclinone B)

3052 (chlorocyclinone A) Cl O

Cl

O O

O

O

MeO2C O

O

HO O

OH

O

OH

3054 (chlorocyclinone C)

OH

O

OH

3055 (chlorocyclinone D)

The deep-sea stalked crinoid Proisocrinus ruberrimus (Plate 64) from Okinawa contains the six brominated proisocrinins A–F (3056–3061), which are the first

368

G. W. Gribble

polybrominated anthraquinones from a natural source [2318]. Another deep-water (358 m) crinoid Holopus rangii (Plate 65) from Curacao, contains the new 7bromoemodic acid (3062) and gymnochromes E (3063) and F (3064). Metabolite E is cytotoxic towards the NCI/ADR-Res cells (IC 50 3.5 μM) and inhibits histone deacetylase-1 (IC 50 3.3 μM), and F inhibits myeloid cell leukemia sequence 1 (MCL-1) binding to Bak [2319].

Plate 64 Proisocrinus ruberrimus (Photograph courtesy of NOAA Photo Library; Flickr: expl5403; Creative Commons Attribution 2.0 Generic)

Plate 65 Holopus rangii (Photograph courtesy of NOAA Okeanos Explorer; Puerto Rico; https:// oceanexplorer.noaa.gov/okeanos/media/exstream/exstream_01.html; Public Domain)

Naturally Occurring Organohalogen Compounds … O

O

369 O

OH R2

Br

Br

R1

O

R2

OSO3Na

Br

OH

O

OH

O

OH Br

OH

HO

HO

OH

O

Br

OH

HO

Br

R1

OH Br

CO2H

HO

O

3059 R1 = R2 = Br (proisocrinin D) 3060 R1 = Br, R2 = H (proisocrinin E) 3061 R1 = H, R2 = Br (proisocrinin F)

3056 R1 = R2 = Br (proisocrinin A) 3057 R1 = Br, R2 = H (proisocrinin B) 3058 R1 = H, R2 = Br (proisocrinin C)

O

OH

HO

HO

OH

O

Br

OSO3Na

HO Br OH

O

OH Br

OH

OH

3063 (gymnochrome E)

3062 (7-bromoemodic acid)

Br O

OH

OH

3064 (gymnochrome F)

Of the six new saliniquinones from the Palau marine actinomycete Salinispora arenicola, saliniquinone C (3065) is chlorinated. Saliniquinone A, the epoxide corresponding to 3065, is a potent inhibitor of the human colon adenocarcinoma cell line (HCT-116) (IC 50 9.9 nM) [2320]. The new angucycline JBIR-88 (3066) is found in a new lichen-derived Streptomyces sp. RI104-LiC106. This novel 1,1dichlorocyclopropane metabolite is active against HeLa and ACC-MESO-1 cells (IC 50 36 and 52 μM, respectively). The possibility of 3066 being an isolation artifact is not mentioned [2321]. The new dianthrone, neobulgarone G (3067), is found in the endophytic fungus Penicillium sp. isolated from the Egyptian plant Limonium tubiflorum [2322]. OH Cl OH

OH

O

Cl O

O

O 3065 (saliniquinone C)

O

OH

HO Cl Cl

O OH

O OH

Cl

O

HO

Cl OH

O

OH

3066 (JBIR-88)

OH

O

O

3067 (neobulgarone G)

A South China Sea sediment sample of Aspergillus sp. SCS1O F063 collected at 1451 m yields seven new halogenated anthraquinones, averantins 3068–3074. One metabolite, 6-O-methyl-7-chloroaverantin (3069), is active against three cancer cell lines, SF-268, MCF-7, and NCI-H460 (IC 50 7.11, 6.64, and 7.42 μM, respectively) [2323]. A Thai mangrove-derived fungus Paradictyoarthrinium diffractum BCC 8704 produces two new hydroanthraquinones, one which, paradictyoarthrin A

370

G. W. Gribble

(3075), is chlorinated, and displays modest cytotoxicity against the KB, MCF-7, and NCI-H187 cell lines, compared to the non-chlorinated paradictyoarthrin B [2324]. OH

O

OH

OR2

OH

O

HO

OH

OH

HO

Cl

Cl

OH R1 O

RO

OH

OH

OH

O

O

3068 R1 = R2 = H 3069 R1 = Me, R2 = H 3070 R1 = H, R2 = Me 3071 R1 = R2 = Me 3072 R1 = H, R2 = n-Bu

3073 R = H 3074 R = Me

Cl

O

OH OH

3075 (paradictyoarthrin A)

Genome sequence analysis of Streptomyces sp. FJS31-2 reveals the new anthrabenzoxocinone, zunyimycin A (3076). The producing organism is found in a Chinese soil sample at 800 m in Guizhou Province [2325]. Subsequent study of this organism finds zunyimycins B (3077) and C (3078), both of which show good activity against MRSA [2326]. Later, an additional large group of chlorinated anthrabenzoxocinones is produced from the gene clusters of Streptomyces sp. MA6657 and the actinomycete MA7150. Of the 14 new examples, 12 are chlorinated (3079–3090), shown below with the three known (+)-zunyimycins A–C (3076–3078). The two groups, (+)-ABX and (–)-ABX, differ in the configuration of the bridging ether oxygen [2327]. Many of these new analogs have improved antimicrobial activity, and both groups show that a C-3 hydroxy group and multiple chlorine atoms increase the potency of the compound. For example, against Bacillus subtilis and Staphylococcus aureus, (–)-ABX-G (3083) (MIC 0.82 and 0.22 μg/cm3 ) is superior to (–)-ABX-D (3081) (MIC 22.65 and 10.06 μg/cm3 ); (+)-ABX-C (3088) (MIC 0.9 and 0.90 μg/ cm3 ) is superior to (+)-ABX-F (3090) (MIC 5.77 and 6.13 μg/cm3 ) [2326].

R4

O

R4 OH

R3 O

O

O OH

OH R3

R1

O

O

O

OH R1

O

OH

OH R2

R2 R1

R2

R3

R4

3076 3077 3078

H Cl Cl

Cl H Cl

Cl Cl Cl

H H H

((+)-zunyimycin A) ((+)-zunyimycin B) ((+)-zunyimycin C)

3087 3088 3089 3090

Cl H Cl H

H Cl H Cl

H H H H

H H Me Me

((+)-ABX–B) ((+)-ABX–C) ((+)-ABX–E) ((+)-ABX–F)

3079 3080 3081 3082 3083 3084 3085 3086

R1

R2

R3

R4

H Cl H Cl H Cl Cl Cl

Cl H Cl H Cl Cl Cl Cl

H H Cl H Cl H Cl Cl

Me Me Me H H H H Me

((–)-ABX–B) ((–)-ABX–C) ((–)-ABX–D) ((–)-ABX–F) ((–)-ABX–G) ((–)-ABX–H) ((–)-ABX–I) ((–)-ABX–J)

The Great Barrier Reef sponge Clathria hirsuta contains three new brominated anthraquinones, rhodocomatulins 3091–3093 [2328]. The mangrove-derived Penicillium citrinum HL-5126 fungus mentioned earlier in Sect. 3.22.6 produces the

Naturally Occurring Organohalogen Compounds …

371

anthraquinone 3094, which shows some antibacterial activity against Staphylococcus aureus and Vibrio parahaemolyticus (MIC 22.8 and 10 μM, respectively) [2313]. A group of hyperchlorinated angucyclinones—allocyclinones—is found in Actinoallomurus sp. ID145698. Allocyclinones A–D (3095–3098) exhibit good antibacterial activity against Gram-positive bacteria (MIC 0.25–1 μg/cm3 ), except for Enterococcus faecium that is about ten times less sensitive. The activity increases with the increasing number of chlorines: 3095 > 3098 > 3097 > 3096 [2329]. Cl

OH

O

O

OH

R2

Br

Cl

O

OH

HO

O

O

O

OH

O

O

OH

O

O

R

O

OAc

O O

R1

3091 R1 = Me, R2 = OMe 3092 R1 = n-Pr, R2 = OMe 3093 R1 = n-Pr, R2 = H

OH

3094 (2'-acetoxy-7-chlorocitreorosein)

3095 R = CCl3 (allocyclinone A) 3096 R = Me (allocyclinone B) 3097 R = CH2Cl (allocyclinone C) 3098 R = CHCl2 (allocyclinone D)

Three chlorinated emodacidamides C (3099), F (3100), and G (3101) are found in the marine-derived fungus Penicillium sp. SCSIO sof101, together with five nonchlorinated analogs. Metabolite C (3099) inhibits the secretion of interleukin-2 from Jurkat cells (IC 50 4.1 μM) [2330]. OH

O

OH

OH

Cl

O

OH

Cl H N

HO O

CO2H

O

3099 R = H (emodacidamide C) 3100 R = Me (emodacidamide F)

R

H N

HO O

CO2H

O

3101 (emodacidamide G)

Three bianthrones, diastereomeric allianthrones A–C (3102–3104), are present in the marine alga-derived Aspergillus alliaceus, and 3102 shows weak activity against SK-Mel-2 and HCT-116 cancer cells (IC 50 11.0 and 9.0 μM, respectively) [2331]. Of eight novel alokicenones A–H found in the mangrove soil-derived Streptomyces sp. HN-A101, only alokicenone D (3105) contains chlorine, but is inactive in the cancer cell lines and protein kinase assays tested [2332]. A collection of the deep-sea (763–852 m) crinoid Hypalocrinus naresianus from Japan produces hypalocrinins A, B, F, and G (3106–3109) along with a few non-brominated analogs and known compounds. Hypalocrinin A is active in five cancer cell lines (HT 29, A549, MDAMB-231, and PSN1 at 25 μg/cm3 ) [2333]. Auxarthrol G (3110) occurs together with four non-halogenated analogs in the marine-derived fungus Sporendonema casei. Metabolite 3110 shows anticoagulant activity [2334].

372

G. W. Gribble OH

O

OH

OH

O

OH

Cl

OH

OR

O

Br H N

10 O

HO

H

HO Cl

H

OH

O

SO3H

O

O

10' OH

Cl OH

O

OH

3102 10α-H,10'α-H (allianthrone A) 3103 10β-H,10'α-H (allianthrone B) 3104 10α-H,10'β-H (allianthrone C)

3105 (alokicenone D)

3106 R = H (hypalocrinin A) 3107 R = SO3H (hypalocrinin B) OH

OR

O

Br H N

HO O O O

HO

SO3H

O

OH

OH O OH

OH

O

Cl

OH

OSO3H

O

OH

O

NH

SO3H 3110 (auxarthrol G)

3108 R = SO3H (hypalocrinin F) 3109 R = H (hypalocrinin G)

Syntheses of the lichen anthraquinones via the electrochemical oxidation of physcion [2335], and the topopyrones [2336] have been reported, and reviews of lichen metabolites [2337], phenanthroperylene quinones [2338], and marine anthraquinones [2339] are available.

3.22.8

Griseofulvin

Despite its longevity, the oral antifungal agent griseofulvin continues to be of interest. The important observation that griseofulvin is an inhibitor of centrosomal clustering in cancer cells has elevated this compound in cancer therapy. An SAR of 34 griseofulvin analogs led to a 25-fold increase activity compared to griseofulvin [2340]. Another SAR study of griseofulvin and 53 analogs involved the dermatophytes Trichophyton mentagrophytes, T. rubrum, and MDA-MB-231 cancer cells [2341]. Synthesis and X-ray crystal analysis established the structures of the two known griseofulvin metabolites, GF-1 and GF-2 [2342]. The new griseofulvin metabolite 3111 is found in the mangrove endophytic fungus Sporothrix sp. 4335 [2343]. The marine-derived fungus Nigrospora sp. MA75 from the semi-mangrove plant Pongamia pinnata contains the new giseofulvin analog 6 -hydroxygriseofulvin (3112) [2344]. A related fungus Nigrosporo sp. 1403 strain from the decaying wood of

Naturally Occurring Organohalogen Compounds …

373

Kandelia candel obtained in Hong Kong produces the novel derivative of griseofulvin diaryl ether 3113 [2345]. The new griseofulvin derivative (+)-5-chlorogriseofulvin (3114) is found in the marine-derived fungus Arthrinium sp. living in the South China Sea [2346]. A collection of marine-derived fungal strains from the French Atlantic coast led to the discovery of both griseophenone I (3115) and griseophenone G (3116) from the marine-derived Penicillium cansecens strain [2347]. Metabolite 3114 is also isolated. The new 4 -demethoxy-4 -N-isopentylisogriseofulvin (3117) is found in Penicillium griseofulvin CPCC 400528 from a Chinese soil sample. This metabolite shows anti-HIV activity (IC 50 33.2 μM) [2348]. The biosynthesis of griseofulvin has been investigated [2349], and an exhaustive review on the chemistry of griseofulvin is available [2350].

O

OO

O O O

O O

O

O

O

OH

Cl

O

Cl

3112 (6'-hydroxygriseofulvin)

3111

OR

OO

O 3113

O

O

O O

Cl

Cl O O

O Cl

NH

O Cl

3114 ((+)-5-chlorogriseofulvin)

3.22.9

OH

O

O

Cl

O

O

HO

O

OH O

OH

3115 R = Me (griseophenone I) 3116 R = H (griseophenone G)

O

O Cl

3117 (4'-demethoxy-4'-N-isopentylisogriseofulvin)

Miscellaneous Fungal Metabolites and Other Complex Phenols

A large number of natural phenols, mainly present in fungi, were not deemed suitable for the earlier described structural categories but are presented here. Conversely, some previously documented phenols could have been treated in this section. The plant endophyte fungus Pestalotiopsis fici affords the highly complex chloropupukeananin (3118) [2351] and chloropestolide A (3119) [2352], both possibly arising via a Diels-Alder cycloaddition from pestheic acid (2714) and iso-A82775C (not shown). Metabolite 3119 is particularly active against HeLa and HT29 cancer cells (GI 50 0.7 and 4.2 μM, respectively) [2352]. Subsequent studies of this fungus identified chloropupukeanone A (3120), chloropupukeanolides A (3121), B (3122) [2353], C (3123), D (3124), and E (3125) [2354]. These stunningly complex natural products show significant anti-HIV and cytotoxicity activities.

374

G. W. Gribble HO O O

OH O

O

O O

O

O O

O

HO O

HO

OH O O

O

O

OH

Cl O

O

H

Cl

HO

O

O

OH

HO O

Cl O

OH

3119 (chloropestolide A)

3118 (chloropupukeananin)

3120 (chloropupukeanone A)

HO

HO

OH O

O

OH O

HO O

O O O

O

HO

O O O

O

O Cl OR

3121 R = Me (chloropupukeanolide A) 3122 R = H (chloropupukeanolide B)

O O

HO O OH

O HO

OH

O O

HO

O

O Cl O

O Cl 3123 (chloropupukeanolide C)

3124 (chloropupukeanolide D)

HO HO

OH O O HO

O O O

Cl O 3125 (chloropupukeanolide E)

Six new metabolites from a culture of Pestalotiopsis fici are chloropestolides B–G (3126–3131). The putative biosynthetic precursor, dechloromaldoxin (not shown), is also found in the culture. Metabolite B shows modest cytotoxicity towards these human cancer cell lines CNE1-LMP1, A375, and MCF-7 (IC 50 16.4, 9.9, and 23.6 μM, respectively) [2355]. HO O HO HO

O O CO2Me

O

OH O

O

O O

O Cl

O

C

HO

O CO2Me

O C

O HO

O MeO2C

OH

O C

OH Cl HO

O

O

Cl

O 3126 (chloropestolide B)

3127 (chloropestolide C)

3128 (chloropestolide D)

Naturally Occurring Organohalogen Compounds …

375 OH

OH

OH O O

O CO2Me

O

O

O CO2Me

O

O Cl

Cl

Cl

O

O HO

O

OH

HO

OH

O

OH

O

O

3130 (chloropestolide F)

3129 (chloropestolide E)

O CO2Me

O

3131 (chloropestolide G)

The plant endophytic fungus Pestalotiopsis adusta contains pestachlorides A– C (3132–3135), the former as a mixture of two inseparable atropisomers (3132, 3133) and the latter as a racemate [2356], similar to the previous pestachloride G (2711) also from Pestalotiopsis [2100]. Pestachlorides A and B are significantly antifungal against Fusarium culmorum, Gibberella zeae, and Verticillium albo-atrum (IC 50 0.89/47, 54.4/1.1, and 58.3/7.9 μM, for A/B respectively) [2356]. A marinederived fungus, Pestalotiopsis sp. from the South China Sea soft coral Sarcophyton sp., contains (±)-pestachloride D (3136) [2294], along with the known epimeric (±)-pestachloride C (3135). Whereas (±)-pestachloride C is teratogenic towards zebrafish (Danio rerio) embryos, the epimeric (±)-pestachloride D is inactive. Total syntheses of (±)-pestachlorides C and D are described [2357], as is a total synthesis of pestalone [2] that surprisingly resulted in its conversion to (±)-pestachloride A (3132/3133) [2358]. The new (±)-pestachlorides E (3137/3138) and F (3139/3140) are found in the marine-derived Pestalotiopsis ZJ-2009-7-6 fungus, and both racemic E and F were resolved into their respective enantiomers using chiral preparative HPLC. All four stereoisomers exhibit antifouling activities against the barnacle Balanus amphitrite (EC 50 1.65 and 0.55 μg/cm3 , respectively, for the racemates) [2359]. OH

O

Cl HN O

O

OH

Cl

O O

OH

OH

8 OH

Cl

Cl

OH O

OH

Cl O

OH

Cl 3132 ((8R)-pestachloride A) 3133 ((8S)-pestachloride A)

3134 (pestachloride B)

3135 (pestachloride C)

376

G. W. Gribble Cl

Cl

O O

OH

Cl

O O

Cl

OH

OH

HO

OH

OH

Cl

Cl O

O O

OH

HO

HO 3136 (pestachloride D)

3137 ((+)-pestachloride E) 3138 ((–)-pestachloride E)

3139 ((+)-pestachloride F) 3140 ((–)-pestachloride F)

Arnamial (3141), the aldehyde corresponding to the known arnamiol [2], is found in the fungus Armillaria mellea and displays cytotoxicity towards HCT-116, MCF-7, Jurkat, and CCRF-CEM cells (IC 50 10.69, 15.4, 3.93, and 8.91 μM, respectively) [2360]. Cultures of Armillaria sp. 543 furnish the new melleolides (3142 and 3143) together with seven known analogs [2361]. A study of the in vitro cytotoxicity of eight known natural melleolide antibiotics covering the structural and mechanistic aspects, concludes that terpene hydroxylation is a major factor, but that the terpene double bond position and the aromatic ring 6 -chlorination are not contributors to cytotoxicity. The melleolides are cytotoxic via inhibition of DNA biosynthesis [2362]. Cultures of the Thai fungus Favolaschia tonkinensis collected on a bamboo stem yield the new 9-methoxystrobilurin B (3144), and 3145–3147 [2363]. Metabolite 3144 displays antifungal (Candida albicans), antimalarial (Plasmodium falciparium K1), and cytotoxicity (KB, MCF-7, NCI-H187) (IC 50 0.22, 0.30, and 0.40–5.45 μg/cm3 , respectively) [2363]. Another Thai investigation of Favolaschia sp. from bamboo results in the three new chlorinated oudemansinol B (3148), O(phenylacetyl)oudemansinol B (3149), and favolasinin (3150), along with many other non-chlorinated analogs [2364]. OH

OH Cl

Cl O

O

O

OH

O OH OH

Cl

OH O 3141 (arnamial)

O O

OH

OH

3142 (10-dehydroxymelleolide D)

OH OH

O

OH

CHO

3143 (13-dehydroxymelleolide K)

Naturally Occurring Organohalogen Compounds …

377

O

O O

O Cl

R

Cl

O

MeO2C

HO

O

3144 (9-methoxystrobilurin B)

3145 R = NH2 3146 R = OH

O

3147

Cl

CO2Me

O

Cl

O

OR

O

O

O

H2N

Cl

O 3148 R = H

3150 (favolasinin)

O Ph

3149 R =

The two new guignardones D (3151) and E (3152) are found in the fungus Guignardia mangiferae living on leaves of Viguiera arenaria from Brazil [2365]. The novel indanone, tripartin (3153), is found in a Streptomyces sp. associated with the Dung beetle larvae (Copris tripartitus); the structure and absolute configuration are confirmed by X-ray crystallography. While tripartin displays no significant cytotoxicity towards seven cancer cell lines, no antibacterial or antifungal activity, and no activity in the amyloid-β42 aggregation assay, it is a specific histone H3 lysine 9 demethylase (KDM4) inhibitor [2366]. The fungus Graphiopsis chlorocephala from sterilized leaves of Paeonia lactiflora affords the novel cephalanones A (3154) and B (3155) together with four non-chlorinated analogs. The addition of nicotinamide, an NAD+ -dependent HDAC inhibitor, to the culture medium significantly stimulates the production of cephalanones A and B [2367].

O

O

OH

Cl O

O

O

O

HO Cl

OH Cl

3151 (guignardone D)

HO

O

HO Cl

3153 (tripartin)

3152 (guignardone E) Cl O O OH

O

O

R

CO2H

3154 R = H (cephalanone A) 3155 R = OH (cephalanone B)

The new ascochlorin derivative, cylindrol A5 (3156), is found in the fungus Cylindrocarpon sp. FK1-4602, and shows moderate antimicrobial activity against

378

G. W. Gribble

Bacillus subtilis, Kocuria rhizophila, Mycobacterium smegmatis, and Acholeplasma laidlawii [2368]. The fungal endophyte, Acremonium sp., in the medicinal plant Ephedra trifurca, produces the new cell migration inhibitor 10 -deoxy10 α-hydroxyascochlorin (3157), together with known analogs. This new metabolite inhibits the migration of metastatic prostate cancer cells PC-3M [2369]. Cultures of the leafhopper pathogenic fungus Microcera sp. BCC 17074 afford the two new ascochlorins, nectchlorins A (3158) and B (3159). This study also establishes the absolute configurations of 3159 and 3160 [2370], the latter being a new LL-Z 1272α epoxide found in a mutant strain of Ascochyta viciae [2371]. Nectchlorins A and B exhibit modest cytotoxicity towards KB cancer cells (IC 50 17 and 25 μg/cm3 , respectively). For comparison, doxorubicin and ellipticine show IC 50 0.46 and 0.55 μg/cm3 , respectively [2371]. Four new metabolites, ilicicolinic acids A (3161), C (3162), D (3163), and ilicicolinal (3164), are found in the fungus, Neonectria discophora SNBCN63, living in a termite (Nasutitermes corniger) nest in French Guiana. Metabolite A is also reported in an unavailable Japanese patent [1994]. These ilicicolinic acids and ilicicolinal show weak antibacterial and cytotoxic activities, except that the former are active against Escherichia coli [1994]. A later study by this research group finds nine additional chlorinated analogs from Neonectria discophora: ilicicolinals B–F, H (3165–3170), ilicicolinic acids E (3171) and F (3172), and ilicicolinol (3173). Only metabolite ilicicolinal C (3166) shows good activity against MRSA and Staphylococcus aureus (MIC 8 μg/cm3 for both), in which vancomycin has MIC 1 μg/cm3 to MRSA [2372]. OH

OH

O

OH

Cl

Cl O HO

O

OH CHO

CHO

3157 (10'-deoxy-10'α-hydroxyascochlorin)

3156 (cylindrol A5)

OH

OH OHC

O O OH

O

Cl 3158 (nectchlorin A)

O

OHC OH Cl 3159 (nectchlorin B)

OH

Naturally Occurring Organohalogen Compounds … OH

379 CO2H

O

OHC

OH Cl

OH

OH

Cl 3160 (LL-Z 1272α epoxide)

3161 (ilicicolinic acid A)

CO2H

CO2H OH

OH

Cl

Cl HO

OH

OHC

Cl

OH

OH

3162 (ilicicolinic acid C)

3163 (ilicicolinic acid D)

OH

Cl

O HO

OHC

3164 (ilicicolinal)

OH

O HO 3165 (ilicicolinal B)

OH

R

3166 R =

(ilicicolinal C)

3167 R =

(ilicicolinal D)

3168 R =

(ilicicolinal E)

Cl

OH OH CHO

OH

OH

R1

OH

3169 R1 = CHO, R2 = Cl (ilicicolinal F) 3170 R1 = Cl, R2 = CHO (ilicicolinal H)

OH

OH

O R2

OH

Cl

R 3171 R = CO2H (ilicicolinic acid E) 3172 R = CO2H (ilicicolinic acid F) 3173 R = H (ilicicolinol)

The edible and medicinal mushroom Hericium erinaceus produces the novel erinaceolactone C (3174), along with two new non-chlorinated metabolites [2373]. Chinese forest leaf litter that contains the fungus Myrotheciun sp. SC0265 yields the quinone sesquiterpene myrothecol A (3175), together with five analogs. This new metabolite is active towards the cancer cell lines A549, HeLa, and HepG2 (IC 50 8.0, 7.9, and 15.2 μM, respectively), and is antibacterial against Staphylococcus aureus and Bacillus cereus (MIC 12.5 and 25.0 μg/cm3 ), but only weakly active against Gram-negative bacteria [2374]. Pestalotiopene C (3176) is produced by the endophytic fungus Acremonium strictum, isolated from the Vietnamese mangrove tree Rhizophora apiculata. Four new non-chlorinated polyketides are also found in this organism [2375]. The epoxide pestalotiopen A (591), shown earlier [610], is also found in this fungus. The fungus Acremonium crotocinigenum BCC 20012 from the brackish water palm Nypa fruticans in Thailand contains the chlorinated trichothecene analog 3177 [2376]. The novel pentacyclic polyketide, daldinone E

380

G. W. Gribble

(3178), is found in the fungus Daldinia sp. pretreated with the epigenetic modifier suberoylanilide hydroxamic acid. A related known epoxide, daldinone B (not shown), is also produced by this fungus and its structure is revised in this study [2377]. A Thai soil fungus, Penicillium copticola PSU-RSPG138, yields the new eremophilane sesquiterpene, penicilleremophilane A (3179), together with three new non-chlorinated analogs and 16 known compounds. This new metabolite has some antimalarial activity against Plasmodium falciparum (IC 50 3.45 μM), but only weak cytotoxicity to KB and MCF-7 cells (IC 50 56.95 and 39.55 μM, respectively) [2378]. Cl HO

O

O

O

OH

O

O

O O

OH

OH HO O

O O

O

Cl

Cl

OH

3174 (erinaceolactone C)

OH

HO

O

3176 (pestalotiopene C)

3175 (myrothecol A)

HO

O

O

O OH

OH

HO

O

O

OH O O

HO

Cl O 3177

Cl 3178 (daldinone E)

Cl

O

O

3179 (penicilleremophilane A)

A marine-derived Penicillium copticola sp. TPU1270 from Okinawa yields the new penicillimide (3180), which is closely related to the known coniothyriomycin [2]. Unlike the latter, which has a double bond connecting the two carbonyl groups, penicillimide shows no antifungal activity [2379]. Of six tanzawaic acids isolated from Penicillium sp. CF07370 found in a marine sediment (100 m) in the Gulf of California, one is chlorinated, tanzawaic acid P (3181). This compound is the most active against human cancer cell lines, and U937 (lymphoma) is the most sensitive; for example, IC 50 5.7 μM [2380]. The fungus Truncatella angustata associated with a Chinese finger sponge Amphimedon sp. produces 14 new truncateols, of which six, G–K, M (3182–3187) contain chlorine [2381]. These metabolites (and the nonchlorinated analogs) are not active against eight pathogenic bacteria. However, some do show activity against the influenza A/WSN/33 virus. In particular, truncateol M (3187) is effective (IC 50 8.8 μM) in targeting the virion assembly/release step [2381].

Naturally Occurring Organohalogen Compounds …

381 CO2H

H N

Cl O

HO

C

CO2Me O

OH OH

OH

3180 (penicillimide)

Cl

Cl

C

Cl

O OH

HO OH

3184 (truncateol I)

OH

3182 β-OH (truncateol G) 3183 α-OH (truncateol H)

O

OH HO

HO

3181 (tanzawaic acid P)

O

O

HO

OH HO

Cl

HO

3185 (truncateol J)

Cl

3186 (truncateol K)

O O OH O Cl

OH

3187 (truncateol M)

A new class of influenza virus inhibitors are the spiromastilactones A–M (3188– 3200) isolated from the deep-sea (2869 m) derived fungus Spiromastix sp. MCCC 3A00308 living in a South Atlantic Ocean sediment. Spiromastilactone D (3191) is the most potent to inhibit a panel of influenza A and B viruses in addition to drugresistant clinical isolates. Evidence indicates that 3191 disrupts the hemagglutinin protein-sialic acid receptor interaction that is essential for the attachment and entry of viral cell entry. Moreover, 3191 also shows inhibition of viral genome replication by targeting the ribonucleoprotein complex [2382]. The mangrove (Avicennia marina) endophytic fungus Amorosia sp. SCS1O 41026 from China affords the new chlorophenols 3201–3205, together with 16 known analogs [2383].

382

G. W. Gribble OH Cl

OH Cl

Cl

Cl

R4

O O

OH

O

R1

O

R3 R2

O 3188 (spiromastilactone A) 3189 3190 3191 3192 3193 3194 3195 3196 3197 3198 3199 3200

R1

R2

R3

R4

OMe OH OMe OMe OH OH OH OMe OH OH OMe OMe

H H H Cl H Cl H H Cl Cl Cl Cl

OMe OMe OH OH OH OH OH OH OH OMe OH OMe

Cl Cl Cl H Cl H H H Cl Cl Cl Cl

OH

O O

O

Cl

Cl

(spiromastilactone B) (spiromastilactone C) (spiromastilactone D) (spiromastilactone E) (spiromastilactone F) (spiromastilactone G) (spiromastilactone H) (spiromastilactone I) (spiromastilactone J) (spiromastilactone K) (spiromastilactone L) (spiromastilactone M)

O

Cl

HO

O

O Cl

Cl

Cl

Cl

O

Cl

OH

O

OH

OH

OH

3201

3202

3203

3204

3205

O

Further examination of the fungus Helminthosporium velutinum, which earlier provided the simple cyclohelminthols 53–55 [358], reveals the complex cyclohelminthols X (3206) [2384] and Y1–Y4 (3207–3210) [2385]. The (6S) isomers Y2 and Y4 exhibit cytotoxicity against the cell line COLO201 (IC 50 11 and 10 μM, respectively). The (6R) isomers are weaker (IC 50 > 180 and 34 μM, respectively) [2385].

O

O O

HN

O Cl O

HN

Cl

Cl

O

O O

O OH

O

O OH

O

HO2C

HO2C O

3206 (cyclohelminthol X)

O

3207 (cyclohelminthol Y1)

Naturally Occurring Organohalogen Compounds …

383

O

O

O

O

Cl

Cl O

HN

Cl O

HN

O

Cl

O O

O OH

O

O

HO2C

O OH

O

HO2C

O

O

3208 (cyclohelminthol Y2)

3209 (cyclohelminthol Y3)

O O Cl O

HN

Cl

O O

O OH

O

HO2C O

3210 (cyclohelminthol Y4)

The marine-derived fungus Stilbella fimetaria contains the new fimetarins A–D (3211–3214). The fimetarin structures B–D are considered as “tentative” [2386]. A collection of 52 specimens of the nudibranch Phyllidiella pustulosa from Indonesia produces four new dichloroimidic sesquiterpenes 3215–3218, along with several ethanol-derived ethyl carbamates (not shown) [2387]. Biosynthesis investigations are described involving the antifungal strobilurins [2388, 2389], which results in the isolation of the new analog, strobilurin Z (3219) [2388], related to the known strobilurin B [1]. The biosynthesis of ascochlorin [2390, 2391] and aspirochlorine are also studied [2392]. Total syntheses of the fungal metabolites (±)-ascofuranone [2393], LL-Z1272α and ilicicolinic acid A [2394], armillarin A [2395], and colletorin A and colletochlorin A [2396] are achieved. OH

OH O

O

O

CO2Me 3211 (fimetarin A)

O

O

O

O Cl

OH

O

Cl

O Cl

3212 (fimetarin B)

OH R

3213 R = OAc (fimetarin C) 3214 R = H (fimetarin D)

384

G. W. Gribble O Cl

Cl

O N

N

Cl

Cl

O Cl

Cl 3216

3215

N

O

O

Cl

Cl Cl

N

HO

Cl 3217

Cl Cl

3218

Cl

MeO2C

O OH O

3219 (strobilurin Z)

3.23 Glycopeptides Vancomycin—the antibiotic of “last resort”! While this was true 50–60 years ago, it is no longer the case. However, the crusade to resurrect vancomycin and related chlorine-containing natural glycopeptides as life-saving drugs continues relentlessly today. The first two monographs in this trilogy thoroughly document the history and development of vancomycin, teicoplanin, avoparcin, actaplanin, parvodicin, aridicin, kibdelin, orienticin, galacardin, balhimycin, complestatin, kistamicin, and their glycopeptide derivatives, all of which contain chlorinated phenolic rings that are essential for biological activity [1, 2]. No new naturally occurring chlorinated glycopeptides are reported for this survey. The importance of the aryl chloride in vancomycin is well known [2397, 2398]. The present survey addresses mainly the myriad recent endeavors to reverse bacterial resistance to vancomycin and other glycopeptides. Several comprehensive reviews are available that report these synthesis efforts [2399–2403]. In addition to an exhaustive review of the syntheses of vancomycin and related glycopeptides [2403], a total synthesis of “next-generation” vancomycin is reported [2404]. The syntheses of new vancomycin and other glycopeptide analogs are innumerable, including vancomycin peptide backbone and side-side modifications [2405–2408], lipid chains [2409], methyl ethers [2410], sugar attachments [2411–2414], brominated analogs [2415], photosensitizers [2416], demethylated vancomycins [2417], thiocarbonylation and deoxygenation [2418], aglycon dimers [2419], cathelicidin peptide conjugates [2420], a dipicolyl conjugate [2421], triazole liners [2422], novel lipid chains [2423], bisphosphonated prodrugs [2424], dechlorinated analogs [2425], and semi-synthetic derivatives [2426]. Similar chemical “adjustments” seeking improved biological activity are described for glycopeptides teicoplanin [2427–2432], ramoplanin [2433], and ristocetin [2427]. The biosynthesis of glycopeptides is reviewed [2434], and more recent studies are available [2435–2437]. Unfortunately, space does not allow for a detailed presentation of these developments.

Naturally Occurring Organohalogen Compounds …

385

3.24 Orthosomycins A subset of the oligosaccharide natural products—the orthosomycins—are the chlorophenol-containing everninomicins and avilamycins, and 19 are cited in the first surveys [1, 2]. An excellent review of these natural products has appeared [2438]. Avilamycins B and C from Streptomyces veridochromogenes sp. NRRL 2860 were cited in the first survey [1], but avilamycins A, A , D1 , D2 , E–N unfortunately were overlooked. These are summarized below (3220–3233) [2439]. R1

O O

R2

O

O

O HO

O

HO HO

R3

O

O O O

HO OH O O

HO R8

O O

3220 3221 3222 3223 3224 3225 3226 3227 3228 3229 3230 3231 3232 3233

O

O

O O

R1

R2

R3

OMe OMe OMe OMe OMe OH OMe OMe OMe OMe OMe OMe OMe OMe

Cl Cl Cl Cl Cl H Cl Cl Cl Cl Cl Cl Cl Cl

Cl Cl Cl Cl Cl Cl Cl H Cl Cl Cl Cl Cl Cl

R6

Me Me Me Me Me Me Me Me Me Me CH2OH Me H Me

O

R4

for R7: a =

O

O R5

R7

R4

O O

for R7: b =

R5

R6

R7

OMe OMe OMe OMe OMe OMe OMe OMe OMe OH OMe OMe OMe OMe

OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OH

a b H Ac H a COBu a b b b b b b

R8 Ac H Ac CH(OH)Me CH(OH)Me Ac Ac Ac Ac Ac Ac CHO Ac Ac

(avilamycin A) (avilamycin A') (avilamycin D1) (avilamycin D2) (avilamycin E) (avilamycin F) (avilamycin G) (avilamycin H) (avilamycin I) (avilamycin J) (avilamycin K) (avilamycin L) (avilamycin M) (avilamycin N)

3.25 Dioxins and Dibenzofurans “Dioxin!”—called by many as “The Doomsday Chemical,” the furor over this word has subsided over the past 25 years. Nevertheless, 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) and its analogs have ubiquitous anthropogenic and natural sources and remain of great concern and of intense interest. The origins and biological effects of halogenated dibenzo-p-dioxins and halogenated dibenzofurans are summarized in the previous surveys [1, 2].

386

G. W. Gribble

Some new reviews include: environmental dioxin trends [2440], dioxins in food [2441], natural dibenzofurans [2442], emissions, environmental levels, sources, formation, and analysis of polybrominated dioxins and dibenzofurans [2443], and contamination in food and dietary exposure to humans of polybrominated dioxins and dibenzofurans [2444]. Only a few new natural halogenated dibenzo-p-dioxins and dibenzofurans are known since the previous surveys. Closely related to the known slime mold metabolite AB0022A [2] are the two new chlorinated dibenzofurans, Pf-1 (3234) and Pf-2 (3235) from the slime mold Polysphondylium filamentosum. Both compounds exhibit stalk cell differentiation-inducing activity in the slime mold Dictyostelium discoideum, inhibitory activities on cell proliferation in K562, HeLa, 3T3-L1 cells, and gene expression in Drosophila melanogaster [2445]. The Papua New Guinea medicinal mushroom, Boletopsis sp., contains the novel polybrominated dibenzofurans, boletopins 13 (3236) and 14 (3237), which show weak antibiotic activity towards Staphylococcus epidermidis and Escherichia coli. The structures are confirmed by synthesis [2446].

OH RO

Cl

O HO

Br AcO

OAc Br

O

O Cl

O

Cl

HO Br

O

OH OH R

3234 R = H (Pf-1) 3235 R = Me (Pf-2)

3236 R = H (boletopsin 13) 3237 R = Br (boletopsin 14)

Several studies find polybrominated dibenzo-p-dioxins (PBDDs) and polybrominated diphenyl ethers (PBDEs) in marine biota in relatively high concentrations, which augment the earlier reported studies [1, 2]. These marine organisms include Swedish fish (di- and tri-BDDs) [2447], the Baltic Sea red alga Ceramium tenuicorne (tri-BDD, seven HO-PBDEs, four MeO-PBDEs) [2448], marine fish, mussels, and shellfish (PBDDs) at much higher levels than found in freshwater samples and much higher than levels of PCDDs [2449], the Baltic Sea sponge Ephydatia fluviatilis tri-BDDs, tetra-BDDs, penta-BDD, Br/Cl-DDs) [2450, 2451], and Baltic Sea cyanobacteria (PBDDs, HO-PBDEs, MeO-PBDEs) [2452]. The previously unidentified PBDDs that are cited in the previous studies have been identified via independent syntheses and/or comparison with known reference samples. The six major PCDDs found in perch are 3238–3243 [2453, 2454]. The two major tri-BDDs (1,3,7 and 1,3,8) [2] are thought to result from biodebromination of the sterically congested peri-bromines in 3240 and 3241. The 1,8-di-BDD (3242) and 2,7-di-BDD (3243) are also found in perch and blue mussels [2453].

Naturally Occurring Organohalogen Compounds … Br

Br

Br

Br Br

O

O Br

387

Br

Br

O

Br

O

O

3238 (1,3,7,9)

Br 3240 (1,2,4,7)

3239 (1,3,6,8)

Br Br

Br

O Br

Br Br

O

Br

Br

O

O Br

O

O

O

Br 3241 (1,2,4,8)

3242 (1,8)

3243 (2,7)

Other studies expand the presence of PBDDs and HO- and MeO-PBDEs in the marine environment to include blue mussels [2455, 2456], pilot whales (Globicephala melas) [2457], cod Gadus morhua [2458], and the marine sponge Hyrtios proteus from the Bahamas [2459]. Several seminal studies present possible formation mechanisms of PBDDs [2449, 2453, 2460–2462]. Thus, the formation of PBDDs via the photolysis of HO-PBDEs and MeO-PBDEs is demonstrated as shown in Scheme 6 in both laboratory and outdoor studies [2461]. Subsequent irradiation of 1,3,7-TriBDD provides 2,8-DBDD (3%), 1,3-DBDD ( Cl. Other indoles are also halogenated [2575]. A large family of flavin-dependent halogenases (e.g., 1-FO8, 1-F11, 2-CO1, 1-B12) was found via a family-wide activity profile [2576]. A selection of the halogenated products so obtained is shown in Scheme 9.

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G. W. Gribble OH

O

O

O

OH

O HO

HO X

HO

O

O X

O

X = Cl (84%) X= Br (80%)

X

Ph

O X

X = Cl (73%) X = Br (68%)

Y OH

X = H, Y = Cl (10%) X = Cl, Y = H (20%)

X = Cl (40%) X = Br (36%)

Scheme 8 Halogenated products from halogenase RadH [2574]

OH CO2H O O

OH HO

O

OH

OH

O

HO

HO

NH

O

Br

O N H

OH

O

Br

Br

56%

63%

57%

Scheme 9 Brominated products from halogenases [2576]

A marine flavin-dependent viral halogenase, VirX1, is found in a cyanophage and displays a strong propensity for bioiodination [2577]. A summary of the resulting iodinated products is shown (Scheme 10). The single-component flavin-dependent halogenase, AoiQ, catalyzes gemdichlorination of 1,3-diketone substrates [2578]. This enzyme is the first biochemically reconstituted flavin-dependent halogenase that can halogenate an enolizable sp3 -hybridized carbon atom [2578]. An important feature of this gem-dichlorination of a terminal 1,3-diketone is the subsequent nucleophilic cleavage (removal) of the terminal acetyl group leading to a 2-carbon chain shortening [2578]. Another synthesis application of flavin-dependent halogenases is their ability to effect enantioselective olefin halocyclization. For example, the enzyme 4 V + S, one of eight investigated, converts the carboxyalkene to bromolactone shown, one of several such transformations (Eq. 8) [2579]. I

I

N

N H

I H 2N

OH N N

HO

N

N I

95%

30%

65%

Scheme 10 Viral halogenase VirX1 iodinated products [2577]

70%

Naturally Occurring Organohalogen Compounds … HO

395

N H O

NH

Cl

Cl

N H

N H

N H Cl

MeO2C

OH

Scheme 11 RebH–variant–catalyzed chlorination reactions [2580]

O O OH O

O

(8)

4V + S NaBr 92%

Br

O 96:4 er

The large scale bromination of tryptophan at C-7 can be performed by an immobilized flavin-dependent RebH halogenase [2580]. The wild-type RebH and the variants 3-SS and 4-V have been employed for the site-selective chlorination of several indoles and carbazoles (Scheme 11). Several studies of halogenation (primarily chlorination) in both forest soil [2582] and hypersaline sediments and acidic lakes in Western Australia [2583, 2584] conclude that the emissions of, for example, chloroacetic acids, chloromethane, hypochlorite, chlorophenols, chloroform, and tribromomethane are mainly biotic.

4.5 Myeloperoxidase The mammalian enzyme myeloperoxidase has a voluminous investigative history [2], and several subsequent reviews are available that cover its importance in kidney disease [2585], the production and role of hypochlorous acid (HOCl) [2586–2588], inflammatory vascular disease [2589], high-density lipoprotein atherogenesis [2590], neurodegeneration [2588], and as a possible target for drug development [2591]. All of these reviews emphasize the role of chlorine (hypochlorite, hypochlorous acid) in these physiological events. Two related reviews summarize the reactions of HOX (X = Cl, Br, SCN), chloramine, and bromamine with biological substrates and their role in inflammatory diseases [2592], and discuss how human neutrophils kill and degrade microbes [2593]. Each of these review articles emphasizes the important function of myeloperoxidase—in concert with hydrogen peroxide and chloride—for the biological generator of hypochlorous acid/hypochlorite as a bacterial oxidant in vivo among other functions [2]. While myeloperoxidase is an important pathophysiological factor in oxidative stress, and plays an important function as a bactericidal agent through

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the generation of hypochlorous acid [2591], the latter species can also inactivate important proteins [2594–2597]. This section on myeloperoxidase concludes with reviews discussing hypochlorous acid as a double-edged “molecular sword” [2598], the role of MPO in inflammation and atherosclerosis [2599], in high-density lipoprotein damage [2600], as a target for the treatment of stroke [2601], and in cancer pathogenesis [2602].

4.6 Abiotic Processes The abiotic generation of organohalogens comprises diagenetic processes in soils and sediments, and emissions from biomass burning and volcanos [2603]. The natural abiotic formation of trihalomethanes in soil (both laboratory and field studies) is confirmed [2604], and the involvement of an iron-catalyzed oxidation/halogenation process is reviewed [2605]. A Fenton-driven oxidation of 2-chlorophenol leads to chlorinated biphenyls, diphenyl ethers, and dibenzofurans [2606]. The formation of iodinated organic compounds, such as iodoform, results when iodide-containing waters are exposed to manganese (IV) dioxide (birnessite) in the presence of natural organic matter [2607]. Irradiation of seawater containing phenol produces chloro- and bromophenols and several related condensed products [2608, 2609]. A related sunlight-promoted photochemical halogenation of dissolved organic matter in seawater affords organobromine and organoiodine compounds, which could represent an unrecognized source of, for example, bromomethane [2610]. Hydroxylated polybrominated diphenyl ethers are formed upon exposure to the naturally occurring manganese (IV) iodide (birnessite), which represents a plausible abiotic route to these HO-PBDEs [299]. This work has been extended to the production of other brominated phenolic compounds (bromophenols, bromobiphenyls, bromodiphenyl ethers) [2611]. A Fenton-like bromination of marine phytoplankton particulate matter, particularly under solar irradiation, leads to aliphatic and aromatic organobromines [2612]. The photochemical bromination of humic acid extracts affords bromophenols [2543].

4.7 Biofluorination The formation of the natural fluoroacetic acid (FA) was presented earlier [1, 2], and two developments were cited [966, 967]. The fluorinase enzyme has received extensive attention for its ability to catalyze SN 2 reactions and for biotechnological applications [2613–2617]. Fluorinase has been used for radiolabeling [18 F] synthesis [2618], and three new fluorinase enzymes are found in Streptomyces sp. MA37, Nocardia brasiliensis, and Actinoplanes sp. N902-109, by genome mining [2619]. Similarly, the first marine-derived fluorinase is found in Streptomyces xinghaiensis NRRL B24674 from a Chinese marine sediment [2620]. The biosynthesis of the

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fluorine-containing antibiotic nucleocidin is shown by isotopic labeling (2 H, 13 C) that glycerol is incorporated into the ribose ring [975]. A coupled chlorinase-fluorinase enzyme system effects enzymatic trans-halogenation and enables radiolabeling under mild, aqueous conditions [2621]. A review covering both natural and engineered production of organofluorine natural products is available [2622].

4.8 Biosynthesis The biosynthesis of naturally occurring organohalogens is of great interest. Space does not permit detailed coverage of this topic, but excellent reviews are “Halogenation Strategies in Natural Product Biosynthesis” [2623], “Genomic Basis for Natural Product Biosynthetic Diversity in the Actinomycetes” [2624], “Divergent Pathways in the Biosynthesis of Bisindole Natural Products” [2625], “New Tricks from Ancient Algae: Natural Products Biosynthesis in Marine Cyanobacteria” [2626], “The Unique Mechanistic Transformations in the Biosynthesis of Modular Natural Products from Marine Cyanobacteria” [2627], “Biosynthesis of Halogenated Alkaloids” [2628], “Biosynthetic Manipulation of Tryptophan in Bacteria: Pathways and Mechanisms” [2629], “Oxidative Cyclization in Natural Product Biosynthesis” [2630], “Unique Marine Derived Cyanobacterial Biosynthetic Genes for Chemical Diversity” [2631], and “Cryptic Halogenation Reactions in Natural Product Biosynthesis” [2632]. The structure of a S-adenosine-l-methionine (SAM)-dependent methyltransferase has been solved by X-ray crystallography. This enzyme from the plant Arabidopsis thaliana produces MeCl, MeBr, and MeI from the respective halide by nucleophilic attack (SN 2) on the methyl group of SAM [2633]. Only fluoride does not engage in this reaction (is the solvation of fluoride too strong?). Several other plants contain methyltransferases, suggesting a wide distribution of these enzymes in the plant kingdom. A methyltransferase is found in the marine diatom Phaeodactylum tricorntum, and the emission of methyl iodide is demonstrated. Some of this methyl iodide is converted to methyl chloride in seawater (SN 2 displacement) [2634]. The effect of halide ions on the biosynthesis of carbamidocyclophane is studied [1963]. A halogenase AscD from Fusarium sp. chlorinates the known (+)-daurichromenic acid to the corresponding unnatural (+)-5-chloro analog, which exceeds the antibacterial activity of the natural product [2635]. A collection of naturally biosynthesized brominated pyrroles, indoles, and diphenyl ethers is produced as disinfection byproducts, for example, during sewage treatment utilizing both chlorine and seawater [2636]. A review of iodine metabolism in several brown algae is available [2637]. The use of natural compounds in conjunction with metal oxides represents a novel approach to emulate and utilize a defense system to combat biofilm formation [2638].

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5 Biodegradation The inevitable—and necessary—fate of naturally produced organohalogens is their recycling to non-halogenated compounds and halide. This process can be accomplished enzymatically, “biodegradation.” The prior two surveys covered this topic in great detail [1, 2]. Nevertheless, many important developments are discussed here. Of enormous utility in organic synthesis is the microbial oxidation of halobenzenes to the corresponding cis-1,2-dihydrocatechols with, for example, Pseudomonas putida. Several examples of these halogenated cis-1,2-dihydrocatechols as a starting point in a synthesis were noted earlier [1, 2], and two new reviews are available [2639, 2640]. Recent syntheses employing this biooxidation of bromobenzene are described for tamiflu [2641, 2642], (–)-balanol [2643, 2644], (+)-balanol [2644], (+)-amabiline [2645], (–)-lycorine [2646], (–)-bromoxone [2647], (+)-bromoxone [2648], fagopyritol analogs [2649], selenyldeoxycyclitols [2650], (+)-galanthamine [2651], methyl d-2,3-dideoxyriboside [2652], narseronine [2653], (+)-clividine [2654], (–)- and (+)epibatidine [2655], conduritol-derivative carboxamides [1238], ribisin C (reassignment) [2656], ribisins A, B, and D [2657], narciclasine analogs [2658], vindoline analogs [2659], and (+)-narseronine [2660]. Iodobenzene is the starting point in biological syntheses of (+)-pericosine C [2661], (+)-isoepiepoformin [2662], (+)asperpentyn and ent-aspergillusol A [2663], (–)-phomentrioloxin [2664], and khusiol from p-iodotoluene [2665]. Chlorobenzene is also a suitable actor in these chemoenzymatic syntheses [2666, 2667]. The cis-1,2-dihydrocatechol from bromobenzene was employed to disprove the structure assigned to nobilisitine A [2668], and also used to prepare several trans-tetrahydrofuran cores of annonaceous acetogenins [2669]. Other halogenated aromatic substrates for microbial oxidation that have been involved in synthesis are halogenated benzoate esters [2670], m-bromobenzoic acid [2671], 3-substituted and 2,5-disubstituted phenols [2672], and β-bromoethylbenzene for syntheses of (+)- and (–)-codeine [2673], and ent-neopinone and ent-codeinone [2674]. The enormous power of this synthesis methodology is further exemplified by application of bromobenzene oxidation to the asymmetric alkylation of aldehydes and hydrogenation of alkenes via a mixed phosphine-phosphine oxide catalyst (Eq. 9) [2675]. Br

O

Br OH OH

7 steps

PPh2

(9)

Ph2P OTBDPS

Several pertinent reviews of organohalogen degradation are available: an analysis of enzymatic degradation mechanisms [2514, 2676], chlorophenols of environmental concern [2677], bioremediation of organohalogens [2678, 2679], dehalogenases [2680–2682], biodegradation of polyfluorinated compounds [2683], biodebromination mechanisms [2684], bioremediation by cyanobacteria [2685], bioremediation by the genus Dehalococcoides [2686], biodegradation of the herbicide bromoxynil

Naturally Occurring Organohalogen Compounds …

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[2687], bioremediation of organohalogens in the gut [2688], microbial dechlorination [2500], and dehalogenation in bacteria [2689]. The highly toxic fluoroacetate is defluorinated by a dehalogenase from Moraxella sp. B (Fac-DEX), which may be the only enzyme to cleave a C–F bond in aliphatic compounds [2690]. Dehaloperoxidase (DHP) from Amphitrite ornata is a hemecontaining hydrogen peroxide-dependent enzyme that oxidatively dehalogenates 2,4,6-trihalophenols to produce the corresponding quinones (halogen = I, Br, Cl, F) [2691–2693]. 4-Fluorophenol is oxidized to benzoquinone by the chloroperoxidase Caldariomyces fumago [2694], and the anthropogenic (and natural) 3,5dibromo-4-hydroxybenzoate is metabolized to 4-hydroxybenzoate by the anaerobic strain of Desulfitobacterium chlororespirans [2695]. The river sediment bacterium Thauera chlorobenzoica 3CB-1T degrades chloro-, bromo-, fluoro-, and iodobenzoates [2696], and strains of Rhodococcus opacus degrade 3-chlorobenzoate [2697]. The biodegradation of several bromophenols by the enzyme laccase from Trametes versicolor [2698], of 4-bromophenol by Ochrobacterium sp. HI1 isolated from desert soil [2699], and of 2,4,6-tribromophenol by rice plants [2700] are reported. A study of the bioremediation of the “priority pollutant” 2,4-dichlorophenol by more than 50 marine-derived fungal isolates finds that Chrysosporium sp. TM9-S2 from Theonella sp. is the most efficient [2701]. The human enzyme iodotyrosine deiodinase is critical for recycling iodide in the thyroid gland [2702], and this mechanism is the subject of a density functional theory study [2703]. A major challenge is the remediation of the ubiquitous polybrominated diphenyl ethers. A study of naturally produced hydroxylated polybrominated diphenyl ethers finds that Baltic Sea sediments have a high capacity for the biodegradation of these compounds [2704]. Similarly, anaerobic bacteria (genera Dehalococcoides, Dehalobacter, and Desulfitobacterium) from soils and sediments reductively debrominate polybrominated diphenyl ethers [2705]. For a discussion of microbial dehalogenation in marine and estuarine environments see [2706]. Several studies focus on the reductive dehalogenation of chlorobenzenes and tetrachloroethene by Dehalobacter spp. [2707–2709], of chloroanilines by Dehalococcoides mccartyi CBDB1 and Dehalobacter 14DCB1 [2710], and of chlorinated xanthones by Firmicutes spp. [2711]. The reductive cleavage of a diaryl ether bond of 2,7-dichlorodibenzo-p-dioxin is performed by the bacterium Geobacillus sp. UZO 3 to give the corresponding diphenyl ether (Eq. 10) [2712]. Cl

O O

Geobacillus sp. UZO 3 Cl

Cl

HO O

(10) Cl

Specific bioremediation strategies are found for dichloromethane via anaerobic bacteria (Dehalobacterium formicoaceticum and “Candidatus Dichloromethanomonas elyunguensis,” a new member of the Peptococcaceae family) [2713–2717]. The biodebromination of 1,2-dibromoethane via several Rhizobium strains (e.g., Bradyrhizobium japonicum) is known [2718]. Several other haloalkane dehalogenases have been discovered [2719–2722], as have

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2-haloalkanoate dehalogenases produced by marine and terrestrial organisms [2723–2728]. Interestingly, the enzyme debrominase Bmp 8 is unique in natural product biosynthesis in that it catalyzes the reductive debromination of 2,3,4,5tetrabromopyrrole in the biosynthesis of the antibiotic pentabromopseudilin (Eq. 11) [2729]. Br

Br

Br

Br

Br

Br

Bmp 8 Br

N H

Br

OH Br

N H

Br

Br N H

(11) Br

pentabromopseudilin

6 Natural Function The important question—“Why does Nature make organohalogens?”—is addressed as far as possible in the prior surveys [1, 2]. Nevertheless, for most organisms that produce halogenated natural products, we can only speculate on the function of these metabolites. An early example of a (painful) defensive secretion from a sponge is that from Tedania ignis, the “Bermuda Fire Sponge,” that a diver experienced while trying barehanded to collect this bright-red sponge from a rock. The resulting severe erythema multiforme lasted for 11 days [2730]. Interestingly, this sponge contains two brominated dibenzo-p-dioxins [1]. A well-known toxic terrestrial plant is Jacobaea vulgaris (Ragwort), which contains chlorinated pyrrolizidine alkaloids that are highly heptatotoxic to livestock [2731]. A father of marine natural products, the late Paul J. Scheuer, has reviewed early of examples of marine defensive strategies [2732]. An examination of 69 marine natural products from collections of algae, sponges, soft corals, and nudibranchs found that 56 of these compounds are active in cytotoxic, antimalarial, and/or antimicrobial assays [2733], illustrating that Nature produces secondary metabolites for specific purposes. The production of volatile organohalogens by peroxidases in marine algae may lower the high concentration of hydrogen peroxide formed in the algal cells during “oxidative stress” [2734]. The common seaweed, Lobophora variegata, is antifungal towards pathogenic and saprophytic fungi [2735]. Some species of filamentous algae (e.g., Asparagopsis armata) employ chemicals to deter herbivore grazing, for example, by the amphipod Hyale nigra [2736]. This red alga is also active against epiphytic bacteria, most likely by release of bromoform and dibromoacetic acid, which are the two major metabolites of Asparagopsis armata [2737]. The major antibacterial (antifouling) agent secreted by Asparagopsis hamifera is 1,1,3,3-tetrabromo-2-heptanone [2738, 2739]. The specific compartments for storage and release of halogenated compounds in the red alga

Naturally Occurring Organohalogen Compounds …

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Laurencia obtusa have been located [2740]. Polar macroalgal defense against herbivores and biofoulers is reviewed [2741], as is the production and role of volatile organohalogens from marine algae [2742]. The latter review discusses the important role that volatile organohalogens play in climate functioning. A review is available on the biological and environmental significance of halogens in seaweeds [2743]. Marine algae can negatively impact marine corals. The brown algal genus Lobophora is considered responsible for the bleaching of the New Caledonia scleractinian coral Acropora muricata and three others, but not the coral host to Lobophora. One of the responsible metabolites is the new lobophorenol A (3244) [2744]. An interaction between the macroalga Asparagopsis taxiformis and the coral Astroides calycularis triggers the biosynthesis of metabolites in the alga and, simultaneously, an increase in its bioactivity [2745]. Another study of Asparagopsis armata finds a strong invasive behavior of this red alga towards both the marine snail Gibbula umbilicalis whole body and the shrimp Palaemon elegans eyes and hepatopancreas, indicative of neurotoxic, inflammatory, and immunity responses [2746]. OH

Cl 3244 (lobophorenol A)

Chemical defenses in the Cladobranchia group of marine animals (e.g., nudibranchs), which lack shells and significant mobility, have been reviewed [2747]. Antarctic bryozoans employ both chemical and physical strategies for defense against predators [2748]. The invasive Brazilian bryozoan Amathia verticillata secretes two brominated indoles, including the new 1794 as a chemical defense [1400]. Several general reviews on quorum sensing and bacterial biofilms are available [2749– 2753], including specialized surveys of anti-biofilm compounds from marine sponges [2754], marine invertebrates [2755], and Red Sea organisms [84]. Extracts from the algae Cystoseira foeniculacea and the halophyte Halocnemum strobilaceum strongly inhibit the growth and adhesion of marine bacteria, and the former affects microalgae growth [2756]. A study of biogenic volatiles from coral endosymbionts identifies their role in regulating metabolic competency during thermal stress events [2757]. Antarctic sponges, particularly of the phylum Porifera, produce sea star feeding deterrents, antifouling compounds, and metabolites that mediate predation via molt inhibition [2758]. Halogenated proteins are found in the jaws of Nereis, the marine clam worm [2759], and in the bromine-rich tips of calcified crab claws [2760]. These proteins are probably mostly halogenated tyrosines. Bromination also promotes elastic behavior in short peptides derived from resilin, which is involved in the jumping and flight systems of insects [2761]. A key role of bromide/bromine in the brown alga Laminaria digitata is one of antioxidation, which is complementary to the function of iodide/iodine in detoxifying superoxide [2762]. The evolutionary significance of iodide/iodine is reviewed [2544].

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It has been known for more than 30 years that the white-rot fungus Bjerkandera sp. BOS55 and other fungi biodegrade lignin [2763, 2764], a process that plays a major role in the biogeochemical cycling of chlorine [245, 2765]. A comprehensive review of this area has appeared [2766], and the chemical defense strategies of higher fungi are discussed [2767]. For example, if the carrot truffle (Stephanospora caroticolor) is damaged, it produces the antifungal 2-chloro-4-nitrophenol from the inactive precursor stephanosporin [2].

7 Significance While the present survey is devoted to naturally occurring organohalogen compounds, it must be stressed that a number of polychlorinated anthropogenic compounds in these chemical groups—biphenyls, dibenzodioxins, dibenzofurans, benzenes, phenols, alkanes, and pesticides—are toxic and persist in the environment. For a review, see Henschler [2768]. Marine natural products display a dazzling array of biological activities. Cancerrelated activity is found in microalgae [2769], macroalgae [2770–2773], marine actinomycetes [2774], and marine fungi [2775]; antibacterial activity is found in marine bacteria [2776, 2777] and in multiple organisms [61, 2778]; antituberculosis activity is found in several marine natural products [2779]; and antiplasmodial activity is found in marine sponges [2780]. Cholinesterase activity is found in several marine organisms [2781], as is antidiabetic activity [2782]. Marine cyanobacteria produce biologically active secondary metabolites [2783], and the bioactive properties of marine phenolics are known [64]. Marine indole alkaloids represent new drug leads for depression and anxiety [2784]. Some reviews of marine natural products as potential anticancer agents are available [2785–2787], as are more general reviews of marine natural products as biomedical compounds [2788–2790] and bioactive macroalgae compounds against neglected diseases [2791]. A review of chiral alkyl halides in medicine is surveyed [2792], and the diverse biological activities of the marine sponge puupehenones are summarized [2793]. Several reviews discuss marine natural products that are either drug leads or in the “pipeline” [73, 2794–2800]. The last review emphasizes the importance of “microbial associants” present in marine organisms, particularly sponges [2800]. Other reviews detail marine natural products as potential anti-HIV agents [2801], antiplasmodial agents [2802], and antimicrobial agents [2803]. The role of drug discovery to combat neglected tropical diseases (e.g., trypanosomiasis, schistosomiasis, malaria) is documented in several reviews [2804–2806], and the red algae Asparagopsis taxiformis and Asparagopsis armata display remarkable anti-protozoal activity against Leishmania [2807]. Finally, “drug discovery from natural products” is reviewed [2808–2811]. The disinfection of drinking water by chlorination has saved millions—if not billions—of human lives since its introduction in 1900. Failure to chlorinate water intended for human use has resulted in worldwide pandemics of cholera and other water-borne diseases (typhoid, Escherichia coli 0157:H7, Campylobacter jejuni,

Naturally Occurring Organohalogen Compounds …

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chronic dysentery, cryptosporidium, and others). An exhaustive, historical review of the benefits and hypothetical risks of drinking water chlorination has appeared [2812].

8 Outlook The first survey of naturally occurring organohalogen compounds in 1996 documented 2448 examples [1]. The second survey in 2010 documented 2266 additional compounds [2]. The present survey documents 3,244 new examples, for a total of 7958 or approximately 8,000 naturally occurring organohalogen compounds. This total will almost certainly be surpassed by the time this volume is published in 2023. Several significant advances in the areas of natural products collection, isolation, identification, and synthesis have been made. Notably are the several deep-sea collections of marine organisms that are cited earlier. Moreover, deep-sea submarines can dive to 6500 m and collect totally new marine species [2813]. Hawaiian deep-sea corals (450 m) grow more slowly and are older than previously believed. A sample of the coral Gerardia sp. had an age of 2742 years [2814]. Colonies of the deep-sea coral (480–788 m) Enallopsammia rostrata have a life-span of 209–605 years [2815]. It is estimated that 17,650 marine species live between 200 and 5000 m in the ocean [2816]. A Japanese remote submersible collected a new species of a thyasirid bivalve at 7326 m, and a second collection at 10,500 m in the Mariana Trench afforded an obligate barophilic microorganism [2817]. New compound detection and isolation techniques are known. An “accelerated solvent extraction” method is found superior to the conventional solvent partitioning method in terms of yields, solvent consumption, processing time, and chemical stability for analyzing, for example, the 12 distinct natural products in five marine sponges [2818]. Ion mobility mass spectrometry can be employed to directly observe organohalogens in cyanobacteria with minimal sample preparation [2819]. A desorption electrospray ionization mass spectrometry method was devised to detect the natural products on tissue surfaces of the red alga Callophycus serratus, which produces bromophycolides A–C [2820]. Two related non-targeted gas chromatography/mass spectrometry methods were developed to screen for polyhalogenated compounds in environmental samples [2821], and to inventory contaminants in marine environments [2822, 2823]. A metrics-based prioritization of samples using exact liquid chromatography–high resolution mass spectrometry and using data for 24,618 marine natural products (PharmaSea database) accelerated the discovery of new natural products [1647]. A simple and accurate method for NMR quantitation of natural products at the nanomolar scale is described that compares integrals of 13 C-satellite peaks of deuterated solvents (CDCl3 ) [2821, 2822]. Improved methods for 13 C NMR chemical shift predictions [2825] and 13 C NMR calculations of organohalogens [2826] are reported. Ultra-high resolution band-selective HSQC is a new technique for nanomolar-scale

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detection of chlorine isotope-shift 13 C chemical shifts in a series of model compounds and natural products [2827]. Two papers reveal structural revisions of natural products as uncovered by synthesis [2828, 2829], and the potential mechanistic value of natural product artifacts is highlighted [2830]. A powerful technique for distinguishing natural from anthropogenic organohalogens is found by employing multi-isotope analyses (e.g., 13 12 C/ C; 37 Cl/35 Cl; Br81 /Br79 ), where the heavier isotopes react slower than lighter isotopes, depending on production pathways and degradation processes [2090, 2831, 2832]. Enantioselective gas chromatography to separate chiral organochlorines has been reviewed [2833], and was used to achieve enantioseparation and absolute configuration determination of the atropisomers of the natural 5,5 -dichloro-1,1 -dimethyl3,3 ,4,4 -tetrabromo-2,2 -bipyrrole [2834]. Recent years have seen new or renewed sources of novel natural products, including plant seeds [2835], animal venoms (e.g., snakes, cone snails, lizards, scorpions, spiders, frogs) [2836], and salt lakes [2837]. Marine algae have been a human food source for centuries, and there is a growing interest to use algae as enrichment ingredients in food products [2838, 2839]. Wild boar meat, which contains the chlorophenol drosophilin A [1995], comprised 40–50% of the human diet in the Mesolithic period (~10,000 years ago) [1996]. One new region of investigation for marine natural products is Indonesia, consisting of more than 10,000 islands [2840], and a renewed interest in the global diversity of sea pens (aka sea feathers); Pennatulacea) living to depths of >6000 m is published [2841]. The growing relevance of sponge-associated bacteria as the biosynthesis origins of natural products is reported for two Jaspis sponges from Indonesia. Thus, 43g-negative bacteria isolates are identified in these sponges and, in fact, the jasplakinolides and bengamides are produced by these bacteria [2842]. Cyanobacteria—the Jekyll and Hyde of marine organisms—are the cause of worldwide toxic algal blooms [2843–2845], but are an emerging source for drug discovery and genome mining [2846, 2847]. For a summary of freshwater toxic algal blooms from ~1000 to 2012, see [2845]. The cyanobacterium Leptolyngbya crossbyana in Hawai’i has overgrown and killed regions of the coral Porites compressa [2844]. Another Dr. Jekyll marine organism is the invasive sea squirt Didemnum sp., large, dense mats of which smother sponges, sedentary shellfish, sea grasses, and seafloor animals. This so-called “tunicate from hell” apparently has no natural predators and some mats in the Atlantic Ocean near Georges Bank are more than 175 km2 in size [2848]. Climate change is adversely affecting coral reefs from global warming and ocean acidification, which compromise carbonate accretion [2849], and this impact on marine ecosystems in the Mediterranean Sea has been evaluated [2868]. A question to be answered, “Will climate change influence production and environmental pathways of halogenated natural products?” [2852]. The role of halogen bonding in drug discovery has received attention in recent years [2853–2856], and the important synthesis tactic of stereoselective halogenation in natural product synthesis was cited earlier [2504]. A device for discovering new terrestrial plant alkaloids is to refactor plant pathways in genetically tractable microbes where the pathways can be easily engineered to improve the rate and yield

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of medicinal natural products, such as halogenated alkaloids in yeast [2856]. A review of the sponge microbiome for producing industrial biocatalysts has appeared [2857], and a review of metabolomics and marine biotechnology for the discovery of new compounds is available [2858]. Other relevant reviews that speak to the future of natural product discovery are “Functional genomics for plant natural product biosynthesis” [2859], “Natural products version 2.0: connecting genes to molecules” [2860], “Lessons from the past and charting the future of marine natural products drug discovery and chemical biology” [2861], “The chemical ecology of sponges on Caribbean reefs: natural products shape natural systems” [2862], and “Charting, navigating, and populating natural product chemical space for drug discovery” [2863]. A new area of study is organohalide-respiring bacteria (OHRB) that reside in pristine environments such as deep-sea sediments and Arctic tundra soil with either limited or no connections to anthropogenic activities. An important natural role of OHRB would seem to be the biodegradation of natural organohalogens in the halogen cycle [2864–2867]. The simplest natural organochlorine compound is methyl chloride (chloromethane) [1, 2]. Global emissions range from 3 to 8 million tons per year, whereas anthropogenic emissions are ca. 25,000 tons/year. It has been calculated that we inhale with each breath between 1012 and 1013 molecules of non-anthropogenic methyl chloride. Given this continuous exposure to small natural concentrations of this organochlorine, a question becomes, “Is there a role for methyl chloride in evolution?” [2868]. Acknowledgements The author is indebted to Ms. Wendy Berryman who typed the manuscript and drew all of the structures, and to Professor Heinz Falk for his enormous assistance with the preparation of this manuscript. A special thanks goes to the several scientists who provided photographs of some of the organisms cited herein, and to Dartmouth College for the use of the facilities.

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Naturally Occurring Organohalogen Compounds …

2428. 2429. 2430.

2431.

2432.

2433. 2434. 2435.

2436.

2437.

2438. 2439. 2440. 2441. 2442. 2443.

2444. 2445.

2446. 2447.

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G. W. Gribble Gordon W. Gribble is a native of San Francisco, California, and completed his undergraduate education at the University of California at Berkeley in 1963. He earned a PhD in organic chemistry at the University of Oregon in 1967. After a NIH Postdoctoral Fellowship at UCLA, he joined the faculty of Dartmouth College in 1968 where since 1980, he was Full Professor of Chemistry, before retiring in 2017. He is currently Professor of Chemistry, Emeritus, and Research Professor of Chemistry. Dr. Gribble has published 410 papers in natural product synthesis, synthesis methodology, heterocyclic chemistry, and synthetic triterpenoids, and two books, “Palladium in Heterocyclic Chemistry”, and “Indole Ring Synthesis—From Natural Products to Drug Discovery”, published in 2016. Dr. Gribble has co-edited “Progress in Heterocyclic Chemistry” since 1995. He is coinventor of “Bardoxolone Methyl” a synthetic triterpenoid now in Phase III clinical trials for the treatment of chronic kidney disease. As an award-winning home winemaker for the past 44 years, he has a strong interest in the chemistry of wine and winemaking.