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

The present volume is the third in a trilogy that documents naturally occurring organohalogen compounds, bringing the to

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Table of contents :
About This Book
Content
Naturally Occurring Organohalogen Compounds—A Comprehensive Review
1 Introduction
2 Origins
2.1 Marine Environment
2.2 Terrestrial Environment
2.3 Extraterrestrial Environment
3 Occurrence
3.1 Simple Alkanes
3.2 Other Functionalized Acyclic Organohalogens
3.3 Simple Functionalized Cyclic Organohalogens
3.4 Terpenes
3.5 Steroids
3.6 Marine Nonterpenes: C15 Acetogenins
3.7 Iridoids
3.8 Lipids, Fatty Acids, and Marine Polyacetylenes
3.9 Fluorine-Containing Natural Products
3.10 Prostaglandins
3.11 Furanones
3.12 Amino Acids and Peptides
3.13 Alkaloids
3.14 Heterocycles
3.15 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
3.22 Complex Phenols
3.23 Glycopeptides
3.24 Orthosomycins
3.25 Dioxins and Dibenzofurans
3.26 Humic Acids
4 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
5 Biodegradation
6 Natural Function
7 Significance
8 Outlook
References
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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.

v

Content

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

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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

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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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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

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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.

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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

316

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].

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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

Naturally Occurring Organohalogen Compounds …

397

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 …

399

[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 …

401

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.

References 1. Gribble GW (1996) Naturally occurring organohalogen compounds—a comprehensive survey. Prog Chem Org Nat Prod 68:1 2. Gribble GW (2010) Naturally occurring organohalogen compounds—a comprehensive update. Prog Chem Org Nat Prod 91:1 3. Gribble GW (2021) Recent discoveries of naturally occurring halogenated nitrogen heterocycles. Prog Heterocycl Chem 33:1 4. Gribble GW (2018) Newly discovered naturally occurring organohalogens. Arkivoc i:372 5. Gribble GW (2015) Biological activity of recently discovered halogenated marine natural products. Mar Drugs 13:4044 6. Gribble GW (2015) A recent survey of naturally occurring organohalogen compounds. Environ Chem 12:396 7. Gribble GW (2012) Occurrence of halogenated alkaloids. The Alkaloids 71:1 8. Gribble GW (2011) Recently discovered naturally occurring heterocyclic organohalogen compounds. Heterocycles 84:157

406

G. W. Gribble

9. Carroll AR, Copp BR, Davis RA, Keyzers RA, Prinsep MR (2021) Marine natural products. Nat Prod Rep 38:362 10. Carroll AR, Copp BR, Davis RA, Keyzers RA, Prinsep MR (2020) Marine natural products. Nat Prod Rep 37:175 11. Carroll AR, Copp BR, Davis RA, Keyzers RA, Prinsep MR (2019) Marine natural products. Nat Prod Rep 36:122 12. Blunt JW, Carroll AR, Copp BR, Davis RA, Keyzers RA, Prinsep MR (2018) Marine natural products. Nat Prod Rep 35:8 13. Blunt JW, Copp BR, Keyzers RA, Munro MHG, Prinsep MR (2017) Marine natural products. Nat Prod Rep 34:235 14. Blunt JW, Copp BR, Keyzers RA, Munro MHG, Prinsep MR (2016) Marine natural products. Nat Prod Rep 33:382 15. Blunt JW, Copp BR, Keyzers RA, Munro MHG, Prinsep MR (2015) Marine natural products. Nat Prod Rep 32:116 16. Blunt JW, Copp BR, Keyzers RA, Munro MHG, Prinsep MR (2014) Marine natural products. Nat Prod Rep 31:160 17. Blunt JW, Copp BR, Keyzers RA, Munro MHG, Prinsep MR (2013) Marine natural products. Nat Prod Rep 30:237 18. Blunt JW, Copp BR, Keyzers RA, Munro MHG, Prinsep MR (2012) Marine natural products. Nat Prod Rep 29:144 19. Blunt JW, Copp BR, Munro MHG, Northcote PT, Prinsep MR (2011) Marine natural products. Nat Prod Rep 28:196 20. Blunt JW, Copp BR, Munro MHG, Northcote PT, Prinsep MR (2010) Marine natural products. Nat Prod Rep 27:165 21. Blunt JW, Copp BR, Hu W-P, Munro MHG, Northcote PT, Prinsep MR (2009) Marine natural products. Nat Prod Rep 26:170 22. Blunt JW, Copp BR, Hu W-P, Munro MHG, Northcote PT, Prinsep MR (2008) Marine natural products. Nat Prod Rep 25:35 23. Vetter W (2012) Polyhalogenated alkaloids in environmental and food samples. The Alkaloids 7:211 24. Pauletti PM, Cintra LS, Braguine CG, da Silva Filho AA, Andrade e Silva ML, Cunha WR, Januário AH (2010) Halogenated indole alkaloids from marine invertebrates. Mar Drugs 8:1526 25. Wang L, Zhou X, Fredimoses M, Liao S, Liu Y (2014) Naturally occurring organoiodines. RSC Adv 4:57350 26. Kundeti LSR, Ambati S, Srividya GS, Yadav JS, Kommu N (2019) A review on chloro substituted marine natural product, chemical examination and biological activity. Curr Trends Biotechnol Pharm 13:83 27. El-Demerdash A, Tammam MA, Atanasov AG, Hooper JNA, Al-Mourabit A, Kijjoa A (2018) Chemistry and biological activities of the marine sponges of the genera Mycale (Arenochalina), Biemna and Clathria. Mar Drugs 16:214 28. Shady NH, Fouad MA, Kamel MS, Schirmeister T, Abdelmohsen UR (2019) Natural product repertoire of the genus Amphimedon. Mar Drugs 17:19 29. Winder PL, Pomponi SA, Wright AE (2011) Natural products from the Lithistida: a review of the literature since 2000. Mar Drugs 9:2643 30. Dembitsky VM (2002) Bromo- and iodo-containing alkaloids from marine microorganisms and sponges. Russ J Bioorg Chem 28:170 31. Noro JC, Kalaitzis JA, Neilan BA (2012) Bioactive natural products from Papua New Guinea marine sponges. Chem Biodivers 9:2077 32. Van Soest RWM, Boury-Esnault N, Vacelet J, Dohrmann M, Erpenbeck D, De Voogd NJ, Santodomingo N, Vanhoorne B, Kelly M, Hooper JNA (2012) Global diversity of sponges (Porifera). PLoS One 7:e35105 33. Zhang H, Dong M, Chen J, Wang H, Tenney K, Crews P (2017) Bioactive secondary metabolites from the marine sponge genus Agelas. Mar Drugs 15:351

Naturally Occurring Organohalogen Compounds …

407

34. Lira NS, Montes RC, Tavares JF, da Silva MS, da Cunha EVL, de Athayde-Filho PF, Rodrigues LC, da Silva DC, Barbosa-Filho JM (2011) Brominated compounds from marine sponges of the genus Aplysina and a compilation of their 13 C NMR spectral data. Mar Drugs 9:2316 35. Proksch P, Putz A, Ortlepp S, Kjer J, Bayer M (2010) Bioactive natural products from marine sponges and fungal endophytes. Phytochem Rev 9:475 36. El-Demerdash A, Atanasov AG, Horbanczuk OK, Tammam MA, Abdel-Mogib M, Hooper JNA, Sekeroglu N, Al-Mourabit A, Kijjoa A (2019) Chemical diversity and biological activities of marine sponges of the genus Suberea: a systematic review. Mar Drugs 17:115 37. Sagar S, Kaur M, Minneman KP (2010) Antiviral lead compounds from marine sponges. Mar Drugs 8:2619 38. Ercolano G, De Cicco P, Ianaro A (2019) New drugs from the sea: pro-apoptotic activity of sponges and algae derived compounds. Mar Drugs 17:31 39. García-Ruiz C, Sarabia F (2014) Chemistry and biology of bengamides and bengazoles, bioactive natural products from Jaspis sponges. Mar Drugs 12:1580 40. Roué M, Quévrain E, Domart-Coulon I, Bourguet-Kondracki M-L (2012) Assessing calcareous sponges and their associated bacteria for the discovery of new bioactive natural products. Nat Prod Rep 29:739 41. Hentschel U, Piel J, Degnan SM, Taylor MW (2012) Genomic insights into the marine sponge microbiome. Microbiology 10:641 42. Protopapa M, Kotsiri M, Mouratidis S, Roussis V, Ioannou E, Dedos SG (2019) Evaluation of antifouling potential and ecotoxicity of secondary metabolites derived from red algae of the genus Laurencia. Mar Drugs 17:646 43. La Barre S, Potin P, Leblanc C, Delage L (2010) The halogenated metabolism of brown algae (Phaeophyta), its biological importance and its environmental significance. Mar Drugs 8:988 44. Cabrita MT, Vale C, Rauter AP (2010) Halogenated compounds from marine algae. Mar Drugs 8:2301 45. Wang B-G, Gloer JB, Ji N-Y, Zhao J-C (2013) Halogenated organic molecules of Rhodomelaceae origin: chemistry and biology. Chem Rev 113:3632 46. Osako K, Teixeira VL (2013) Natural products from marine algae of the genus Osmundaria (Rhodophyceae, Ceramiales). Nat Prod Commun 8:533 47. Harizani M, Ioannou E, Roussis V (2016) The Laurencia paradox: an endless source of chemodiversity. In: Kinghorn AD, Falk H, Gibbons S, Kobayashi J (eds) Progress in the chemistry of organic natural products, vol 102. Springer International Publishing Switzerland, p 91 48. Shukla V, Joshi GP, Rawat MSM (2010) Lichens as a potential natural source of bioactive compounds: a review. Phytochem Rev 9:303 49. Rateb ME, Ebel R (2011) Secondary metabolites of fungi from marine habitats. Nat Prod Rep 28:290 50. Saleem M, Ali MS, Hussain S, Jabbar A, Ashraf M, Lee YS (2007) Marine natural products of fungal origin. Nat Prod Rep 24:1142 51. Xu K, Yuan X-L, Li C, Li X-D (2020) Recent discovery of heterocyclic alkaloids from marine-derived Aspergillus species. Mar Drugs 18:54 52. Wang C, Lu H, Lan J, Zaman KHAU, Cao S (2021) A review: halogenated compounds from marine fungi. Molecules 26:458 53. Deshmukh SK, Gupta MK, Prakash V, Reddy MS (2018) Mangrove-associated fungi: A novel source of potential anticancer compounds. J Fungi 4:101 54. Taylor MW, Radax R, Steger D, Wagner M (2007) Sponge-associated microorganisms: evolution, ecology, and biotechnological potential. Microbiol Mol Biol Rev 71:295 55. Piel J (2009) Metabolites from symbiotic bacteria. Nat Prod Rep 26:338 56. Xiong Z-Q, Wang J-F, Hao Y-Y, Wang Y (2013) Recent advances in the discovery and development of marine microbial natural products. Mar Drugs 11:700 57. Dávila-Céspedes A, Hufendiek P, Crüsemann M, Schäberle TF, König GM (2016) Marinederived myxobacteria of the suborder Nannocystineae: an underexplored source of structurally intriguing and biologically active metabolites. Beilstein J Org Chem 12:969

408

G. W. Gribble

58. Albataineh H, Stevens DC (2018) Marine myxobacteria: a few good halophiles. Mar Drugs 16:209 59. Gross H, Loper JE (2009) Genomics of secondary metabolite production by Pseudomonas spp. Nat Prod Rep 26:1408 60. Jensen PR, Moore BS, Fenical W (2015) The marine actinomycete genus Salinispora: a model organism for secondary metabolite discovery. Nat Prod Rep 32:738 61. Rahman H, Austin B, Mitchell WJ, Morris PC, Jamieson DJ, Adams DR, Spragg AM, Schweizer M (2010) Novel anti-infective compounds from marine bacteria. Mar Drugs 8:498 62. Genilloud O (2018) Mining actinomycetes for novel antibiotics in the omics era: are we ready to exploit this new paradigm? Antibiotics 7:85 63. Kasanah N, Triyanto T (2019) Bioactivities of halometabolites from marine actinobacteria. Biomolecules 9:225 64. Nunnery JK, Mevers E, Gerwick WH (2010) Biologically active secondary metabolites from marine cyanobacteria. Curr Opin Biotechnol 21:787 65. Corbel S, Mougin C, Bouaïcha N (2014) Cyanobacterial toxins: modes of actions, fate in aquatic and soil eosystems, phytotoxicity and bioaccumulation in agricultural crops. Chemosphere 96:1 66. Shah SAA, Akhter N, Auckloo BN, Khan I, Lu Y, Wang K, Wu B, Guo Y-W (2017) Structural diversity, biological properties and applications of natural products from cyanobacteria. A review. Mar Drugs 15:354 67. Leão PN, Engene N, Antunes A, Gerwick WH, Vasconcelos V (2012) The chemical ecology of cyanobacteria. Nat Prod Rep 29:372 68. Paerl HW, Huisman J (2009) Climate change: a catalyst for global expansion of harmful cyanobacterial blooms. Environ Microbiol Rep 1:27 69. Mondal A, Bose S, Banerjee S, Patra JK, Malik J, Mandal SK, Kilpatrick KL, Das G, Kerry RG, Fimognari C, Bishayee A (2020) Marine cyanobacteria and microalgae metabolites—a rich source of potential anticancer drugs. Mar Drugs 18:476 70. Engene N, Choi H, Esquenazi E, Rottacker EC, Ellisman MH, Dorrestein PC, Gerwick WH (2011) Underestimated biodiversity as a major explanation for the perceived rich secondary metabolite capacity of the cyanobacterial genus Lyngbya. Environ Microbiol 13:1601 71. Salvador-Reyes LA, Luesch H (2015) Biological targets and mechanisms of action of natural products from marine cyanobacteria. Nat Prod Rep 32:478 72. Shenkar N, Swalla BJ (2011) Global diversity of Ascidiacea. PLoS One 6:e20657 73. Palanisamy SK, Rajendran NM, Marino A (2017) Natural products diversity of marine ascidians (tunicates; Ascidiacea) and successful drugs in clinical development. Nat Prod Bioprospect 7:1 74. Feng Y, Khokhar S, Davis RA (2017) Crinoids: ancient organisms, modern chemistry. Nat Prod Rep 34:571 75. Pereira RB, Andrade PB, Valentão P (2016) Chemical diversity and biological properties of secondary metabolites from sea hares of Aplysia genus. Mar Drugs 14:39 76. Asakawa Y, Ludwiczuk A, Nagashima F, Toyota M, Hashimoto T, Tori M, Fukuyama Y, Harinantenaina L (2009) Bryophytes: bio- and chemical diversity, bioactivity and chemosystematics. Heterocycles 77:99 77. Asakawa Y, Ludwiczuk A, Nagashima F (2013) Phytochemical and biological studies of bryophytes. Phytochemistry 91:52 78. Asakawa Y, Ludwiczuk A (2018) Chemical constituents of bryophytes: structures and biological activity. J Nat Prod 81:641 79. Dean LJ, Prinsep MR (2017) The chemistry and chemical ecology of nudibranchs. Nat Prod Rep 34:1359 80. Turner AH, Craik DJ, Kaas Q, Schroeder CI (2018) Bioactive compounds isolated from neglected predatory marine gastropods. Mar Drugs 16:118 81. Wu Y-C, Su J-H, Chou T-T, Cheng Y-P, Weng C-F, Lee C-H, Fang L-S, Wang W-H, Li J-J, Lu M-C, Kuo J, Sheu J-H, Sung P-J (2011) Natural product chemistry of gorgonian corals of genus Junceella—Part II. Mar Drugs 9:2773

Naturally Occurring Organohalogen Compounds …

409

82. Qian P-Y, Xu Y, Fusetani N (2010) Natural products as antifouling compounds: recent progress and future perspectives. Biofouling 26:223 83. Fusetani N (2011) Antifouling marine natural products. Nat Prod Rep 28:400 84. Qi S-H, Ma X (2017) Antifouling compounds from marine invertebrates. Mar Drugs 15:263 85. Worthington RJ, Richards JJ, Melander C (2012) Small molecule control of bacterial biofilms. Org Biomol Chem 10:7457 86. Armstrong E, Boyd KG, Burgess JG (2000) Prevention of marine biofouling using natural compounds from marine organisms. Biotechnol Ann Rev 6:221 87. Skropeta D (2008) Deep-sea natural products. Nat Prod Rep 25:1131 88. Skropeta D, Wei L (2014) Recent advances in deep-sea natural products. Nat Prod Rep 31:999 89. Lebar MD, Heimbegner JL, Baker BJ (2007) Cold-water marine natural products. Nat Prod Rep 24:774 90. Soldatou S, Baker BJ (2017) Cold-water marine natural products, 2006 to 2016. Nat Prod Rep 34:585 91. Puglisi MP, Sneed JM, Sharp KH, Ritson-Williams R, Paul VJ (2014) Marine chemical ecology in benthic environments. Nat Prod Rep 31:1510 92. Schwarzbauer J (2020) Organic matter in the hydrosphere. In: Wilkes H (ed) Hydrocarbons, oils and lipids: diversity, origin, chemistry and fate, handbook of hydrocarbon and lipid microbiology. Springer Nature Switzerland AG, p 823 93. Wu J, Xiao Q, Xu J, Li M-Y, Pan J-Y, Yang M (2008) Natural products from true mangrove flora: source, chemistry and bioactivities. Nat Prod Rep 25:955 94. Solntsev KM, Schramm S, Kremb S, Gunsalus KC, Amin SA (2019) Isolation of biologically active compounds from mangrove sediments. Anal Bioanal Chem 411:6521 95. Li K, Chen S, Pang X, Cai J, Zhang X, Liu Y, Zhu Y, Zhou X (2022) Natural products from mangrove sediments-derived microbes: structural diversity, bioactivities, biosynthesis, and total synthesis. Eur J Med Chem 230:114117 96. El-Hossary EM, Abdel-Halim M, Ibrahim ES, Pimentel-Elardo SM, Nodwell JR, Handoussa H, Abdelwahab MF, Holzgrabe U, Abdelmohsen UR (2020) Natural products repertoire of the Red Sea. Mar Drugs 18:457 97. Kobayashi J (2009) Chemistry and biology of Okinawan marine natural products. Pure Appl Chem 81:1009 98. Morris JC, Phillips AJ (2011) Marine natural products: synthetic aspects. Nat Prod Rep 28:269 99. Le Bideau F, Kousara M, Chen L, Wei L, Dumas F (2017) Tricyclic sesquiterpenes from marine origin. Chem Rev 117:6110 100. Berlinck RGS, Burtoloso ACB, Trindade-Silva AE, Romminger S, Morais RP, Bandeira K, Mizuno CM (2010) The chemistry and biology of organic guanidine derivatives. Nat Prod Rep 27:1871 101. Berlinck RGS, Burtoloso ACB, Kossuga MH (2008) The chemistry and biology of organic guanidine derivatives. Nat Prod Rep 25:919 102. Emsermann J, Kauhl U, Opatz T (2016) Marine isonitriles and their related compounds. Mar Drugs 14:16 103. Hille-Rehfeld A (2014) Halogenierte naturstoffe. Chem Unserer Zeit 48:402 104. Crawford JM, Clardy J (2011) Bacterial symbionts and natural products. Chem Commun 47:7559 105. Goldberg ED (1963) The oceans as a chemical system. In: Hill MN (ed) The sea, vol 2. Wiley-Interscience, New York, p 3 106. Hylin JW, Spenger RE, Gunther FA (1969) Potential interferences in certain pesticide residue analyses from organochlorine compounds occurring naturally in plants. Residue Rev 26:127 107. Harper DB, O’Hagan D (1994) The fluorinated natural products. Nat Prod Rep 11:123 108. Stijve T (1984) Inorganic bromide in higher fungi. Z Naturforsch 39C:863 109. Isidorov VA (1990) Organic chemistry of the earth’s atmosphere. Springer, Berlin, Heidelberg, p 72

410

G. W. Gribble

110. Harper DB (1985) Halomethane from halide ion—a highly efficient fungal conversion of environmental significance. Nature 315:55 111. Read KA, Mahajan AS, Carpenter LJ, Faria BE, Heard DE, Hopkins JR, Lee JD, Moller SJ, Lewis AC, Mendes L, McQuaid JB, Oetjen H, Saiz-Lopez A, Pilling MJ, Plane JMC (2008) Extensive halogen-mediated ozone destruction over the tropical Atlantic Ocean. Nature 453:1232 112. Simpson WR, Brown SS, Saiz-Lopez A, Thornton JA, von Glasow R (2015) Tropospheric halogen chemistry: sources, cycling and impacts. Chem Rev 115:4035 113. Carpenter LJ, Nightingale PD (2015) Chemistry and release of gases from the surface ocean. Chem Rev 115:4015 114. Burkholder JB, Cox RA, Ravishankara AR (2015) Atmospheric degradation of ozone depleting substances, their substitutes, and related species. Chem Rev 115:3704 115. Singh HB, Kasting JF (1988) Chlorine-hydrocarbon photochemistry in the marine troposphere and lower stratosphere. J Atmos Chem 7:261 116. Pszenny AAP, Keene WC, Jacob DJ, Fan S, Maben JR, Zetwo MP, Springer-Young M, Galloway JN (1993) Evidence of inorganic chlorine gases other than hydrogen chloride in marine surface air. Geophys Res Lett 20:699 117. Erickson DJ III, Seuzaret C, Keene WC, Gong SL (1999) A general circulation model based calculation of HCl and ClNO2 production from sea salt dechlorination: reactive chlorine emissions inventory. J Geophys Res 104:8347 118. Osthoff HD, Roberts JM, Ravishankara AR, Williams EJ, Lerner BM, Sommariva R, Bates TS, Coffman D, Quinn PK, Dibb JE, Stark H, Burkholder JB, Talukdar RK, Meagher J, Fehsenfeld FC, Brown SS (2008) High levels of nitryl chloride in the polluted subtropical marine boundary layer. Nature Geosci 1:324 119. Thornton JA, Kercher JP, Riedel TP, Wagner NL, Cozic J, Holloway JS, Dubé WP, Wolfe GM, Quinn PK, Middlebrook AM, Alexander B, Brown SS (2010) A large atomic chlorine source inferred from mid-continental reactive nitrogen chemistry. Nature 464:271 120. Finlayson-Pitts BJ (1983) Reaction of NO2 with NaCl and atmospheric implications of NOCl formation. Nature 306:676 121. Keene WC, Stutz J, Pszenny AAP, Maben JR, Fischer EV, Smith AM, von Glasow R, Pechtl S, Sive BC, Varner RK (2007) Inorganic chlorine and bromine in coastal New England air during summer. J Geophys Res 112:D10S12 122. Kamilli KA, Ofner J, Krause T, Sattler T, Schmitt-Kopplin P, Eitenberger E, Friedbacher G, Lendl B, Lohninger H, Schöler HF, Held A (2016) How salt lakes affect atmospheric new particle formation: a case study in Western Australia. Sci Total Environ 573:985 123. Knipping EM, Dabdub D (2003) Impact of chlorine emissions from sea-salt aerosol on coastal urban ozone. Environ Sci Technol 37:275 124. Stutz J, Ackermann R, Fast JD, Barrie L (2002) Atmospheric reactive chlorine and bromine at the Great Salt Lake, Utah. Geophys Res Lett 29:18–21 125. Holla R, Schmitt S, Frieβ U, Pöhler D, Zingler J, Corsmeier U, Platt U (2015) Vertical distribution of BrO in the boundary layer at the Dead Sea. Environ Chem 12:438 126. Keil AD, Shepson PB (2006) Chlorine and bromine atom ratios in the springtime Arctic troposphere as determined from measurements of halogenated volatile organic compounds. J Geophys Res 111:D17303 127. McConnell JC, Henderson GS, Barrie L, Bottenheim J, Niki H, Langford CH, Templeton EMJ (1992) Photochemical bromine production implicated in Arctic boundary-layer ozone depletion. Nature 355:150 128. Pratt KA, Custard KD, Shepson PB, Douglas TA, Pöhler D, General S, Zielcke J, Simpson WR, Platt U, Tanner DJ, Huey LG, Carlsen M, Stirm BH (2013) Photochemical production of molecular bromine in Arctic surface snowpacks. Nature Geosci 6:351 129. Wittmer J, Bleicher S, Ofner J, Zetzsch C (2015) Iron(III)-induced activation of chloride from artificial sea-salt aerosol. Environ Chem 12:461 130. Buxmann J, Bleicher S, Platt U, von Glasow R, Sommariva R, Held A, Zetzsch C, Ofner J (2015) Consumption of reactive halogen species from sea-salt aerosol by secondary organic aerosol: slowing down the bromine explosion. Environ Chem 12:476

Naturally Occurring Organohalogen Compounds …

411

131. Putschew A, Mania M, Jekel M (2003) Occurrence and source of brominated organic compounds in surface waters. Chemosphere 52:399 132. Moreno F, Moreno J, Fatela F, Guise L, Vieira C, Leira M (2020) Bromine biogeodynamics in the NE Atlantic: a perspective from natural wetlands of western Portugal. Sci Total Environ 722:137649 133. De Laurentiis E, Minella M, Maurino V, Minero C, Mailhot G, Sarakha M, Brigante M, Vione D (2012) Assessing the occurrence of the dibromide radical (Br2–• ) in natural waters: measures of triplet-sensitised formation, reactivity, and modelling. Sci Total Environ 439:299 134. Solomon S, Garcia RR, Ravishankara AR (1994) On the role of iodine in ozone depletion. J Geophys Res 99(20):491 135. Zingler J, Platt U (2005) Iodine oxide in the Dead Sea Valley: evidence for inorganic sources of boundary layer IO. J Geophys Res 110:D07307 136. Küpper FC, Carpenter LJ, McFiggans GB, Palmer CJ, Waite TJ, Boneberg E-M, Woitsch S, Weiller M, Abela R, Grolimund D, Potin P, Butler A, Luther GW III, Kroneck PMH, Meyer-Klaucke W, Feiters MC (2008) Iodide accumulation provides kelp with an inorganic antioxidant impacting atmospheric chemistry. Proc Natl Acad Soc USA 105:6954 137. Alicke B, Hebestreit K, Stutz J, Platt U (1999) Iodine oxide in the marine boundary layer. Nature 397:572 138. O’Dowd CD, Jimenez JL, Bahreini R, Flagan RC, Seinfeld JH, Hameri K, Pirjola L, Kulmala M, Jennings SG, Hoffmann T (2002) Marine aerosol formation from biogenic iodine emissions. Nature 417:632 139. Fuge R (2019) Fluorine in the environment, a review of its sources and geochemistry. Appl Geochem 100:393 140. auf der Günne JS, Mangstl M, Kraus F (2012) Occurrence of difluorine F2 in nature—in situ proof and quantification by NMR spectroscopy. Angew Chem Int Ed 51:7847 141. Sekimoto S, Ebihara M (2013) Accurate determination of chlorine, bromine, and iodine in sedimentary rock reference samples by radiochemical neutron activation analysis and a detailed comparison with inductively coupled plasma mass spectrometry literature data. Anal Chem 85:6336 142. Sharp ZD, Draper DS (2013) The chlorine abundance of Earth: implications for a habitable planet. Earth Planet Sci Lett 369–370:71 143. Leri AC, Mayer LM, Thornton KR, Northrup PA, Dunigan MR, Ness KJ, Gellis AB (2015) A marine sink for chlorine in natural organic matter. Nat Geosci 8:620 144. Song Y, Müller G (1993) Freshwater sediments: sinks and sources of bromine. Naturwissenschaften 80:558 145. Leri AC, Hakala JA, Marcus MA, Lanzirotti A, Reddy CM, Myneni SCB (2010) Natural organobromine in marine sediments: new evidence of biogeochemical Br cycling. Global Biogeochem Cycl 24:GB4017 146. Leri AC, Myneni SCB (2012) Natural organobromine in terrestrial ecosystems. Geochim Cosmochim Acta 77:1 147. Leri AC, Ravel B (2015) Abiotic bromination of soil organic matter. Environ Sci Technol 49:13350 148. Zlamal JE, Raab TK, Little M, Edwards RA, Lipson DA (2017) Biological chlorine cycling in the Arctic Coastal Plain. Biogeochemistry 134:243 149. Johansson E, Sandén P, Öberg G (2003) Spatial patterns of organic chlorine and chloride in Swedish forest soil. Chemosphere 52:391 150. Johansson E, Sandén P, Öberg G (2003) Organic chlorine in deciduous and coniferous forest soils in southern Sweden. Soil Sci 168:347 151. Öberg G, Holm M, Sandén P, Svensson T, Parikka M (2005) The role of organic-matterbound chlorine in the chlorine cycle: a case study of the Stubbetorp catchment, Sweden. Biogeochemistry 75:241 152. Rohlenová J, Gryndler M, Forczek ST, Fuksová K, Handová V, Matucha M (2009) Microbial chlorination of organic matter in forest soil: investigation using 36 Cl-chloride and its methodology. Environ Sci Technol 43:3652

412

G. W. Gribble

153. Matucha M, Clarke N, Lachmanová Z, Forczek ST, Fuksová K, Gryndler M (2010) Biogeochemical cycles of chlorine in the coniferous forest ecosystem: practical implications. Plant Soil Environ 56:357 154. Leri AC, Myneni SCB (2010) Organochlorine turnover in forest ecosystems: the missing link in the terrestrial chlorine cycle. Global Biogeochem Cycl 24:GB4021 155. Gustavsson M, Karlsson S, Öberg G, Sandén P, Svensson T, Valinia S, Thiry Y, Bastviken D (2012) Organic matter chlorination rates in different boreal soils: the role of soil organic matter content. Environ Sci Technol 46:1504 156. Redon P-O, Abdelouas A, Bastviken D, Cecchini S, Nicolas M, Thiry Y (2011) Chloride and organic chlorine in forest soils: storage, residence times, and influence of ecological conditions. Environ Sci Technol 45:7202 157. Montelius M, Thiry Y, Marang L, Ranger J, Cornelis J-T, Svensson T, Bastviken D (2015) Experimental evidence of large changes in terrestrial chlorine cycling following altered tree species composition. Environ Sci Technol 49:4921 158. Montelius M, Svensson T, Lourino-Cabana B, Thiry Y, Bastviken D (2016) Chlorination and dechlorination rates in a forest soil—a combined modeling and experimental approach. Sci Total Environ 554–555:203 159. Montelius M, Svensson T, Lourino-Cabana B, Thiry Y, Bastviken D (2019) Radiotracer evidence that the rhizosphere is a hot-spot for chlorination of soil organic matter. Plant Soil 443:245 160. Svensson T, Kylin H, Montelius M, Sandén P, Bastviken D (2021) Chlorine cycling and the fate of Cl in terrestrial environments. Environ Sci Pollut Res 28:7691 161. Biester H, Selimovi´c D, Hemmerich S, Petri M (2005) Halogens in porewater of peat bogs— the role of peat decomposition and dissolved organic matter. Biogeosci Disc 2:1457 162. Biester H, Selimovi´c D, Hemmerich S, Petri M (2006) Halogens in pore water of peat bogs—the role of peat decomposition and dissolved organic matter. Biogeosciences 3:53 163. Cadle RD (1975) Volcanic emissions of halides and sulfur compounds to the troposphere and stratosphere. J Geophys Res 80:1650 164. Aiuppa A, Baker DR, Webster JD (2009) Halogens in volcanic systems. Chem Geol 263:1 165. Graeber EJ, Modreski PJ, Gerlach TM (1979) Compositions of gases collected during the 1977 East Rift Eruption, Kilauea, Hawaii. J Volcanol Geotherm Res 5:337 166. Zelenski M, Taran Y (2012) Volcanic emissions of molecular chlorine. Geochim Cosmochim Acta 87:210 167. Bani P, Boudon G, Balcone-Boissard H, Delmelle P, Quiniou T, Lefevre J, Bule EG, Hiroshi S, Lardy M (2016) The 2009–2010 eruption of Gaua volcano (Vanuatu archipelago): eruptive dynamics and unsuspected strong halogens source. J Volcan Geotherm Res 322:63 168. Anazawa K, Wood CP, Browne PRL (2011) Fluorine and chlorine behavior in chlorine-rich volcanic rocks from White Island, New Zealand. J Fluorine Chem 132:1182 169. Kutterolf S, Hansteen TH, Appel K, Freundt A, Krüger K, Pérez W, Wehrmann H (2013) Combined bromine and chlorine release from large explosive volcanic eruptions: a threat to stratospheric ozone? Geology 41:707 170. Kutterolf S, Hansteen TH, Freundt A, Wehrmann H, Appel K, Krüger K, Pérez W (2015) Bromine and chlorine emissions from Plinian eruptions along the Central American Volcanic Arc: from source to atmosphere. Earth Planet Sci Lett 429:234 171. Gutmann A, Bobrowski N, Liotta M, Hoffmann T (2021) Bromine speciation in volcanic plumes: new in situ derivatization LC-MS method for the determination of gaseous hydrogen bromide by gas diffusion denuder samping. Atmos Meas Tech 14:6395 172. Snyder GT, Fehn U (2002) Origin of iodine in volcanic fluids: 129 I results from the Central American volcanic arc. Geochim Cosmochim Acta 66:3827 173. Takeda A, Nakao A, Yamasaki S, Tsuchiya N (2018) Distribution and speciation of bromine and iodine in volcanic ash soil profiles. Soil Sci Soc Am J 82:815 174. Teiber H, Marks MAW, Wenzel T, Siebel W, Altherr R, Markl G (2014) The distribution of halogens (F, Cl, Br) in granitoid rocks. Chem Geol 374:92

Naturally Occurring Organohalogen Compounds …

413

175. Aiuppa A, Federico C, Franco A, Giudice G, Gurrieri S, Inguaggiato S, Liuzzo M, McGonigle AJS, Valenza M (2005) Emission of bromine and iodine from Mount Etna volcano. Geochem Geophys Geosyst 6. https://doi.org/10.1029/2005GC000965 176. General S, Bobrowski N, Pöhler D, Weber K, Fischer C, Platt U (2015) Airborne I-DOAS measurements at Mt. Etna: BrO and OClO evolution in the plume. J Volcanol Geoth Res 300:175 177. Bobrowski N, Hönninger G, Galle B, Platt U (2003) Detection of bromine monoxide in a volcanic plume. Nature 423:273 178. Kern C, Lyons JJ (2018) Spatial distribution of halogen oxides in the plume of Mount Pagan volcano, Mariana Islands. Geophys Res Lett 45:9588 179. Self S, Blake S, Sharma K, Widdowson M, Sephton S (2008) Sulfur and chlorine in Late Cretaceous deccan magmas and eruptive gas release. Science 319:1654 180. Kendrick MA, Danyushevsky LV, Falloon TJ, Woodhead JD, Arculus RJ, Ireland T (2020) SW Pacific arc and backarc lavas and the role of slab-bend serpentinites in the global halogen cycle. Earth Planet Sci Lett 530:115921 181. Connes P, Connes J, Benedict WS, Kaplan LD (1967) Traces of HCl and HF in the atmosphere of Venus. Astrophys J 147:1230 182. Krasnopolsky VA (2010) Spatially-resolved high-resolution spectroscopy of Venus 1. Variations of CO2 , CO, HF, and HCl at the cloud tops. Icarus 208:539 183. Sandor BJ, Clancy RT (2017) Diurnal observations of HCl altitude variation in the 70–100 km mesosphere of Venus. Icarus 290:156 184. Sandor BJ, Clancy RT (2018) First measurements of ClO in the Venus atmosphere—altitude dependence and temporal variation. Icarus 313:15 185. Krasnopolsky VA, Belyaev DA (2017) Search for HBr and bromine photochemistry on Venus. Icarus 293:114 186. Boyce JW, Kanee SA, McCubbin FM, Barnes JJ, Bricker H, Treiman AH (2018) Early loss, fractionation, and redistribution of chlorine in the Moon as revealed by the low-Ti lunar mare basalt suite. Earth Planet Sci Lett 500:205 187. Stephant A, Anand M, Zhao X, Chan QHS, Bonifacie M, Franchi IA (2019) The chlorine isotopic composition of the Moon: insights from melt inclusions. Earth Planet Sci Lett 523:115715 188. Filiberto J, Treiman AH (2009) The effect of chlorine on the liquidus of basalt: first results and implications for basalt genesis on Mars and Earth. Chem Geol 263:60 189. Bellucci JJ, Whitehouse MJ, John T, Nemchin AA, Snape JF, Bland PA, Benedix GK (2017) Halogen and Cl isotopic systematics in Martian phosphates: implications for the Cl cycle and surface halogen reservoirs on Mars. Earth Planet Sci Lett 458:192 190. Shearer CK, Messenger S, Sharp ZD, Burger PV, Nguyen AN, McCubbin FM (2018) Distinct chlorine isotopic reservoirs on Mars. Implications for character, extent and relative timing of crustal interactions with mantle-derived magmas, evolution of the Martian atmosphere, and the building blocks of an early Mars. Geochim Cosmochim Acta 234:24 191. Filiberto J, Treiman AH (2009) Martian magmas contained abundant chlorine, but little water. Geology 37:1087 192. Schuttlefield JD, Sambur JB, Gelwicks M, Eggleston CM, Parkinson BA (2011) Photooxidation of chloride by oxide minerals: implications for perchlorate on Mars. J Am Chem Soc 133:17521 193. Kolb VM, Hoover R (2013) Perchlorates are compatible with life on Earth—why not Mars? In: Hoover RB, Levin GV, Rozanov A Y, Wickramasisnghe NC (eds) Instruments, Methods, and Missions for Astrobiology XVI, Proc SPIE, vol 8865, p 886504-1 194. Hecht MH, Kounaves SP, Quinn RC, West SJ, Young SMM, Ming DW, Catling DC, Clark BC, Boynton WV, Hoffman J, DeFlores LP, Gospodinova K, Kapit J, Smith PH (2009) Detection of perchlorate and the soluble chemistry of Martian soil at the Phoenix Lander site. Science 325:64 195. Korablev O, Olsen KS, Trokhimovskiy A, Lefèvre F, Montmessin F, Fedorova AA, Toplis MJ, Alday J, Belyaev DA, Patrakeev A, Ignatiev NI, Shakum AV, Grigoriev AV, Baggio L,

414

196.

197. 198.

199.

200. 201.

202.

203.

204. 205. 206.

207.

G. W. Gribble Abdenour I, Lacombe G, Ivanov YS, Aoki S, Thomas IR, Daerden F, Ristic B, Erwin JT, Patel M, Bellucci G, Lopez-Moreno J-J, Vandaele AC (2021) Transient HCl in the atmosphere of Mars. Sci Adv 7:eabe4386 Aoki S, Daerden F, Viscardy S, Thomas IR, Erwin JT, Robert S, Trompet L, Neary L, Villanueva GL, Liuzzi G, Crismani MMJ, Clancy RT, Whiteway J, Schmidt F, LopezValverde MA, Ristic B, Patel MR, Bellucci G, Lopez-Moreno J-J, Olsen KS, Lefèvre F, Montmessin F, Trokhimovskiy A, Fedorova AA, Korablev O, Vandaele AC (2021) Annual appearance of hydrogen chloride in Mars and a striking similarity with the water vapor vertical distribution observed by TGO/NOMAD. Geophys Res Lett 48:e2021GL092506 Krasnopolsky VA (2022) Photochemistry of HCl in the martial atmosphere. Icarus 374:114807 Forni O, Gaft M, Toplis MJ, Clegg SM, Maurice S, Wiens RC, Mangold N, Gasnault O, Sautter V, Le Mouélic S, Meslin P-Y, Nachon M, McInroy RE, Ollila AM, Cousin A, Bridges JC, Lanza NL, Dyar MD (2015) First detection of fluorine on Mars: implications for Gale Crater’s geochemistry. Geophys Res Lett 42:1020 Evans LG, Peplowski PN, McCubbin FM, McCoy TJ, Nittler LR, Zolotov MY, Ebel DS, Lawrence DJ, Starr RD, Weider SZ, Solomon SC (2015) Chlorine on the surface of Mercury: MESSENGER gamma-ray measurements and implications for the planet’s formation and evolution. Icarus 257:417 Sarafian AR, John T, Roszjar J, Whitehouse MJ (2017) Chlorine and hydrogen degassing in Vesta’s magna ocean. Earth Planet Sci Lett 459:311 Bockelée-Morvan D, Biver N, Crovisier J, Lis DC, Hartogh P, Moreno R, de Val-Borro M, Blake GA, Szutowicz S, Boissier J, Cernicharo J, Charnley SB, Combi M, Cordiner MA, de Graauw T, Encrenaz P, Jarchow C, Kidger M, Küppers M, Milam SN, Müller HSP, Phillips TG, Rengel M (2014) Searches for HCl and HF in comets 103P/Hartley 2 and C/2009 P1 (Garradd) with the Herschel Space Observatory. Astron Astrophys 526:A51 Dhooghe F, De Keyser J, Altwegg K, Briois C, Balsiger H, Berthelier J-J, Calmonte U, Cessateur G, Combi MR, Equeter E, Fiethe B, Fray N, Fuselier S, Gasc S, Gibbons A, Gombosi T, Gunell H, Hässig M, Hilchenbach M, Le Roy L, Maggiolo R, Mall U, Marty B, Neefs E, Rème H, Rubin M, Sémon T, Tzou C-Y, Wurz P (2017) Halogens as tracers of protosolar nebula material in comet 67P/Churyumov-Gerasimenko. MNRAS 472:1336 De Keyser J, Dhooghe F, Altwegg K, Balsiger H, Berthelier J-J, Briois C, Calmonte U, Cessateur G, Combi MR, Equeter E, Fiethe B, Fuselier S, Gasc S, Gibbons A, Gombosi T, Gunell H, Hässig M, Le Roy L, Maggiolo R, Mall U, Marty B, Neefs E, Rème H, Rubin M, Sémon T, Tzou C-Y, Wurz P (2017) Evidence for distributed gas sources of hydrogen halides in the coma of comet 67P/Churyumov-Gerasimenko. MNRAS 469:S695 Neufeld DA, Zmuidzinas J, Schilke P, Phillips TG (1997) Discovery of interstellar hydrogen fluoride. Astrophys J 488:L141 Peng R, Yoshida H, Chamberlin RA, Phillips TG, Lis DC, Gerin M (2010) A comprehensive survey of hydrogen chloride in the galaxy. Astrophys J 723:218 De Luca M, Gupta H, Neufeld D, Gerin M, Teyssier D, Drouin BJ, Pearson JC, Lis DC, Monie R, Phillips TG, Goicoechea JR, Godard B, Falgarone E, Coutens A, Bell TA (2012) Herschel/HIFI discovery of HCl+ in the interstellar medium. Astrophys J Lett 751:L37 Lis DC, Pearson JC, Neufeld DA, Schilke P, Müller HSP, Gupta H, Bell TA, Comito C, Phillips TG, Bergin EA, Ceccarelli C, Goldsmith PF, Blake GA, Bacmann A, Baudry A, Benedettini M, Benz A, Black J, Boogert A, Bottinelli S, Cabrit S, Caselli P, Castets A, Caux E, Cernicharo J, Codella C, Coutens A, Crimier N, Crockett NR, Daniel F, Demyk K, Dominic C, Dubernet M-L, Emprechtinger M, Encrenaz P, Falgarone E, Fuente A, Gerin M, Giesen TF, Goicoechea JR, Helmich F, Hennebelle P, Henning T, Herbst E, Hily-Blant P, Hjalmarson Å, Hollenbach D, Jack T, Joblin C, Johnstone D, Kahane C, Kama M, Kaufman M, Klotz A, Langer WD, Larsson B, Le Bourlot J, Lefloch B, Le Petit F, Li D, Liseau R, Lord SD, Lorenzani A, Maret S, Martin PG, Melnick GJ, Menten KM, Morris P, Murphy JA, Nagy Z, Nisini B, Ossenkopf V, Pacheco S, Pagani L, Parise B, Pérault M, Plume R, Qin S-L, Roueff E, Salez M, Sandqvist A, Saraceno P, Schlemmer S, Schuster K, Snell R,

Naturally Occurring Organohalogen Compounds …

208.

209.

210. 211. 212. 213. 214. 215.

216.

217.

218. 219. 220. 221.

222.

223.

224.

225.

226. 227.

415

Stutzki J, Tielens A, Trappe N, van der Tak FFS, van der Wiel MHD, van Dishoeck E, Vastel C, Viti S, Wakelam V, Walters A, Wang S, Wyrowski F, Yorke HW, Yu S, Zmuidzinas J, Delorme Y, Desbat J-P, Güsten R, Krieg J-M, Delforge B (2010) Herschel/HIFI discovery of interstellar chloronium (H2 Cl+ ). Astron Astrophys 521:L9 Neufeld DA, Schilke P, Menten KM, Wolfire MG, Black JH, Schuller F, Müller HSP, Thorwirth S, Güsten R, Philipp S (2006) Discovery of interstellar CF+ . Astron Astrophys 454:L37 Neufeld DA, Schilke P, Menten KM, Wolfire MG, Black JH, Schuller F, Müller H, Thorwirth S, Güsten R, Philipp S (2006) First astronomical detection of the CF+ ion. In: Lis DC, Blake GA, Herbst E (eds) Astrochemistry: recent successes and current challenges, proceedings IAU symposium No 231, 2005, p 163 Neufeld DA, Wolfire MG, Schilke P (2005) The chemistry of fluorine-bearing molecules in diffuse and dense interstellar gas clouds. Astrophys J 628:260 Koga KT, Rose-Koga EF (2018) Fluorine in the Earth and the solar system, where does it come from and can it be found? C R Chimie 21:749 Guaita C (2017) Did Viking discover life on Mars? Eur Phys J Plus 132:346 Tanaka N, Rye DM (1991) Chlorine in the stratosphere. Nature 353:707 Yoshida Y, Wang Y, Shim C, Cunnold D, Blake DR, Dutton GS (2006) Inverse modeling of the global methyl chloride sources. J Geophys Res 111:D16307 Bahlmann E, Keppler F, Wittmer J, Greule M, Schöler HF, Seifert R, Zetzsch C (2019) Evidence for a major missing source in the global chloromethane budget from stable carbon isotopes. Atmos Chem Phys 19:1703 Moore RM (2000) The solubility of a suite of low molecular weight organochlorine compounds in seawater and implications for estimating the marine source of methyl chloride to the atmosphere. Chemosphere: Global Change Sci 2:95 Rhew RC, Miller BR, Bill M, Goldstein AH, Weiss RF (2002) Environmental and biological controls on methyl halide emissions from southern California coastal salt marshes. Biogeochemistry 60:141 Bill M, Rhew RC, Weiss RF, Goldstein AH (2002) Carbon isotope ratios of methyl bromide and methyl chloride emitted from a coastal salt marsh. Geophys Res Lett 29:1045 Rhew R, Mazéas O (2010) Gross production exceeds gross consumption of methyl halides in northern California salt marshes. Geophys Res Lett 37:L18813 Blei E, Heal MR, Heal KV (2010) Long-term CH3 Br and CH3 Cl flux measurements in temperate salt marshes. Biogeosciences 7:3657 Ooki A, Tsuda A, Kameyama S, Takeda S, Itoh S, Suga T, Tazoe H, Okubo A, Yokouchi Y (2010) Methyl halides in surface seawater and marine boundary layer of the northwest Pacific. J Geophys Res 115:C10013 Hu L, Yvon-Lewis SA, Liu Y, Salisbury JE, O’Hern JE (2010) Coastal emissions of methyl bromide and methyl chloride along the eastern Gulf of Mexico and the east coast of the United States. Global Biogeochem Cycl 24:GB1007 Khan MAH, Rhew RC, Whelan ME, Zhou K, Deverel SJ (2011) Methyl halide and chloroform emissions from a subsiding Sacramento-San Joaquin delta island converted to rice fields. Atmos Environ 45:977 Kotte K, Löw F, Huber SG, Krause T, Mulder I, Schöler HF (2012) Organohalogen emissions from saline environments—spatial extrapolation using remote sensing as most promising tool. Biogeosciences 9:1225 Mulder I, Krause T, Sattler T, Tubbesing C, Studenroth S, Bukowski K, Atlas E, Schöler HF (2015) Thermolytic degradation of methylmethionine and implications for its role in DMS and MeCl formation in hypersaline environments. Environ Chem 12:415 Lim Y-K, Phang S-M, Rahman NA, Sturges WT, Malin G (2017) Halocarbon emissions from marine phytoplankton and climate change. Int J Environ Sci Technol 14:1355 Xiao X, Prinn RG, Fraser PJ, Simmonds PG, Weiss RF, O’Doherty S, Miller BR, Salameh PK, Harth CM, Krummel PB, Porter LW, Mühle J, Greally BR, Cunnold D, Wang R, Montzka SA, Elkins JW, Dutton GS, Thompson TM, Butler JH, Hall BD, Reimann S, Vollmer MK,

416

228. 229.

230. 231. 232. 233.

234. 235.

236.

237.

238.

239. 240.

241. 242. 243. 244.

245. 246.

247. 248.

G. W. Gribble Stordal F, Lunder C, Maione M, Arduini J, Yokouchi Y (2010) Optimal estimation of the surface fluxes of methyl chloride using a 3-D global chemical transport model. Atmos Chem Phys 10:5515 Moore RM (2008) A photochemical source of methyl chloride in saline waters. Environ Sci Technol 42:1933 Keppler F, Kalin RM, Harper DB, McRoberts WC, Hamilton JTG (2004) Carbon isotope anomaly in the major plant C1 pool and its global biogeochemical implications. Biogeosciences 1:123 McAnulla C, McDonald IR, Murrell JC (2001) Methyl chloride utilising bacteria are ubiquitous in the natural environment. FEMS Microbiol Lett 201:151 Rhew RC, Aydin M, Saltzman ES (2003) Measuring terrestrial fluxes of methyl chloride and methyl bromide using a stable isotope tracer technique. Geophys Res Lett 30:2103 Rhew RC, Teh YA, Abel T (2007) Methyl halide and methane fluxes in the northern Alaskan coastal tundra. J Geophys Res 112:G02009 Teh YA, Mazéas O, Atwood AR, Abel T, Rhew RC (2009) Hydrologic regulation of gross methyl chloride and methyl bromide uptake from Alaskan Arctic tundra. Global Change Biol 15:330 Blei E, Heal MR (2011) Methyl bromide and methyl chloride fluxes from temperate forest litter. Atmos Environ 45:1543 Derendorp L, Holzinger R, Wishkerman A, Keppler F, Röckmann T (2011) Methyl chloride and C2 –C5 hydrocarbon emissions from dry leaf litter and their dependence on temperature. Atmos Environ 45:3112 Derendorp L, Wishkerman A, Keppler F, McRoberts C, Holzinger R, Röckmann T (2012) Methyl chloride emissions from halophyte leaf litter: dependence on temperature and chloride content. Chemosphere 87:483 Rhew RC, Abel T (2007) Measuring simultaneous production and consumption fluxes of methyl chloride and methyl bromide in annual temperate grasslands. Environ Sci Technol 41:7837 Teh YA, Rhew RC, Atwood A, Abel T (2008) Water, temperature, and vegetation regulation of methyl chloride and methyl bromide fluxes from a shortgrass steppe ecosystem. Global Change Biol 14:77 Yokouchi Y, Saito T, Ishigaki C, Aramoto M (2007) Identification of methyl chloride-emitting plants and atmospheric measurements on a subtropical island. Chemosphere 69:549 Saito T, Yokouchi Y (2008) Stable carbon isotope ratio of methyl chloride emitted from glasshouse-grown tropical plants and its implication for the global methyl chloride budget. Geophys Res Lett 35:L08807 Blei E, Hardacre CJ, Mills GP, Heal KV, Heal MR (2010) Identification and quantification of methyl halide sources in a lowland tropical rainforest. Atmos Environ 44:1005 Saito T, Yokouchi Y, Kosugi Y, Tani M, Philip E, Okuda T (2008) Methyl chloride and isoprene emissions from tropical rain forest in southeast Asia. Geophys Res Lett 35:L19812 Manley SL, Wang N-Y, Walser ML, Cicerone RJ (2007) Methyl halide emissions from greenhouse-grown mangroves. Geophys Res Lett 34:L01806 Berberich GM, Sattler T, Klimetzek D, Benk SA, Berberich MB, Polag D, Schöler HF, Atlas E (2017) Halogenation processes linked to red wood ant nests (Formica spp.) and tectonics. J Atmos Chem 74:261 Anke H, Weber RWS (2006) White-rots, chlorine and the environment—a tale of many twists. Mycologist 20:83 McRoberts WC, Keppler F, Harper DB, Hamilton JTG (2015) Seasonal changes in chlorine and methoxyl content of leaves of deciduous trees and their impact on release of chloromethane and methanol at elevated temperatures. Environ Chem 12:426 Inn ECY, Vedder JF, Concon EP, O’Hara D (1981) Gaseous constituents in the plume from eruptions of Mount St. Helens. Science 211:821 Frische M, Garofalo K, Hansteen TH, Borchers R (2006) Fluxes and origin of halogenated organic trace gases from Momotombo volcano (Nicaragua). Geochem Geophys Geosyst 7:Q05020

Naturally Occurring Organohalogen Compounds …

417

249. Tassi F, Capecchiacci F, Cabassi J, Calabrese S, Vaselli O, Rouwet D, Pecoraino G, Chiodini G (2012) Geogenic and atmospheric sources for volatile organic compounds in fumarolic emissions from Mt. Etna and Vulcano Island (Sicily, Italy). J Geophys Res 117:D17305 250. Schwandner FM, Seward TM, Gi˙ze AP, Hall K, Dietrich VJ (2013) Halocarbons and other trace heteroatomic organic compounds in volcanic gases from Vulcano (Aeolian Islands, Italy). Geochim Cosmochim Acta 101:191 251. Blake D, Hinwood AL, Horwitz P (2009) Peat fires and air quality: volatile organic compounds and particulates. Chemosphere 76:419 252. Mulder I, Huber SG, Krause T, Zetzsch C, Kotte K, Dultz S, Schöler HF (2013) A new purge and trap headspace technique to analyze low volatile compounds from fluid inclusions of rock and minerals. Chem Geol 358:148 253. Svensen H, Planke S, Polozov AG, Schmidbauer N, Corfu F, Podladchikov YY, Jamtveit B (2009) Siberian gas venting and the end-Permian environment crisis. Earth Planet Sci Lett 277:490 254. Clay PL, Burgess R, Busemann H, Ruzié-Hamilton L, Joachim B, Day JMD, Ballentine CJ (2017) Halogens in chondritic meteorites and terrestrial accretion. Nature 551:614 255. Keppler F, Harper DB, Greule M, Ott U, Sattler T, Schöler HF, Hamilton JTG (2014) Chloromethane release from carbonaceous meteorite affords new insight into Mars lander findings. Sci Rep 4:7010 256. Navarro-González R, Vargas E, de la Rosa J, Raga AC, McKay CP (2010) Reanalysis of the Viking results suggests perchlorate and organics at midlatitudes on Mars. J Geophys Res 115:E12010 257. Glavin DP, Freissinet C, Miller KE, Eigenbrode JL, Brunner AE, Buch A, Sutter B, Archer PD Jr, Atreya SK, Brinckerhoff WB, Cabane M, Coll P, Conrad PG, Coscia D, Dworkin JP, Franz HB, Grotzinger JP, Leshin LA, Martin MG, McKay C, Ming DW, Navarro-González R, Pavlov A, Steele A, Summons RE, Szopa C, Teinturier S, Mahaffy PR (2013) Evidence for perchlorates and the origin of chlorinated hydrocarbons detected by SAM at the Rocknest Aeolian deposit in Gale Crater. J Geophys Res: Planets 118:1955 258. Fernanders MS, Gough RV, Chevrier VF, Schiffman ZR, Ushijima SB, Martinez GM, RiveraValentín EG, Archer PD Jr, Clark JV, Sutter B, Tolbert MA (2022) Water uptake by chlorate salts under Mars-relevant conditions. Icarus 371:114715 259. Fayolle EC, Öberg KI, Jørgensen JK, Altwegg K, Calcutt H, Müller HSP, Rubin M, van der Wiel MHD, Bjerkeli P, Bourke TL, Coutens A, van Dishoeck EF, Drozdovskaya MN, Garrod RT, Ligterink NFW, Persson MV, Wampfler SF, ROSINA Team (2017) Protostellar and cometary detections of organohalogens. Nat Astron 1:703 260. Jordan A, Stoy P, Sneddon HF (2021) Chlorinated solvents: their advantages, disadvantages, and alternatives in organic and medicinal chemistry. Chem Rev 121:1582 261. Peng P, Lu Y, Bosma TNP, Nijenhuis I, Nijsse B, Shetty SA, Ruecker A, Umanets A, RamiroGarcia J, Kappler A, Sipkema D, Smidt H, Atashgahi S (2020) Metagenomic- and cultivationbased exploration of anaerobic chloroform biotransformation in hypersaline sediments as natural source of chloromethanes. Microorganisms 8:665 262. Colomb A, Yassaa N, Williams J, Peeken I, Lochte K (2008) Screening volatile organic compounds (VOCs) emissions from five marine phytoplankton species by head space gas chromatography/mass spectrometry (HS-GC/MS). J Environ Monit 10:325 263. Andrews S (2014) Review of the chlorine revolution: water disinfection and the fight to save lives. J Chem Educ 91:466 264. Matucha M, Gryndler M, Schröder P, Forczek ST, Uhlíˇrová H, Fuksová K, Rohlenová J (2007) Chloroacetic acids—degradation intermediates of organic matter in forest soil. Soil Biol Biochem 39:382 265. Albers CN, Jacobsen OS, Flores EMM, Pereira JSF, Laier T (2011) Spatial variation in natural formation of chloroform in the soils of four coniferous forests. Biogeochemistry 103:317 266. Albers CN, Laier T, Jacobsen OS (2010) Formation, fate and leaching of chloroform in coniferous forest soils. Appl Geochem 25:1525

418

G. W. Gribble

267. Hunkeler D, Laier T, Breider F, Jacobsen OS (2012) Demonstrating a natural origin of chloroform in groundwater using stable carbon isotopes. Environ Sci Technol 46:6096 268. Grøn C, Laturnus F, Jacobsen OS (2012) Reliable test methods for the determination of a natural production of chloroform in soils. Environ Monit Assess 184:1231 269. Wang JJ, Ng TW, Zhang Q, Yang XB, Dahlgren RA, Chow AT, Wong PK (2012) Technical note: Reactivity of C1 and C2 organohalogens formation—from plant litter to bacteria. Biogeosciences 9:3721 270. Breider F, Hunkeler D (2014) Mechanistic insights into the formation of chloroform from natural organic matter using stable carbon isotope analysis. Geochim Cosmochim Acta 125:85 271. Weigold P, Ruecker A, Jochmann M, Barajas XLO, Lege S, Zwiener C, Kappler A, Behrens S (2015) Formation of chloroform and tetrachloroethene by Sinorhizobium meliloti strain 1021. Lett Appl Microbiol 61:346 272. Forczek ST, Pavlík M, Holík J, Rederer L, Ferenˇcík M (2016) The natural chlorine cycle— formation of the carcinogenic and greenhouse gas compound chloroform in drinking water reservoirs. Chemosphere 157:190 273. Johnsen AR, Jacobsen OS, Gudmundsson L, Albers CN (2016) Chloroform emissions from arctic and subarctic ecosystems in Greenland and Northern Scandinavia. Biogeochemistry 130:53 274. Albers CN, Jacobsen OS, Flores EMM, Johnsen AR (2017) Arctic and subarctic natural soils emit chloroform and brominated analogues by alkaline hydrolysis of trihaloacetyl compounds. Environ Sci Technol 51:6131 275. Boyce SD, Hornig JF (1983) Reaction processes effecting the analysis of chloroform by direct aqueous injection gas chromatography. Water Res 17:685 276. Breider F, Albers CN, Hunkeler D (2013) Assessing the role of trichloroacetyl-containing compounds in the natural formation of chloroform using stable carbon isotopes analysis. Chemosphere 90:441 277. Lim Y-K, Phang S-M, Sturges WT, Malin G, Rahman NBA (2018) Emission of short-lived halocarbons by three common tropical marine microalgae during batch culture. J Appl Phycol 30:341 278. Orlikowska A, Stolle C, Pollehne F, Jürgens K, Schulz-Bull DE (2015) Dynamics of halocarbons in coastal surface waters during short term mesocosm experiments. Environ Chem 12:515 279. Bahlmann E, Stolle C, Weinberg I, Seifert R, Schulz-Bull DE, Michaelis W (2015) Isotopic composition of polyhalomethanes from marine macrophytes—systematic effects of the halogen substituents on isotopic composition. Environ Chem 12:504 280. Hellén H, Hakola H, Pystynen K-H, Rinne J, Haapanala S (2006) C2 –C10 hydrocarbon emissions from a boreal wetland and forest floor. Biogeosciences 3:167 281. Forczek ST, Laturnus F, Doležalová J, Holík J, Wimmer Z (2015) Emission of climate relevant volatile organochlorines by plants occurring in temperate forests. Plant Soil Environ 61:103 282. Rhew RC, Teh YA, Abel T, Atwood A, Mazéas O (2008) Chloroform emissions from the Alaskan Arctic tundra. Geophys Res Lett 35:L21811 283. Rhew RC, Miller BR, Weiss RF (2008) Chloroform, carbon tetrachloride and methyl chloroform fluxes in Southern California ecosystems. Atmos Environ 42:7135 284. Weissflog L, Elansky N, Putz E, Krueger G, Lange CA, Lisitzina L, Pfennigsdorff A (2004) Trichloroacetic acid in the vegetation of polluted and remote areas of both hemispheres—Part II: salt lakes as novel sources of natural chlorohydrocarbons. Atmos Environ 38:4197 285. Breider F, Albers CN (2015) Formation mechanisms of trichloromethyl-containing compounds in the terrestrial environment: a critical review. Chemosphere 119:145 286. Evans MV, Sumner AJ, Daly RA, Luek JL, Plata DL, Wrighton KC, Mouser PJ (2019) Hydraulically fractured natural-gas well microbial communities contain genomic halogenation and dehalogenation potential. Environ Sci Technol Lett 6:585 287. Khalil MAK, Rasmussen RA (1999) Atmospheric chloroform. Atmos Environ 33:1151

Naturally Occurring Organohalogen Compounds …

419

288. Xiao X, Prinn RG, Fraser PJ, Weiss RF, Simmonds PG, O’Doherty S, Miller BR, Salameh PK, Harth CM, Krummel PB, Golombek A, Porter LW, Butler JH, Elkins JW, Dutton GS, Hall BD, Steele LP, Wang RHJ, Cunnold DM (2010) Atmospheric three-dimensional inverse modeling of regional industrial emissions and global oceanic uptake of carbon tetrachloride. Atmos Chem Phys 10:10421 289. Movafeghi A, Djozan DJ, Razeghi JA, Baheri T (2010) Identification of volatile organic compounds in leaves, roots and gum of Astragalus compactus Lam. using solid phase microextraction followed by GC-MS analysis. Nat Prod Res 24:703 290. Tulipani S, Schwark L, Holman AI, Bush RT, Grice K (2017) 1-Chloro-n-alkanes: potential mangrove and saltmarsh vegetation biomarkers. Org Geochem 107:54 291. Zhang Z, Metzger P, Sachs JP (2013) Unprecedented long chain 1-chloroalkenes and 1chloroalkanes in the Holocene sediments of Lake El Junco. Galápagos Islands. Org Geochem 57:1 292. Freissinet C, Glavin DP, Mahaffy PR, Miller KE, Eigenbrode JL, Summons RE, Brunner AE, Buch A, Szopa C, Archer PD Jr, Franz HB, Atreya SK, Brinkerhoff WB, Cabane M, Coll P, Conrad PG, Des Marais DJ, Dworkin JP, Fairén AG, François P, Grotzinger JP, Kashyap S, ten Kate IL, Leshin LA, Malespin CA, Martin MG, Martin-Torres FJ, McAdam AC, Ming DW, Navarro-González R, Pavlov AA, Prats BD, Squyres SW, Steele A, Stern JC, Sumners DY, Sutter B, Zorzano M-P, MSL Science Team (2015) Organic molecules in the sheepbed mudstone, Gale Crater, Mars. J Geophys Res: Planets 120:495 293. Butler JH (2000) Better budgets for methyl halides? Nature 403:260 294. Singh ON, Fabian P (1999) Reactive bromine compounds. In: Fabian P, Singh ON (eds) Reactive halogen compounds in the atmosphere. The handbook of environmental chemistry, vol 4, part E. Springer-Verlag, Berlin Heidelberg, p 1 295. Hu L, Yvon-Lewis S, Liu Y, Bianchi TS (2012) The ocean in near equilibrium with atmospheric methyl bromide. Global Biogeochem Cycl 26:GB3016 296. Sa’undsdóttir S, Matrai PA (1998) Biological production of methyl bromide by cultures of marine phytoplankton. Limnol Oceanogr 43:81 297. Moore RM, Webb M (1996) The relationship between methyl bromide and chlorophyll α in high latitude ocean waters. Geophys Res Lett 23:2951 298. Méndez-Díaz JD, Shimabuku KK, Ma J, Enumah ZO, Pignatello JJ, Mitch WA, Dodd MC (2014) Sunlight-driven photochemical halogenation of dissolved organic matter in seawater: a natural abiotic source of organobromine and organoiodine. Environ Sci Technol 48:7418 299. Wishkerman A, Gebhardt S, McRoberts CW, Hamilton JTG, Williams J, Keppler F (2008) Abiotic methyl bromide formation from vegetation, and its strong dependence on temperature. Environ Sci Technol 42:6837 300. Carpenter LJ, Liss, PS, Penkett SA (2003) Marine organohalogens in the atmosphere over the Atlantic and Southern Oceans. J Geophys Res 108:ACH1-1 301. Liu Y, Yvon-Lewis SA, Hu L, Salisbury JE, O’Hern JE (2011) CHBr3 , CH2 Br2 , and CHClBr2 in U.S. coastal waters during the Gulf of Mexico and east coast Carbon Cruise. J Geophys Res 116:C10004 302. Hughes C, Johnson M, Utting R, Turner S, Malin G, Clarke A, Liss PS (2013) Microbial control of bromocarbon concentrations in coastal waters of the western Antarctic Peninsula. Mar Chem 151:35 303. Liu Y, Yvon-Lewis SA, Thornton DCO, Campbell L, Bianchi TS (2013) Spatial distribution of brominated very short-lived substances in the eastern Pacific. J Geophys Res Oceans 118:2318 304. Hepach H, Quack B, Ziska F, Fuhlbrügge S, Atlas EL, Krüger K, Peeken I, Wallace DWR (2014) Drivers of diel and regional variations of halocarbon emissions from the tropical North East Atlantic. Atmos Chem Phys 14:1255 305. Hepach H, Quack B, Tegtmeier S, Engel A, Bracher A, Fuhlbrügge S, Galgani L, Atlas EL, Lampel J, Frieβ U, Krüger K (2016) Biogenic halocarbons from the Peruvian upwelling region as tropospheric halogen source. Atmos Chem Phys 16:12219

420

G. W. Gribble

306. Feng L, Palmer PI, Butler R, Andrews SJ, Atlas EL, Carpenter LJ, Donets V, Harris NRP, Salawitch RJ, Pan LL, Schauffler SM (2018) Surface fluxes of bromoform and dibromomethane over the tropical western Pacific inferred from airborne in situ measurements. Atmos Chem Phys 18:14787 307. Liu Y, Yvon-Lewis SA, Thornton DCO, Butler JH, Bianchi TS, Campbell L, Hu L, Smith RW (2013) Spatial and temporal distributions of bromoform and dibromomethane in the Atlantic Ocean and their relationship with photosynthetic biomass. J Geophys Res: Oceans 118:3950 308. Leedham EC, Hughes C, Keng FSL, Phang S-M, Malin G, Sturges WT (2013) Emission of atmospherically significant halocarbons by naturally occurring and farmed tropical macroalgae. Biogeosciences 10:3615 309. Elvidge ECL, Phang S-M, Sturges WT, Malin G (2015) The effect of desiccation on the emission of volatile bromocarbons from two common temperate macroalgae. Biogeosciences 12:387 310. Mithoo-Singh PK, Keng FS-L, Phang S-M, Elvidge ECL, Sturges WT, Malin G, Rahman NA (2017) Halocarbon emissions by selected tropical seaweeds: species-specific and compoundspecific responses under changing pH. PeerJ 5:e2918 311. Lim Y-K, Keng FS-L, Phang S-M, Sturges WT, Malin G, Rahman NA (2019) Effect of irradiance on the emission of short-lived halocarbons from three common tropical marine microalgae. PeerJ 7:e6758 312. Tegtmeier S, Ziska F, Pisso I, Quack B, Velders GJM, Yang X, Krüger K (2015) Oceanic bromoform emissions weighted by their ozone depletion potential. Atmos Chem Phys 15:13647 313. Carpenter LJ (2003) Iodine in the marine boundary layer. Chem Rev 103:4953 314. Moore RM, Tokarczyk R (1992) Chloro-iodomethane in N. Atlantic waters: a potentially significant source of atmospheric iodine. Geophys Res Lett 19:1779 315. Campos MLAM, Nightingale PD, Jickells TD (1996) A comparison of methyl iodide emissions from seawater and wet depositional fluxes of iodine over the southern North Sea. Tellus 48B:106 316. Tegtmeier S, Krüger K, Quack B, Atlas E, Blake DR, Boenisch H, Engel A, Hepach H, Hossaini R, Navarro MA, Raimund S, Sala S, Shi Q, Ziska F (2013) The contribution of oceanic methyl iodide to stratospheric iodine. Atmos Chem Phys 13:11869 317. Manley SL, de la Cuesta JL (1997) Methyl iodide production from marine phytoplankton cultures. Limnol Oceanogr 42:142 318. Amachi S, Kamagata Y, Kanagawa T, Muramatsu Y (2001) Bacteria mediate methylation of iodine in marine and terrestrial environments. Appl Environ Microbiol 67:2718 319. Allard S, Gallard H (2013) Abiotic formation of methyl iodide on synthetic birnessite: a mechanistic study. Sci Total Environ 463–464:169 320. Keppler F, Borchers R, Elsner P, Fahimi I, Pracht J, Schöler HF (2003) Formation of volatile iodinated alkanes in soil: results from laboratory studies. Chemosphere 52:477 321. Amachi S, Kasahara M, Hanada S, Kamagata Y, Shinoyama H, Fujii T, Muramatsu Y (2003) Microbial participation in iodine volatilization from soils. Environ Sci Technol 37:3885 322. Sive BC, Varner RK, Mao H, Blake DR, Wingenter OW, Talbot R (2007) A large terrestrial source of methyl iodide. Geophys Res Lett 34:L17808 323. Martino M, Mills GP, Woeltjen J, Liss PS (2009) A new source of volatile organoiodine compounds in surface seawater. Geophys Res Lett 36:L01609 324. Jones CE, Carpenter LJ (2005) Solar photolysis of CH2 I2 , CH2 ICI, and CH2 IBr in water, saltwater, and seawater. Environ Sci Technol 39:6130 325. Christof O, Seifert R, Michaelis W (2002) Volatile halogenated organic compounds distribution in a coastal salt marsh in Northern Germany. Goldschmidt Conf Abstr: A141 326. Anke T, Kupka J, Schramm G, Steglich W (1980) Antibiotics from basidiomycetes. X. Scorodonin, a new antibacterial and antifungal metabolite from Marasmius scorodonius (Fr.) Fr. J Antibiot 33:463

Naturally Occurring Organohalogen Compounds …

421

327. Zhang Y, Wu Y (2010) An elimination approach to the synthesis of (+)-scorodonin. Chin J Chem 28:1635 328. Jian Y-J, Wu Y (2010) Synthesis of the structure proposed for the natural allenic antibiotic scorodonin. Org Biomol Chem 8:1905 329. Wu G, Yao Y, Li G, Zhang X, Qian H, Ma S (2022) Enantioselective allenation of terminal alkynes catalyzed by copper halides of mixed oxidation states and its application to the total synthesis of scorodonin. Angew Chem Int Ed 61:e202112427 330. Wang S, Chen R-Y, Yu S-S, Yu D-Q (2003) Uvamalols D-G: novel polyoxygenated secocyclohexenes from the roots of Uvaria macrophylla. J Asian Nat Prod Res 5:17 331. Macabeo APG, Letada AG, Budde S, Faderl C, Dahse H-M, Franzblau SG, Alejandro GJD, Pierens GK, Garson MJ (2017) Antitubercular and cytotoxic chlorinated seco-cyclohexenes from Uvaria alba. J Nat Prod 80:3319 332. Schock TB, Huncik K, Beauchesne KR, Villareal TA, Moeller PDR (2011) Identification of trichotoxin, a novel chlorinated compound associated with the bloom forming cyanobacterium, Trichodesmium thiebautii. Environ Sci Technol 45:7503 333. El-Gendy MMA, Hawas UW, Jaspars M (2008) Novel bioactive metabolites from a marine derived bacterium Nocardia sp. ALAA 2000. J Antibiot 61:379 334. Tang X-X, Liu S-Z, Yan X, Tang B-W, Fang M-J, Wang X-M, Wu Z, Qiu Y-K (2019) Two new cytotoxic compounds from a deep-sea Penicillium citreonigrum XT20-134. Mar Drugs 17:509 335. Citron CA, Rabe P, Dickschat JS (2012) The scent of bacteria: headspace analysis for the discovery of natural products. J Nat Prod 75:1765 336. Chen W, Weisburger JH, Flala ES, Carmella SG, Chen D, Spratt TE, Hecht SS (1995) Unexpected mutagen in fish. Nature 374:599 337. Vanelslander B, Paul C, Grueneberg J, Prince EK, Gillard J, Sabbe K, Pohnert G, Vyverman W (2012) Daily bursts of biogenic cyanogen bromide (BrCN) control biofilm formation around a marine benthic diatom. Proc Natl Acad Sci USA 109:2412 338. Prithiviraj B, Vikram A, Kushalappa AC, Yaylayan V (2004) Volatile metabolite profiling for the discrimination of onion bulbs infected by Erwinia carotovora ssp. carotovora, Fusarium oxysporum and Botrytis allii. Eur J Plant Pathol 110:371 339. Wang J, Han N, Wang Y, Wang Y, Liu Z, Wang Y, Yin J (2014) Three alkaloids from Reineckia carnea herba and their antitussive and expectorant activities. Nat Prod Res 28:1306 340. Rosy BA, Rosakutty PJ (2012) GC-MS analysis of methanol wild plant and callus extracts from three Cissus species, family Vitaceae. J Chem Pharm Res 4:3420 341. Shaala LA, Youssef DTA (2020) Pseudoceratonic acid and moloka’iamine derivatives from the Red Sea Verongiid sponge Pseudoceratina arabica. Mar Drugs 18:525 342. Sattler T, Sörgel M, Wittmer J, Bourtsoukidis E, Krause T, Atlas E, Benk S, Bleicher S, Kamilli K, Ofner J, Kopetzky R, Held A, Palm W-U, Williams J, Zetzsch C, Schöler H-F (2019) Natural formation of chloro- and bromoacetone in Salt Lakes of Western Australia. Atmosphere 10:663 343. Scott BF, Mactavish D, Spencer C, Strachan WMJ, Muir DCG (2000) Haloacetic acids in Canadian lake waters and precipitation. Environ Sci Technol 34:4266 344. Berg M, Müller SR, Mühlemann J, Wiedmer A, Schwarzenbach RP (2000) Concentrations and mass fluxes of chloroacetic acids and trifluoroacetic acid in rain and natural waters in Switzerland. Environ Sci Technol 34:2675 345. Scott BF, Spencer C, Marvin CH, Mactavish DC, Muir DCG (2002) Distribution of haloacetic acids in the water columns of the Laurentian Great Lakes and Lake Malawi. Environ Sci Technol 36:1893 346. Weissflog L, Pfennigsdorff A, Martinez-Pastur G, Puliafito E, Figueroa D, Elansky N, Nikonov V, Putz E, Krüger G, Kellner K (2001) Trichloroacetic acid in the vegetation of polluted and remote areas of both hemispheres—Part I. Its formation, uptake and geographical distribution. Atmos Environ 35:4511 347. Albers CN, Hansen PE, Jacobsen OS (2010) Trichloromethyl compounds—natural background concentrations and fates within and below coniferous forests. Sci Total Environ 408:6223

422

G. W. Gribble

348. Heal MR, Dickey CA, Heal KV, Stidson RT, Matucha M, Cape JN (2010) The production and degradation of trichloroacetic acid in soil: results from in situ soil column experiments. Chemosphere 79:401 349. Albers CN, Hansen PE, Jacobsen OS (2010) Methodological problems in determining TCAA in soils—the discovery of novel natural trichloroacetyl containing compounds and their interference with a common method for determining TCAA in soil and vegetation. J Environ Monit 12:672 350. Matucha M, Gryndler M, Forczek ST, Uhlíˇrová H, Fuksová K, Schröder P (2003) Chloroacetic acids in environmental processes. Environ Chem Lett 1:127 351. Von Sydow LM, Nielsen AT, Grimvall AB, Borén HB (2000) Chloro- and bromoacetates in natural archives of firn from Antarctica. Environ Sci Technol 34:239 352. Yoshino T, Jaseem V (2018) Fluorine solubility in bridgmanite: a potential fluorine reservoir in the Earth’s mantle. Earth Planet Sci Lett 504:106 353. Teuscher F, Lin W, Wray V, Edrada R, Padmakumar K, Proksch P, Ebel R (2006) Two new cyclopentanoids from the endophytic fungus Aspergillus sydowii associated with the marine alga Acanthophora spicifera. Nat Prod Commun 1:927 354. Song Y-P, Miao F-P, Fang S-T, Yin X-L, Ji N-Y (2018) Halogenated and nonhalogenated metabolites from the marine-alga-endophytic fungus Trichoderma assperellum cf44-2. Mar Drugs 16:266 355. Qiu P, Ding L, Su D, He S (2018) A new cyclopentenone derivative from the spongeassociated fungus Hypocrea koningii. Chem Nat Comp 54:631 356. Ferreira ELF, Williams DE, Ióca LP, Morais-Urano RP, Santos MFC, Patrick BO, Elias LM, Lira SP, Ferreira AG, Passarini MRZ, Sette LD, Andersen RJ, Berlinck RGS (2015) Structure and biogenesis of roussoellatide, a dichlorinated polyketide from the marine-derived fungus Roussoella sp. DLM33. Org Lett 17:5152 357. Elsebai MF, Ghabbour HA, Legrave N, Fontaine-Vive F, Wehiri M (2018) New bioactive chlorinated cyclopentene derivatives from the marine-derived fungus Phoma sp. Med Chem Res 27:1885 358. Honmura Y, Uesugi S, Maeda H, Tanaka K, Nehira T, Kimura K, Okazaki M, Hashimoto M (2016) Isolation, absolute structures, and biological properties of cyclohelminthols I-IV from Helminthosporium velutinum yone96. Tetrahedron 72:1400 359. Inose K, Tanaka K, Koshino H, Hashimoto M (2019) Cyclopericodiol and new chlorinated melleins isolated from Periconia macrospinosa KT3863. Tetrahedron 75:130470 360. Matsumoto T, Hosoya T, Tomoda H, Shiro M, Shigemori H (2011) Palmaenones A and B, two new antimicrobial chlorinated cyclopentenones from discomycete Lachnum palmae. Chem Pharm Bull 59:1559 361. Li X, Zhang D, Lee U, Li X, Cheng J, Zhu W, Jung JH, Choi HD, Son BW (2007) Bromomyrothenone B and botrytinone, cyclopentenone derivatives from a marine isolate of the fungus Botrytis. J Nat Prod 70:307 362. Greff S, Zubia M, Genta-Jouve G, Massi L, Perez T, Thomas OP (2014) Mahorones, highly brominated cyclopentenones from the red alga Asparagopsis taxiformis. J Nat Prod 77:1150 363. Tran TD, Pham NB, Quinn RJ (2016) Unique polybrominated hydrocarbons from the Australian endemic red alga Ptilonia australasica. J Nat Prod 79:570 364. Tansuwan S, Pornpakakul S, Roengsumran S, Petsom A, Muangsin N, Sihanonta P, Chaichit N (2007) Antimalarial benzoquinones from an endophytic fungus, Xylaria sp.. J Nat Prod 70:1620 365. Zhang P-L, Han Y, Zhang L-T, Wang X-L, Shen T, Ren D, Lou H, Wang X-N (2017) Botrysphones A-C and botrysphins A–F, triketides and diterpenoids from the fungus Botrysphaeria laricina. J Nat Prod 80:1791 366. Evidente A, Maddau L, Scanu B, Andolfi A, Masi M, Motta A, Tuzi A (2011) Sphaeropsidones, phytotoxic dimedone methyl ethers produced by Diplodia cupressi: a structure– activity relationship study. J Nat Prod 74:757 367. Auranwiwat C, Wongsomboon P, Thaima T, Rattanajak R, Kamchonwongpaisan S, Willis AC, Laphookhieo S, Pyne SG, Limtharakul T (2019) Polyoxygenated cyclohexenes and their chlorinated derivatives from the leaves of Uvaria cherrevensis. J Nat Prod 82:101

Naturally Occurring Organohalogen Compounds …

423

368. Maeda G, van der Wal J, Gupta AK, Munissi JJE, Orthaber A, Sunnerhagen P, Nyandoro SS, Erdélyi M (2020) Oxygenated cyclohexene derivatives and other constituents from the roots of Monathotaxis trichocarpa. J Nat Prod 83:210 369. Nyandoro SS, Munissi JJE, Gruhonjic A, Duffy S, Pan F, Puttreddy R, Holleran JP, Fitzpatrick PA, Pelletier J, Avery VM, Rissanen K, Erdélyi M (2017) Polyoxygenated cyclohexenes and other constituents of Cleistochlamys kirkii leaves. J Nat Prod 80:114 370. Ali T, Inagaki M, Chai H, Wieboldt T, Rapplye C, Rakotondraibe LH (2017) Halogenated compounds from directed fermentation of Penicillium concentricum, an endophytic fungus of the liverwort Trichocolea tomentella. J Nat Prod 80:1397 371. Piovano M, Garbarino J, Tomassini L, Nicoletti M (2009) Cyclohexanones from Mimulus glabratus and M. luteus. Nat Prod Commun 4:1637 372. Okanya PW, Mohr KI, Gerth K, Steinmetz H, Huch V, Jansen R, Müller R (2012) Hyaladione, an S-methyl cyclohexadiene-dione from Hyalangium minutum. J Nat Prod 75:768 373. Yamada T, Iritani M, Ohishi H, Tanaka K, Minoura K, Doi M, Numata A (2007) Pericosines, antitumour metabolites from the sea hare-derived fungus Periconia byssoides. Structures and biological activities. Org Biomol Chem 5:3979 374. Usami Y, Mizuki K, Ichikawa H, Arimoto M (2008) Determination of the absolute configuration of the cytotoxic natural product pericosine D. Tetrahedron: Asymmetry 19:1461 375. Usami Y, Mizuki K (2011) Stereostructure reassignment and determination of the absolute configuration of pericosine Do by a synthetic approach. J Nat Prod 74:877 376. Mizuki K, Iwahashi K, Murata N, Ikeda M, Nakai Y, Yoneyama H, Harusawa S, Usami Y (2014) Synthesis of marine natural product (–)-pericosine E. Org Lett 16:3760 377. Kong F, Zhao C, Hao J, Wang C, Wang W, Huang X, Zhu W (2015) New α-glucosidase inhibitors from a marine sponge-derived fungus, Aspergillus sp. OUCMDZ-1583. RSC Adv 5:68852 378. Nenkep VN, Yun K, Li Y, Choi HD, Kang JS, Son BW (2010) New production of haloquinones, bromochlorogentisylquinones A and B, by a halide salt from a marine isolate of the fungus Phoma herbarum. J Antibiot 63:199 379. Zhang X, Shu C, Li Q, Lian X-Y, Zhang Z (2019) Novel cyclohexene and benzamide derivatives from marine-associated Streptomyces sp. ZZ502. Nat Prod Res 33:2151 380. Suciati FJA, Lambert LK, Pierens GK, Bernhardt PV, Garson MJ (2013) Secondary metabolites of the sponge-derived fungus Acremonium persicinum. J Nat Prod 76:1432 381. Kim S-H, Shin Y, Lee S-H, Oh K-B, Lee SK, Shin J, Oh D-C (2015) Salternamides A–D from a halophilic Streptomyces sp. actinobacterium. J Nat Prod 78:836 382. Bach D-H, Kim S-H, Hong J-Y, Park HJ, Oh D-C, Lee SK (2015) Salternamide A suppresses hypoxia-induced accumulation of HIF-1α and induces apoptosis in human colorectal cancer cells. Mar Drugs 13:6962 383. Yi X-X, Chen Y, Xie W-P, Xu M-B, Chen Y-N, Gao C-H, Huang R-M (2014) Four new jacaranone analogs from the fruits of a Beibu Gulf mangrove Avicennia marina. Mar Drugs 12:2515 384. Bunyapaiboonsri T, Yoiprommarat S, Intereya K, Rachtawee P, Hywel-Jones NL, Isaka M (2009) Isariotins E and F, spirocyclic and bicyclic hemiacetals from the entomopathogenic fungus Isaria tenuipes BCC 12625. J Nat Prod 72:756 385. Cha JY, Huang Y, Pettus TRR (2009) Total synthesis of TK-57-164A, isariotin F, and their putative progenitor isariotin E. Angew Chem Int Ed 48:9519 386. Zhao Y, Liu D, Proksch P, Zhou D, Lin W (2018) Truncateols O-V, further isoprenylated cyclohexanols from the sponge-associated fungus Truncatella angustata with antiviral activities. Phytochemistry 155:61 387. Liu D-H, Sun Y-Z, Kurtán T, Mándi A, Tang H, Li J, Su L, Zhuang C-L, Liu Z-Y, Zhang W (2019) Osteoclastogenesis regulation metabolites from the coral-associated fungus Pseudallescheria boydii TW-1024-3. J Nat Prod 82:1274 388. Li D, Chen L, Zhu T, Kurtán T, Mándi A, Zhao Z, Li J, Gu Q (2011) Chloctanspirones A and B, novel chlorinated polyketides with an unprecedented skeleton, from marine sediment derived fungus Penicillium terrestre. Tetrahedron 67:7913

424

G. W. Gribble

389. Osmanova N, Schultze W, Ayoub N (2010) Azaphilones: a class of fungal metabolites with diverse biological activities. Phytochem Rev 9:315 390. Gao J-M, Yang S-X, Qin J-C (2013) Azaphilones: chemistry and biology. Chem Rev 113:4755 391. Winter JM, Cascio D, Dietrich D, Sato M, Watanabe K, Sawaya MR, Vederas JC, Tang Y (2015) Biochemical and structural basis for controlling chemical modularity in fungal polyketide biosynthesis. J Am Chem Soc 137:9885 392. Pavesi C, Flon V, Mann S, Leleu S, Prado S, Franck X (2021) Biosynthesis of azaphilones: a review. Nat Prod Rep 38:1058 393. Williams K, Greco C, Bailey AM, Willis CL (2021) Core steps to the azaphilone family of fungal natural products. ChemBioChem 22:3027 394. Winter JM, Sato M, Sugimoto S, Chiou G, Garg NK, Tang Y, Watanabe K (2012) Identification and characterization of the chaetoviridin and chaetomugilin gene cluster in Chaetomium globosum reveal dual functions of an iterative highly-reducing polyketide synthase. J Am Chem Soc 134:17900 395. Sato M, Winter JM, Kishimoto S, Noguchi H, Tang Y, Watanabe K (2016) Combinatorial generation of chemical diversity by redox enzymes in chaetoviridin biosynthesis. Org Lett 18:1446 396. Makrerougras M, Coffinier R, Oger S, Chevalier A, Sabot C, Franck X (2017) Total synthesis and structural revision of chaetoviridins A. Org Lett 19:4146 397. Kingsland SR, Barrow RA (2009) Identification of chaetoviridin E from a cultured microfungus, Chaetomium sp. and structural reassignment of chaetoviridins B and D. Aust J Chem 62:269 398. Takahashi M, Koyama K, Natori S (1990) Four new azaphilones from Chaetomium globosum var. flavo-viridae. Chem Pharm Bull 38:625 399. Zhang Q, Li H-Q, Zong S-C, Gao J-M, Zhang A-L (2012) Chemical and bioactive diversities of the genus Chaetomium secondary metabolites. Mini-Rev Med Chem 12:127 400. Chen G-D, Li Y-J, Gao H, Chen Y, Li X-X, Li J, Guo L-D, Cen Y-Z, Yao X-S (2012) New azaphilones and chlorinated phenolic glycosides from Chaetomium elatum with caspase-3 inhibitory activity. Planta Med 78:1683 401. Phonkerd N, Kanokmedhakul S, Kanokmedhakul K, Soytong K, Prabpai S, Kongsearee P (2008) Bis-spiro-azaphilones and azaphilones from the fungi Chaetomium cochliodes VTh01 and C. cochliodes CTh05. Tetrahedron 64:9636 402. Borges WS, Mancilla G, Guimarães DO, Durán-Patrón R, Collado IG, Pupo MT (2011) Azaphilones from the endophyte Chaetomium globosum. J Nat Prod 74:1182 403. Borges WS, Mancilla G, Guimarães DO, Durán-Patrón R, Collado IG, Pupo MT (2011) Correction to azaphilones from the endophyte Chaetomium globosum. J Nat Prod 74:2028 404. McMullin DR, Sumarah MW, Blackwell BA, Miller JD (2013) New azaphilones from Chaetomium globosum isolated from the built environment. Tetrahedron Lett 54:568 405. Youn UJ, Sripisut T, Park E-J, Kondratyuk TP, Fatima N, Simmons CJ, Wall MM, Sun D, Pezzuto JM, Chang LC (2015) Determination of the absolute configuration of chaetoviridins and other bioactive azaphilones from the endophytic fungus Chaetomium globosum. Bioorg Med Chem Lett 25:4719 406. Sun C, Ge X, Mudassir S, Zhou L, Yu G, Che Q, Zhang G, Peng J, Gu Q, Zhu T, Li D (2019) New glutamine-containing azaphilone alkaloids from deep-sea-derived fungus Chaetomium globosum HDN151398. Mar Drugs 17:253 407. Wang W, Yang J, Liao Y-Y, Cheng G, Chen J, Cheng X-D, Qin J-J, Shao Z (2020) Cytotoxic nitrogenated azaphilones from the deep-sea-derived fungus Chaetomium globosum MP4S01-7. J Nat Prod 83:1157 408. Wang W, Liao Y, Chen R, Hou Y, Ke W, Zhang B, Gao M, Shao Z, Chen J, Li F (2018) Chlorinated azaphilone pigments with antimicrobial and cytotoxic activities isolated from the deep sea derived fungus Chaetomium sp. NA-S01-R1. Mar Drugs 16:61 409. Zhang X-Y, Tan X-M, Yu M, Yang J, Sun B-D, Qin J-C, Guo L-P, Ding G (2021) Bioactive metabolites from the desert plant-associated endophytic fungus Chaetomium globosum (Chaetomiaceae). Phytochemistry 185:112701

Naturally Occurring Organohalogen Compounds …

425

410. Yamada T, Doi M, Shigeta H, Muroga Y, Hosoe S, Numata A, Tanaka R (2008) Absolute stereostructures of cytotoxic metabolites, chaetomugilins A-C, produced by a Chaetomium species separated from a marine fish. Tetrahedron Lett 49:4192 411. Yasuhide M, Yamada T, Numata A, Tanaka R (2008) Chaetomugilins, new selectively cytotoxic metabolites, produced by a marine fish-derived Chaetomium species. J Antibiot 61:615 412. Qin J-C, Zhang Y-M, Gao J-M, Bai M-S, Yang S-X, Laatsch H, Zhang A-L (2009) Bioactive metabolites produced by Chaetomium globosum, an endophytic fungus isolated from Ginkgo biloba. Bioorg Med Chem Lett 19:1572 413. Yamada T, Yasuhide M, Shigeta H, Numata A, Tanaka R (2009) Absolute stereostructures of chaetomugilins G and H produced by a marine-fish-derived Chaetomium species. J Antibiot 62:353 414. Muroga Y, Yamada T, Numata A, Tanaka R (2009) Chaetomugilins I-O, new potent cytotoxic metabolites from a marine-fish-derived Chaetomium species. Stereochemistry and biological activities. Tetrahedron 65:7580 415. Yamada T, Muroga Y, Tanaka R (2009) New azaphilones, seco-chaetomugilins A and D, produced by a marine-fish-derived Chaetomium globosum. Mar Drugs 7:249 416. Muroga Y, Yamada T, Numata A, Tanaka R (2010) 11- and 4 -Epimers of chaetomugilin A, novel cytostatic metabolites from marine fish-derived fungus Chaetomium globosum. Helv Chim Acta 93:542 417. Yamada T, Muroga Y, Jinno M, Kajimoto T, Usami Y, Numata A, Tanaka R (2011) New class azaphilone produced by a marine fish-derived Chaetomium globosum. The stereochemistry and biological activities. Bioorg Med Chem 19:4106 418. Yamada T, Jinno M, Kikuchi T, Kajimoto T, Numata A, Tanaka R (2012) Three new azaphilones produced by a marine fish-derived Chaetomium globosum. J Antibiot 65:413 419. Li X, Tian Y, Yang S, Zhang Y, Qin J (2013) Cytotoxic azaphilone alkaloids from Chaetomium globosum TY1. Bioorg Med Chem Lett 23:2945 420. Zu W-Y, Tang J-W, Hu K, Zhou Y-F, Gou L-L, Su X-Z, Lei X, Sun H-D, Puno P-T (2021) Chaetolactam A, an azaphilone derivative from the endophytic fungus Chaetomium sp. g1. J Org Chem 86:475 421. Chen C, Wang J, Zhu H, Wang J, Xue Y, Wei G, Guo Y, Tan D, Zhang J, Yin C, Zhang Y (2016) Chaephilones A and B, two new azaphilone derivatives isolated from Chaetomium globosum. Chem Biodivers 13:422 422. Gao W, Chai C, Li X-N, Sun W, Li F, Chen C, Wang J, Zhu H, Wang Y, Hu Z, Zhang Y (2020) Two anti-inflammatory chlorinated azaphilones from Chaetomium globosum TW1-1 cultured with 1-methyl-l-tryptophan and structure revision of chaephilone C. Tetrahedron Lett 61:151516 423. Zhou S, Wang M, Zhao H, Huang Y, Lin Y, Tan G, Chen S (2016) Penicilazaphilone C, a new antineoplastic and antibacterial azaphilone from the marine fungus Penicillium sclerotiorum. Arch Pharm Res 39:1621 424. Wang C-Y, Hao J-D, Ning X-Y, Wu J-S, Zhao D-L, Kong C-J, Shao C-L, Wang C-Y (2018) Penicilazaphilones D and E: two new azaphilones from a sponge-derived strain of the fungus Penicillium sclerotiorum. RSC Adv 8:4348 425. Tang J-L, Zhou Z-Y, Yang T, Yao C, Wu L-W, Li G-Y (2019) Azaphilone alkaloids with antiinflammatory activity from fungus Penicillium sclerotiorum cib-411. J Agric Food Chem 67:2175 426. Jia Q, Du Y, Wang C, Wang Y, Zhu T, Zhu W (2019) Azaphilones from the marine spongederived fungus Penicillium sclerotiorum OUCMDZ-3839. Mar Drugs 17:260 427. Liu Z, Qiu P, Liu H, Li J, Shao C, Yan T, Cao W, She Z (2019) Identification of antiinflammatory polyketides from the coral-derived fungus Penicillium sclerotiorum: in vitro approaches and molecular-modeling. Bioorg Chem 88:102973 428. Zhang L, Long Y, Lei X, Xu J, Huang Z, She Z, Lin Y, Li J, Liu L (2016) Azaphilones isolated from an alga-derived fungus Penicillium sp. ZJ-27. Phytochem Lett 18:180

426

G. W. Gribble

429. Kim SM, Son S, Kim JW, Jeon ES, Ko S-K, Ryoo I-J, Shin K-S, Hirota H, Takahashi S, Osada H, Jang J-H, Ahn JS (2015) Penidioxolanes A and B, 1,3-dioxolane containing azaphilone derivatives from marine-derived Penicillium sp. KCB12C078. Nat Prod Sci 21:231 430. Hemtasin C, Kanokmedhakul S, Moosophon P, Soytong K, Kanokmedhakul K (2016) Bioactive azaphilones from the fungus Penicillium multicolor CM01. Phytochem Lett 16:56 431. Son S, Ko S-K, Kim JW, Lee JK, Jang M, Ryoo I-J, Hwang GJ, Kwon MC, Shin K-S, Futamura Y, Hong Y-S, Oh H, Kim BY, Ueki M, Takahashi S, Osada H, Jang J-H, Ahn JS (2016) Structures and biological activities of azaphilones produced by Penicillium sp. KCB11A109 from a ginseng field. Phytochemistry 122:154 432. Chen M, Shen N-X, Chen Z-Q, Zhang F-M, Chen Y (2017) Penicilones A-D, anti-MRSA azaphilones from the marine-derived fungus Penicillium janthinellum HK1-6. J Nat Prod 80:1081 433. Chen M, Zheng Y-Y, Chen Z-Q, Shen N-X, Shen L, Zhang F-M, Zhou X-J, Wang C-Y (2019) NaBr-Induced production of brominated azaphilones and related tricyclic polyketides by the marine-derived fungus Penicillium janthinellum HK1-6. J Nat Prod 82:368 434. Frank M, Hartmann R, Plenker M, Mándi A, Kurtán T, Özkaya FC, Müller WEG, Kassack MU, Hamacher A, Lin W, Liu Z, Proksch P (2019) Brominated azaphilones from the spongeassociated fungus Penicillium canescens strain 4.14.6a. J Nat Prod 82:2159 435. Bang S, Baek JY, Kim GJ, Kim J, Kim S, Deyrup ST, Choi H, Kang KS, Shim SH (2021) Azaphilones from an endophytic Penicillium sp. prevent neuronal cell death via inhibition of MAPKs and reduction of Bax/Bcl-2 ratio. J Nat Prod 84:2226 436. Jansen N, Ohlendorf B, Erhard A, Bruhn T, Bringmann G, Imhoff JF (2013) Helicusin E, isochromophilone X and isochromophilone XI: new chloroazaphilones produced by the fungus Bartalinia robillardoides strain LF550. Mar Drugs 11:800 437. Zang L-Y, Wei W, Wang T, Guo Y, Tan R-X, Ge H-M (2012) Isochromophilones from an endophytic fungus Diaporthe sp. Nat Prod Bioprospect 2:117 438. Luo X, Lin X, Tao H, Wang J, Li J, Yang B, Zhou X, Liu Y (2018) Isochromophilones A–F, cytotoxic chloroazaphilones from the marine mangrove endophytic fungus Diaporthe sp. SCSIO 41011. J Nat Prod 81:934 439. Guo Q, Dong L, Zang X, Gu Z, He X, Yao L, Cao L, Qiu J, Guan X (2015) A new azaphilone from the entomopathogenic fungus Hypocrella sp. Nat Prod Res 29:2000 440. Gu B-B, Wu Y, Tang J, Jiao W, Li L, Sun F, Wang S-P, Yang F, Lin H-W (2018) Azaphilone and isocoumarin derivatives from the sponge-derived fungus Eupenicillium sp. 6A-9. Tetrahedron Lett 59:3345 441. Cao F, Meng Z-H, Mu X, Yue Y-F, Zhu H-J (2019) Absolute configuration of bioactive azaphilones from the marine-derived fungus Pleosporales sp. CF09-1. J Nat Prod 82:386 442. El-Kashef DH, Youssel FS, Hartmann R, Knedel T-O, Janiak C, Lin W, Reimche I, Teusch N, Liu Z, Proksch P (2020) Azaphilones from the Red Sea fungus Aspergillus falconensis. Mar Drugs 18:204 443. Chen S, Liu Z, Chen Y, Tan H, Liu H, Zhang W (2021) Tersaphilones A-E, cytotoxic chlorinated azaphilones from the deep-sea-derived fungus Phomopsis tersa FS441. Tetrahedron 78:131806 ˇ 444. Cikoš A-M, Jurin M, Což-Rakovac R, Joki´c S, Jerkovi´c I (2019) Update on monoterpenes from red macroalgae: isolation, analysis, and bioactivity. Mar Drugs 17:537 445. Mann MGA, Mkwananzi HB, Antunes EM, Whibley CE, Hendricks DT, Bolton JJ, Beukes DR (2007) Halogenated monoterpene aldehydes from the South African marine alga Plocamium corallorhiza. J Nat Prod 70:596 446. Afolayan AF, Mann MGA, Lategan CA, Smith PJ, Bolton JJ, Beukes DR (2009) Antiplasmodial halogenated monoterpenes from the marine red alga Plocamium cornutum. Phytochemistry 70:597 447. Antunes EM, Afolayan AF, Chiwakata MT, Fakee J, Knott MG, Whibley CE, Hendricks DT, Bolton JJ, Beukes DR (2011) Identification and in vitro anti-esophageal cancer activity of a series of halogenated monoterpenes isolated from the South African seaweeds Plocamium suhrii and Plocamium cornutum. Phytochemistry 72:769

Naturally Occurring Organohalogen Compounds …

427

448. Vasconcelos MA, Ferreira WJ, Pereira RC, Cavalcanti DN, Teixeira VL (2010) Chemical constituents from the red alga Plocamium brasiliense (Greville) M. Howe and W.R. Taylor. Biochem Syst Ecol 38:119 449. Timmers MA, Dias DA, Urban S (2012) Application of HPLC-NMR in the identification of plocamenone and isoplocamenone from the marine red alga Plocamium angustum. Mar Drugs 10:2089 450. Bucher C, Deans RM, Burns NZ (2015) Highly selective synthesis of halomon, plocamenone, and isoplocamenone. J Am Chem Soc 137:12784 451. Kutateladze AG, Reddy DS (2017) High-throughput in silico structure validation and revision of halogenated natural products is enabled by parametric corrections to DFT-computed 13 C NMR chemical shifts and spin–spin coupling constants. J Org Chem 82:3368 452. Vogel CV, Pietraszkiewicz H, Sabry OM, Gerwick WH, Valeriote FA, Vanderwal CD (2014) Enantioselective divergent syntheses of several polyhalogenated Plocamium monoterpenes and evaluation of their selectivity for solid tumors. Angew Chem Int Ed 53:12205 453. Hu DX, Seidl FJ, Bucher C, Burns NZ (2015) Catalytic chemo-, regio-, and enantioselective bromochlorination of allylic alcohols. J Am Chem Soc 137:3795 454. Cheng J, Li Y-H, Huang J, Yang Z (2021) Total syntheses of vicinal dichloride monoterpenes enabled by aza-Belluš–Claisen rearrangement. Org Lett 23:8465 455. Motti CA, Thomas-Hall P. Hagiwara KA, Simmons CJ, Willis R, Wright AD (2014) Accelerated identification of halogenated monoterpenes from Australian specimens of the red algae Plocamium hamatum and Plocamium costatum. J Nat Prod 77:1193 456. Sabry OMM, Goeger DE, Valeriote FA, Gerwick WH (2017) Cytotoxic halogenated monoterpenes from Plocamium cartilagineum. Nat Prod Res 31:261 457. Shilling AJ, von Salm JL, Sanchez AR, Kee Y, Amsler CD, McClintock JB, Baker BJ (2019) Anverenes B-E, new polyhalogenated monoterpenes from the Antarctic red alga Plocamium cartilagineum. Mar Drugs 17:230 458. Vetter W, Rosenfelder N, Kraan S, Hiebl J (2008) Structure and origin of the natural halogenated monoterpene MHC-1 and its concentrations in marine mammals and fish. Chemosphere 73:7 459. Covaci A, Losada S, Roosens L, Vetter W, Santos FJ, Neels H, Storelli A, Storelli MM (2008) Anthropogenic and naturally occurring organobrominated compounds in two deep-sea fish species from the Mediterranean Sea. Environ Sci Technol 42:8654 460. Vetter W, Haase-Aschoff P, Rosenfelder N, Komarova T, Mueller JF (2009) Determination of halogenated natural products in passive samplers deployed along the Great Barrier Reef, Queensland/Australia. Environ Sci Technol 43:6131 461. Rosenfelder N, Vetter W (2012) Stable carbon isotope composition (δ13 C values) of the halogenated monoterpene MHC-1 as found in fish and seaweed from different marine regions. J Environ Monit 14:845 462. Hauler C, Rimkus G, Risacher C, Knölker H-J, Vetter W (2014) Concentrations of halogenated natural products versus PCB 153 in bivalves from the North and Baltic Seas. Sci Total Environ 490:994 463. Wu Q, Bouwman H, Uren RC, van der Lingen CD, Vetter W (2019) Halogenated natural products and anthropogenic persistent organic pollutants in chokka squid (Loligo reynaudii) from three sites along the South Atlantic and Indian Ocean coasts of South Africa. Environ Pollut 255:113282 464. Wu Q, Krauß S, Vetter W (2020) Occurrence and fate studies (sunlight exposure and stable carbon isotope analysis) of the halogenated natural product MHC-1 and its producer Plocamium cartilagineum. Sci Total Environ 736:139680 465. Wu Q, Schlag S, Uren R, van der Lingen CD, Bouwman H, Vetter W (2020) Polyhalogenated compounds (halogenated natural products and POPs) in sardine (Sardinops sagax) from the South Atlantic and Indian Oceans. J Agric Food Chem 68:6084 466. Cariou R, Méndez-Fernandez P, Hutinet S, Guitton Y, Caurant F, Bruno LB, Spitz J, Vetter W, Dervilly G (2021) Nontargeted LC/ESI-HRMS detection of polyhalogenated compounds in marine mammals stranded on French Atlantic coasts. ACS EST Water 1:309

428

G. W. Gribble

467. Wu Q, Munschy C, Aminot Y, Bodin N, Vetter W (2021) High levels of halogenated natural products in large pelagic fish from the Western Indian Ocean. Environ Sci Pollut Res 28:55252 468. Wu Q, Müller M, Hammerschick T, Mitschang W, Kuhlenkamp R, Vetter W (2021) Fast isolation of the environmentally relevant halogenated natural product MHC-1 by means of countercurrent chromatography. Chemosphere 284:131310 469. Bracegirdle J, Sohail Z, Fairhurst MJ, Gerth ML, Zuccarello GC, Hashmi MA, Keyzers RA (2019) Costatone C—a new halogenated monoterpene from the New Zealand red alga Plocamium angustum. Mar Drugs 17:418 470. Chen J-J, Li W-X, Gao K, Jin X-J, Yao X-J (2012) Absolute structures of monoterpenoids with a δ-lactone-containing skeleton from Ligularia hodgsonii. J Nat Prod 75:1184 471. Aguinaldo AM, Abe F, Yamauchi T, Padolina WG (1995) Germacranolides of Mikania cordata. Phytochemistry 38:1441 472. Khan SB, Riaz N, Afza N, Malik A, Azhar-ul-Haq AZ, Lodhi MA, Choudhary MI (2004) Urease inhibiting guaianolides from Amberboa ramosa. Polish J Chem 78:2075 473. Chen X, Zhan Z-J, Yue J-M (2006) Sesquiterpenoids from Vernonia cinerea. Nat Prod Res 20:125 474. Dall’Acqua S, Viola G, Giorgetti M, Loi MC, Innocenti G (2006) Two new sesquiterpene lactones from the leaves of Laurus nobilis. Chem Pharm Bull 54:1187 475. Boudjerda A, Zater H, Benayache S, Chalchat J-C, González-Platas J, León F, Brouard I, Bermejo J, Benayache F (2008) A new guaianolide and other constituents from Achillea ligustica. Biochem Syst Ecol 36:461 476. Hegazy M-EF, Mohamed AE-HH, El-Sayed MA, Ohta S (2008) A new chlorine-containing sesquiterpene lactone from Achillea ligustica. Z Naturforsch 63b:105 477. Huang Z-S, Pei Y-H, Liu C-M, Lin S, Tang J, Huang D-S, Song T-F, Lu L-H, Gao Y-P, Zhang W-D (2010) Highly oxygenated guaianolides from Artemisia dubia. Planta Med 76:1710 478. Liu S, Zhao Y, Herring C, Janiak C, Müller WEG, Akoné SH, Liu Z, Proksch P (2019) Sesquiterpenoids from the endophytic fungus Rhinocladiella similis. J Nat Prod 82:1055 479. Yamada K, Ojika M, Kigoshi H (2007) Ptaquiloside, the major toxin of bracken, and related terpene glycosides: chemistry, biology and ecology. Nat Prod Rep 24:798 480. Jensen PH, Jacobsen OS, Hansen HCB, Juhler RK (2008) Quantification of ptaquiloside and pterosin B in soil and groundwater using liquid chromatography-tandem mass spectrometry (LC-MS/MS). J Agric Food Chem 56:9848 481. Mohammad RH, Nur-e-Alam M, Lahmann M, Parveen I, Tizzard GJ, Coles SJ, Fowler M, Drake AF, Heyes D, Thoss V (2016) Isolation and characterisation of 13 pterosins and pterosides from bracken (Pteridium aquilinum (L.) (Kuhn) rhizome. Phytochemistry 128:82 482. Kang H-S, Ji S-A, Park S-H, Kim J-P (2017) Lepistatins A-C, chlorinated sesquiterpenes from the cultured basidiomycete Lepista sordida. Phytochemistry 143:111 483. Shi H-M, Long B-S, Cui X-M, Min Z-D (2005) A new bisabolane sesquiterpenoid from Euphorbia chrysocoma. J Asian Nat Prod Res 7:857 484. Shi S-Y, Zhao Y, Zhang Y-P, Huang K-L (2008) Furanoeremophilanes from Ligularia atroviolacea. Fitoterapia 79:476 485. Zhao J, Wu H, Huang KX, Shi SY, Peng H, Sun XF, Chen LR, Zheng QX, Zhang QJ, Hao XJ, Stöckigt J, Li XK, Zhao Y, Qu J (2008) One chloro-furoeremophilanoid and two new natural dimers from Ligularia atroviolacea. Chin Chem Lett 19:1319 486. Wang X, Sun L, Huang K, Shi S, Zhang L, Xu J, Peng H, Sun X, Wang L, Wu X, Zhao Y, Li X, Stöckigt J, Qu J (2009) Phytochemical investigation and cytotoxic evaluation of the components of the medicinal plant Ligularia atroviolacea. Chem Biodivers 6:1053 487. Onuki H, Yamazaki M, Nakamura A, Hanai R, Kuroda C, Gong X, Shen Y, Hirota H (2008) Chemical constituents and diversity of Ligularia lankongensis in Yunnan Province of China. J Nat Prod 71:520 488. Gan L-S, Zheng Y-L, Mo J-X, Liu X, Li X-H, Zhou C-X (2009) Sesquiterpene lactones from the root tubers of Lindera aggregata. J Nat Prod 72:1497

Naturally Occurring Organohalogen Compounds …

429

489. Wang Q, Chen T-H, Bastow KF, Morris-Natschke SL, Lee K-H, Chen D-F (2013) Songaricalarins A-E, cytotoxic oplopane sesquiterpenes from Ligularia songarica. J Nat Prod 76:305 490. Chen P, Qu L, Wang P-P, Xiang L (2013) Two halogenated sesquiterpenoids from the fruits of Alpinia oxyphylla. Helv Chim Acta 96:1163 491. Zhang G, Sun S, Zhu T, Lin Z, Gu J, Li D, Gu Q (2011) Antiviral isoindolone derivatives from an endophytic fungus Emericella sp. associated with Aegiceras corniculatum. Phytochemistry 72:1436 492. Daengrot C, Rukachaisirikul V, Tansakul C, Thongpachang T, Phongpaichit S, Bowornwiriyapan K, Sakayaroj J (2015) Eremophilane sesquiterpenes and diphenyl thioesters from the soil fungus Penicillium copticola PSU-RSPG138. J Nat Prod 78:615 493. Yang H-X, Ai H-L, Feng T, Wang W-X, Wu B, Zheng Y-S, Sun H, He J, Li Z-H, Liu J-K (2018) Trichothecrotocins A-C, antiphytopathogenic agents from potato endophytic fungus Trichothecium crotocinigenum. Org Lett 20:8069 494. Hao Z-Y, Ni G, Liang D, Liu Y-F, Zhang C-L, Wang Y, Zhang Q-J, Chen R-Y, Yu D-Q (2021) A new brominated norsesquiterpene glycoside from the rhizomes of Acorus tatarinowii Schott. Nat Prod Commun 16:1 495. Wen J, Shi H, Xu Z, Chang H, Jia C, Zan K, Jiang Y, Tu P (2010) Dimeric guaianolides and sesquiterpenoids from Artemisia anomala. J Nat Prod 73:67 496. Monde K, Taniguchi T, Miuri N, Vairappan CS, Suzuki M (2006) Absolute configurations of brominated sesquiterpenes determined by vibrational circular dichroism. Chirality 18:335 497. Monde K, Taniguchi T, Miura N, Vairappan CS, Suzuki M (2006) Absolute configurations of endoperoxides determined by vibrational circular dichroism (VCD). Tetrahedron Lett 47:4389 498. Vairappan CS, Suzuki M, Ishii T, Okino T, Abe T, Masuda M (2008) Antibacterial activity of halogenated sesquiterpenes from Malaysian Laurencia spp. Phytochemistry 69:2490 499. Sung P-J, Chuang L-F, Kuo J, Fan T-Y, Hu W-P (2007) Rumphellatin A, the first chloridecontaining caryophyllane-type norsesquiterpenoid from Rumphella antipathies. Tetrahedron Lett 48:3987 500. Sung P-J, Chuang L-F, Hu W-P (2007) Rumphellatins B and C, two new caryophyllane-type hemiketal norsesquiterpenoids from the Formosan gorgonian coral Rumphella antipathies. Bull Chem Soc Jpn 80:2395 501. Sung P-J, Su Y-D, Hwang T-L, Chuang L-F, Chen J-J, Li J-J, Fang L-S, Wang W-H (2008) Rumphellatin D, a novel chlorinated caryophyllane from Gorgonian coral Rumphella antipathies. Chem Lett 37:1244 502. Su H, Yuan Z-H, Li J, Guo S-J, Deng L-P, Han L-J, Zhu X-B, Shi D-Y (2009) Sesquiterpenes from the marine red alga Laurencia saitoi. Helv Chim Acta 92:1291 503. Su H, Shi D-Y, Li J, Guo S-J, Li L-L, Yuan Z-H, Zhu X-B (2009) Sesquiterpenes from Laurencia similis. Molecules 14:1889 504. Ioannou E, Nappo M, Avila C, Vagias C, Roussis V (2009) Metabolites from the sea hare Aplysia fasciata. J Nat Prod 72:1716 505. Bogdanov A, Papu A, Kehraus S, Cruesemann M, Wägele H, König GM (2020) Metabolome of the Phyllidiella pustulosa species complex (Nudibranchia, hHeterobranchia, Gastropoda) reveals rare dichloroimidic sesquiterpene derivatives from a phylogenetically distinct and undescribed clade. J Nat Prod 83:2785 506. Vansteelandt M, Blanchet E, Egorov M, Petit F, Toupet L, Bondon A, Montaeu F, Le Bizec B, Thomas OP, Pouchus YF, Le Bot R, Grovel O (2013) Ligerin, an antiproliferative chlorinated sesquiterpenoid from a marine-derived Penicillium strain. J Nat Prod 76:297 507. Makhanu DS, Yokoyama M, Miono T, Maesato T, Maedomari M, Wisespongpand P, Kuniyoshi M (2006) New sesquiterpenes from the Okinawan red alga Laurencia luzonensis. Bull Fac Sci Univ Ryukyus 81:115 508. Ji N-Y, Li X-M, Zhang Y, Wang B-G (2007) Two new halogenated chamigrane-type sesquiterpenes and other secondary metabolites from the marine red alga Laurencia okamurai and their chemotaxonomic significance. Biochem Syst Ecol 35:627

430

G. W. Gribble

509. Liang Y, Li XM, Cui CM, Li CS, Wang BG (2009) A new rearranged chamigrane sesquiterpene from Laurencia okamurai. Chin Chem Lett 20:190 510. Li X-D, Ding W, Miao F-P, Ji N-Y (2012) Halogenated chamigrane sesquiterpenes from Laurencia okamurae. Magn Reson Chem 50:174 511. Li X-D, Miao F-P, Li K, Ji N-Y (2012) Sesquiterpenes and acetogenins from the marine red alga Laurencia okamurai. Fitoterapia 83:518 512. Liang Y, Li X-M, Cui C-M, Li C-S, Sun H, Wang B-G (2012) Sesquiterpene and acetogenin derivatives from the marine red alga Laurencia okamurai. Mar Drugs 10:2817 513. Shubina LK, Fedorov SN, Kalinovskiy AI, Dmitrenok AS, Jin JO, Song MG, Kwak JY, Stonik VA (2007) Four new chamigrane sesquiterpenoids from the opistobranch mollusk Aplysia dactylomela. Russ Chem Bull Int Ed 56:2109 514. Diaz-Marrero A-R, de la Rosa JM, Brito I, Darias J, Cueto M (2012) Dactylomelatriol, a biogenetically intriguing omphalane-derived marine sesquiterpene. J Nat Prod 75:115 515. Hegazy M-EF, Moustfa AY, Mohamed AE-HH, Alhammady MA, Elbehairi SEI, Ohta S, Paré PW (2014) New cytotoxic halogenated sesquiterpenes from the Egyptian sea hare, Aplysia oculifera. Tetrahedron Lett 55:1711 516. Ji N-Y, Li X-M, Li K, Gloer JB, Wang B-G (2009) Halogenated sesquiterpenes and nonhalogenated linear C15 -acetogenins from the marine red alga Laurencia composita and their chemotaxonomic significance. Biochem Syst Ecol 36:938 517. Ji N-Y, Li X-M, Wang B-G (2010) Sesquiterpenes and other metabolites from the marine red alga Laurencia composita (Rhodomelaceae). Helv Chim Acta 93:2281 518. Li X-D, Miao F-P, Yin X-L, Liu J-L, Ji N-Y (2012) Sesquiterpenes from the marine red alga Laurencia composita. Fitoterapia 83:1191 519. Li X-D, Miao F-P, Liang X-R, Wang B-G, Ji N-Y (2013) Two halosesquiterpenes from Laurencia composita. RSC Adv 3:1953 520. Yu X-Q, Jiang C-S, Zhang Y, Sun P, Kurtán T, Mándi A, Li X-L, Yao L-G, Liu AH, Wang B, Guo Y-W, Mao S-C (2017) Compositacins A-K: bioactive chamigrane-type halosesquiterpenoids from the red alga Laurencia composita Yamada. Phytochemistry 136:81 521. Díaz-Marrero AR, Brito I, de la Rosa JM, D’Croz L, Fabelo O, Ruiz-Pérez C, Darias J, Cueto M (2009) Novel lactone chamigrene-derived metabolites from Laurencia majuscula. Eur J Org Chem:1407 522. Ji N-Y, Li X-M, Li K, Wang B-G (2009) Halogenated sesquiterpenes from the marine red alga Laurencia saitoi (Rhodomelaceae). Helv Chim Acta 92:1873 523. Dias DA, Urban S (2011) Phytochemical studies of the Southern Australian marine alga, Laurencia elata. Phytochemistry 72:2081 524. da Silva Machado FL, Ventura TLB, de Souza Gestinari LM, Cassano V, Resende JALC, Kaiser CR, Lasunskaia EB, Muzitano MF, Soares AR (2014) Sesquiterpenes from the Brazilian red alga Laurencia dendroidea. J. Agardh. Moleules 19:3181 525. Chen J-Y, Huang C-Y, Lin Y-S, Hwang T-L, Wang W-L, Chiou S-F, Sheu J-H (2016) Halogenated sesquiterpenoids from the red alga Laurencia tristicha collected in Taiwan. J Nat Prod 79:2315 526. Nuzzo G, Gomes BA, Amodeo P, Matthews-Cascon H, Cutignano A, Costa-Lotufo LV, Monteiro FAC, Pessoa ODL, Fontana A (2017) Isolation of chamigrene sesquiterpenes and absolute configuration of isoobtusadiene from the brittle star Ophionereis reticulata. J Nat Prod 80:3049 527. Ji N-Y, Wen W, Li X-M, Xue Q-Z, Xiao H-L, Wang B-G (2009) Brominated selinane sesquiterpenes from the marine brown alga Dictyopteris divaricata. Mar Drugs 7:355 528. Lane AL, Mular L, Drenkard EJ, Shearer TL, Engel S, Fredericq S, Fairchild CR, Prudhomme J, Le Roch K, Haye ME, Aalbersberg W, Kubanek J (2010) Ecological leads for natural product discovery: novel sesquiterpene hydroquinones from the red macroalga Peyssonnelia sp. Tetrahedron 66:455 529. Wu G, Lin A, Gu Q, Zhu T, Li D (2013) Four new chloro-eremophilane sesquiterpenes from an Antarctic deep-sea derived fungus, Penicillium sp. PR19N-1. Mar Drugs 11:1399

Naturally Occurring Organohalogen Compounds …

431

530. Ji N-Y, Li X-M, Ding L-P, Wang B-G (2016) Halogenated eudesmane derivatives and other terpenes from the marine red alga Laurencia pinnata and their chemotaxonomic significance. Biochem Syst Ecol 64:1 531. Ngokpol S, Suwakulsiri W, Sureram S, Lirdprapamongkol K, Aree T, Wiyakrutta S, Mahidol C, Ruchirawat S, Kittakoop P (2015) Drimane sesquiterpene-conjugated amino acids from a marine isolate of the fungus Talaromyces minioluteus (Penicillium minioluteum). Mar Drugs 13:3567 532. Kamada T, Phan C-S, Vairappan CS (2019) New anti-bacterial halogenated tricyclic sesquiterpenes from Bornean Laurencia majuscula (Harvey) Lucas. Nat Prod Res 33:464 533. Lhullier C, Falkenberg M, Ioannou E, Quesada A, Papazafiri P, Horta PA, Schenkel EP, Vagias C, Roussis V (2010) Cytotoxic halogenated metabolites from the Brazilian red alga Laurencia catarinensis. J Nat Prod 73:27 534. Díaz-Marrero AR, Brito I, de la Rosa JM, Darias J, Cueto M (2008) Gomerones A-C, halogenated sesquiterpenoids with a novel carbon skeleton from Laurencia majuscula. Tetrahedron 64:10821 535. Huwyler N, Carreira EM (2012) Total synthesis and stereochemical revision of the chlorinated sesquiterpene (±)-gomerone C. Angew Chem Int Ed 51:13066 536. Crimmins MT, Hughes CO (2012) Total synthesis of the proposed structure of aldingenin B. Org Lett 14:2168 537. Takahashi S, Yasuda M, Nakamura T, Hatano K, Matsuoka K, Koshino H (2014) Synthesis and structural revision of a brominated sesquiterpenoid, aldingenin C. J Org Chem 79:9373 538. Mukhina OA, Koshino H, Crimmins MT, Kutateladze AG (2015) Computationally driven reassignment of the structures of aldingenins A and B. Tetrahedron Lett 56:4900 539. Sun J, Shi D, Ma M, Li S, Wang S, Han L, Yang Y, Fan X, Shi J, He L (2005) Sesquiterpenes from the red alga Laurencia tristicha. J Nat Prod 68:915 540. Sun J, Shi D-Y, Li S, Wang S-J, Han L-J, Fan X, Yang Y-C, Shi J-G (2007) Chemical constituents of the red alga Laurencia tristicha. J Asian Nat Prod Res 9:725 541. Ji NY, Li XM, Li K, Ding L-P, Wang B-G (2008) Laurane-derived sesquiterpenes from the marine red alga Laurencia tristicha (Rhodomelaceae). Nat Prod Res 22:715 542. Yu X-Q, He W-F, Liu D-Q, Feng M-T, Fang Y, Wang B, Feng L-H, Guo Y-W, Mao S-C (2014) A seco-laurane sesquiterpene and related laurane derivatives from the red alga Laurencia okamurai Yamada. Phytochemistry 103:162 543. Li X-L, Kurtán T, Hu J-C, Mándi A, Li J, Li X-W, Guo Y-W (2017) Structural and stereochemical studies of laurokamurols A-C, uncommon bis-sesquiterpenoids from the Chinese red alga Laurencia okamurai Yamada. J Agric Food Chem 65:1550 544. Yang X-X, Su Y-Z, Tan J, Cai C-E, He P-M, Jia R (2018) A new dimeric sesquiterpene and other related derivatives from the marine red alga Laurencia okamurai. Biochem Syst Ecol 79:57 545. Srikrishna A, Beeraiah B, Babu RR (2008) Enantioselective total synthesis and assignment of the absolute configuration of (+)-laurokamurene B. Tetrahedron: Asymmetry 19:624 546. Kladi M, Vagias C, Papazafiri P, Furnari G, Serio D, Roussis V (2007) New sesquiterpenes from the red alga Laurencia microcladia. Tetrahedron 63:7606 547. Dias DA, White JM, Urban S (2009) Laurencia filiformis: phytochemical profiling by conventional and HPLC-NMR approaches. Nat Prod Commun 4:157 548. Su S, Sun W-S, Wang B, Cheng W, Liang H, Zhao Y-Y, Zhang Q-Y, Wu J (2010) A novel brominated cuparene-derived sesquiterpene ether from the red alga Laurencia sp. J Asian Nat Prod Res 12:916 549. Bawakid NO, Alarif WM, Alorfi HS, Al-Footy KO, Alburae NA, Ghandourah MA, AlLihaibi SS, Abdul-Hameed ZH (2017) Antimicrobial sesquiterpenoids from Laurencia obtusa Lamouroux. Open Chem 15:219 550. Rengasamy KRR, Slavˇetínská LP, Kulkarni MG, Stirk WA, Van Staden J (2017) Cuparane sesquiterpenes from Laurencia natalensis Kylin as inhibitors of α-glucosidase, dipeptidyl peptidase IV and xanthine oxidase. Algal Res 25:178

432

G. W. Gribble

551. Singh AJ, Dattelbaum JD, Field JJ, Smart Z, Woolly EF, Barber JM, Heathcott R, Miller JH, Northcote PT (2013) Structurally diverse hamigerans from the New Zealand marine sponge Hamigera tarangaensis: NMR-directed isolation structure elucidation and antifungal activity. Org Biomol Chem 11:8041 552. Dattelbaum JD, Singh AJ, Field JJ, Miller JH, Northcote PT (2015) The nitrogenous hamigerans: unusual amino acid-derivatized aromatic diterpenoid metabolites from the New Zealand marine sponge Hamigera tarangaensis. J Org Chem 80:304 553. Woolly EF, Singh AJ, Russell ER, Miller JH, Northcote PT (2018) Hamigerans R and S: nitrogenous diterpenoids from the New Zealand marine sponge Hamigera tarangaensis. J Nat Prod 81:387 554. Núñez-Pons L, Carbone M, Vázquez J, Gavagnin M, Avila C (2013) Lipophilic defenses from alcyonium soft corals of Antarctica. J Chem Ecol 39:675 555. Prawat H, Mahidol C, Kaweetripob W, Wittayalai S, Ruchirawat S (2012) Iodo-sesquiterpene hydroquinone and brominated indole alkaloids from the Thai sponge Smenospongia sp. Tetrahedron 68:6881 556. Wu Q, Gao Y, Zhang M-M, Sheng L, Li J, Li X-W, Wang H, Guo Y-W (2019) New sesquiterpenoids from the South China Sea soft corals Clavularia viridis and Lemnalia flava. Beilstein J Org Chem 15:695 557. Dembitsky VM, Tolstikov AG, Tolstikov GA (2002) Natural halogenated diterpenoids. Chem Sustain Dev 10:253 558. Fang WS, Fang QC, Liang XT, Lu Y, Wu N, Zheng QT (1997) Taxuchin B, a new chlorinecontaining taxoid. Chin Chem Lett 8:231 559. Li S-H, Zhang H-J, Niu X-M, Yao P, Sun H-D, Fong HHS (2003) Novel taxoids from the Chinese yew Taxus yunnanensis. Tetrahedron 59:37 560. Sato K, Inaba Y, Park H-S, Akiyama T, Koyama T, Fukaya H, Aoyagi Y, Takeya K (2009) Cytotoxic bisnor- and norditerpene dilactones having 7α,8α-epoxy-9,11-enolide substructure from Podocarpus macrophyllus D. Don. Chem Pharm Bull 57:668 561. Guo P, Li Y, Xu J, Guo Y, Jin D-Q, Gao J, Hou W, Zhang T (2011) neo-Clerodane diterpenes from Ajuga ciliata Bunge and their neuroprotective activities. Fitoterapia 82:1123 562. Sun Z, Li Y, Jin D, Guo P, Song H, Xu J, Guo Y, Zhang L (2012) neo-Clerodane diterpenes from Ajuga decumbens and their inhibitory activities on LPS-induced NO production. Fitoterapia 83:1409 563. Dong B, Yang X, Liu W, An L, Zhang X, Tuerhong M, Du Q, Wang C, Abudukeremu M, Xu J, Lee D, Shuai L, Lall N, Guo Y (2020) Anti-inflammatory neo-clerodane diterpenoids from Ajuga pantantha. J Nat Prod 83:894 564. Mu Z-Q, Gao H, Huang Z-Y, Feng X-L, Yao X-S (2012) Puberunine and puberudine, two new C18 -diterpenoid alkaloids from Aconitum barbatum var. puberulum. Org Lett 14:2758 565. Li Y, Zhu Y-X, Zhang Z-X, Liu Y-L, Liu Y, Qu J, Ma S-G, Wang X-J, Yu S-S (2018) Diterpenoids from the fruits of Rhododendron molle, potent analgesics for acute pain. Tetrahedron 74:693 566. Zhou SZ, Yao S, Tang C, Ke C, Li L, Lin G, Ye Y (2014) Diterpenoids from the flowers of Rhododendron molle. J Nat Prod 77:1185 567. Allard P-M, Martin M-T, Dau M-ETH, Leyssen P, Guéritte F, Litaudon M (2012) Trigocherrin A, the first natural chlorinated daphnane diterpene orthoester from Trigonostemon cherrieri. Org Lett 14:342 568. Allard P-M, Leyssen P, Martin M-T, Bourjot M, Dumontet V, Eydoux C, Guillemot JC, Canard B, Poullain C, Guéritte F, Litaudon M (2012) Antiviral chlorinated daphnane diterpenoid orthoesters from the bark and wood of Trigonostemon cherrieri. Phytochemistry 84:160 569. Sato K, Sugawara K, Takeuchi H, Park H-S, Akiyama T, Koyama T, Fukaya H, Aoyagi Y, Takeya K (2009) New cytotoxic nor- and bisnorditerpene dilactones, makilactones A-D, from Podocarpus macrophyllus D. Don. Heterocycles 78:1453 570. Kladi M, Ntountaniotis D, Zervou M, Vagias C, Ioannou E, Roussis V (2014) Glandulaurencianols A-C, brominated diterpenes from the red alga, Laurencia glandulifera and the sea hare, Aplysia punctata. Tetrahedron Lett 55:2835

Naturally Occurring Organohalogen Compounds …

433

571. Petraki A, Ioannou E, Papazafiri P, Roussis V (2015) Dactylomelane diterpenes from the sea hare Aplysia depilans. J Nat Prod 78:462 572. Wu Q, Chen W-T, Li S-W, Ye J-Y, Huan X-J, Gavagnin M, Yao L-G, Wang H, Miao ZH, Li X-W, Guo Y-W (2019) Cytotoxic nitrogenous terpenoids from two South China Sea nudibranchs Phyllidiella pustulosa, Phyllidia coelestis, and their sponge-prey Acanthella cavernosa. Mar Drugs 17:56 573. Maschek JA, Mevers E, Diyabalanage T, Chen L, Ren Y, McClintock JB, Amsler CD, Wu J, Baker BJ (2012) Palmadorin chemodiversity from the Antarctic nudibranch Austrodoris kerguelenensis and inhibition of Jak2/STAT5-dependent HEL leukemia cells. Tetrahedron 68:9095 574. Takahashi H, Takahashi Y, Suzuki M, Abe T, Masuda M (2007) Crystal structure and absolute stereochemistry of neoirietetraol. Anal Sci 23:x103 575. Ji NY, Li XM, Cui CM, Wang BG (2007) Two new brominated diterpenes from Laurencia decumbens. Chin Chem Lett 18:957 576. Ji N-Y, Li X-M, Cui C-M, Wang B-G (2007) Terpenes and polybromoindoles from the marine red alga Laurencia decumbens (Rhodomelaceae). Helv Chim Acta 90:1731 577. Oguri Y, Watanabe M, Ishikawa T, Kamada T, Vairappan CS, Matsuura H, Kaneko K, Ishii T, Suzuki M, Yoshimura E, Nogata Y, Okino T (2017) New marine antifouling compounds from the red alga Laurencia sp. Mar Drugs 15:267 578. Vairappan CS, Ishii T, Lee TK, Suzuki M, Zhaoqi Z (2010) Antibacterial activities of a new brominated diterpene from Borneon Laurencia spp. Mar Drugs 8:1743 579. Dziwornu GA, Caira MR, de la Mare J-A, Edkins AL, Bolton JJ, Beukes DR, Sunassee SN (2017) Isolation, characterization and antiproliferative activity of new metabolites from the South African endemic red algal species Laurencia alfredensis. Molecules 22:513 580. Shaaban M, Abou-El-Wafa GSE, Golz C, Laatsch H (2021) New haloterpenes from the marine red alga Laurencia papillosa: structure elucidation and biological activity. Mar Drugs 19:35 581. Smyrniotopoulos V, Quesada A, Vagias C, Moreau D, Roussakis C, Roussis V (2008) Cytotoxic bromoditerpenes from the red alga Sphaerococcus coronopifolius. Tetrahedron 64:5184 582. Smyrniotopoulos V, Vagias C, Rahman MM, Gibbons S, Roussis V (2008) Brominated diterpenes with antibacterial activity from the red alga Sphaerococcus coronopifolius. J Nat Prod 71:1386 583. Smyrniotopoulos V, Vagias C, Rahman MM, Gibbons S, Roussis V (2010) Structure and antibacterial activity of brominated diterpenes from the red alga Sphaerococcus coronopifolius. Chem Biodivers 7:186 584. Smyrniotopoulos V, Vagias C, Rahman MM, Gibbons S, Roussis V (2010) Ioniols I and II, tetracyclic diterpenes with antibacterial activity, from Sphaerococcus coronopifolius. Chem Biodivers 7:666 585. Smyrniotopoulos V, Vagias C, Bruyère C, Lamoral-Theys D, Kiss R, Roussis V (2010) Structure and in vitro antitumor activity evaluation of brominated diterpenes from the red alga Sphaerococcus coronopifolius. Bioorg Med Chem 18:1321 586. Smyrniotopoulos V, Kiss R, Mathieu V, Vagias C, Roussis V (2015) Diterpenes with unprecedented skeletons from the red alga Sphaerococcus coronopifolius. Eur J Org Chem, 2848 587. Smyrniotopoulos V, de Andrade Tomaz AC, de Souza MFV, da Cunha EVL, Kiss R, Mathieu V, Ioannou E, Roussis V (2020) Halogenated diterpenes with in vitro antitumor activity from the red alga Sphaerococcus coronopifolius. Mar Drugs 18:29 588. Rodrigues D, Alves C, Horta A, Pinteus S, Silva J, Culioli G, Thomas OP, Pedrosa R (2015) Antitumor and antimicrobial potential of bromoditerpenes isolated from the red alga, Sphaerococcus coronopifolius. Mar Drugs 13:713 589. Lane AL, Stout EP, Hay ME, Prusak AC, Hardcastle K, Fairchild CR, Franzblau SG, Le Roch K, Prudhomme J, Aalbersberg W, Kubanek J (2007) Callophycoic acids and callophycols from the Fijian red alga Callophycus serratus. J Org Chem 72:7343

434

G. W. Gribble

590. Lane AL, Stout EP, Lin A-S, Prudhomme J, Le Roch K, Fairchild CR, Franzblau SG, Hay ME, Aalbersberg W, Kubanek J (2009) Antimalarial bromophycolides J-Q from the Fijian red alga Callophycus serratus. J Org Chem 74:2736 591. Teasdale ME, Shearer TL, Engel S, Alexander TS, Fairchild CR, Prudhomme J, Torres M, Le Roch K, Aalbersberg W, Hay ME, Kubanek J (2012) Bromophycoic acids: bioactive natural products from a Fijian red alga Callophycus sp. J Org Chem 77:8000 592. Lavoie S, Brumley D, Alexander TS, Jasmin C, Carranza FA, Nelson K, Quave CL, Kubanek J (2017) Iodinated meroditerpenes from a red alga Callophycus sp. J Org Chem 82:4160 593. Woolner VH, Gordon RMA, Miller JH, Lein M, Northcote PT, Keyzers RA (2018) Halogenated meroditerpenoids from a South Pacific collection of the red alga Callophycus serratus. J Nat Prod 81:2446 594. Kim JY, Alamsjah MA, Hamada A, Fujita Y, Ishibashi F (2006) Algicidal diterpenes from the brown alga Dictyota dichotoma. Biosci Biotechnol Biochem 70:2571 595. Kolesnikova SA, Lyakhova EG, Kalinovsky AI, Dmitrenok PS, Dyshlovoy SA, Stonik VA (2009) Diterpenoid hydroperoxides from the Far-Eastern brown alga Dictyota dichotoma. Aust J Chem 62:1185 596. Chen J, Li H, Zhao Z, Xia X, Li B, Zhang J, Yan X (2018) Diterpenes from the marine algae of the genus Dictyota. Mar Drugs 16:159 597. Reddy P, Urban S (2009) Meroditerpenoids from the southern Australian marine brown alga Sargassum fallax. Phytochemistry 70:250 598. Areche C, San-Martín A, Rovirosa J, Soto-Delgado J, Contreras R (2009) An unusual halogenated meroditerpenoid from Stypopodium flabelliforme: studies by NMR spectroscopic and computational methods. Phytochemistry 70:1315 599. Bugni TS, Singh MP, Chen L, Arias DA, Harper MK, Greenstein M, Maiese WM, Concepción GP, Mangalindan GC, Ireland CM (2004) Kalihinols from two Acanthella cavernosa sponges: inhibitors of bacterial folate biosynthesis. Tetrahedron 60:6981 600. Sun J-Z, Chen K-S, Yao L, Liu H-L, Guo Y-W (2009) A new kalihinol diterpene from the Hainan sponge Acanthella sp. Arch Pharm Res 32:1581 601. Xu Y, Li N, Jiao W-H, Wang R-P, Peng Y, Qi S-H, Song S-J, Chen W-S, Lin H-W (2012) Antifouling and cytotoxic constituents from the South China sea sponge Acanthella cavernosa. Tetrahedron 68:2876 602. Xu Y, Lang J-H, Jiao W-H, Wang R-P, Peng Y, Song S-J, Zhang B-H, Lin H-W (2012) Formamido-diterpenes from the South China sea sponge Acanthella cavernosa. Mar Drugs 10:1445 603. Rudi A, Benayahu Y, Kashman Y (2007) Negombins A-I, new chlorinated polyfunctional diterpenoids from the marine sponge Negombata species. Org Lett 9:2337 604. Costantino V, Fattorusso E, Mangoni A, Perinu C, Cirino G, De Gruttola L, Roviezzo F (2009) Tedanol: a potent anti-inflammatory ent-pimarane diterpene from the Caribbean sponge Tedania ignis. Bioorg Med Chem 17:7542 605. Kubota T, Iwai T, Takahashi-Nakaguchi A, Fromont J, Gonoi T, Kobayashi J (2012) Agelasines O-U, new diterpene alkaloids with a 9-N-methyladenine unit from a marine sponge Agelas sp. Tetrahedron 68:9738 606. Machida K, Matsumoto T, Fusetani N, Nakao Y (2017) Dolabellol A, a new halogenated diterpene isolated from the opisthobranch Dolabella auricularia. Chem Lett 46:1676 607. Kontiza I, Stavri M, Zloh M, Vagias C, Gibbons S, Roussis V (2008) New metabolites with antibacterial activity from the marine angiosperm Cymodocea nodosa. Tetrahedron 64:1696 608. Zhang Y, Adnani N, Braun DR, Ellis GA, Barns KJ, Parker-Nance S, Guzei IA, Bugni TS (2016) Micromonohalimanes A and B: antibacterial halimane-type diterpenoids from a marine Micromonospora species. J Nat Prod 79:2968 609. Meng L-H, Li X-M, Zhang F-Z, Wang Y-N, Wang B-G (2020) Talascortenes A-G, highly oxygenated diterpenoid acids from the sea-anemone-derived endozoic fungus Talaromyces scorteus AS-242. J Nat Prod 83:2528 610. Hemberger Y, Xu J, Wray V, Proksch P, Wu J, Bringmann G (2013) Pestalotiopens A and B: stereochemically challenging flexible sesquiterpene-cyclopaldic acid hybrids from Pestalotiopsis sp. Chem Eur J 19:15556

Naturally Occurring Organohalogen Compounds …

435

611. Afiyatullov SS, Kalinovsky AI, Antonov AS (2011) New virescenosides from the marinederived fungus Acremonium striatisporum. Nat Prod Commun 6:1063 612. Kong F-D, Ma Q-Y, Huang S-Z, Wang P, Wang J-F, Zhou L-M, Yuan J-Z, Dai H-F, Zhao Y-X (2017) Chrodrimanins K–N and related meroterpenoids from the fungus Penicillium sp. SCS-KFD09 isolated from a marine worm, Sipunculus nudus. J Nat Prod 80:1039 613. Kong F-D, Zhang R-S, Ma Q-Y, Xie Q-Y, Wang P, Chen P-W, Zhou L-M, Dai H-F, Luo D-Q, Zhao Y-X (2017) Chrodrimanins O–S from the fungus Penicillium sp. SCS-KFD09 isolated from a marine worm, Sipunculus nudus. Fitoterapia 122:1 614. Rodríguez AD (1995) The natural products chemistry of West Indian gorgonian octocorals. Tetrahedron 51:4571 615. Sung P-J, Sheu J-H, Wang W-H, Fang L-S, Chung H-M, Pai C-H, Su Y-D, Tsai W-T, Chen B-Y, Lin M-R, Li G-Y (2008) Survey of briarane-type diterpenoids—Part III. Heterocycles 75:2627 616. Sung P-J, Su J-H, Wang W-H, Sheu J-H, Fang L-S, Wu Y-C, Chen Y-H, Chung H-M, Su Y-D, Chang Y-C (2011) Survey of briarane-type diterpenoids—Part IV. Heterocycles 83:1241 617. Berrue F, Kerr RG (2009) Diterpenes from gorgonian corals. Nat Prod Rep 26:681 618. Welford AJ, Collins I (2011) The 2,11-cyclized cembranoids: cladiellins asbestinins and briarellins (period 1998–2010). J Nat Prod 74:2318 619. Sheu J-H, Chen Y-H, Chen Y-H, Su Y-D, Chang Y-C, Su J-H, Weng C-F, Lee C-H, Fang L-S, Wang W-H, Wen Z-H, Wu Y-C, Sung P-J (2014) Briarane diterpenoids isolated from gorgonian corals between 2011 and 2013. Mar Drugs 12:2164 620. Su Y-D, Su J-H, Hwang T-L, Wen Z-H, Sheu J-H, Wu Y-C, Sung P-J (2017) Briarane diterpenoids isolated from octocorals between 2014 and 2016. Mar Drugs 15:44 621. Lei H (2016) Diterpenoids of gorgonian corals: chemistry and bioactivity. Chem Biodivers 13:345 622. Rodríguez AD, Li Y, Dhasmana H, Barnes CL (1993) New marine cembrane diterpenoids isolated from the Caribbean gorgonian Eunicea mammosa. J Nat Prod 56:1101 623. Su Y-M, Fan T-Y, Sung P-J (2007) 11,20-Epoxybriaranes from the gorgonian coral Ellisella robusta (Ellisellidae). Nat Prod Res 21:1085 624. Sung P-J, Tsai W-T, Chiang MY, Su Y-M, Kuo J (2007) Robustolides A-C, three new briarane-type diterpenoids from the female gorgonian coral Ellisella robusta (Ellisellidae). Tetrahedron 63:7582 625. Sung P-J, Chiang MY, Tsai W-T, Su J-H, Su Y-M, Wu Y-C (2007) Chlorinated briarane-type diterpenoids from the gorgonian coral Ellisella robusta (Ellisellidae). Tetrahedron 63:12860 626. Sung P-J, Tsai W-T, Lin M-R, Su Y-D, Pai C-H, Chung H-M, Su J-H, Chiang MY (2008) Robustolides H and I, chlorinated briaranes from the gorgonian Ellisella robusta (Ellisellidae). Chem Lett 37:88 627. Chang Y-C, Hwang T-L, Huang S-K, Huang L-W, Lin M-R, Sung P-J (2010) 12-epi-Fragilide G, a new briarane-type diterpenoid from the gorgonian coral Ellisella robusta. Heterocycles 81:991 628. Sung P-J, Chen Y-P, Su Y-M, Hwang T-L, Hu W-P, Fan T-Y, Wang W-H (2007) Fragilide B: a novel briarane-type diterpenoid with a s-cis diene moiety. Bull Chem Soc Jpn 80:1205 629. Shen Y-C, Chen Y-H, Hwang T-L, Guh J-H, Khalil AT (2007) Four new briarane diterpenoids from the gorgonian coral Junceella fragilis. Helv Chim Acta 90:1391 630. Liaw C-C, Shen Y-C, Lin Y-S, Hwang T-L, Kuo Y-H, Khalil AT (2008) Frajunolides E-K, briarane diterpenes from Junceella fragilis. J Nat Prod 71:1551 631. Sung P-J, Pai C-H, Su Y-D, Hwang T-L, Kuo F-W, Fan T-Y, Li J-J (2008) New 8hydroxybriarane diterpenoids from the gorgonians Junceella juncea and Junceella fragilis (Ellisellidae). Tetrahedron 64:4224 632. Sung P-J, Lin M-R, Su Y-D, Chiang MY, Hu W-P, Su J-H, Cheng M-C, Hwang T-L, Sheu J-H (2008) New briaranes from the octocorals Briareum excavatum (Briareidae) and Junceella fragilis (Ellisellidae). Tetrahedron 64:2596 633. Sung P-J, Li G-Y, Chen Y-P, Huang I-C, Chen B-Y, Wang S-H, Huang S-K (2009) Fragilide E, a novel chlorinated 20-acetoxybriarane from the gorgonian coral Junceella fragilis. Chem Lett 38:454

436

G. W. Gribble

634. Sung P-J, Wang S-H, Chiang MY, Su Y-D, Chang Y-C, Hu W-P, Tai C-Y, Liu C-Y (2009) Discovery of new chlorinated briaranes from Junceella fragilis. Bull Chem Soc Jpn 82:1426 635. Sung P-J, Wang S-H, Chang Y-C, Chen Y-H, Lin M-R, Huang I-C, Chen J-J, Li J-J, Kung T-H, Fang L-S, Wang W-H, Weng C-F (2010) New briarane-related diterpenoids from the sea whip gorgonian coral Junceella fraglis (Ellisellidae). Bull Chem Soc Jpn 83:1074 636. Wang S-H, Chang Y-C, Chiang MY, Chen Y-H, Hwang T-L, Weng C-F, Sung P-J (2010) Chlorinated briarane diterpenoids from the sea whip gorgonian corals Junceella fragilis and Ellisella robusta (Ellisellidae). Chem Pharm Bull 58:928 637. Qi SH, Zhang S, Qian PY, Xu HH (2009) Antifeedant and antifouling briaranes from the South China Sea gorgonian Junceella juncea. Chem Nat Comp 45:49 638. Wang S-S, Chen Y-H, Chang J-Y, Hwang T-L, Chen C-H, Khalil AT, Shen Y-C (2009) Juncenolides H-K, new briarane diterpenoids from Junceella juncea. Helv Chim Acta 92:2092 639. Chang J-Y, Liaw C-C, Fazary AE, Hwang T-L, Shen Y-C (2012) New briarane diterpenoids from the gorgonian coral Junceella juncea. Mar Drugs 10:1321 640. Liaw C-C, Kuo Y-H, Lin Y-S, Hwang T-L, Shen Y-C (2011) Frajunolides L-O, four new 8-hydroxybriarane diterpenoids from the gorgonian Junceella fragilis. Mar Drugs 9:1477 641. Lei H, Sun J-F, Han Z, Zhou X-F, Yang B, Liu Y (2014) Fragilisinins A-L, new briarane-type diterpenoids from gorgonian Junceella fragilis. RSC Adv 4:5261 642. Zhou W, Li J, E H-C, Liu B-S, Tang H, Gerwick WH, Hua H-M, Zhang W (2014) Briarane diterpenes from the South China Sea gorgonian coral, Junceella gemmacea. Mar Drugs 12:589 643. Cheng W, Ji M, Li X, Ren J, Yin F, van Ofwegen L, Yu S, Chen X, Lin W (2017) Fragilolides A-Q, norditerpenoid and briarane diterpenoids from the gorgonian coral Junceella fragilis. Tetrahedron 73:2518 644. Cheng W, Li X, Yin F, van Ofwegen L, Lin W (2017) Halogenated briarane diterpenes with acetyl migration from the gorgonian coral Junceella fragilis. Chem Biodivers 14:e1700053 645. Zheng L-G, Chang Y-C, Hu C-C, Wen Z-H, Wu Y-C, Sung P-J (2018) Fragilides K and L, new briaranes from the gorgonian coral Junceella fragilis. Molecules 23:1510 646. Zheng L-G, Chang Y-C, Chen J-J, Wen Z-H, Hwang T-L, Sung P-J (2018) (+)-12-epiFragilide G, a new chlorinated briarane from the sea whip gorgonian coral Junceella fragilis. Heterocycles 96:1601 647. Chang Y-C, Hwang T-L, Huang S-K, Huang L-W, Lin M-R, Sung P-J (2010) 12-epi-Fragilide G, a new briarane-type diterpenoid from the gorgonian coral Ellisella robusta. Heterocycles 81:9091 648. Lin C-C, Su J-H, Chen W-F, Wen Z-H, Peng B-R, Huang L-C, Hwang T-L, Sung P-J (2019) New 11,20-epoxybriaranes from the gorgonian coral Junceella fragilis (Ellisellidae). Molecules 24:2487 649. Su T-P, Yuan C-H, Jhu Y-M, Peng B-R, Wen Z-H, Wu Y-J, Wu T-Y, Liu H-W, Sung PJ (2019) Fragilides U-W: new 11,20-epoxybriaranes from the sea whip gorgonian coral Junceella fragilis. Mar Drugs 17:706 650. Lin C-C, Chen W-F, Lee G-H, Wen Z-H, Fang L-S, Kuo Y-H, Lee C-Y, Sung P-J (2019) Fragilides M-O, new triacetoxybriaranes from the gorgonian coral Junceella fragilis (Ellisellidae). Heterocycles 98:984 651. Chen Y-Y, Fang L-S, Chen Y-H, Peng B-R, Su T-P, Huynh T-H, Lin F-Y, Hu C-C, Lin N-C, Wen Z-H, Chen J-J, Lee C-Y, Wang J-W, Sung P-J (2019) New 8-hydroxybriaranes from the gorgonian coral Junceella fragilis (Ellisellidae). Mar Drugs 17:534 652. Chung H-M, Wang Y-C, Tseng C-C, Chen N-F, Wen Z-H, Fang L-S, Hwang T-L, Wu Y-C, Sung P-J (2018) Natural product chemistry of gorgonian corals of genus Junceella—Part III. Mar Drugs 16:339 653. Su J-H, Sung P-J, Kuo Y-H, Hsu C-H, Sheu J-H (2007) Briarenolides A-C, briarane diterpenoids from the gorgonian coral Briareum sp. Tetrahedron 63:8282 654. Hwang T-L, Lin M-R, Tsai W-T, Yeh H-C, Hu W-P, Sheu J-H, Sung P-J (2008) New polyoxygenated briaranes from octocorals Briareum excavatum and Ellisella robusta. Bull Chem Soc Jpn 81:1638

Naturally Occurring Organohalogen Compounds …

437

655. Sung P-J, Lin M-R, Chiang MY (2009) The structure and absolute stereochemistry of briaexcavatin U, a new chlorinated briarane from a cultured octocoral Briareum excavatum. Chem Lett 38:154 656. Sung P-J, Li G-Y, Su Y-D, Lin M-R, Chang Y-C, Kung T-H, Lin C-S, Chen Y-H, Su J-H, Lu M-C, Kuo J, Weng C-F, Hwang T-L (2010) Excavatoids O and P, new 12-hydroxybriaranes from the octocoral Briareum excavatum. Mar Drugs 8:2639 657. Liaw C-C, Lin Y-C, Lin Y-S, Chen C-H, Hwang T-L, Shen Y-C (2013) Four new briarane diterpenoids from Taiwanese gorgonian Junceella fragilis. Mar Drugs 11:2042 658. Liaw C-C, Cheng Y-B, Lin Y-S, Kuo Y-H, Hwang T-L, Shen Y-C (2014) New briarane diterpenoids from Taiwanese soft coral Briareum violacea. Mar Drugs 12:4677 659. Su Y-D, Cheng C-H, Chen W-F, Chang Y-C, Chen Y-H, Hwang T-L, Wen Z-H, Wang W-H, Fang L-S, Chen J-J, Wu Y-C, Sheu J-H, Sung P-J (2014) Briarenolide J, the first 12chlorobriarane diterpenoid from an octocoral Briareum sp. (Briareidae). Tetrahedron Lett 55:6065 660. Su Y-D, Wu T-Y, Wen Z-H, Su C-C, Chen Y-H, Chang Y-C, Wu Y-C, Sheu J-H, Sung P-J (2015) Briarenolides U–Y, new anti-inflammatory briarane diterpenoids from an octocoral Briareum sp. (Briareidae). Mar Drugs 13:7138 661. Su Y-D, Wen Z-H, Wu Y-C, Fang L-S, Chen Y-H, Chang Y-C, Sheu J-H, Sung P-J (2016) Briarenolides M-T, new briarane diterpenoids from a Formosan octocoral Briareum sp. Tetrahedron 72:944 662. Su Y-D, Sung C-S, Wen Z-H, Chen Y-H, Chang Y-C, Chen J-J, Fang L-S, Wu Y-C, Sheu J-H, Sung P-J (2016) New 9-hydroxybriarane diterpenoids from a gorgonian coral Briareum sp. (Briareidae). Int J Mol Sci 17:79 663. Chen N-F, Su Y-D, Hwang T-L, Liao Z-J, Tsui K-H, Wen Z-H, Wu Y-C, Sung P-J (2017) Briarenols C-E, new polyoxygenated briaranes from the octocoral Briareum excavatum. Molecules 22:475 664. Zhang Y-L, Chiang C-C, Lee Y-T, Wen Z-H, Wu Y-C, Wu Y-J, Hwang T-L, Wu T-Y, Chang C-Y, Sung P-J (2020) Briarenols Q-T: briaranes from a cultured octocoral Briareum stechei (Kükenthal, 1908). Mar Drugs 18:383 665. Chen Y-Y, Zhang Y-L, Lee G-H, Tsou LK, Zhang MM, Hsieh H-P, Chen J-J, Ko C-Y, Wen Z-H, Sung P-J (2021) Briarenols W-Z: chlorine-containing polyoxygenated briaranes from octocoral Briareum stechei (Kükenthal, 1908). Mar Drugs 19:77 666. Sun J-F, Huang H, Chai X-Y, Yang X-W, Meng L, Huang C-G, Zhou X-F, Yang B, Hu J, Chen X-Q, Lei H, Wang L, Liu Y (2011) Dichotellides A-E, five new iodine-containing briarane type diterpenoids from Dichotella gemmacea. Tetrahedron 67:1245 667. Sun J-F, Han Z, Zhou X-F, Yang B, Lin X, Liu J, Peng Y, Yang X-W, Liu Y (2013) Antifouling briarane type diterpenoids from South China Sea gorgonians Dichotella gemmacea. Tetrahedron 69:871 668. Li C, La M-P, Li L, Li X-B, Tang H, Liu B-S, Krohn K, Sun P, Yi Y-H, Zhang W (2011) Bioactive 11,20-epoxy-3,5(16)-diene briarane diterpenoids from the South China Sea gorgonian Dichotella gemmacea. J Nat Prod 74:1658 669. Li C, La M-P, Sun P, Kurtan T, Mandi A, Tang H, Liu B-S, Yi Y-H, Li L, Zhang W (2011) Bioactive (3Z,5E)-11,20-epoxybriara-3,5-dien-7,18-olide diterpenoids from the South China Sea gorgonian Dichotella gemmacea. Mar Drugs 9:1403 670. Li C, La M-P, Tang H, Pan W-H, Sun P, Krohn K, Yi Y-H, Li L, Zhang W (2012) Bioactive briarane diterpenoids from the South China Sea gorgonian Dichotella gemmacea. Bioorg Med Chem Lett 22:4368 671. Li C, Jiang M, La M-P, Li T-J, Tang H, Sun P, Liu B-S, Yi Y-H, Liu Z, Zhang W (2013) Chemistry and tumor cell growth inhibitory activity of 11,20-epoxy-3Z,5(6)E-diene briaranes from the South China Sea gorgonian Dichotella gemmacea. Mar Drugs 11:1565 672. La M-P, Li J, Li C, Tang H, Liu B-S, Sun P, Zhuang C-L, Li T-J, Zhang W (2014) Briarane diterpenoids from the Gorgonian Dichotella gemmacea. Mar Drugs 12:6178 673. Jia R, Guo Y-W, Chen P, Yang Y-M, Mollo E, Gavagnin M, Cimino G (2007) Biscembranoids and their probable biogenetic precursor from the Hainan soft coral Sarcophyton tortuosum. J Nat Prod 70:1158

438

G. W. Gribble

674. Huang H-C, Chao C-H, Kuo Y-H, Sheu J-H (2009) Crassocolides G-M, cembranoids from the Formosan soft coral Sarcophyton crassocaule. Chem Biodivers 6:1232 675. Elkhateeb A, El-Beih AA, Gamal-Eldeen AM, Alhammady MA, Ohta S, Paré PW, Hegazy M-EF (2014) New terpenes from the Egyptian soft coral Sarcophyton ehrenbergi. Mar Drugs 12:1977 676. Yang J, Zhang S, Qia S, Pan J, Qiu Y, Tao S, Yin H, Li Q (2007) Briarane-type diterpenoids from the China gorgonian coral Subergorgia reticulata. Biochem Syst Ecol 35:770 677. Ito H, Iwasaki J, Sato Y, Aoyagi M, Iguchi K, Yamori T (2007) Marine diterpenoids with a briarane skeleton from the Okinawan soft coral Pachyclavularia violacea. Chem Pharm Bull 55:1671 678. Kate AS, Richard K, Ramanathan B, Kerr RG (2010) A halogenated pseudopterane diterpene from the Bahamian octocoral Pseudopterogorgia acerosa. Can J Chem 88:318 679. Lai D, Li Y, Xu M, Deng Z, van Ofwegen L, Qian P, Proksch P, Lin W (2011) Sinulariols A-S, 19-oxygenated cembranoids from the Chinese soft coral Sinularia rigida. Tetrahedron 67:6018 680. Fattorusso E, Luciano P, Putra MY, Taglialatela-Scafati O, Ianaro A, Panza E, Bavestrello G, Cerrano C (2011) Chloroscabrolides, chlorinated norcembranoids from the Indonesian soft coral Sinularia sp. Tetrahedron 67:7983 681. Kao C-Y, Su J-H, Lu M-C, Hwang T-L, Wang W-H, Chen J-J, Sheu J-H, Kuo Y-H, Weng C-F, Fang L-S, Wen Z-H, Sung P-J (2011) Lobocrassins A-E: new cembrane-type diterpenoids from the soft coral Lobophytum crassum. Mar Drugs 9:1319 682. Hsu F-J, Chen B-W, Wen Z-H, Huang C-Y, Dai C-F, Su J-H, Wu Y-C, Sheu J-H (2011) Klymollins A-H, bioactive eunicellin-based diterpenoids from the Formosan soft coral Klyxum molle. J Nat Prod 74:2467 683. Lin M-C, Chen B-W, Huang C-Y, Dai C-F, Hwang T-L, Sheu J-H (2013) Eunicellinbased diterpenoids from the Formosan soft coral Klyxum molle with inhibitory activity on superoxide generation and elastase release by neutrophils. J Nat Prod 76:1661 684. Nguyen HP, Zhang D, Lee U, Kang JS, Choi HD, Son BW (2007) Dehydroxychlorofusarielin B, an antibacterial polyoxygenated decalin derivative from the marine-derived fungus Aspergillus sp. J Nat Prod 70:1188 685. Gai Y, Zhao LL, Hu CQ, Zhang HP (2007) Fusarielin E, a new antifungal antibiotic from Fusarium sp. Chin Chem Lett 18:954 686. Lee Y, Wang W, Kim H, Giri AG, Won DH, Hahn D, Baek KR, Lee J, Yang I, Choi H, Nam S-J, Kang H (2014) Phorbaketals L-N, cytotoxic sesterterpenoids isolated from the marine sponge of the genus Phorbas. Bioorg Med Chem Lett 24:4095 687. Manzo E, Gavagnin M, Bifulco G, Cimino P, Di Micco S, Ciavatta ML, Guo YW, Cimino G (2007) Aplysiols A and B, squalene-derived polyethers from the mantle of the sea hare Aplysia dactylomela. Tetrahedron 63:9970 688. Matsuo Y, Suzuki M, Masuda M, Iwai T, Morimoto Y (2008) Squalene-derived triterpene polyethers from the red alga Laurencia omaezakiana. Helv Chim Acta 91:1261 689. Ji N-Y, Li X-M, Xie H, Ding J, Li K, Ding L-P, Wang B-G (2008) Highly oxygenated triterpenoids from the marine red alga Laurencia mariannensis (Rhodomelaceae). Helv Chim Acta 91:1940 690. Vera B, Rodríguez AD, Avilés E, Ishikawa Y (2009) Aplysqualenols A and B: squalenederived polyethers with antitumoral and antiviral activity from the Caribbean sea slug Aplysia dactylomela. Eur J Org Chem, 5327 691. Vera B, Rodríguez AD, La Clair JJ (2011) Aplysqualenol A binds to the light chain of dynein type 1 (DYNLL1). Angew Chem Int Ed 50:8134 692. Cen-Pacheco F, Nordström L, Souto ML, Martín MN, Fernández JJ, Daranas AH (2010) Studies on polyethers produced by red algae. Mar Drugs 8:1178 693. Ola ARB, Babey A-M, Motti C, Bowden BF (2010) Aplysiols C-E, brominated triterpene polyethers from the marine alga Chondria armata and a revision of the structure of aplysiol B. Aust J Chem 63:907

Naturally Occurring Organohalogen Compounds …

439

694. Cen-Pacheco F, Mollinedo F, Villa-Pulgarín JA, Norte M, Fernández JJ, Daranas AH (2012) Saiyacenols A and B: the key to solve the controversy about the configuration of aplysiols. Tetrahedron 68:7275 695. Cen-Pacheco F, Villa-Pulgarin JA, Mollinedo F, Norte M, Daranas AH, Fernández JJ (2011) Cytotoxic oxasqualenoids from the red alga Laurencia viridis. Eur J Med Chem 46:3302 696. Cen-Pacheco F, Villa-Pulgarin JA, Mollinedo F, Martín MN, Fernández JJ, Daranas AH (2011) New polyether triterpenoids from Laurencia viridis and their biological evaluation. Mar Drugs 9:2220 697. Cen-Pacheco F, Santiago-Benítez AJ, Garcia C, Álvarez-Méndez SJ, Martín-Rodríguez AJ, Norte M, Martín VS, Gavín JA, Fernández JJ, Daranas AH (2015) Oxasqualenoids from Laurencia viridis: combined spectroscopic-computational analysis and antifouling potential. J Nat Prod 78:712 698. Cen-Pacheco F, Santiago-Benítez AJ, Tsui KY, Tantillo DJ, Fernández JJ, Daranas AH (2021) Structure and computational basis for backbone rearrangement in marine oxasqualenoids. J Org Chem 86:2437 699. Morimoto Y, Yata H, Nishikawa Y (2007) Assignment of the absolute configuration of the marine pentacyclic polyether (+)-enshuol by total synthesis. Angew Chem Int Ed 46:6481 700. Morimoto Y, Okita T, Takaishi M, Tanaka T (2007) Total synthesis and determination of the absolute configuration of (+)-intricatetraol. Angew Chem Int Ed 46:1132 701. Hoshino A, Nakai H, Morino M, Nishikawa K, Kodama T, Nishikibe K, Morimoto Y (2017) Total synthesis of the cytotoxic marine triterpenoid isodehydrothyrsiferol reveals partial enantiodivergency in the thyrsiferol family of natural products. Angew Chem Int Ed 56:3064 702. Tanuwidjaja J, Ng S-S, Jamison TF (2009) Total synthesis of ent-dioxepandehydrothyrsiferol via a bromonium-initiated epoxide-opening cascade. J Am Chem Soc 131:12084 703. Chen L-X, He H, Qiu F (2011) Natural withanolides: an overview. Nat Prod Rep 28:705 704. Dembitsky VM, Gloriozova TA, Poroikov VV (2017) Chlorinated plant steroids and their biological activities. Int J Curr Res Biosci Plant Biol 4:70 705. Nicotra VE, Ramacciotti NS, Gil RR, Oberti JC, Feresin GE, Guerrero CA, Baggio RF, Garland MT, Burton G (2006) Phytotoxic withanolides from Jaborosa rotacea. J Nat Prod 69:783 706. Hsieh P-W, Huang Z-Y, Chen J-H, Chang F-R, Wu C-C, Yang Y-L, Chiang MY, Yen M-H, Chen S-L, Yen H-F, Lübken T, Hung W-C, Wu Y-C (2007) Cytotoxic withanolides from Tubocapsicum anomalum. J Nat Prod 70:747 707. Nicotra VE, Gil RR, Oberti JC, Burton G (2007) Withanolides with phytotoxic activity from Jaborosa caulescens var. caulescens and J. caulescens var. bipinnatifida. J Nat Prod 70:808 708. Pramanick S, Roy A, Ghosh S, Majumder HK, Mukhopadhyay S (2008) Withanolide Z, a new chlorinated withanolide from Withania somnifera. Planta Med 74:1745 709. Li Y-Z, Pan Y-M, Huang X-Y, Wang H-S (2008) Withanolides from Physalis alkekengi var. francheti. Helv Chim Acta 91:2284 710. García ME, Pagola S, Navarro-Vázquez A, Phillips DD, Gayathri C, Krakauer H, Stephens PW, Nicotra VE, Gil RR (2009) Stereochemistry determination by powder X-ray diffraction analysis and NMR spectroscopy residual dipolar couplings. Angew Chem Int Ed 48:5670 711. Choudhary MI, Hussain S, Yousuf S, Dar A, Mudassar, Atta-ur-Rahman (2010) Chlorinated and diepoxy withanolides from Withania somnifera and their cytotoxic effects against human lung cancer cell line. Phytochemistry 71:2205 712. Xu Y-X, Xiang Z-B, Jin Y-S, Shen Y, Chen H-S (2010) Two new triterpenoids from the roots of Actinidia chinensis. Fitoterapia 81:920 713. Maia AIV, Braz-Filho R, Silveira ER, de Simone CA, Pessoa ODL (2012) Further withaphysalin derivatives from Acnistus arborescens. Helv Chim Acta 95:1387 714. Quang TH, Ngan NTT, Minh CV, Kiem PV, Yen PH, Tai BH, Nhiem NX, Thao NP, Anh HLT, Luyen BTT, Yang SY, Kim YH (2012) Plantagiolides I and J, two new withanolide glucosides from Tacca plantaginea with nuclear factor-kappaB inhibitory and peroxisome proliferator-activated receptor transactivational activities. Chem Pharm Bull 60:1494

440

G. W. Gribble

715. Batista PHJ, de Lima KSB, Pinto FCL, Tavares JL, Uchoa DEA, Costa-Lotufo LV, Rocha DD, Silveira ER, Bezerra AME, Canuto KM, Pessoa ODL (2016) Withanolides from leaves of cultivated Acnistus arborescens. Phytochemistry 130:321 716. Yan C, Zhang Y-D, Wang X-H, Geng S-D, Wang T-Y, Sun M, Liang W, Zhang W-Q, Zhang X-D, Luo H (2016) Tirucallane-type triterpenoids from the fruits of Phellodendron chinense Schneid and their cytotoxic activities. Fitoterapia 113:132 717. Torres FR, Pérez-Castorena AL, Arredondo L, Toscano RA, Nieto-Camacho A, Martínez M, Maldonado E (2019) Labdanes, withanolides, and other constituents from Physalis nicandroides. J Nat Prod 82:2489 718. Xu G-B, Xu Y-M, Wijeratne EMK, Ranjbar F, Liu MX, Gunatilaka AAL (2021) Cytotoxic physalins from aeroponically grown Physalis acutifolia. J Nat Prod 84:187 719. Choudhary MI, Yousuf S, Samreen SSAA, Ahmed S, Atta-ur-Rahman (2006) Biotransformation of physalin H and leishmanicidal activity of its transformed products. Chem Pharm Bull 54:927 720. Men R-Z, Li N, Ding W-J, Hu Z-J, Ma Z-J, Cheng L (2014) Unprecedent aminophysalin from Physalis angulata. Steroids 88:60 721. Basso AV, González SL, Barboza GE, Careaga VP, Calvo JC, Sacca PA, Nicotra VE (2017) Phytochemical study of the genus Salpichroa (Solanaceae), chemotaxonomic considerations, and biological evaluation in prostate and breast cancer cells. Chem Biodivers 14:e1700118 722. Machin RP, Veleiro AS, Nicotra VE, Oberti JC, Padrón JM (2010) Antiproliferative activity of withanolides against human breast cancer cell lines. J Nat Prod 73:966 723. Zhukova NV, Gloriozova TA, Poroikov VV, Dembitsky VM (2017) Halogenated (Cl, Br and I) marine steroids and their biological activities: A brief review. Pharma Innov J 6:456 724. Guzii AG, Makarieva TN, Denisenko VA, Dmitrenok PS, Burtseva YV, Krasokhin VB, Stonik VA (2008) Topsentiasterol sulfates with novel iodinated and chlorinated side chains from the marine sponge Topsentia sp. Tetrahedron Lett 49:7191 725. Teta R, Della Sala G, Renga B, Mangoni A, Fiorucci S, Costantino V (2012) Chalinulasterol, a chlorinated steroid disulfate from the Caribbean sponge Chalinula molitba. Evaluation of its role as PXR receptor modulator. Mar Drugs 10:1383 726. Tabakmakher KM, Makarieva TN, Denisenko VA, Popov RS, Dmitrenok PS, Dyshlovoy SA, Grebnev BB, Bokemeyer C, von Amsberg G, Cuong NX (2019) New trisulfated steroids from the Vietnamese marine sponge Halichondria vansoesti and their PSA expression and glucose uptake inhibitory activities. Mar Drugs 17:445 727. Lyakhova EG, Kolesnikova SA, Kalinovsky AI, Dmitrenok PS, Nam NH, Stonik VA (2015) Further study on Penares sp. from Vietnamese waters: minor lanostane and nor-lanostane triterpenes. Steroids 96:37 728. Dai J, Yoshida WY, Kelly M, Williams P (2016) Pregnane-10,2-carbolactones from a Hawaiian marine sponge in the genus Myrmekioderman. J Nat Prod 79:1464 729. He H, Bertin MJ, Wu S, Wahome PG, Beauchesne KR, Youngs RO, Zimba PV, Moeller PDR, Sauri J, Carter GT (2018) Cyanobufalins: cardioactive toxins from cyanobacterial blooms. J Nat Prod 81:2576 730. Tartakoff SS, Vanderwal CD (2014) A synthesis of the ABC tricyclic core of the clionastatins serves to corroborate their proposed structures. Org Lett 16:1458 731. Gao S, Wang Q, Chen C (2009) Synthesis and structure revision of nakiterpiosin. J Am Chem Soc 131:1410 732. Gao S, Wang Q, Huang LJ-S, Lum L, Chen C (2010) Chemical and biological studies of nakiterpiosin and nakiterpiosinone. J Am Chem Soc 132:371 733. Gao S, Wang Q, Wang G, Lomenick B, Liu J, Fan C-W, Deng L-W, Huang J, Lum L, Chen C (2012) The chemistry and biology of nakiterpiosin—C-nor-D-homosteroids. Synlett 23:2298 734. Wanke T, Philippus AC, Zatelli GA, Vieira LFO, Lhullier C, Falkenberg M (2015) C15 acetogenins from the Laurencia complex: 50 years of research—an overview. Rev Brasil Farmacog 25:569 735. Kladi M, Vagias C, Stavri M, Rahman MM, Gibbons S, Roussis V (2008) C15 acetogenins with antistaphylococcal activity from the red alga Laurencia glandulifera. Phytochem Lett 1:31

Naturally Occurring Organohalogen Compounds …

441

736. Kladi M, Vagias C, Papazafiri P, Brogi S, Tafi A, Roussis V (2009) Tetrahydrofuran acetogenins from Laurencia glandulifera. J Nat Prod 72:190 737. Gutiérrez-Cepeda A, Fernández JJ, Gil LV, López-Rodríguez M, Norte M, Souto ML (2011) Nonterpenoid C15 acetogenins from Laurencia marilzae. J Nat Prod 74:441 738. Ayyad S-EN, Al-Footy KO, Alarif WM, Sobahi TR, Bassaif SA, Makki MS, Asiri AM, Al Halawani AY, Badria AF, Badria FAA (2011) Bioactive C15 acetogenins from the red alga Laurencia obtusa. Chem Pharm Bull 59:1294 739. Kamada T, Vairappan CS (2012) A new bromoallene-producing chemical type of the red alga Laurencia nangii Masuda. Molecules 17:2119 740. Kokkotou K, Ioannou E, Nomikou M, Pitterl F, Vonaparti A, Siapi E, Zervou M, Roussis V (2014) An integrated approach using UHPLC–PDA–HRMS and 2D HSQC NMR for the metabolic profiling of the red alga Laurencia: dereplication and tracing of natural products. Phytochemistry 108:208 741. Gutiérrez-Cepeda A, Daranas AH, Fernández JJ, Norte M, Souto ML (2014) Stereochemical determination of five-membered cyclic ether acetogenins using a spin-spin coupling constant approach and DFT calculations. Mar Drugs 12:4031 742. Gutiérrez-Cepeda A, Fernández JJ, Norte M, López-Rodríguez M, Brito I, Muller CD, Souto ML (2016) Additional insights into the obtusallene family: components of Laurencia marilzae. J Nat Prod 79:1184 743. Bawakid NO, Alarif WM, Ismail AI, El-Hefnawy ME, Al-Footy KO, Al-Lihaibi SS (2017) Bio-active maneonenes and isomaneonene from the red alga Laurencia obtusa. Phytochemistry 143:180 744. Bawakid NO, Alarif WM, Alburae NA, Alorfi HS, Al-Footy KO, Al-Lihaibi SS, Ghandourah MA (2017) Isolaurenidificin and bromlaurenidificin, two new C15 -acetogenins from the red alga Laurencia obtusa. Molecules 22:807 745. Liu X, Li XM, Li CS, Ji NY, Wang BG (2010) Laurenidificin, a new brominated C15 acetogenin from the marine red alga Laurencia nidifica. Chin Chem Lett 21:1213 746. Yoshikawa Y, Yamakawa M, Kobayashi T, Murai K, Arisawa M, Sumimoto M, Fujioka H (2017) First asymmetric total synthesis and insight into the structure of laurenidificin. Eur J Org Chem: 2715 747. Esselin H, Sutour S, Liberal J, Cruz MT, Salgueiro L, Siegler B, Freuze I, Castola V, Paoli M, Bighelli A, Tomi F (2017) Chemical composition of Laurencia obtusa extract and isolation of a new C15 -acetogenin. Molecules 22:779 748. Ji N-Y, Li X-M, Li K, Wang B-G (2007) Laurendecumallenes A-B and laurendecumenynes A-B, halogenated nonterpenoid C15 -acetogenins from the marine red alga Laurencia decumbens. J Nat Prod 70:1499 749. Ji N-Y, Li X-M, Li K, Wang B-G (2010) Laurendecumallenes A-B and laurendecumenynes A–B, halogenated nonterpenoid C15 -acetogenins from the marine red alga Laurencia decumbens. J Nat Prod 73:1192 750. Umezawa T, Oguri Y, Matsuura H, Yamazaki S, Suzuki M, Yoshimura E, Furuta T, Nogata Y, Serisawa Y, Matsuyama-Serisawa K, Abe T, Matsuda F, Suzuki M, Okino T (2014) Omaezallene from red alga Laurencia sp.: structure elucidation, total synthesis, and antifouling activity. Angew Chem Int Ed 53:3909 751. Gutiérrez-Cepeda A, Fernández JJ, Norte M, Souto ML (2011) New bicyclotridecane C15 nonterpenoid bromoallenes from Laurencia marilzae. Org Lett 13:2690 752. Braddock DC (2006) A hypothesis concerning the biosynthesis of the obtusallene family of marine natural products via electrophilic bromination. Org Lett 8:6055 753. Clarke J, Bonney KJ, Yaqoob M, Solanki S, Rzepa HS, White AJP, Millan DS, Braddock DC (2016) Epimeric face-selective oxidations and diastereodivergent transannular oxonium ion formation fragmentations: computational modeling and total syntheses of 12epoxyobtusallene IV, 12-epoxyobtusallene II, obtusallene X, marilzabicycloallene C, and marilzabicycloallene D. J Org Chem 81:9539 754. Esselin H, Tomi F, Bighelli A, Sutour S (2018) New metabolites isolated from a Laurencia obtusa population collected in Corsica. Molecules 23:720

442

G. W. Gribble

755. Sutour S, Therrien B, von Reuss SH, Tomi F (2018) Halogenated C15 acetogenin analogues of obtusallene III from a Laurenciella sp. collected in Corsica. J Nat Prod 81:279 756. Morales-Amador A, de Vera CR, Márquez-Fernández O, Daranas AH, Padrón JM, Fernández JJ, Souto ML, Norte M (2018) Pinnatifidenyne-derived ethynyl oxirane acetogenins from Laurencia viridis. Mar Drugs 16:5 757. Kamada T, Phan C-S, Vairappan CS (2019) Nangallenes A and B, halogenated nonterpenoid C15 -acetogenins from the Bornean red alga Laurencia nangii. J Asian Nat Prod Res 31:241 758. Perdikaris S, Mangoni A, Grauso L, Papazafiri P, Roussis V, Ioannou E (2019) Vagiallene, a rearranged C15 acetogenin from Laurencia obtusa. Org Lett 21:3183 759. Koutsaviti A, Daskalaki MG, Agusti S, Kampranis SC, Tsatsanis C, Duarte CM, Roussis V, Ioannou E (2019) Thuwalallenes A–E and thuwalenynes A–C: new C15 acetogenins with anti-inflammatory activity from a Saudi Arabian Red Sea Laurencia sp. Mar Drugs 17:644 760. Alarif WM, Al-Lihaibi SS, Bawakid NO, Abdel-Lateff A, Al-Malky HS (2019) Rare acetogenins with anti-inflammatory effect from the red alga Laurencia obtusa. Molecules 24:476 761. Ghandourah MA, Alarif WM, Bawakid NO (2019) New bioactive C15 acetogenins from the red alga Laurencia obtusa. Pharmacog Mag 15:199 762. Ishii T, Miyagi M, Shinjo Y, Minamida Y, Matsuura H, Abe T, Kikuchi N, Suzuki M (2020) Two new brominated C15 -acetogenins from the red alga Laurencia japonensis. Nat Prod Res 34:2787 763. Gallardo AB, Cueto M, Díaz-Marrero AR, de la Rosa JM, Fajardo V, San-Martín A, Darias J (2018) A set of biogenetically interesting polyhalogenated acetogenins from Ptilonia magellanica. Phytochemistry 145:111 764. Abdel-Mageed WM, Ebel R, Valeriote FA, Jaspars M (2010) Laurefurenynes A-F, new cyclic ether acetogenins from a marine red alga, Laurencia sp.. Tetrahedron 66:2855 765. Chan HSS, Thompson AL, Christensen KE, Burton JW (2020) Forwards and backwards— synthesis of Laurencia natural products using a biomimetic and retrobiomimetic strategy incorporating structural reassignment of laurefurenynes C-F. Chem Sci 11:11592 766. Shin I, Lee D, Kim H (2016) Substrate-controlled asymmetric total synthesis and structure revision of (–)-bisezakyne A. Org Lett 18:4420 767. Wang J, Pagenkopf BL (2007) First total synthesis and structural reassignment of (–)aplysiallene. Org Lett 9:3703 768. Sheldrake HM, Jamieson C, Burton JW (2006) The changing faces of halogenated marine natural products: total synthesis of the reported structures of elatenyne and an enyne from Laurencia majuscula. Angew Chem Int Ed 45:7199 769. Sheldrake HM, Jamieson C, Pascu SI, Burton JW (2009) Synthesis of the originally proposed structures of elatenyne and an enyne from Laurencia majuscula. Org Biomol Chem 7:238 770. Smith SG, Paton RS, Burton JW, Goodman JM (2008) Stereostructure assignment of flexible five-membered rings by GIAO 13 C NMR calculations: prediction of the stereochemistry of elatenyne. J Org Chem 73:4053 771. Brkljaˇca R, Urban S (2013) Relative configuration of the marine natural product elatenyne using NMR spectroscopic and chemical derivatization methodologies. Nat Prod Commun 8:729 772. Dyson BS, Burton JW, Sohn T, Kim B, Bae H, Kim D (2012) Total synthesis and structure confirmation of elatenyne: success of computational methods for NMR prediction with highly flexible diastereomers. J Am Chem Soc 134:11781 773. Urban S, Brkljaˇca R, Hoshino M, Lee S, Fujita M (2016) Determination of the absolute configuration of the pseudo-symmetric natural product elatenyne by the crystalline sponge method. Angew Chem Int Ed 55:2678 774. Jeong W, Kim MJ, Kim H, Kim S, Kim D, Shin KJ (2010) Substrate-controlled asymmetric total synthesis and structure revision of (+)-itomanallene A. Angew Chem Int Ed 49:752 775. Braddock DC, Rzepa HS (2008) Structural reassignment of obtusallenes V, VI, and VII by GIAO-Based density functional prediction. J Nat Prod 71:728

Naturally Occurring Organohalogen Compounds …

443

776. Braddock DC, Millan DS, Pérez-Fuertes Y, Pouwer RH, Sheppard RN, Solanki S, White AJP (2009) Bromonium ion induced transannular oxonium ion formation–fragmentation in model obtusallene systems and structural reassignment of obtusallenes V-VII. J Org Chem 74:1835 777. Denmark SE, Yang S-M (2004) Total synthesis of (+)-brasilenyne. Application of an intramolecular silicon-assisted cross-coupling reaction. J Am Chem Soc 126:12432 778. Lim C, Ahn J, Sim J, Yun H, Hur J, An H, Jang J, Lee S, Suh Y-G (2018) Total synthesis of (+)-brasilenyne via concise construction of an oxonane framework containing a 1,3-cis, cis-diene. Chem Commun 54:467 779. Park J, Kim B, Kim H, Kim S, Kim D (2007) Substrate-controlled asymmetric total synthesis of (+)-microcladallene B with a bromination strategy based on a nucleophile-assisting leaving group. Angew Chem Int Ed 46:4726 780. Lee H, Kim KW, Park J, Kim H, Kim S, Kim D, Hu X, Yang W, Hong J (2008) A general strategy for construction of both 2,6-cis- and 2,6-trans-disubstituted tetrahydropyrans: substrate-controlled asymmetric total synthesis of (+)-scanlonenyne. Angew Chem Int Ed 47:4200 781. Kim B, Lee M, Kim MJ, Lee H, Kim S, Kim D, Koh M, Park SB, Shin KJ (2008) Biomimetic asymmetric total synthesis of (–)-laurefucin via an organoselenium-mediated intramolecular hydroxyetherification. J Am Chem Soc 130:16807 782. Snyder SA, Brucks AP, Treitler DS, Moga I (2012) Concise synthetic approaches for the Laurencia family: formal total syntheses of (±)-laurefucin and (±)-E- and (±)-Zpinnatifidenyne. J Am Chem Soc 134:17714 783. Sohn T, Kim B, Kim D, Paton RS (2018) Asymmetric total synthesis and structure confirmation of (+)-(3E)-isolaurefucin methyl ether. Heterocycles 97:179 784. Kim H, Lee H, Lee D, Kim S, Kim D (2007) Asymmetric total syntheses of (+)-3(Z)-laurentin and (+)-3-(Z)-isolaureatin by “lone pair–lone pair interaction-controlled” isomerization. J Am Chem Soc 129:2269 785. Lanier ML, Park H, Mukherjee P, Timmerman JC, Ribeiro AA, Widenhoefer RA, Hong J (2017) Formal synthesis of (+)-laurencin by gold(I)-catalyzed intramolecular dehydrative alkoxylation. Chem Eur J 23:7180 786. Werness JB, Tang W (2011) Stereoselective total synthesis of (–)-kumausallene. Org Lett 13:3664 787. Kim HS, Kim T, Ahn J, Yun H, Lim C, Jang J, Sim J, An H, Surh Y-J, Lee J, Suh Y-G (2018) Asymmetric total synthesis of (+)-(3E)-pinnatifidenyne via abnormally regioselective Pd(0)-catalyzed endocyclization. J Org Chem 83:1997 788. Sabot C, Bérard D, Canesi S (2008) Expeditious total syntheses of natural allenic products via aromatic ring umpolung. Org Lett 10:4629 789. Kim B, Sohn T, Kim S, Kim D, Lee J (2011) Concise substrate-controlled asymmetric total synthesis of (+)-3-(Z)-dihydrorhodophytin. Heterocycles 82:1113 790. Kim MJ, Sohn T, Kim D, Paton RS (2012) Concise substrate-controlled asymmetric total syntheses of dioxabicyclic marine natural products with 2,10-dioxabicyclo[7.3.0]dodecene and 2,9-dioxabicyclo[6.3.0]undecene skeletons. J Am Chem Soc 134:20178 791. Rodriguez-López J, Ortega N, Martin VS, Martin T (2014) β-Hydroxy-γ-lactones as nucleophiles in the Nicholas reaction for the synthesis of oxepene rings. Enantioselective formal synthesis of (–)-isolaurepinnacin and (+)-rogioloxepane A. Chem Commun 50: 3685 792. Kim G, Sohn T, Kim D, Paton RS (2014) Asymmetric total synthesis of (+)-bermudenynol, a C15 Laurencia metabolite with a vinyl chloride containing oxocene skeleton, through intramolecular amide enolate alkylation. Angew Chem Int Ed 53:272 793. Yamakawa M, Kurachi T, Yoshikawa Y, Arisawa M, Okino Y, Suzuki K, Fujioka H (2015) Stereoselective construction of 2,7-disubstituted fused-bis tetrahydrofuran skeletons: biomimetic-type synthesis and biological evaluation of (±)- and (–)-aplysiallene and their derivatives. J Org Chem 80:10261 794. Ahn J, Lim C, Yun H, Kim HS, Kwon S, Lee J, Lee S, An H, Park H, Suh Y-G (2017) Asymmetric total synthesis of (+)-intricenyne via an endocyclization route to oxocane skeleton. Org Lett 19:6642

444

G. W. Gribble

795. Jang H, Kwak SY, Lee D, Alegre-Requena JV, Kim H, Paton RS, Kim D (2021) Asymmetric total synthesis and determination of the absolute configuration of (+)-srilankenyne via sequence-sensitive halogenations guided by conformational analysis. Org Lett 23:1321 796. Taylor CA, Zhang Y-A, Snyder SA (2020) The enantioselective total synthesis of laurendecumallene B. Chem Sci 11:3036 797. Yoshimura F, Okada T, Tanino K (2019) Asymmetric total synthesis of laurallene. Org Lett 21:559 798. Senapati S, Das S, Ramana CV (2018) Total synthesis of notoryne. J Org Chem 83:12863 799. Shepherd ED, Dyson BS, Hak WE, Nguyen QNN, Lee M, Kim MJ, Sohn T, Kim D, Burton JW, Paton RS (2019) Structure determination of a chloroenyne from Laurencia majuscula using computational methods and total synthesis. J Org Chem 84:4971 800. Takamura H, Katsube T, Okamoto K, Kadota I (2017) Total synthesis of two possible diastereomers of natural 6-chlorotetrahydrofuran acetogenin and its stereostructural elucidation. Chem Eur J 23:17191 801. Kim B, Sohn T, Kim D, Paton RS (2018) Asymmetric total syntheses and structure confirmation of chlorofucins and bromofucins. Chem Eur J 24:2634 802. Dinda B, Chowdhury DR, Mohanta BC (2009) Naturally occurring iridoids, secoiridoids and their bioactivity. An updated review, Part 3. Chem Pharm Bull 57:765 803. Dinda B, Debnath S, Banik R (2011) Naturally occurring iridoids and secoiridoids. An updated review, Part 4. Chem Pharm Bull 59:803 804. Yang X-P, Li E-W, Zhang Q, Yuan C-S, Jia Z-J (2006) Five new iridoids from Patrinia rupestris. Chem Biodivers 3:762 805. Teng J, Zhang FG, Zhang YW, Takaishi Y, Duan HQ (2008) A new iridoid glycoside from Veronica sibirica. Chin Chem Lett 19:450 806. Jensen SR, Gotfredsen CH, Grayer RJ (2008) Unusual iridoid glycosides in Veronica sects. Hebe and Labiatoides. Biochem Syst Ecol 36:207 807. Taskova RM, Gotfredsen CH, Jensen SR (2006) Chemotaxonomy of Veroniceae and its allies in the Plantaginaceae. Phytochemistry 67:286 808. Kanemoto M, Matsunami K, Otsuka H, Shinzato T, Ishigaki C, Takeda Y (2008) Chlorinecontaining iridoid and iridoid glucoside, and other glucosides from leaves of Myoporum bontioides. Phytochemistry 69:2517 809. Wang R, Xiao D, Bian Y-H, Zhang X-Y, Li B-J, Ding L-S, Peng S-L (2008) Minor iridoids from the roots of Valeriana wallichii. J Nat Prod 71:1254 810. Wang P-C, Hu J-M, Ran X-H, Chen Z-Q, Jiang H-Z, Liu Y-Q, Zhou J, Zhao Y-X (2009) Iridoids and sesquiterpenoids from the roots of Valeriana officinalis. J Nat Prod 72:1682 811. Lin S, Shen Y-H, Zhang Z-X, Li H-L, Shan L, Liu R-H, Xu X-K, Zhang W-D (2010) Revision of the structures of 1,5-dihydroxy-3,8-epoxyvalechlorine, volvaltrate B, and valeriotetrate C from Valeriana jatamansi and V. officinalis. J Nat Prod 73:1723 812. Jensen SR, Gotfredsen CH, Harput US, Saracoglu I (2010) Chlorinated iridoid glucosides from Veronica longifolia and their antioxidant activity. J Nat Prod 73:1593 813. Xu J, Zhao P, Guo Y, Xie C, Jin D-Q, Ma Y, Hou W, Zhang T (2011) Iridoids from the roots of Valeriana jatamansi and their neuroprotective effects. Fitoterapia 82:1133 814. Xu J, Guo P, Guo Y, Fang L, Li Y, Sun Z, Gui L (2012) Iridoids from the roots of Valeriana jatamansi and their biological activities. Nat Prod Res 26:1996 815. Lin S, Zhang Z-X, Chen T, Ye J, Dai W-X, Shan L, Su J, Shen Y-H, Li H-L, Liu R-H, Xu X, Wang H, Zhang W (2013) Characterization of chlorinated valepotriates from Valeriana jatamansi. Phytochemistry 85:185 816. Wang R-J, Chen H-M, Yang F, Deng Y, AO H, Xie X-F, Li H-X, Zhang H, Cao Z-X, Zhu L-X, Chen Y, Peng C, Tan Y-Z (2017) Iridoids from the roots of Valeriana jatamansi Jones. Phytochemistry 141:156 817. Li X-H, Li X-H, Yao Q, Lu L-H, Li Y-B, Wu D-S, Fu D-H, Mei S-X, Cui T, Wang J-K, Zhu Z-Y (2017) Phlolosides A-F, iridoids from Phlomis likiangensis with a carbonate ester substituent. Tetrahedron Lett 58:3112

Naturally Occurring Organohalogen Compounds …

445

818. Lee DH, Shin J-S, Kang S-Y, Lee S-B, Lee JS, Ryu SM, Lee KT, Lee D, Jang DS (2018) Iridoids from the roots of Patrinia scabra and their inhibitory potential on LPS-induced nitric oxide production. J Nat Prod 81:1468 819. Li H, Yang S-Q, Wang H, Tian J, Gao W-Y (2010) Biosynthesis of the iridoid glucoside, lamalbid, in Lamium barbatum. Phytochemistry 71:1690 820. Geu-Flores F, Sherden NH, Courdavault V, Burlat V, Glenn WS, Wu C, Nims E, Cui Y, O’Connor SE (2012) An alternative route to cyclic terpenes by reductive cyclization in iridoid biosynthesis. Nature 492:138 821. Carbone M, Núñez-Pons L, Castelluccio F, Avila C, Gavagnin M (2009) Illudalane sesquiterpenoids of the alcyopterosin series from the Antarctic marine soft coral Alcyonium grandis. J Nat Prod 72:1357 822. Gerwick WH (1994) Structure and biosynthesis of marine algal oxylipins. Biochim Biophys Acta 1211:243 823. Zhou Z-F, Menna M, Cai Y-S, Guo Y-W (2015) Polyacetylenes of marine origin: chemistry and bioactivity. Chem Rev 115:1543 824. Barrow RA, Capon RJ (1994) Carduusynes (A-E): acetylenic acids from a Great Australian Bight marine sponge Phakellia carduus. Aust J Chem 47:1901 825. Lerch ML, Harper MK, Faulkner DJ (2003) Brominated polyacetylenes from the Philippines sponge Diplastrella sp. J Nat Prod 66:667 826. Gung BW, Gibeau C, Jones A (2004) First total synthesis of the brominated polyacetylenes (+)-diplyne A and D: proof of absolute configuration. Tetrahedron: Asymmetry 15:3973 827. Gung BW, Gibeau C, Jones A (2005) Total synthesis of two novel brominated acetylenic diols (+)-diplyne C and E: stereoselective construction of the (E)-1-bromo-1-alkene. Tetrahedron: Asymmetry 16:3107 828. de Jesus RP, Faulkner DJ (2003) Chlorinated acetylenes from the San Diego sponge Haliclona lunisimilis. J Nat Prod 66:671 829. Aratake S, Trianto A, Hanif N, de Voogd NJ, Tanaka J (2009) A new polyunsaturated brominated fatty acid from a Haliclona sponge. Mar Drugs 7:523 830. Alarif WM, Abdel-Lateff A, Al-Lihaibi SS, Ayyad S-EN, Badria FA (2013) A new cytotoxic brominated acetylenic hydrocarbon from the marine sponge Haliclona sp. with a selective effect against human breast cancer. Z Naturforsch 68c:70 831. Zhao C, Gu Q, Xu W-G, Xing G-S, Jin D-J, Xu R, Li H, Duan H-Q, Zhou J, Tang S-A (2015) Three new polyunsaturated lipids from a Guangxi marine sponge Haliclona sp. J Asian Nat Prod Res 17:114 832. Taniguchi M, Uchio Y, Yasumoto K, Kumusi T, Ooi T (2008) Brominated unsaturated fatty acids from marine sponge collected in Papua New Guinea. Chem Pharm Bull 56:378 833. Morinaka BI, Skepper CK, Molinski TF (2007) Ene-yne tetrahydrofurans from the sponge Xestospongia muta. Exploiting a weak CD effect for assignment of configuration. Org Lett 9:1975 834. Liu D, Xu J, Jiang W, Deng Z, de Voogd NJ, Proksch P, Lin W (2011) Xestospongienols AL, brominated acetylenic acids from the Chinese marine sponge Xestospongia testudinaria. Helv Chim Acta 94:1600 835. Jiang W, Liu D, Deng Z, de Voogd NJ, Proksch P, Lin W (2011) Brominated polyunsaturated lipids and their stereochemistry from the Chinese marine sponge Xestospongia testudinaria. Tetrahedron 67:58 836. Zhou X, Lu Y, Lin X, Yang B, Yang X, Liu Y (2011) Brominated aliphatic hydrocarbons and sterols from the sponge Xestospongia testudinaria with their bioactivities. Chem Phys Lipids 164:703 837. Akiyama T, Takada K, Oikawa T, Matsuura N, Ise Y, Okada S, Matsunaga S (2013) Stimulators of adipogenesis from the marine sponge Xestospongia testudinaria. Tetrahedron 69:6560 838. Liang L-F, Wang T, Cai Y-S, He W-F, Sun P, Li Y-F, Huang Q, Taglialatela-Scafati O, Wang H-Y, Guo Y-W (2014) Brominated polyunsaturated lipids from the Chinese sponge Xestospongia testudinaria as a new class of pancreatic lipase inhibitors. Eur J Med Chem 79:290

446

G. W. Gribble

839. He W-F, Liang L-F, Cai Y-S, Gao L-X, Li Y-F, Li J, Liu H-L, Guo Y-W (2015) Brominated polyunsaturated lipids with protein tyrosine phosphatase-1B inhibitory activity from Chinese marine sponge Xestospongia testudinaria. J Asian Nat Prod Res 17:861 840. Yang M, Liang L-F, Wang T, Wang H-Y, Liu H-L, Guo Y-W (2017) Further brominated polyacetylenes with pancreatic lipase inhibitory activity from Chinese marine sponge Xestospongia testudinaria. J Asian Nat Prod Res 19:732 841. Yang M, Liang L-F, Yao L-G, Liu H-L, Guo Y-W (2019) A new brominated polyacetylene from Chinese marine sponge Xestospongia testudinaria. J Asian Nat Prod Res 21:573 842. Gong J-X, He W-F, Liu H-L, Jiang C-S, Wang T, Wang H-Y, Guo Y-W (2016) Synthesis and evaluation of pancreatic lipase inhibitory effects halogenated polyunsaturated lipids from marine natural products: methyl xestospongoate and analogs. Helv Chim Acta 99:78 843. Gong J-X, Wang H-Y, Yao L-G, Li X-W, Guo Y-W (2016) First total synthesis of the marine natural brominated polyunsaturated lipid xestospongenyne as a potent pancreatic lipase inhibitory agent. Synlett 27:391 844. El-Gamal AA, Al-Massarani SM, Shaala LA, Alahdald AM, Al-Said MS, Ashour AE, Kumar A, Abdel-Kader MS, Abdel-Mageed WM, Youssef DTA (2016) Cytotoxic compounds from the Saudi Red Sea sponge Xestospongia testudinaria. Mar Drugs 14:82 845. Ayyad S-EN, Katoua DF, Alarif WM, Sobahi TR, Aly MM, Shaala LA, Ghandourah MA (2015) Two new polyacetylene derivatives from the Red Sea sponge Xestospongia sp. Z Naturforsch 70c:297 846. Angawi RF, Calcinai B, Cerrano C, Dien HA, Fattorusso E, Scala F, Taglialatela-Scafati O (2009) Dehydroconicasterol and aurantoic acid, a chlorinated polyene derivative, from the Indonesian sponge Theonella swinhoei. J Nat Prod 72:2195 847. Angawi RF, Bavestrello G, Calcinai B, Dien HA, Donnarumma G, Tufano MA, Paoletti I, Grimaldi E, Chianese G, Fattorusso E, Taglialatela-Scafati O (2011) Aurantoside J: a new tetramic acid glycoside from Theonella swinhoei. Insights into the antifungal potential of aurantosides. Mar Drugs 9:2809 848. Aoki N, Yamamoto K, Ogawa T, Ohta E, Ikeuchi T, Kamemura K, Ikegami S, Ohta S (2013) Bromotheoynic acid, a brominated acetylenic acid from the marine sponge Theonella swinhoei. Nat Prod Res 27:117 849. Skepper CK, Molinski TF (2008) Long-chain 2H-azirines with heterogeneous terminal halogenation from the marine sponge Dysidea fragilis. J Org Chem 73:2592 850. Trianto A, de Voodg NJ, Tanaka J (2014) Two new compounds from an Indonesian sponge Dysidea sp. J Asian Nat Prod Res 16:163 851. Keffer JL, Plaza A, Bewley CA (2009) Motualevic acids A-F, antimicrobial acids from the sponge Siliquariaspongia sp. Org Lett 11:1087 852. Cheruku P, Keffer JL, Dogo-Isonagie C, Bewley CA (2010) Motualevic acids and analogs: synthesis and antimicrobial structure-activity relationships. Bioorg Med Chem Lett 20:4108 853. Sudhakar G, Kadam VD, Reddy VVN (2010) Total synthesis of motualevic acids A-E. Tetrahedron Lett 51:1124 854. Kadam VD, Sudhakar G (2015) Total synthesis of motualevic acids A-F, (E) and (Z)-antazirines. Tetrahedron 71:1058 855. Ando H, Ueoka R, Okada S, Fujita T, Iwashita T, Imai T, Yokoyama T, Matsumoto Y, van Soest RWM, Matsunaga S (2010) Penasins A-E, long-chain cytotoxic sphingoid bases, from a marine sponge Penares sp. J Nat Prod 73:1947 856. Zhang H, Conte MM, Capon RJ (2010) Franklinolides A-C from an Australian marine sponge complex: phosphodiesters strongly enhance polyketide cytotoxicity. Angew Chem Int Ed 49:9904 857. Ko J, Morinaka BI, Molinski TF (2011) Faulknerynes A–C from a Bahamian sponge Diplastrella sp.: stereoassignment by critical application of two exciton coupled CD methods. J Org Chem 76:894 858. Morinaka BI, Molinski TF (2011) Mollenyne A, a long-chain chlorodibromohydrin amide from the sponge Spirastrella mollis. Org Lett 13:6338

Naturally Occurring Organohalogen Compounds …

447

859. Wang X, Duggan BM, Molinski TF (2015) Mollenynes B–E from the marine sponge Spirastrella mollis. Band-selective heteronuclear single quantum coherence for discrimination of bromo–chloro regioisomerism in natural products. J Am Chem Soc 137:12343 860. Chianese G, Fattorusso E, Scala F, Teta R, Calcinai B, Bavestrello G, Dien HA, Kaiser M, Tasdemir D, Taglialatela-Scafati O (2012) Manadoperoxides, a new class of potent antitrypanosomal agents of marine origin. Org Biomol Chem 10:7197 861. Kumar R, Subramani R, Feussner K-D, Aalbersberg W (2012) Aurantoside K, a new antifungal tetramic acid glycoside from a Fijian marine sponge of the genus Melophlus. Mar Drugs 10:200 862. Teta R, Irollo E, Della Sala G, Pirozzi G, Mangoni A, Costantino V (2013) Smenamides A and B, chlorinated peptide/polyketide hybrids containing a dolapyrrolidinone unit from the Caribbean sponge Smenospongia aurea. Evaluation of their role as leads in antitumor drug research. Mar Drugs 11:4451 863. Caso A, Laurenzana I, Lamorte D, Trino S, Esposito G, Piccialli V, Costantino V (2018) Smenamide A analogues. Synthesis and biological activity on multiple myeloma cells. Mar Drugs 16:206 864. Martín MJ, Coello L, Fernández R, Reyes F, Rodríguez A, Murcia C, Garranzo M, Mateo C, Sánchez-Sancho F, Bueno S, de Eguilior C, Francesch A, Munt S, Cuevas C (2013) Isolation and first total synthesis of PM050489 and PM060184, two new marine anticancer compounds. J Am Chem Soc 135:10164 865. Hwang BS, Lee K, Yang C, Jeong EJ, Rho J-R (2013) Characterization and anti-inflammatory effects of iodinated acetylenic acids isolated from the marine sponges Suberites mammilaris and Suberites japonicus. J Nat Prod 76:2355 866. Kim H, Chin J, Choi H, Baek K, Lee T-G, Park SE, Wang W, Hahn D, Yang I, Lee J, Mun B, Ekins M, Nam S-J, Kang H (2013) Phosphoiodyns A and B, unique phosphorus-containing iodinated polyacetylenes from a Korean sponge Placospongia sp. Org Lett 15:100 867. Kim H, Chin J, Choi H, Baek K, Lee T-G, Park SE Wang W, Hahn D, Yang I, Lee J, Mun B, Ekins M, Nam S-J, Kang H (2013) Phosphoiodyns A and B, unique phosphorus-containing iodinated polyacetylenes from a Korean sponge Placospongia sp. Org Lett 15:5614 868. Kim H, Kim K-J, Yeon J-T, Kim SH, Won DH, Choi H, Nam S-J, Son Y-J, Kang H (2014) Placotylene A, an inhibitor of the receptor activator of nuclear factor-κB ligand-induced osteoclast differentiation, from a Korean sponge Placospongia sp. Mar Drugs 12:2054 869. Galler DJ, Parker KA (2015) Five easy pieces. The total synthesis of phosphoiodyn A (and placotylene A). Org Lett 17:5544 870. Esposito G, Teta R, Miceli R, Ceccarelli LS, Della Sala G, Camerlingo R, Irollo E, Mangoni A, Pirozzi G, Costantino V (2015) Isolation and assessment of the in vitro anti-tumor activity of smenothiazole A and B, chlorinated thiazole-containing peptide/polyketides from the Caribbean sponge, Smenospongia aurea. Mar Drugs 13:444 871. Ma X, Chen Y, Chen S, Xu Z, Ye T (2017) Total syntheses of smenothiazoles A and B. Org Biomol Chem 15:7196 872. Esposito G, Della Sala G, Teta R, Caso A, Bourguet-Kondracki M-L, Pawlik JR, Mangoni A, Costantino V (2016) Chlorinated thiazole-containing polyketide-peptides from the Caribbean sponge Smenospongia conulosa: structure elucidation on microgram scale. Eur J Org Chem:2871 873. Teta R, Della Sala G, Esposito G, Via CW, Mazzoccoli C, Piccoli C, Bertin MJ, Costantino V, Mangoni A (2019) A joint molecular networking study of a Smenospongia sponge and a cyanobacterial bloom revealed new antiproliferative chlorinated polyketides. Org Chem Front 6:1762 874. Via CW, Glukhov E, Costa S, Zimba PV, Moeller PDR, Gerwick WH, Bertin MJ (2018) The metabolome of a cyanobacterial bloom visualized by MS/MS-based molecular networking reveals new neurotoxic smenamide analogs (C, D, and E). Front Chem 6:316 875. Caso A, Esposito G, Della Sala G, Pawlik JR, Teta R, Mangoni A, Costantino V (2019) Fast detection of two smenamide family members using molecular networking. Mar Drugs 17:618

448

G. W. Gribble

876. Kotoku N, Ishida R, Matsumoto H, Arai M, Toda K, Setiawan A, Muraoka O, Kobayashi M (2017) Biakamides A-D, unique polyketides from a marine sponge, act as selective growth inhibitors of tumor cells adapted to nutrient starvation. J Org Chem 82:1705 877. Kaweetripob W, Mahidol C, Wongbundit S, Tuntiwachwuttikul P, Ruchirawat S, Prawat H (2018) Sesterterpenes and phenolic alkenes from the Thai sponge Hyrtios erectus. Tetrahedron 74:316 878. Gerwick L, Boudreau P, Choi H, Mascuch S, Villa FA, Balunas MJ, Malloy KL, Teasdale ME, Rowley DC, Gerwick WH (2013) Interkingdom signaling by structurally related cyanobacterial and algal secondary metabolites. Phytochem Rev 12:459 879. Engene N, Rottacker EC, Kaštovský J, Byrum T, Choi H, Ellisman MH, Komárek J, Gerwick WH (2012) Moorea producens gen. nov., sp. nov. and Moorea bouillonii comb. nov., tropical marine cyanobacteria rich in bioactive secondary metabolites. Int J Syst Evol Microbiol 62:1171 880. Jiménez JI, Vansach T, Yoshida WY, Sakamoto B, Pörzgen P, Horgen FD (2009) Halogenated fatty acid amides and cyclic depsipeptides from an eastern Caribbean collection of the cyanobacterium Lyngbya majuscula. J Nat Prod 72:1573 881. Kwan JC, Teplitski M, Gunasekera SP, Paul VJ, Luesch H (2010) Isolation and biological evaluation of 8-epi-malyngamide C from the Floridian marine cyanobacterium Lyngbya majuscula. J Nat Prod 73:463 882. Gross H, McPhail KL, Goeger DE, Valeriote FA, Gerwick WH (2010) Two cytotoxic stereoisomers of malyngamide C, 8-epi-malyngamide C and 8-O-acetyl-8-epi-malyngamide C, from the marine cyanobacterium Lyngbya majuscula. Phytochemistry 71:1729 883. Malloy KL, Villa FA, Engene N, Matainaho T, Gerwick L, Gerwick WH (2011) Malyngamide 2, an oxidized lipopeptide with nitric oxide inhibiting activity from a Papua New Guinea marine cyanobacterium. J Nat Prod 74:95 884. Gunasekera SP, Owle CS, Montaser R, Luesch H, Paul VJ (2011) Malyngamide 3 and cocosamides A and B from the marine cyanobacterium Lyngbya majuscula from Cocos Lagoon, Guam. J Nat Prod 74:871 885. Shaala LA, Youssef DTA, McPhail KL, Elbandy M (2013) Malyngamide 4, a new lipopeptide from the Red Sea marine cyanobacterium Moorea producens (formerly Lyngbya majuscula). Phytochem Lett 6:183 886. Chang TT, More SV, Lu I-H, Hsu J-C, Chen T-J, Jen YC, Lu C-K, Li W-S (2011) Isomalyngamide A, A-1 and their analogs suppress cancer cell migration in vitro. Eur J Med Chem 46:3810 887. Han B, Reinscheid UM, Gerwick WH, Gross H (2011) The structure elucidation of isomalyngamide K from the marine cyanobacterium Lyngbya majuscula by experimental and DFT computational methods. J Mol Struct 989:109 888. Sabry OM, Goeger DE, Gerwick WH (2017) Biologically active new metabolites from a Florida collection of Moorea producens. Nat Prod Res 31:555 889. Jiang W, Zhou W, Othman R, Uchida H, Watanabe R, Suzuki T, Sakamoto B, Nagai H (2018) A new malyngamide from the marine cyanobacterium Moorea producens. Nat Prod Res 32:97 890. Sueyoshi K, Yamano A, Ozaki K, Sumimoto S, Iwasaki A, Suenaga K, Teruya T (2017) Three new malyngamides from the marine cyanobacterium Moorea producens. Mar Drugs 15:367 891. Kleigrewe K, Almaliti J, Tian IY, Kinnel RB, Korobeynikov A, Monroe EA, Duggan BM, Di Marzo V, Sherman DH, Dorrestein PC, Gerwick L, Gerwick WH (2015) Combining mass spectrometric metabolic profiling with genomic analysis: a powerful approach for discovering natural products from cyanobacteria. J Nat Prod 78:1671 892. Lopez JAV, Petitbois JG, Vairappan CS, Umezawa T, Matsuda F, Okino T (2017) Columbamides D and E: chlorinated fatty acid amides from the marine cyanobacterium Moorea bouillonii collected in Malaysia. Org Lett 19:4231 893. Mehjabin JJ, Wei L, Petitbois JG, Umezawa T, Matsuda F, Vairappan CS, Morikawa M, Olino T (2020) Biosurfactants from marine cyanobacteria collected in Sabah, Malaysia. J Nat Prod 83:1925

Naturally Occurring Organohalogen Compounds …

449

894. Williamson RT, Singh IP, Gerwick WH (2004) Taveuniamides: new chlorinated toxins from a mixed assemblage of marine cyanobacteria. Tetrahedron 60:7025 895. Bertin MJ, Zimba PV, He H, Moeller PDR (2016) Structure revision of trichotoxin, a chlorinated polyketide isolated from a Trichodesmium thiebautii bloom. Tetrahedron Lett 57:5864 896. Bertin MJ, Wahome PG, Zimba PV, He H, Moeller PDR (2017) Trichophycin A, a cytotoxic linear polyketide isolated from a Trichodesmium thiebautii bloom. Mar Drugs 15:10 897. Belisle RS, Via CW, Schock TB, Villareal TA, Zimba PV, Beauchesne KR, Moeller PDR, Bertin MJ (2017) Trichothiazole A, a dichlorinated polyketide containing an embedded thiazole isolated from Trichodesmium blooms. Tetrahedron Lett 58:4066 898. Bertin MJ, Saurí J, Liu Y, Via CW, Roduit AF, Williamson RT (2018) Trichophycins B-F, chlorovinylidene-containing polyketides isolated from a cyanobacterial bloom. J Org Chem 83:13256 899. McManus KM, Kirk RD, Via CW, Lotti JS, Roduit AF, Teta R, Scarpato S, Mangoni A, Bertin MJ (2020) Isolation of isotrichophycin C and trichophycins G-I from a collection of Trichodesmium thiebautii. J Nat Prod 83:2664 900. Malloy KL, Suyama TL, Engene N, Debonsi H, Cao Z, Matainaho T, Spadafora C, Murray TF, Gerwick WH (2012) Credneramides A and B: neuromodulatory phenethylamine and isopentylamine derivatives of a vinyl chloride-containing fatty acid from cf. Trichodesmium sp. nov. J Nat Prod 75:60 901. Balunas MJ, Grosso MF, Villa FA, Engene N, McPhail KL, Tidgewell K, Pineda LM, Gerwick L, Spadafora C, Kyle DE, Gerwick WH (2012) Coibacins A-D, antileishmanial marine cyanobacterial polyketides with intriguing biosynthetic origins. Org Lett 14:3878 902. Choi H, Mascuch SJ, Villa FA, Byrum T, Teasdale ME, Smith JE, Preskitt LB, Rowley DC, Gerwick L, Gerwick WH (2012) Honaucins A-C, potent inhibitors of inflammation and bacterial quorum sensing: synthetic derivatives and structure-activity relationships. Chem Biol 19:589 903. Mascuch SJ, Boudreau PD, Carland TM, Pierce NT, Olson J, Hensler ME, Choi H, Campanale J, Hamdoun A, Nizet V, Gerwick WH, Gaasterland T, Gerwick L (2018) Marine natural product honaucin A attenuates inflammation by activating the Nrf2-ARE pathway. J Nat Prod 81:506 904. Boudreau PD, Monroe EA, Mehrotra S, Desfor S, Korobeynikov A, Sherman DH, Murray TF, Gerwick L, Dorrestein PC, Gerwick WH (2015) Expanding the described metabolome of the marine cyanobacterium Moorea producens JHB through orthogonal natural products workflows. PLoS One 10:e0133297 905. Nunnery JK, Engene N, Byrum T, Cao Z, Jabba SV, Pereira AR, Matainaho T, Murray TF, Gerwick WH (2012) Biosynthetically intriguing chlorinated lipophilic metabolites from geographically distant tropical marine cyanobacteria. J Org Chem 77:4198 906. Montaser R, Paul VJ, Luesch H (2013) Modular strategies for structure and function employed by marine cyanobacteria: characterization and synthesis of pitinoic acids. Org Lett 15:4050 907. Leão PN, Nakamura H, Costa M, Pereira AR, Martins R, Vasconcelos V, Gerwick WH, Balskus EP (2015) Biosynthesis-assisted structural elucidation of the bartolosides, chlorinated aromatic glycolipids from cyanobacteria. Angew Chem Int Ed 54:11063 908. Cai W, Matthews JH, Paul VJ, Luesch H (2016) Pitiamides A and B, multifunctional fatty acid amides from marine cyanobacteria. Planta Med 82:897 909. Naman CB, Almaliti J, Armstrong L, Caro-Díaz EJ, Pierce ML, Glukhov E, Fenner A, Spadafora C, Debonsi HM, Dorrestein PC, Murray TF, Gerwick WH (2017) Discovery and synthesis of caracolamide A, an ion channel modulating dichlorovinylidene containing phenethylamide from a Panamanian marine cyanobacterium cf. Symploca species. J Nat Prod 80:2328 910. Sueyoshi K, Yamada M, Yamano A, Ozaki K, Sumimoto S, Iwasaki A, Suenaga K, Teruya T (2018) Ypaoamides B and C, linear lipopeptides from an Okeania sp. marine cyanobacterium. J Nat Prod 81:1103

450

G. W. Gribble

911. Moosmann P, Ueoka R, Gugger M, Piel J (2018) Aranazoles: extensively chlorinated nonribosomal peptide–polyketide hybrids from the cyanobacterium Fischerella sp. PCC 9339. Org Lett 20:5238 912. Moss NA, Seiler G, Leão TF, Castro-Falcón G, Gerwick L, Hughes CC, Gerwick WH (2019) Nature’s combinatorial biosynthesis produces vatiamides A-F. Angew Chem Int Ed 58:9027 913. Gutiérrez-del-Rio I, de Fraissinette NB, Castelo-Branco R, Oliveira F, Morais J, RedondoBlanco S, Villar CJ, Iglesias MJ, Soengas R, Cepas V, Cubillos YL, Sampietro G, Rodolfi L, Lombó F, González SMS, Ortiz FL, Vasconcelos V, Reis MA (2020) Chlorosphaerolactylates A–D: natural lactylates of chlorinated fatty acids isolated from the cyanobacterium Sphaerospermopsis sp. LEGE 00249. J Nat Prod 83:1885 914. Abt K, Castelo-Branco R, Leão PN (2021) Biosynthesis of chlorinated lactylates in Sphaerospermopsis sp. LEGE 00249. J Nat Prod 84:278 915. Figueiredo SAC, Preto M, Moreira G, Martins TP, Abt K, Melo A, Vasconcelos VM, Leão PN (2021) Discovery of cyanobacterial natural products containing fatty acid residues. Angew Chem Int Ed 60:10064 916. Van Wagoner RM, Deeds JR, Tatters AO, Place AR, Tomas CR, Wright JLC (2010) Structure and relative potency of several karlotoxins from Karlodinium veneficum. J Nat Prod 73:1360 917. Waters AL, Oh J, Place AR, Hamann MT (2015) Stereochemical studies of the karlotoxin class using NMR spectroscopy and DP4 chemical-shift analysis: insights into their mechanism of action. Angew Chem Int Ed 54:15705 918. Cai P, He S, Zhou C, Place AR, Haq S, Ding L, Chen H, Jiang Y, Guo C, Xu Y, Zhang J, Yan X (2016) Two new karlotoxins found in Karlodinium veneficum (strain GM2) from the East China Sea. Harmful Algae 58:66 919. Peng J, Place AR, Yoshida W, Anklin C, Hamann MT (2010) Structure and absolute configuration of karlotoxin-2, an ichthyotoxin from the marine dinoflagellate Karlodinium veneficum. J Am Chem Soc 132:3277 920. Furukawa H, Kiyota H, Yamada T, Yaosaka M, Takeuchi R, Watanabe T, Kuwahara S (2007) Stereochemistry of enacyloxins. Part 4. Complete structural and configurational assignment of the enacyloxin family, a series of antibiotics from Frateuria sp. W-315. Chem Biodivers 4:1601 921. Masschelein J, Sydor PK, Hobson C, Howe R, Jones C, Roberts DM, Yap ZL, Parkhill J, Mahenthiralingam E, Challis GL (2019) A dual transacylation mechanism for polyketide synthase chain release in enacyloxin antibiotic biosynthesis. Nature Chem 11:906 922. Kosol S, Gallo A, Griffiths D, Valentic TR, Masschelein J, Jenner M, de los Santos ELC, Manzi L, Sydor PK, Rea D, Zhou S, Fülöp V, Oldham NJ, Tsai S-C, Challis GL, Lewandowski JR (2019) Structural basis for chain release from the enacyloxin polyketide synthase. Nature Chem 11:913 923. Liu X, Biswas S, Berg MG, Antapli CM, Xie F, Wang Q, Tang M-C, Tang G-L, Zhang L, Dreyfuss G, Cheng Y-Q (2013) Genomics-guided discovery of thailanstatins A, B, and C as pre-mRNA splicing inhibitors and antiproliferative agents from Burkholderia thailandensis MSMB43. J Nat Prod 76:685 924. Nicolaou KC, Rhoades D, Kumar SM (2018) Total syntheses of thailanstatins A–C, spliceostatin D, and analogues thereof. Stereodivergent synthesis of tetrasubstituted dihydroand tetrahydropyrans and design, synthesis, biological evaluation, and discovery of potent antitumor agents. J Am Chem Soc 140:8303 925. Amagata T, Tanaka M, Yamada T, Minoura K, Numata A (2008) Gymnastatins and dankastatins, growth inhibitory metabolites of a Gymnascella species from a Halichondria sponge. J Nat Prod 71:340 926. Murayama K, Tanabe T, Ishikawa Y, Nakamura K, Nishiyama S (2009) A synthetic study on gymnastatins F and Q: the tandem Michael and aldol reaction approach. Tetrahedron Lett 50:3191 927. Amagata T, Takigawa K, Minoura K, Numata A (2010) Gymnastatins I-K, cancer cell growth inhibitors from a sponge-derived Gymnascella dankaliensis. Heterocycles 81:897

Naturally Occurring Organohalogen Compounds …

451

928. Bunyapaiboonsri T, Yoiprommarat S, Srisanoh U, Choowong W, Tasanathai K, HywelJones NL, Luangsa-ard JJ, Isaka M (2011) Isariotins G-J from cultures of the Lepidoptera pathogenic fungus Isaria tenuipes. Phytochem Lett 4:283 929. Amagata T, Tanaka M, Yamada T, Chen Y-P, Minoura K, Numata A (2013) Additional cytotoxic substances isolated from the sponge-derived Gymnascella dankaliensis. Tetrahedron Lett 54:5960 930. Xie J, Li J, Yang Y-H, Chen Y-H, Zhao P-J (2014) Two new ambuic acid analogs from Pestalotiopsis sp. cr013. Phytochem Lett 10:291 931. Wu Q, Wu C, Long H, Chen R, Liu D, Proksch P, Guo P, Lin W (2015) Varioxiranols A-G and 19-O-methyl-22-methoxypre-shamixanthone, PKS and hybrid PKS-derived metabolites from a sponge-associated Emericella variecolor fungus. J Nat Prod 78:2461 932. He X, Zhang Z, Chen Y, Che Q, Zhu T, Gu Q, Li D (2015) Varitatin A, a highly modified fatty acid amide from Penicillium variabile cultured with a DNA methyltransferase inhibitor. J Nat Prod 78:2841 933. Sobolevskaya MP, Leshchenko EV, Hoai TPT, Denisenko VA, Dyshlovoy SA, Kirichuk NN, Khudyakova YV, Kim NY, Berdyshev DV, Pislyagin EA, Kuzmich AS, Gerasimenko AV, Popov RS, von Amsberg G, Antonov AS, Afiyatullov SS (2016) Pallidopenillines: polyketides from the alga-derived fungus Penicillium thomii Maire KMM 4675. J Nat Prod 79:3031 934. Lee M-S, Wang S-W, Wang G-J, Pang K-L, Lee C-K, Kuo Y-H, Cha H-J, Lin R-K, Lee T-H (2016) Angiogenesis inhibitors and anti-inflammatory agents from Phoma sp. NTOU4195. J Nat Prod 79:2983 935. Smetanina OF, Yurchenko AN, Ivanets EV, Kalinovsky AI, Khudyakova YV, Dyshlovoy SA, von Amsberg G, Yurchenko EA, Afiyatullov SS (2017) Unique prostate cancer-toxic polyketides from marine sediment-derived fungus Isaria felina. J Antibiot 70:856 936. Kobayashi H, Ohashi J, Fujita T, Iwashita T, Nakao Y, Matsunaga S, Fusetani N (2007) Complete structure elucidation of shishididemniols, complex lipids with tyramine-derived tether and two serinol units, from a marine tunicate of the family Didemnidae. J Org Chem 72:1218 937. Kobayashi H, Miyata Y, Okada K, Fujita T, Iwashita T, Nakao Y, Fusetani N, Matsunaga S (2007) The structures of three new shishididemniols from a tunicate of the family Didemnidae. Tetrahedron 63:6748 938. Bedke DK, Vanderwal CD (2011) Chlorosulfolipids: structure, synthesis, and biological relevance. Nat Prod Rep 28:15 939. Darsow KH, Lange HA, Resch M, Walter C, Buchholz R (2007) Analysis of a chlorosulfolipid from Ochromonas danica by matrix-assisted laser desorption/ionization quadrupole ion trap time-of-flight mass spectrometry. Rapid Commun Mass Spectrom 21:2188 940. Kawahara T, Kumaki Y, Kamada T, Ishii T, Okino T (2009) Absolute configuration of chlorosulfolipids from the chrysophyta Ochromonas danica. J Org Chem 74:6016 941. Chao C-H, Huang H-C, Wang G-H, Wen Z-H, Wang W-H, Chen I-M, Sheu J-H (2010) Chlorosulfolipids and the corresponding alcohols from the octocoral Dendronephthya griffini. Chem Pharm Bull 58:944 942. Nilewski C, Carreira EM (2012) Recent advances in the total synthesis of chlorosulfolipids. Eur J Org Chem: 1685 943. Chung W-J, Vanderwal CD (2014) Approaches to the chemical synthesis of the chlorosulfolipids. Acc Chem Res 47:718 944. Umezawa T, Matsuda F (2014) Recent progress toward synthesis of chlorosulfolipids: total synthesis and methodology. Tetrahedron Lett 55:3003 945. Pereira AR, Byrum T, Shibuya GM, Vanderwal CD, Gerwick WH (2010) Structure revision and absolute configuration of malhamensilipin A from the freshwater chrysophyte Poterioochromonas malhamensis. J Nat Prod 73:279 946. Yoshimitsu T, Fukumoto N, Nakatani R, Kojima N, Tanaka T (2010) Asymmetric total synthesis of (+)-hexachlorosulfolipid, a cytotoxin isolated from Adriatic mussels. J Org Chem 75:5425

452

G. W. Gribble

947. Umezawa T, Shibata M, Kaneko K, Okino T, Matsuda F (2011) Asymmetric total synthesis of danicalipin A and evaluation of biological activity. Org Lett 13:904 948. Chung W, Carlson JS, Vanderwal CD (2014) General approach to the synthesis of the chlorosulfolipids danicalipin A, mytilipin A, and malhamensilipin A in enantioenriched form. J Org Chem 79:2226 949. Landry ML, Hu DX, McKenna GM, Burns NZ (2016) Catalytic enantioselective dihalogenation and the selective synthesis of (–)-deschloromytilipin A and (–)-danicalipin A. J Am Chem Soc 138:5150 950. Boshkow J, Fischer S, Bailey AM, Wolfrum S, Carreira EM (2017) Stereochemistry and biological activity of chlorinated lipids: a study of danicalipin A and selected diastereomers. Chem Sci 8:6904 951. Bailey AM, Wolfrum S, Carreira EM (2016) Biological investigations of (+)-danicalipin A enabled through synthesis. Angew Chem Int Ed 55:639 952. Chung W, Carlson JS, Bedke DK, Vanderwal CD (2013) A synthesis of the chlorosulfolipid mytilipin A via a longest linear sequence of seven steps. Angew Chem Int Ed 52:10052 953. Nilewski C, Deprez NR, Fessard TC, Li DB, Geisser RW, Carreira EM (2011) Synthesis of undecachlorosulfolipid A: re-evaluation of the nominal structure. Angew Chem Int Ed 50:7940 954. White AR, Duggan BM, Tsai S-C, Vanderwal CD (2016) The alga Ochromonas danica produces bromosulfolipids. Org Lett 18:1124 955. Boshkow J, Scattolin T, Schoenebeck F, Carreira EM (2018) [1,3]-Sigmatropic shift of an allylic chloride. Helv Chim Acta 101:e1800148 956. Bedke DK, Vanderwal CD (2009) Chlorine lends a helping hand. Nature 457:548 957. Peterson PE, Bopp RJ, Chevli DM, Curran EL, Dillard DE, Kamat RJ (1967) Solvents of low nucleophilicity. IX. Inductive and participation effects in carbonium ion reactions in acetic, formic, and trifluoroacetic acid. J Am Chem Soc 89:5902 958. Peterson PE, Clifford PR, Slama FJ (1970) Reactions of tetramethylenehalonium ions. J Am Chem Soc 92:2840 959. Chen J, Fu X-G, Zhou L, Zhang J-T, Qi X-L, Cao X-P (2009) A convergent route for the total synthesis of malyngamides O, P, Q, and R. J Org Chem 74:4149 960. Chen J, Shi Z-F, Zhou L, Xie A-L, Cao X-P (2010) Total synthesis of malyngamide M and isomalyngamide M. Tetrahedron 66:3499 961. Zhang J-T, Qi X-L, Chen J, Li B-S, Zhou Y-B, Cao X-P (2011) Total synthesis of malyngamides K, L, and 5 -epi-C and absolute configuration of malyngamide L. J Org Chem 76:3946 962. Erver F, Hilt G (2012) Cobalt- versus ruthenium-catalyzed Alder–ene reaction for the synthesis of credneramide A and B. J Org Chem 77:5215 963. Petermichl M, Loscher S, Schobert R (2016) Total synthesis of aurantoside G, an Nβ-glycosylated 3-oligoenoyltetramic acid from Theonella swinhoei. Angew Chem Int Ed 55:10122 964. Chen R, Li L, Lin N, Zhou R, Hua Y, Deng H, Zhang Y (2018) Asymmetric total synthesis of (+)-majusculoic acid via a dimerization–dedimerization strategy and absolute configuration assignment. Org Lett 20:1477 965. Peacock DE, Williams BD, Christensen PE (2007) ‘Total fluorine’ analysis of seed of Australian Gastrolobium spp. showing temporal, spatial and morphological variation. J Fluorine Chem 128:631 966. Onega M, McGlinchey RP, Deng H, Hamilton JTG, O’Hagan D (2007) The identification of (3R,4S)-5-fluoro-5-deoxy-d-ribulose-1-phosphate as an intermediate in fluorometabolite biosynthesis in Streptomyces cattleya. Bioorg Chem 35:375 967. Deng H, Cross SM, McGlinchey RP, Hamilton JTG, O’Hagan D (2008) In vitro reconstituted biotransformation of 4-fluorothreonine from fluoride ion: application of the fluorinase. Chem Biol 15:1268 968. Donnelly C, Murphy CD (2009) Purification and properties of fluoroacetate dehalogenase from Pseudomonas fluorescens DSM 8341. Biotechnol Lett 31:245

Naturally Occurring Organohalogen Compounds …

453

969. Weeks AM, Coyle SM, Jinek M, Doudna JA, Chang MCY (2010) Structural and biochemical studies of a fluoroacetyl-CoA-specific thioesterase reveal a molecular basis for fluorine selectivity. Biochemistry 49:9269 970. Eustáquio AS, O’Hagan D, Moore BS (2010) Engineering fluorometabolite production: fluorinase expression in Salinispora tropica yields fluorosalinosporamide. J Nat Prod 73:378 971. Li X-G, Domarkas J, O’Hagan D (2010) Fluorinase mediated chemoenzymatic synthesis of [18 F]-fluoroacetate. Chem Commun 46:7819 972. Li X-G, Dall’Angelo S, Schweiger LF, Zanda M, O’Hagan D (2012) [18 F]-5-Fluoro-5deoxyribose, an efficient peptide bioconjugation ligand for positron emission tomography (PET) imaging. Chem Commun 48:5247 973. Wadoux RDP, Lin X, Keddie NS, O’Hagan D (2013) Chiral fluoroacetic acid: synthesis of (R)- and (S)-[2 H1 ]-fluoroacetate in high enantiopurity. Tetrahedron: Asymmetry 24:719 974. Huang S, Ma L, Tong MH, Yu Y, O’Hagan D, Deng H (2014) Fluoroacetate biosynthesis from the marine-derived bacterium Streptomyces xinghaiensis NRRL B-24674. Org Biomol Chem 12:4828 975. Ma L, Li Y, Meng L, Deng H, Li Y, Zhang Q, Diao A (2016) Biological fluorination from the sea: discovery of a SAM-dependent nucleophilic fluorinating enzyme from the marinederived bacterium Streptomyces xinghaiensis NRRL B24674. RSC Adv 6:27047 976. Ma L, Bartholome A, Tong MH, Qin Z, Yu Y, Shepherd T, Kyeremeh K, Deng H, O’Hagan D (2015) Identification of a fluorometabolite from Streptomyces sp. MA37: (2R3S4S)-5fluoro-2,3,4-trihydroxypentanoic acid. Chem Sci 6:1414 977. Nielsen OJ, Scott BF, Spencer C, Wallington TJ, Ball JC (2001) Trifluoroacetic acid in ancient freshwater. Atmos Environ 35:2799 978. Nielsen OJ (2002) Trifluoroacetic acid—what are the new findings? Dansk Kemi 83:28 979. Scheurer M, Nödler K, Freeling F, Janda J, Happel O, Riegel M, Müller U, Storck FR, Fleig M, Lange FT, Brunsch A, Brauch H-J (2017) Small, mobile, persistent: trifluoroacetate in the water cycle—overlooked sources, pathways, and consquences for drinking water supply. Water Res 126:460 980. Joudan S, De Silva AO, Young CJ (2021) Insufficient evidence for the existence of natural trifluoroacetic acid. Environ Sci Processes Impacts 23:1641 981. Slaughter JC (1999) The naturally occurring furanones: formation and function from pheromone to food. Biol Rev 74:259 982. de Nys R, Givskov M, Kumar N, Kjelleberg S, Steinberg PD (2006) Furanones. In: Fusetani N, Clare AS (eds) Progress in molecular and subcellular biology, subseries marine molecular biotechnology, antifouling compounds. Springer, Berlin, Heidelberg, p 55 983. Ren D, Sims JJ, Wood TK (2001) Inhibition of biofilm formation and swarming of Escherichia coli by (5Z)-4-bromo-5-(bromomethylene)-3-butyl-2(5H)-furanone. Environ Microbiol 3:731 984. Ren D, Sims JJ, Wood TK (2002) Inhibition of biofilm formation and swarming of Bacillus subtilis by (5Z)-4-bromo-5-(bromomethylene)-3-butyl-2(5H)-furanone. Lett Appl Microbiol 34:293 985. Han Y, Hou S, Simon KA, Ren D, Luk Y-Y (2008) Identifying the important structural elements of brominated furanones for inhibiting biofilm formation by Escherichia coli. Bioorg Med Chem Lett 18:1006 986. Givskov M, de Nys R, Manefield M, Gram L, Maximilien R, Eberl L, Molin S, Steinberg PD, Kjelleberg S (1996) Eukaryotic interference with homoserine lactone-mediated prokaryotic sgnalling. J Bacteriol 178:6618 987. Manefield M, Harris L, Rice SA, de Nys R, Kjelleberg S (2000) Inhibition of luminescence and virulence in the black tiger prawn (Penaeus monodon) pathogen Vibrio harveyi by intercellular signal antagonists. Appl Environ Microbiol 66:2079 988. Thorson MK, Van Wagoner RM, Harper MK, Ireland CM, Majtan T, Kraus JP, Barrios AM (2015) Marine natural products as inhibitors of cystathionine beta-synthase activity. Bioorg Med Chem Lett 25:1064

454

G. W. Gribble

989. Zang T, Lee BWK, Cannon LM, Ritter KA, Dai S, Ren D, Wood TK, Zhou ZS (2009) A naturally occurring brominated furanone covalently modifies and inactivates LuxS. Bioorg Med Chem Lett 19:6200 990. Bjarnsholt T, Givskov M (2008) Quorum sensing inhibitory drugs as next generation antimicrobials: worth the effort? Curr Infect Dis Rep 10:22 991. Wang W, Kim H, Nam S-J, Rho BJ, Kang H (2012) Antibacterial butenolides from the Korean tunicate Pseudodistoma antinboja. J Nat Prod 75:2049 992. Wang W, Kim H, Patil RS, Giri AG, Won DH, Hahn D, Sung Y, Lee J, Choi H, Nam SJ, Kang H (2017) Cadiolides J-M, antibacterial polyphenyl butenolides from the Korean tunicate Pseudodistoma antinboja. Bioorg Med Chem Lett 27:574 993. Won TH, Jeon J, Kim S-H, Lee S-H, Rho BJ, Oh D-C, Oh K-B, Shin J (2012) Brominated aromatic furanones and related esters from the ascidian Synoicum sp. J Nat Prod 75:2055 994. Ahn C-H, Won TH, Kim H, Shin J, Oh K-B (2013) Inhibition of Candida albicans isocitrate lyase activity by cadiolides and synoilides from the ascidian Synoicum sp. Bioorg Med Chem Lett 23:4099 995. Sikorska J, Parker-Nance S, Davies-Coleman MT, Vining OB, Sikora AE, McPhail KL (2012) Antimicrobial rubrolides from a South African species of Synoicum tunicate. J Nat Prod 75:1824 996. Smitha D, Kumar MMK, Ramana H, Rao DV (2014) Rubrolide R: a new furanone metabolite from the Ascidian Synoicum of the Indian Ocean. Nat Prod Res 28:12 997. Chang Y-C, Lu C-K, Chiang Y-R, Wang G-J, Ju Y-M, Kuo Y-H, Lee T-H (2014) Diterpene glycosides and polyketides from Xylotumulus gibbisporus. J Nat Prod 77:751 998. Gallardo AB, Díaz-Marrero AR, de la Rosa JM, D’Croz L, Perdomo G, Cózar-Castellano I, Darias J, Cueto M (2018) Chloro-furanocembranolides from Leptogorgia sp. improve pancreatic beta-cell proliferation. Mar Drugs 16:49 999. Jennings LK, Robertson LP, Rudolph KE, Munn AL, Carroll AR (2019) Anti-prion butenolides and diphenylpropanones from the Australian ascidian Polycarpa procera. J Nat Prod 82:2620 1000. Bae J Cho E, Park JS, Won TH, Seo S-Y, Oh D-C, Oh K-B, Shin J (2020) Isocadiolides A–H: polybrominated aromatics from a Synoicum sp. ascidian. J Nat Prod 83:429 1001. Bracegirdle J, Stevenson LJ, Page MJ, Owen JG, Keyzers RA (2020) Targeted isolation of rubrolides from the New Zealand marine tunicate Synoicum kuranui. Mar Drugs 18:337 1002. Bracegirdle J, Stevenson LJ, Sharrock AV, Page MJ, Vorster JA, Owen JG, Ackerley DF, Keyzers RA (2021) Hydrated rubrolides from the New Zealand tunicate Synoicum kuranui. J Nat Prod 84:544 1003. Haval KP, Argade NP (2007) Synthesis of natural fimbrolides. Synthesis:2198 1004. Boukouvalas J, McCann LC (2010) Synthesis of the human aldose reductase inhibitor rubrolide L. Tetrahedron Lett 51:4636 1005. Tale NP, Shelke AV, Tiwari GB, Thorat PB, Karade NN (2012) New concise and efficient synthesis of rubrolides C and E via intramolecular Wittig reaction. Helv Chim Acta 95:852 1006. Karak M, Acosta JAM, Barbosa LCA, Boukouvalas J (2016) Late-stage bromination enables the synthesis of rubrolides B, I, K, and O. Eur J Org Chem 3780 1007. Kutty SK, Barraud N, Pham A, Iskander G, Rice SA, Black DStC, Kumar N (2013) Design, synthesis, and evaluation of fimbrolide–nitric oxide donor hybrids as antimicrobial agents. J Med Chem 56:9517 1008. Nasrin S, Ganji S, Kakirde KS, Jacob MR, Wang M, Ravu RR, Cobine PA, Khan IA, Wu C-C, Mead DA, Li X-C, Liles MR (2018) Chloramphenicol derivatives with antibacterial activity identified by functional metagenomics. J Nat Prod 81:1321 1009. Aouiche A, Sabaou N, Meklat A, Zitouni A, Bijani C, Mathieu F, Lebrihi A (2012) Saccharothrix sp. PAL54, a new chloramphenicol-producing strain isolated from a Saharan soil. World J Microbiol Biotechnol 28:943 1010. Berendsen BJA, Zuidema T, de Jong J, Stolker LAAM, Nielen MWF (2011) Discrimination of eight chloramphenicol isomers by liquid chromatography tandem mass spectrometry in order to investigate the natural occurrence of chloramphenicol. Anal Chim Acta 700:78

Naturally Occurring Organohalogen Compounds …

455

1011. Berendsen BJA, Essers ML, Stolker LAAM, Nielen MWF (2011) Quantitative trace analysis of eight chloramphenicol isomers in urine by chiral liquid chromatography coupled to tandem mass spectrometry. J Chromatogr A 1218:7331 1012. Hanekamp JC, Bast A (2015) Antibiotics exposure and health risks: chloramphenicol. Environ Toxicol Pharmacol 39:213 1013. Sadar MD, Williams DE, Mawji NR, Patrick BO, Wikanta T, Chasanah E, Irianto HE, Van Soest R, Andersen RJ (2008) Sintokamides A to E, chlorinated peptides from the sponge Dysidea sp. that inhibit transactivation of the N-terminus of the androgen receptor in prostate cancer cells. Org Lett 10:4947 1014. Kapojos MM, Abdjul DB, Yamazaki H, Ohshiro T, Rotinsulu H, Wewengkang DS, Sumilat DA, Tomoda H, Namikoshi M, Uchida R (2018) Callyspongiamides A and B, sterol Oacyltransferase inhibitors, from the Indonesian marine sponge Callyspongia sp. Bioorg Med Chem Lett 28:1911 1015. Schieferdecker S, Domin N, Hoffmeier C, Bryant DA, Roth M, Nett M (2015) Structure and absolute configuration of auriculamide, a natural product from the predatory bacterium Herpetosiphon aurantiacus. Eur J Org Chem: 3057 1016. Manam RR, Macherla VR, Tsueng G, Dring CW, Weiss J, Neuteboom STC, Lam KS, Potts BC (2009) Antiprotealide is a natural product. J Nat Prod 72:295 1017. Gulder TAM, Moore BS (2010) Salinosporamide natural products: potent 20S proteasome inhibitors as promising cancer chemotherapeutics. Angew Chem Int Ed 49:9346 1018. Kim EJ, Lee JH, Choi H, Pereira AR, Ban YH, Yoo YJ, Kim E, Park JW, Sherman DH, Gerwick WH, Yoon YJ (2012) Heterologous production of 4-O-demethylbarbamide, a marine cyanobacterial natural product. Org Lett 14:5824 1019. Seyedsayamdost MR, Chandler JR, Blodgett JAV, Lima PS, Duerkop BA, Oinuma KI, Greenberg EP, Clardy J (2010) Quorum-sensing-regulated bactobolin production by Burkholderia thailandensis E264. Org Lett 12:716 1020. Won TH, Kim C-K, Lee S-H, Rho BJ, Lee SK, Oh D-C, Oh K-B, Shin J (2015) Amino acid-derived metabolies from the ascidian Aplidium sp. Mar Drugs 13:3836 1021. Motohashi K, Takagi M, Shin-ya K (2010) Tetrapeptides possessing a unique skeleton, JBIR-34 and JBIR-35, isolated from a sponge-derived actinomycete, Streptomyces sp. Sp080513GE-23. J Nat Prod 73:226 1022. Izumikawa M, Kawahara T, Kagaya N, Yamamura H, Hayakawa M, Takagi M, Yoshida M, Doi T, Shin-ya K (2015) Pyrrolidine-containing peptides, JBIR-126, -148 and -149, from Streptomyces sp. NBRC 111228. Tetrahedron Lett 56:5333 1023. Brandi L, Lazzarini A, Cavaletti L, Abbondi M, Corti E, Ciciliato I, Gastaldo L, Marazzi A, Feroggio M, Fabbretti A, Maio A, Colombo L, Donadio S, Marinelli F, Losi D, Gualerzi CO, Selva E (2006) Novel tetrapeptide inhibitors of bacterial protein synthesis produced by a Streptomyces sp. Biochemistry 45:3692 1024. Brumley DA, Gunasekera SP, Chen Q-Y, Paul VJ, Luesch H (2020) Discovery, total synthesis, and SAR of anaenamides A and B: anticancer cyanobacterial depsipeptides with a chlorinated pharmacophore. Org Lett 22:4235 1025. Hedner E, Sjögren M, Hodzic S, Andersson R, Göransson U, Jonsson PR, Bohlin L (2008) Antifouling activity of a dibrominated cyclopeptide from the marine sponge Geodia barretti. J Nat Prod 71:330 1026. Ersmark K, Del Valle JR, Hanessian S (2008) Chemistry and biology of the aeruginosin family of serine protease inhibitors. Angew Chem Int Ed 47:1202 1027. Raveh A, Carmeli S (2009) Two novel biological active modified peptides from the cyanobacterium Microcystis sp. Phytochem Lett 2:10 1028. Gesner-Apter S, Carmeli S (2009) Protease inhibitors from a water bloom of the cyanobacterium Microcystis aeruginosa. J Nat Prod 72:1429 1029. Gesner-Apter S, Carmeli S (2008) Three novel metabolites from a bloom of the cyanobacterium Microcystis sp. Tetrahedron 64:6628 1030. Elkobi-Peer S, Faigenbaum R, Carmeli S (2012) Bromine- and chlorine-containing aeruginosins from Microcystis aeruginosa bloom material collected in Kibbutz Geva, Israel. J Nat Prod 75:2144

456

G. W. Gribble

1031. Elkobi-Peer S, Singh RK, Mohapatra TM, Tiwari SP, Carmeli S (2013) Aeruginosins from a Microcystis sp. bloom material collected in Varanasi, India. J Nat Prod 76:1187 1032. Vegman M, Carmeli S (2014) Three aeruginosins and a microviridin from a bloom assembly of Microcystis spp. collected from a fishpond near Kibbutz Lehavot HaBashan, Israel. Tetrahedron 70:6817 1033. Fontanillo M, Köhn M (2018) Microcystins: synthesis and structure-activity relationship studies toward PP1 and PP2A. Bioorg Med Chem 26:1118 1034. Lodin-Friedman A, Carmeli S (2018) Microginins from a Microcystis sp. bloom material collected from the Kishon Reservoir, Israel. Mar Drugs 16:78 1035. Petitbois JG, Casalme LO, Lopez JAV, Alarif WM, Abdel-Lateff A, Al-Lihaibi SS, Yoshimura E, Nogata Y, Umezawa T, Matsuda F, Okino T (2017) Serinolamides and lyngbyabellins from an Okeania sp. cyanobacterium collected from the Red Sea. J Nat Prod 80:2708 1036. Teruya T, Sasaki H, Fukazawa H, Suenaga K (2009) Bisebromoamide, a potent cytotoxic peptide from the marine cyanobacterium Lyngbya sp.: isolation, stereostructure, and biological activity. Org Lett 11:5062 1037. Gao X, Liu Y, Kwong S, Xu Z, Ye T (2010) Total synthesis and stereochemical reassignment of bisebromoamide. Org Lett 12:3018 1038. Sasaki H, Teruya T, Fukazawa H, Suenaga K (2011) Revised structure and structure– activity relationship of bisebromoamide and structure of norbisebromoamide from the marine cyanobacterium Lyngbya sp. Tetrahedron 67:990 1039. Li JL, Xiao B, Park M, Yoo ES, Shin S, Hong J, Chung HY, Kim HS, Jung JH (2012) PPAR-γ agonistic metabolites from the ascidian Herdmania momus. J Nat Prod 75:2082 1040. Feng Y, Carroll AR, Pass DM, Archbold JK, Avery VM, Quinn RJ (2008) Polydiscamides B-D from a marine sponge Ircinia sp. as potent human sensory neuron-specific G protein coupled receptor agonists. J Nat Prod 71:8 1041. Kishimoto S, Nishimura S, Hattori A, Tsujimoto M, Hatano M, Igarashi M, Kakeya H (2014) Chlorocatechelins A and B from Streptomyces sp.: new siderophores containing chlorinated catecholate groups and an acylguanidine structure. Org Lett 16:6108 1042. Borthwick AD (2012) 2,5-Diketopiperazines: synthesis, reactions, medicinal chemistry, and bioactive natural products. Chem Rev 112:3641 1043. Orfali RS, Aly AH, Ebrahim W, Abdel-Aziz MS, Müller WEG, Lin W, Daletos G, Proksch P (2015) Pretrichodermamide C and N-methylpretrichodermamide B, two new cytotoxic epidithiodiketopiperazines from hyper saline lake derived Penicillium sp. Phytochem Lett 11:168 1044. Liu Y, Li X-M, Meng L-H, Jiang W-L, Xu G-M, Huang C-G, Wang B-G (2015) Bisthiodiketopiperazines and acorane sesquiterpenes produced by the marine-derived fungus Penicillium adametzioides AS-53 on different culture media. J Nat Prod 78:1294 1045. Yamazaki H, Takahashi O, Murakami K, Namikoshi M (2015) Induced production of a new unprecedented epitrithiodiketopiperazine, chlorotrithiobrevamide, by a culture of the marine-derived Trichoderma cf. brevicompactum with dimethyl sulfoxide. Tetrahedron Lett 56:6262 1046. Yamazaki H, Rotinsulu H, Narita R, Takahashi R, Namikoshi M (2015) Induced production of halogenated epidithiodiketopiperazines by a marine-derived Trichoderma cf. brevicompactum with sodium halides. J Nat Prod 78:2319 1047. Zhu M, Zhang X, Feng H, Dai J, Li J, Che Q, Gu Q, Zhu T, Li D (2017) Penicisulfuranols A-F, alkaloids from the mangrove endophytic fungus Penicillium janthinellum HDN13-309. J Nat Prod 80:71 1048. Shi J, Zeng YJ, Zhang B, Shao FL, Chen YC, Xu X, Sun Y, Xu Q, Tan RX, Ge HM (2019) Comparative genome mining and heterologous expression of an orphan NRPS gene cluster direct the production of ashimides. Chem Sci 10:3042 1049. Harizani M, Katsini E, Georgantea P, Roussis V, Ioannou E (2020) New chlorinated 2,5diketopiperazines from marine-derived bacteria isolated from sediments of the Eastern Mediterranean Sea. Molecules 25:1509

Naturally Occurring Organohalogen Compounds …

457

1050. Yang Z, Zhu M, Li D, Zeng R, Han B (2017) N-Me-trichodermamide B isolated from Penicillium janthinellum, with antioxidant properties through Nrf2-mediated signaling pathway. Bioorg Med Chem 25:6614 1051. Jans PE, Mfuh AM, Arman HD, Shaffer CV, Larionov OV, Mooberry SL (2017) Cytotoxicity and mechanism of action of the marine-derived fungal metabolite trichodermamide B and synthetic analogues. J Nat Prod 80:676 1052. Gorges J, Panter F, Kjaerulff L, Hoffmann T, Kazmaier U, Müller R (2018) Structure, total synthesis, and biosynthesis of chloromyxamides: Myxobacterial tetrapeptides featuring an uncommon 6-chloromethyl-5-methoxypipecolic acid building block. Angew Chem Int Ed 57:14270 1053. Rubio BK, Parrish SM, Yoshida W, Schupp PJ, Schils T, Williams PG (2010) Depsipeptides from a Guamanian marine cyanobacterium, Lyngbya bouillonii, with selective inhibition of serine proteases. Tetrahedron Lett 51:6718 1054. Wang X, Lv C, Liu J, Tang L, Feng J, Tang S, Wang Z, Liu Y, Meng Y, Ye T, Xu Z (2014) Total synthesis of the proposed structure for itralamide B. Synlett 25:1014 1055. Wang X, Lv C, Feng J, Tang L, Wang Z, Liu Y, Meng Y, Ye T, Xu Z (2015) Studies toward the total synthesis of itralamide B and biological evaluation of its structural analogs. Mar Drugs 13:2085 1056. Lifshits M, Zafrir-Ilan E, Raveh A, Carmeli S (2011) Protease inhibitors from three fishpond water blooms of Microcystis spp. Tetrahedron 67:4017 1057. Strangman WK, Wright JLC (2016) Microginins 680, 646, and 612—new chlorinated Ahoacontaining peptides from a strain of cultured Microcystis aeruginosa. Tetrahedron Lett 57:1801 1058. Sueyoshi K, Kudo T, Yamano A, Sumimoto S, Iwasaki A, Suenaga K, Teruya T (2017) Odobromoamide, a terminal alkynyl bromide-containing cyclodepsipeptide from the marine cyanobacterium Okeania sp. Bull Chem Soc Jpn 90:436 1059. Gala F, D’Auria MV, De Marino S, Zollo F, Smith CD, Copper JE, Zampella A (2007) New jaspamide derivatives with antimicrofilament activity from the sponge Jaspis splendans. Tetrahedron 63:5212 1060. Gala F, D’Auria MV, De Marino S, Sepe V, Zollo F, Smith CD, Copper JE, Zampella A (2008) Jaspamides H-L, new actin-targeting depsipeptides from the sponge Jaspis splendans. Tetrahedron 64:7127 1061. Gala F, D’Auria MV, De Marino S, Sepe V, Zollo F, Smith CD, Keller SN, Zampella A (2009) Jaspamides M-P: new tryptophan modified jaspamide derivatives from the sponge Jaspis splendans. Tetrahedron 65:51 1062. Ebada SS, Wray V, de Voogd NJ, Deng Z, Lin W, Proksch P (2009) Two new jaspamide derivatives from the marine sponge Jaspis splendens. Mar Drugs 7:435 1063. Watts KR, Morinaka BI, Amagata T, Robinson SJ, Tenney K, Bray WM, Gassner NC, Lokey RS, Media J, Valeriote FA, Crews P (2011) Biostructural features of additional jasplakinolide (jaspamide) analogues. J Nat Prod 74:341 1064. Robinson SJ, Morinaka BI, Amagata T, Tenney K, Bray WM, Gassner NC, Lokey RS, Crews P (2010) New structures and bioactivity properties of jasplakinolide (jaspamide) analogues from marine sponges. J Med Chem 53:1651 1065. Ebada SS, Müller WEG, Lin W, Proksch P (2019) New acyclic cytotoxic jasplakinolide derivative from the marine sponge Jaspis splendens. Mar Drugs 17:100 1066. Rubio BK, Robinson SJ, Avalos CE, Valeriote FA, de Voogd NJ, Crews P (2008) Revisiting the sponge sources, stereostructure, and biological activity of cyclocinamide A. J Nat Prod 71:1475 1067. Garcia JM, Curzon SS, Watts KR, Konopelski JP (2012) Total synthesis of nominal (11S)and (11R)-cyclocinamide A. Org Lett 14:2054 1068. Curzon SS, Garcia JM, Konopelski JP (2015) Total synthesis of nominal cyclocinamide B and investigation into the identity of the cyclocinamides. Tetrahedron Lett 56:2991 1069. Cooper JK, Li K, Aubé J, Coppage DA, Konopelski JP (2018) Application of the DP4 probability method to flexible cyclic peptides with multiple independent stereocenters: the true structure of cyclocinamide A. Org Lett 20:4314

458

G. W. Gribble

1070. Fernández R, Bayu A, Hadi TA, Bueno S, Pérez M, Cuevas C, Putra MY (2020) Unique polyhalogenated peptides from the marine sponge Ircinia sp. Mar Drugs 18:396 1071. Pérez-Bonilla M, Oves-Costales D, González I, de la Cruz M, Martín J, Vicente F, Genilloud O, Reyes F (2020) Krisynomycins, imipenem potentiators against methicillin-resistant Staphylococcus aureus, produced by Streptomyces canus. J Nat Prod 83:2597 1072. Therien AG, Huber JL, Wilson KE, Beaulieu P, Caron A, Claveau D, Deschamps K, Donald RGK, Galgoci AM, Gallant M, Gu X, Kevin NJ, Lafleur J, Leavitt PS, Lebeau-Jacob C, Lee SS, Lin MM, Michels AA, Ogawa AM, Painter RE, Parish CA, Park Y-W, Benton-Perdomo L, Petcu M, Phillips JW, Powles MA, Skorey KI, Tam J, Tan CM, Young K, Wong S, Waddell ST, Miesel L (2012) Broadening the spectrum of β-lactam antibiotics through inhibition of signal peptidase type I. Antimicrob Agents Chemother 56:4662 1073. Speitling M, Smetanina OF, Kuznetsova TA, Laatsch H (2007) Bromoalterochromides A and A , unprecedented chromopeptides from a marine Pseudoalteromonas maricaloris strain KMM 636. J Antibiot 60:36 1074. Robinson SJ, Tenney K, Yee DF, Martinez L, Media JE, Valeriote FA, van Soest RWM, Crews P (2007) Probing the bioactive constituents from chemotypes of the sponge Psammocinia aff. bulbosa. J Nat Prod 70:1002 1075. Plaza A, Keffer JL, Lloyd JR, Colin PL, Bewley CA (2010) Paltolides A-C, anabaenopeptintype peptides from the Palau sponge Theonella swinhoei. J Nat Prod 73:485 1076. Mizutani K, Hirasawa Y, Sugita-Konishi Y, Mochizuki N, Morita H (2008) Structural and conformational analysis of hydroxycyclochlorotine and cyclochlorotine, chlorinated cyclic peptides from Penicillium islandicum. J Nat Prod 71:1297 1077. Plaza A, Bewley CA (2006) Largamides A-H, unusual cyclic peptides from the marine cyanobacterium Oscillatoria sp. J Org Chem 71:6898 1078. Miller ED, Kauffman CA, Jensen PR, Fenical W (2007) Piperazimycins: cytotoxic hexadepsipeptides from a marine-derived bacterium of the genus Streptomyces. J Org Chem 72:323 1079. Shaaban KA, Shaaban M, Facey P, Fotso S, Frauendorf H, Helmke E, Maier A, Fiebig HH, Laatsch H (2008) Electrospray ionization mass spectra of piperazimycins A and B and γ-butyrolactones from a marine-derived Streptomyces sp. J Antibiot 61:736 1080. Guo Z, Shen L, Ji Z, Zhang J, Huang L, Wu W (2009) NW-GO1, a novel cyclic hexadepsipeptide antibiotic, produced by Streptomyces alboflavus 313: I. Taxonomy, fermentation, isolation, physicochemical properties and antibacterial activities. J Antibiot 62:201 1081. Guo Z, Ji Z, Zhang J, Deng J, Shen L, Liu W, Wu W (2010) NW-GO1, a novel cyclic hexapeptide antibiotic, produced by Streptomyces alboflavus 313: II. Structural elucidation. J Antibiot 63:231 1082. Guo Z, Ji Z, Zhang J, Deng J, Shen L, Liu W, Wu W (2010) NW-GO1, a novel cyclic hexapeptide antibiotic, produced by Streptomyces alboflavus 313: II. Structural elucidation. J Antibiot 63:733 1083. Guo Z, Shen L, Zhang J, Xin H, Liu W, Ji Z, Wu W (2011) NW-G03, a related cyclic hexapeptide compound of NW-G01, produced by Streptomyces alboflavus 313. J Antibiot 64:789 1084. Ji Z, Wei S, Fan L, Wu W (2012) Three novel cyclic hexapeptides from Streptomyces alboflavus 313 and their antibacterial activity. Eur J Med Chem 50:296 1085. Ji Z, Qiao G, Wei S, Fan L, Wu W (2012) Isolation and characterization of two novel antibacterial cyclic hexapeptides from Streptomyces alboflavus 313. Chem Biodivers 9:1567 1086. Wei S, Fan L, Wu W, Ji Z (2012) Two piperazic acid-containing cyclic hexapeptides from Streptomyces alboflavus 313. Amino Acids 43:2191 1087. Ji Z, Xu N, Gang Q, Wei S (2013) Identification of pyrroloindoline-containing cyclic hexapeptides in the metabolites of Streptomyces alboflavus 313 by HPLC-DAD-ESI-MS/ MS. J Antibiot 66:265 1088. Li W, Gan J, Ma D (2009) Total synthesis of piperazimycin A: a cytotoxic cyclic hexadepsipeptide. Angew Chem Int Ed 48:8891

Naturally Occurring Organohalogen Compounds …

459

1089. Yu S-M, Hong W-X, Wu Y, Zhong C-L, Yao Z-J (2010) Total synthesis of chloptosin, a potent apoptosis-inducing cyclopeptide. Org Lett 12:1124 1090. Oelke AJ, Antonietti F, Bertone L, Cranwell PB, France DJ, Goss RJM, Hofmann T, Knauer S, Moss SJ, Skelton PC, Turner RM, Wuitschik G, Ley SV (2011) Total synthesis of chloptosin: a dimeric cyclohexapeptide. Chem Eur J 17:4183 1091. Salvador LA, Biggs JS, Paul VJ, Luesch H (2011) Veraguamides A–G, cyclic hexadepsipeptides from a dolastatin 16-producing cyanobacterium Symploca cf. hydnoides from Guam. J Nat Prod 74:917 1092. Mevers E, Liu W-T, Engene N, Mohimani H, Byrum T, Pevzner PA, Dorrestein PC, Spadafora C, Gerwick WH (2011) Cytotoxic veraguamides, alkynyl bromide-containing cyclic depsipeptides from the marine cyanobacterium cf. Oscillatoria margaritifera. J Nat Prod 74:928 1093. Wang D, Jia X, Zhang A (2012) Total synthesis of the proposed structure of cyclic hexadepsipeptide veraguamide A. Org Biomol Chem 10:7027 1094. Plaza A, Gustchina E, Baker HL, Kelly M, Bewley CA (2007) Mirabamides A-D, depsipeptides from the sponge Siliquariaspongia mirabilis that inhibit HIV-1 fusion. J Nat Prod 70:1753 1095. Lu Z, Van Wagoner RM, Harper MK, Baker HL, Hooper JNA, Bewley CA, Ireland CM (2011) Mirabamides E-H, HIV-inhibitory depsipeptides from the sponge Stelletta clavosa. J Nat Prod 74:185 1096. Ojika M, Inukai Y, Kito Y, Hirata M, Iizuka T, Fudou R (2008) Miuraenamides: antimicrobial cyclic depsipeptides isolated from a rare and slightly halophilic myxobacterium. Chem Asian J 3:126 1097. Karmann L, Schultz K, Herrmann J, Müller R, Kazmaier U (2015) Total syntheses and biological evaluation of miuraenamides. Angew Chem Int Ed 54:4502 1098. Durow AC, Butts C, Willis CL (2009) Stereochemical assignments of the chlorinated residues in victorin C. Synthesis:2954 1099. Morita H, Takeya K (2010) Bioactive cyclic peptides from higher plants. Heterocycles 80:739 1100. Xu H-M, Zeng G-Z, Zhou W-B, He W-J, Tan N-H (2013) Astins K-P, six new chlorinated cyclopentapeptides from Aster tataricus. Tetrahedron 69:7964 1101. Schafhauser T, Jahn L, Kirchner N, Kulik A, Flor L, Lang A, Caradec T, Fewer DP, Sivonen K, van Berkel WJH, Jacques P, Weber T, Gross H, van Pée K-H, Wohlleben W, LudwigMüller J (2019) Antitumor astins originate from the fungal endophyte Cyanodermella asteris living with the medicinal plant Aster tataricus. Proc Natl Acad Sci USA 116:26909 1102. Lin Z, Flores M, Forteza I, Henriksen NM, Concepcion GP, Rosenberg G, Haygood MG, Olivera BM, Light AR, Cheatham TE III, Schmidt EW (2012) Totopotensamides, polyketide–cyclic peptide hybrids from a mollusk-associated bacterium Streptomyces sp. J Nat Prod 75:644 1103. Chen R, Zhang Q, Tan B, Zheng L, Li H, Zhu Y, Zhang C (2017) Genome mining and activation of a silent PKS/NRPS gene cluster direct the production of totopotensamides. Org Lett 19:5697 1104. Schloß S, Hackl T, Herz C, Lamy E, Koch M, Rohn S, Maul R (2017) Detection of a toxic methylated derivative of phomopsin A produced by the legume-infesting fungus Diaporthe toxica. J Nat Prod 80:1930 1105. Matthew S, Ross C, Paul VJ, Luesch H (2008) Pompanopeptins A and B, new cyclic peptides from the marine cyanobacterium Lyngbya confervoides. Tetrahedron 64:4081 1106. Taori K, Paul VJ, Luesch H (2008) Kempopeptins A and B, serine protease inhibitors with different selectivity profiles from a marine cyanobacterium, Lyngbya sp. J Nat Prod 71:1625 1107. Kwan JC, Taori K, Paul VJ, Luesch H (2009) Lyngbyastatins 8–10, elastase inhibitors with cyclic depsipeptide scaffolds isolated from the marine cyanobacterium Lyngbya semiplena. Mar Drugs 7:528 1108. Kunze B, Böhlendorf B, Reichenbach H, Höfle G (2008) Pedein A and B: production, isolation, structure elucidation and biological properties of new antifungal cyclopeptides from Chondromyces pediculatus (Myxobacteria). J Antibiot 61:18

460

G. W. Gribble

1109. Choi H, Oh SK, Yih W, Chin J, Kang H, Rho J-R (2008) Cyanopeptoline CB071: a cyclic depsipeptide isolated from the freshwater cyanobacterium Aphanocapsa sp. Chem Pharm Bull 56:1191 1110. Dardi´c D, Lauro G, Bifulco G, Laboudie P, Sakhaii P, Bauer A, Vilcinskas A, Hammann PE, Plaza A (2017) Svetamycins A-G, unusual piperazic acid-containing peptides from Streptomyces sp. J Org Chem 82:6032 1111. Sorres J, Martin M-T, Petek S, Levaique H, Cresteil T, Ramos S, Thoison O, Debitus C, Al-Mourabit A (2012) Pipestelides A-C: cyclodepsipeptides from the Pacific marine sponge Pipestela candelabra. J Nat Prod 75:759 1112. Ankisetty S, Khan SI, Avula B, Gochfeld D, Khan IA, Slattery M (2013) Chlorinated didemnins from the tunicate Trididemnum solidum. Mar Drugs 11:4478 1113. Hoffmann T, Müller S, Nadmid S, Garcia R, Müller R (2013) Microsclerodermins from terrestrial myxobacteria: an intriguing biosynthesis likely connected to a sponge symbiont. J Am Chem Soc 135:16904 1114. Laird DW, LaBarbera DV, Feng X, Bugni TS, Harper MK, Ireland CM (2007) Halogenated cyclic peptides isolated from the sponge Corticium sp. J Nat Prod 70:741 1115. Castiglione F, Marazzi A, Meli M, Colombo G (2005) Structure elucidation and 3D solution conformation of the antibiotic enduracidin determined by NMR spectroscopy and molecular dynamics. Magn Reson Chem 43:603 1116. McCafferty DG, Cudic P, Frankel BA, Barkallah S, Kruger RG, Li W (2002) Chemistry and biology of the ramoplanin family of peptide antibiotics. Biopolymers 66:261 1117. Yin X, Chen Y, Zhang L, Wang Y, Zabriskie TM (2010) Enduracidin analogues with altered halogenation patterns produced by genetically engineered strains of Streptomyces fungicidicus. J Nat Prod 73:583 1118. Linington RG, Edwards DJ, Shuman CF, McPhail KL, Matainaho T, Gerwick WH (2008) Symplocamide A, a potent cytotoxin and chymotrypsin inhibitor from the marine cyanobacterium Symploca sp. J Nat Prod 71:22 1119. Kang H-S, Krunic A, Shen Q, Swanson SM, Orjala J (2011) Minutissamides A-D, antiproliferative cyclic decapeptides from the cultured cyanobacterium Anabaena minutissima. J Nat Prod 74:1597 1120. Bui T-H, Wray V, Nimtz M, Fossen T, Preisitsch M, Schröder G, Wende K, Heiden SE, Mundt S (2014) Balticidins A-D, antifungal hassallidin-like lipopeptides from the Baltic Sea cyanobacterium Anabaena cylindrica Bio33. J Nat Prod 77:1287 1121. Bui T-H, Wray V, Nimtz M, Fossen T, Preisitsch M, Schröder G, Wende K, Heiden SE, Mundt S (2015) Correction to balticidins A-D, antifungal hassallidin-like lipopeptides from the Baltic Sea cyanobacterium Anabaena cylindrica Bio33. J Nat Prod 78:345 1122. Gallegos DA, Saurí J, Cohen RD, Wan X, Videau P, Vallota-Eastman AO, Shaala LA, Youssef DTA, Williamson RT, Martin GE, Philmus B, Sikora AE, Ishmael JE, McPhail KL (2018) Jizanpeptins, cyanobacterial protease inhibitors from a Symploca sp. cyanobacterium collected in the Red Sea. J Nat Prod 81:1417 1123. Keller L, Canuto KM, Liu C, Suzuki BM, Almaliti J, Sikandar A, Naman CB, Glukhov E, Luo D, Duggan BM, Luesch H, Koehnke J, O’Donoghue AJ, Gerwick WH (2020) Tutuilamides A-C: vinyl-chloride-containing cyclodepsipeptides from marine cyanobacteria with potent elastase inhibitory properties. ACS Chem Biol 15:751 1124. Matthew S, Ratnayake R, Becerro MA, Ritson-Williams R, Paul VJ, Luesch H (2010) Intramolecular modulation of serine protease inhibitor activity in a marine cyanobacterium with antifeedant properties. Mar Drugs 8:1803 1125. Bitzer J, Streibel M, Langer H-J, Grond S (2009) First Y-type actinomycins from Streptomyces with divergent structure-activity relationships for antibacterial and cytotoxic properties. Org Biomol Chem 7:444 1126. Son S, Hong Y-S, Jang M, Heo KT, Lee B, Jang J-P, Kim J-W, Ryoo I-J, Kim W-G, Ko SK, Kim BY, Jang J-H, Ahn JS (2017) Genomics-driven discovery of chlorinated cyclic hexapeptides ulleungmycins A and B from a Streptomyces species. J Nat Prod 80:3025

Naturally Occurring Organohalogen Compounds …

461

1127. Shin Y-H, Bae S, Sim J, Hur J, Jo S-I, Shin J, Suh Y-G, Oh K-B, Oh D-C (2017) Nicrophorusamides A and B, antibacterial chlorinated cyclic peptides from a gut bacterium of the carrion beetle Nicrophorus concolor. J Nat Prod 80:2962 1128. Bae M, Chung B, Oh K-B, Shin J, Oh D-C (2015) Hormaomycins B and C: new antibiotic cyclic depsipeptides from a marine mudflat-derived Streptomyces sp. Mar Drugs 13:5187 1129. Wu G, Nielson JR, Peterson RT, Winter JM (2017) Bonnevillamides, linear heptapeptides isolated from a Great Salt Lake-derived Streptomyces sp. Mar Drugs 15:195 1130. Al-Awadhi FH, Salvador LA, Law BK, Paul VJ, Luesch H (2017) Kempopeptin C, a novel marine-derived serine protease inhibitor targeting invasive breast cancer. Mar Drugs 15:290 1131. Hoffmann H, Kogler H, Heyse W, Matter H, Caspers M, Schummer D, Klemke-Jahn C, Bauer A, Penarier G, Debussche L, Brönstrup M (2015) Discovery, structure elucidation, and biological characterization of nannocystin A, a macrocyclic myxobacterial metabolite with potent antiproliferative properties. Angew Chem Int Ed 54:10145 1132. Krastel P, Roggo S, Schirle M, Ross NT, Perruccio F, Aspesi P Jr, Aust T, Buntin K, Estoppey D, Liechty B, Mapa F, Memmert K, Miller H, Pan X, Riedl R, Thibaut C, Thomas J, Wagner T, Weber E, Xie X, Schmitt EK, Hoepfner D (2015) Nannocystin A: an elongation factor 1 inhibitor from myxobacteria with differential anti-cancer properties. Angew Chem Int Ed 54:10149 1133. Liao L, Zhou J, Xu Z, Ye T (2016) Concise total synthesis of nannocystin A. Angew Chem Int Ed 55:13263 1134. Yang Z, Xu X, Yang C-H, Tian Y, Chen X, Lian L, Pan W, Su X, Zhang W, Chen Y (2016) Total synthesis of nannocystin A. Org Lett 18:5768 1135. Liu Q, Hu P, He Y (2017) Asymmetric total synthesis of nannocystin A. J Org Chem 82:9217 1136. Poock C, Kalesse M (2017) Total synthesis of nannocystin Ax. Org Lett 19:4536 1137. Meng Z, Souillart L, Monks B, Huwyler N, Herrmann J, Müller R, Fürstner A (2018) A “motif-oriented” total synthesis of nannocystin Ax. Preparation and biological assessment of analogues. J Org Chem 83:6977 1138. Tian Y, Ding Y, Xu X, Bai Y, Tang Y, Hao X, Zhang W, Chen Y (2018) Total synthesis and biological evaluation of nannocystin analogues modified at the polyketide phenyl moiety. Tetrahedron Lett 59:3206 1139. Fernández R, Martín MJ, Rodríguez-Acebes R, Reyes F, Francesch A, Cuevas C (2008) Diazonamides C-E, new cytotoxic metabolites from the ascidian Diazona sp. Tetrahedron Lett 49:2283 1140. Lachia M, Moody CJ (2008) The synthetic challenge of diazonamide A, a macrocyclic indole bis-oxazole marine natural product. Nat Prod Rep 25:227 1141. David N, Pasceri R, Kitson RRA, Pradal A, Moody CJ (2016) Formal total synthesis of diazonamide A by indole oxidative rearrangement. Chem Eur J 22:10867 1142. Youssef DTA, Shaala LA, Mohamed GA, Badr JM, Bamanie FH, Ibrahim SRM (2014) Theonellamide G, a potent antifungal and cytotoxic bicyclic glycopeptide from the Red Sea marine sponge Theonella swinhoei. Mar Drugs 12:1911 1143. Fukuhara K, Takada K, Watanabe R, Suzuki T, Okada S, Matsunaga S (2018) Colony-wise analysis of a Theonella swinhoei marine sponge with a yellow interior permitted the isolation of theonellamide I. J Nat Prod 81:2595 1144. Yamanaka K, Reynolds KA, Kersten RD, Ryan KS, Gonzalez DJ, Nizet V, Dorrestein PC, Moore BS (2014) Direct cloning and refactoring of a silent lipopeptide biosynthetic gene cluster yields the antibiotic taromycin A. Proc Natl Acad Sci USA 111:1957 1145. Reynolds KA, Luhavaya H, Li J, Dahesh S, Nizet V, Yamanaka K, Moore BS (2018) Isolation and structure elucidation of lipopeptide antibiotic taromycin B from the activated taromycin biosynthetic gene cluster. J Antibiot 71:333 1146. Saha S, Zhang W, Zhang G, Zhu Y, Chen Y, Liu W, Yuan C, Zhang Q, Zhang H, Zhang L, Zhang W, Zhang C (2017) Activation and characterization of a cryptic gene cluster reveals a cyclization cascade for polycyclic tetramate macrolactams. Chem Sci 8:1607

462

G. W. Gribble

1147. Yu H-L, Jiang S-H, Bu X-L, Wang J-H, Weng J-Y, Yang X-M, He K-Y, Zhang Z-G, Ao P, Xu J, Xu M-J (2017) Structural diversity of anti-pancreatic cancer capsimycins identified in mangrove-derived Streptomyces xiamenensis 318 and post-modification via a novel cytochrome P450 monnoxygenase. Sci Rep 7:40689 1148. Zhou Y-M, Ju G-L, Xiao L, Zhang X-F, Du F-Y (2018) Cyclodepsipeptides and sesquiterpenes from marine-derived fungus Trichothecium roseum and their biological functions. Mar Drugs 16:519 1149. Kawahara T, Itoh M, Izumikawa M, Hashimoto J, Sakata N, Tsuchida T, Shin-ya K (2015) MBJ-0086 and MGJ-0087, new bicyclic depsipeptides, from Sphaerisporangium sp. 33226. J Antibiot 68:67 1150. Neupane RP, Parrish SM, Newpane JB, Yoshida WY, Yip MLR, Turkson J, Harper MK, Head JD, Williams PG (2019) Cytotoxic sesquiterpenoid quinones and quinols, and an 11-membered heterocycle, kauamide, from the Hawaiian marine sponge Dactylospongia elegans. Mar Drugs 17:423 1151. Hahn D, Kim H, Yang I, Chin J, Hwang H, Won DH, Lee B, Nam S-J, Ekins M, Choi H, Kang H (2016) The halicylindramides, farnesoid X receptor antagonizing depsipeptides from a Petrosia sp. marine sponge collected in Korea. J Nat Prod 79:499 1152. Yamazaki Y, Someno T, Igarashi M, Kinoshita N, Hatano M, Kawada M, Momose I, Nomoto A (2015) Androprostamines A and B, the new anti-prostate cancer agents produced by Streptomyces sp. MK932-CF8. J Antibiot 68:279 1153. Tajima H, Wakimoto T, Takada K, Ise Y, Abe I (2014) Revised structure of cyclolithistide A, a cyclic depsipeptide from the marine sponge Discodermia japonica. J Nat Prod 77:154 1154. Shabahara S, Matsubara T, Takahashi K, Ishihara J, Hatakeyama S (2011) Total synthesis of NW-G01, a cyclic hexapeptide antibiotic, and 34-epi-NW-G01. Org Lett 13:4700 1155. Gu Z, Zakarian A (2010) Concise total synthesis of sintokamides A, B, and E by a unified, protecting-group-free strategy. Angew Chem Int Ed 49:9702 1156. Jin Y, Liu Y, Wang Z, Kwong S, Xu Z, Ye T (2010) Total synthesis of sintokamide C. Org Lett 12:1100 1157. Miley GP, Rote JC, Silverman RB, Kelleher NL, Thomson RJ (2018) Total synthesis of tambromycin enabled by indole C-H functionalization. Org Lett 20:2369 1158. Li W, Yu S, Jin M, Xia H, Ma D (2011) Total synthesis and cytotoxicity of bisebromoamide and its analogues. Tetrahedron Lett 52:2124 1159. Santhakumar G, Payne RJ (2014) Total synthesis of polydiscamides B, C, and D via a convergent native chemical ligation–oxidation strategy. Org Lett 16:4500 1160. Kishimoto S, Nishimura S, Hatano M, Igarashi M, Kakeya H (2015) Total synthesis and antimicrobial activity of chlorocatechelin A. J Org Chem 80:6076 1161. Abe H, Yamazaki Y, Sakashita C, Momose I, Watanabe T, Shibasaki M (2016) Synthesis of androprostamine A and resormycin. Chem Pharm Bull 64:982 1162. Wan X, Joullié MM (2008) Enantioselective total syntheses of trichodermamides A and B. J Am Chem Soc 130:17236 1163. Lu C-D, Zakarian A (2008) Total synthesis of (±)-trichodermamide B and of a putative biosynthetic precursor to aspergillazine A using an Oxaza-Cope rearrangement. Angew Chem Int Ed 47:6829 1164. Mfuh AM, Zhang Y, Stephens DE, Vo AXT, Arman HD, Larionov OV (2015) Concise total synthesis of trichodermamides A, B, and C enabled by an efficient construction of the 1,2-oxazadecaline core. J Am Chem Soc 137:8050 1165. Seo H, Lim D (2009) Total synthesis of halicylindramide A. J Org Chem 74:906 1166. Ardá A, Soengas RG, Nieto MI, Jiménez C, Rodríguez J (2008) Total synthesis of (–)dysithiazolamide. Org Lett 10:2175 1167. Beaumont S, Ilardi EA, Monroe LR, Zakarian A (2010) Valence tautomerism in titanium enolates: catalytic radical haloalkylation and application in the total synthesis of neodysidenin. J Am Chem Soc 132:1482 1168. Owusu-Ansah E, Durow AC, Harding JR, Jordan AC, O’Connell SJ, Willis CL (2011) Synthesis of dysideaproline E using organocatalysis. Org Biomol Chem 9:265

Naturally Occurring Organohalogen Compounds …

463

1169. Ilardi EA, Zakarian A (2011) Efficient total synthesis of dysidenin, dysidin, and barbamide. Chem Asian J 6:2260 1170. Pirovani RV, Brito GA, Barcelos RC, Pilli RA (2015) Enantioselective total synthesis of (+)-lyngbyabellin M. Mar Drugs 13:3309 1171. Qui H-B, Chen X-Y, Li Q, Qian W-J, Yu S-M, Tang G-L, Yao Z-J (2014) Unified flexible total synthesis of chlorofusin and artificial click mimics as antagonists against p53-HDM2 interactions. Tetrahedron Lett 55:6055 1172. Dailler D, Danoun G, Ourri B, Baudoin O (2015) Diverent synthesis of aeruginosins based on a C(sp3 )–H activation strategy. Chem Eur J 21:9370 1173. Dailler D, Danoun G, Baudoin O (2015) A general and scalable synthesis of aeruginosin marine natural products based on two strategic C(sp3 )–H activation reactions. Angew Chem Int Ed 54:4919 1174. Fong HKH, Brunel JM, Longeon A, Bourguet-Kondracki M-L, Barker D, Copp BR (2017) Synthesis and biological evaluation of the ascidian blood-pigment halocyamine A. Org Biomol Chem 15:6194 1175. Pinto A, Conti P, Tamborini L, De Micheli C (2009) A novel simplified synthesis of acivicin. Tetrahedron: Asymmetry 20:508 1176. Vaswani RG, Chamberlin AR (2008) Stereocontrolled total synthesis of (–)-kaitocephalin. J Org Chem 73:1661 1177. Hamada M, Shinada T, Ohfune Y (2009) Efficient total synthesis of (–)-kaitocephalin. Org Lett 11:4664 1178. Yu S, Zhu S, Pan X, Yang J, Ma D (2011) Reinvestigation on total synthesis of kaitocephalin and its isomers. Tetrahedron 67:1673 1179. Takahashi K, Yamaguchi D, Ishihara J, Hatakeyama S (2012) Total synthesis of (–)kaitocephalin based on a Rh-catalyzed C-H amination. Org Lett 14:1644 1180. Lee W, Youn J-H, Kang SH (2013) Total synthesis of (–)-kaitocephalin. Chem Commun 49:5231 1181. Garner P, Weerasinghe L, Van Houten I, Hu J (2014) A concise [C+NC+CC] couplingenabled synthesis of kaitocephalin. Chem Commun 50:4908 1182. Junk L, Kazmaier U (2018) Total synthesis of keramamides A and L from a common precursor by late-stage indole synthesis and configurational revision. Angew Chem Int Ed 57:11432 1183. Weiss C, Sammet B, Sewald N (2013) Recent approaches for the synthesis of modified cryptophycins. Nat Prod Rep 30:924 1184. Kennedy JP, Brogan JT, Lindsley CW (2008) Progress toward the synthesis of piperazimycin A: exploration of the synthesis of γ-hydroxy and γ-chloropiperazic acids. Tetrahedron Lett 49:4116 1185. Bittner S, Scherzer R, Harlev E (2007) The five bromotryptophans. Amino Acids 33:19 1186. Craik DJ, Adams DJ (2007) Chemical modification of conotoxins to improve stability and activity. ACS Chem Biol 2:457 1187. Han TS, Teichert RW, Olivera BM, Bulaj G (2008) Conus venoms—a rich source of peptidebased therapeutics. Curr Pharm Design 14:2462 1188. Daly NL, Craik DJ (2009) Structural studies of conotoxins. Life 61:144 1189. Akondi KB, Muttenthaler M, Dutertre S, Kaas Q, Craik DJ, Lewis RJ, Alewood PF (2014) Discovery, synthesis, and structure-activity relationships of conotoxins. Chem Rev 114:5815 1190. Nguyen B, Le Caer J-P, Mourier G, Thai R, Lamthanh H, Servent D, Benoit E, Molgó J (2014) Characterization of a novel Conus bandanus conopeptide belonging to the M-superfamily containing bromotryptophan. Mar Drugs 12:3449 1191. Halai R, Craik DJ (2009) Conotoxins: natural product drug leads. Nat Prod Rep 26:526 1192. Bingham J-P, Mitsunaga E, Bergeron ZL (2010) Drugs from slugs—past, present and future perspectives of ω-conotoxin research. Chem-Biol Interact 183:1 1193. Vetter I, Lewis RJ (2012) Therapeutic potential of cone snail venom peptides (conopeptides). Curr Topics Med Chem 12:1546

464

G. W. Gribble

1194. Lewis RJ, Dutertre S, Vetter I, Christie MJ (2012) Conus venum peptide pharmacology. Pharmacol Rev 64:259 1195. Clark RJ, Jensen J, Nevin ST, Callaghan BP, Adams DJ, Craik DJ (2010) The engineering of an orally active conotoxin for the treatment of neuropathic pain. Angew Chem Int Ed 49:6545 1196. Jin A-H, Daly NL, Nevin ST, Wang C-IA, Dutertre S, Lewis RJ, Adams DJ, Craik DJ, Alewood PF (2008) Molecular engineering of conotoxins: the importance of loop size to α-conotoxin structure and function. J Med Chem 51:5575 1197. Walewska A, Zhang M-M, Skalicky JJ, Yoshikami D, Olivera BM, Bulaj G (2009) Integrated oxidative folding of cysteine/selenocysteine containing peptides: improving chemical synthesis of conotoxins. Angew Chem Int Ed 48:2221 1198. Yu R, Kompella SN, Adams DJ, Craik DJ, Kaas Q (2013) Determination of the α-conotoxin Vc1.1 binding site on the α9α10 nicotinic acetylcholine receptor. J Med Chem 56:3557 1199. Luo S, Zhangsun D, Zhu X, Wu Y, Hu Y, Christensen S, Harvey PJ, Akcan M, Craik DJ, McIntosh JM (2013) Characterization of a novel α-conotoxin TxID from Conus textile that potently blocks rat α3α4 nicotinic acetylcholine receptors. J Med Chem 56:9655 1200. Dutertre S, Jin A-H, Alewood PF, Lewis RJ (2014) Intraspecific variations in Conus geographus defence-evoked venom and estimation of the human lethal dose. Toxicon 91:135 1201. Dutt M, Dutertre S, Jin A-H, Lavergne V, Alewood PF, Lewis RJ (2019) Venomics reveals venom complexity of the piscivorous cone snail, Conus tulipa. Mar Drugs 17:71 1202. Rice RD, Halstead BW (1968) Report of fatal cone shell sting by Conus geographus Linnaeus. Toxicon 5:223 1203. Clench WJ, Kondo Y (1943) The poison cone shell. Amer J Trop Med 23:105 1204. Muth OH (1968) Tansy ragwort (Senecio jacobaea), a potential menace to livestock. J Amer Vet Med Assoc 153:310 1205. Daly JW (2003) Ernest Guenther award in chemistry of natural products. Amphibian skin: a remarkable source of biologically active arthropod alkaloids. J Med Chem 46:445 1206. Garraffo HM, Spande TF, Williams M (2009) Epibatidine: from frog alkaloid to analgesic clinical candidates. A testimonial to "True Grit"! Heterocycles 79:207 1207. Fitch RW, Spande TF, Garraffo HM, Yeh HJC, Daly JW (2010) Phantasmidine: an epibatidine congener from the Ecuadorian poison frog Epipedobates anthonyi. J Nat Prod 73:331 1208. Zhou Q, Snider BB (2011) Synthesis of phantasmidine. Org Lett 13:526 1209. Zhou Q, Snider BB (2014) Mosher’s amide-based assignment of the absolute configuration of phantasmidine. Heterocycles 88:779 1210. Fitch RW, Snider BB, Zhou Q, Foxman BM, Pandya AA, Yakel JL, Olson TT, Al-Muhtasib N, Xiao Y, Welch KD, Panter KE (2018) Absolute configuration and pharmacology of the poison frog alkaloid phantasmidine. J Nat Prod 81:1029 1211. Choi H, Engene N, Byrum T, Hwang S, Oh D-C, Gerwick WH (2019) Dragocins A-D, structurally intriguing cytotoxic metabolites from a Panamanian marine cyanobacterium. Org Lett 21:266 1212. Ibrahim SRM, Mohamed GA, Moharram AM, Youssef DTA (2015) Aegyptolidines A and B: new pyrrolidine alkaloids from the fungus Aspergillus aegyptiacus. Phytochem Lett 12:90 1213. Jiang Y-J, Li J-Q, Zhang H-J, Ding W-J, Ma Z-J (2018) Cyclizidine-type alkaloids from Streptomyces sp. HNA39. J Nat Prod 81:394 1214. Al-Khdhairawi AAQ, Krishnan P, Mai C-W, Chung FF-L, Leong C-O, Yong K-T, Chong K-W, Low Y-Y, Kam T-S, Lim K-H (2017) A bis-benzopyrroloisoquinoline alkaloid incorporating a cyclobutane core and a chlorophenanthroindolizidine alkaloid with cytotoxic activity from Ficus fistulosa var. tengerensis. J Nat Prod 80:2734 1215. Xu S, Yoshimura H, Maru N, Ohno O, Arimoto H, Uemura D (2011) Pinnarine, another member of the halichlorine family. Isolation and preparation from pinnaic acid. J Nat Prod 74:1323 1216. Christie HS, Heathcock CH (2004) Total synthesis of (±)-halichlorine, (±)-pinnaic acid, and (±)-tauropinnaic acid. Proc Natl Acad Sci USA 101:12079

Naturally Occurring Organohalogen Compounds …

465

1217. Wu H, Zhang H, Zhao G (2007) An enantioselective total synthesis of pinnaic acid. Tetrahedron 63:6454 1218. Xu S, Arimoto H, Uemura D (2007) Asymmetric total synthesis of pinnaic acid. Angew Chem Int Ed 46:5746 1219. Liu D, Acharya HP, Yu M, Wang J, Yeh VSC, Kang S, Chiruta C, Jachak SM, Clive DLJ (2009) Total synthesis of the marine alkaloid halichlorine: development and use of a general route to chiral piperidines. J Org Chem 74:7417 1220. Xu S, Unabara D, Uemura D, Arimoto H (2014) Enantioselective total synthesis of pinnaic acid and halichlorine. Chem Asian J 9:367 1221. Nukoolkarn VS, Saen-oon S, Rungrotmongkol T, Hannongbua S, Ingkaninan K, Suwanborirux K (2008) Petrosamine, a potent anticholinesterase pyridoacridine alkaloid from a Thai marine sponge Petrosia n. sp. Bioorg Med Chem 16:6560 1222. Hsu Y-M, Chang F-R, Lo I-W, Lai K-H, El-Shazly M, Wu T-Y, Du Y-C, Hwang T-L, Cheng Y-B, Wu Y-C (2016) Zoanthamine-type alkaloids from the zoanthid Zoanthus kuroshio collected in Taiwan and their effects on inflammation. J Nat Prod 79:2674 1223. Wang W-X, Lei X, Yang Y-L, Li Z-H, Ai H-L, Li J, Feng T, Liu J-K (2019) Xylarichalasin A, a halogenated hexacyclic cytochalasan from the fungus Xylaria cf. curta. Org Lett 21:6957 1224. Yu B-W, Chen J-Y, Zhou T-X, Cheng K-F, Qin G-W (2002) Nitrotyrasacutuminine from Menispermum dauricum. Nat Prod Lett 16:155 1225. Cheng P, Ma Y, Yao S, Zhang Q, Wang E, Yan M, Zhang X, Zhang F, Chen J (2007) Two new alkaloids and active anti-hepatitis B virus constituents from Hypserpa nitida. Bioorg Med Chem Lett 17:5316 1226. Kato A, Yasui M, Yano N, Kawata Y, Moriki K, Adachi I, Hollinshead J, Nash RJ (2009) Alkaloids inhibiting l-histidine decarboxylase from Sinomenium acutum. Phytochem Lett 2:77 1227. Sugimoto Y, Matsui M, Babiker HAA (2007) Conversion of dechlorodauricumine into chlorinated alkaloids in Menispermum dauricum root culture. Phytochemistry 68:493 1228. Hori R, Sugimoto G, Matsui M, Yamauchi Y, Takikawa H, Sugimoto Y (2009) Conversion of dechlorodauricumine into miharumine by a cell-free preparation from cultured roots of Menispermum dauricum. Biosci Biotechnol Biochem 73:440 1229. Li F, Tartakoff SS, Castle SL (2009) Enantioselective total synthesis of (–)-acutumine. J Org Chem 74:9082 1230. King SM, Calandra NA, Herzon SB (2013) Total syntheses of (–)-acutumine and (–)dechloroacutumine. Angew Chem Int Ed 52:3642 1231. Beniddir MA, Martin M-T, Tran Huu Dau M-E, Rasoanaivo P, Gueritte F, Litaudon M (2013) Bisindole alkaloid artifacts from Gonioma malagasy. Tetrahedron Lett 54:2115 1232. Shi Y, Liu Y, Ma S, Li L, Qu J, Li Y, Yu S (2014) Four new minor alkaloids from the seeds of Strychnos nux-vomica. Tetrahedron Lett 55:6538 1233. Esposito G, Bourguet-Kondracki M-L, Mai LH, Longeon A, Teta R, Meijer L, Van Soest R, Mangoni A, Costantino V (2016) Chloromethylhalicyclamine B, a marine-derived protein kinase CK1δ/ε inhibitor. J Nat Prod 79:2953 1234. Nodwell M, Pereira A, Riffell JL, Zimmerman C, Patrick BO, Roberge M, Andersen RJ (2009) Synthetic approaches to the microtubule-stabilizing sponge alkaloid ceratamine A and desbromo analogues. J Org Chem 74:995 1235. Coleman RS, Campbell EL, Carper DJ (2009) A direct and efficient total synthesis of the tubulin-binding agents ceratamine A and B: use of IBX for a remarkable heterocycle dehydrogenation. Org Lett 11:2133 1236. Armstrong A, Bhonoah Y, Shanahan SE (2007) Aza-Prins-Pinacol approach to 7azabicyclo[2.2.1]heptanes: syntheses of (±)-epibatidine and (±)-epiboxidine. J Org Chem 72:8019 1237. Boyd DR, Sharma ND, Kaik M, McIntyre PBA, Stevenson PJ, Allen CCR (2012) Chemoenzymatic formal synthesis of (–)- and (+)-epibatidine. Org Biomol Chem 10:2774 1238. Carroll FI (2009) Epibatidine analogs synthesized for characterization of nicotinic pharmacophores—a review. Heterocycles 79:99

466

G. W. Gribble

1239. Tempone AG, Pieper P, Borborema SET, Thevenard F, Lago JHG, Croft SL, Anderson EA (2021) Marine alkaloids as bioactive agents against protozoal neglected tropical diseases and malaria. Nat Prod Rep 38:2214 1240. Young IS, Thornton PD, Thompson A (2010) Synthesis of natural products containing the pyrrolic ring. Nat Prod Rep 27:1801 1241. Clark BR, Capon RJ, Lacey E, Tennant S, Gill JH (2006) Polyenylpyrroles and polyenylfurans from an Australian isolate of the soil ascomycete Gymnoascus reessii. Org Lett 8:701 1242. Clark BR, Lacey E, Gill JH, Capon RJ (2007) The effect of halide salts on the production of Gymnoascus reessii polyenylpyrroles. J Nat Prod 70:665 1243. Clark BR, Murphy CD (2009) Biosynthesis of pyrrolylpolyenes in Auxarthron umbrinum. Org Biomol Chem 7:111 1244. Clark BR, O’Connor S, Fox D, Leroy J, Murphy CD (2011) Production of anticancer polyenes through precursor-directed biosynthesis. Org Biomol Chem 9:6306 1245. Aiello A, Fattorusso E, Giordano A, Menna M, Müller WEG, Perovi´c-Ottstadt S, Schröder HC (2007) Damipipecolin and damituricin, novel bioactive bromopyrrole alkaloids from the Mediterranean sponge Axinella damicornis. Bioorg Med Chem 15:5877 1246. Hassan W, Elkhayat ES, Edrada RA, Ebel R, Proksch P (2007) New bromopyrrole alkaloids from the marine sponges Axinella damicornis and Stylissa flabelliformis. Nat Prod Commun 2:1149 1247. Piña IC, White KN, Cabrera G, Rivero E, Crews P (2007) Bromopyrrole carboxamide biosynthetic products from the Caribbean sponge Agelas dispar. J Nat Prod 70:613 1248. Kuramoto M, Miyake N, Ishimaru Y, Ono N, Uno H (2008) Cylindradines A and B: novel bromopyrrole alkaloids from the marine sponge Axinella cylindratus. Org Lett 10:5465 1249. Iwata M, Kanoh K, Imaoka T, Nagasawa K (2014) Total synthesis of (+)-cylindradine A. Chem Commun 50:6991 1250. Iwata M, Kamijoh Y, Yamamoto E, Yamanaka M, Nagasawa K (2017) Total synthesis of pyrrole–imidazole alkaloids (+)-cylindradine B. Org Lett 19:420 1251. Tanaka N, Kusama T, Kashiwada Y, Kobayashi J (2016) Bromopyrrole alkaloids from Okinawan marine sponges Agelas spp. Chem Pharm Bull 64:691 1252. Araki A, Tsuda M, Kubota T, Mikami Y, Fromont J, Kobayashi J (2007) Nagelamide J, a novel dimeric bromopyrrole alkaloid from a sponge Agelas species. Org Lett 9:2369 1253. Araki A, Kubota T, Tsuda M, Mikami Y, Fromont J, Kobayashi J (2008) Nagelamides K and L, dimeric bromopyrrole alkaloids from sponge Agelas species. Org Lett 10:2099 1254. Kubota T, Araki A, Ito J, Mikami Y, Fromont J, Kobayashi J (2008) Nagelamides M and N, new bromopyrrole alkaloids from sponge Agelas species. Tetrahedron 64:10810 1255. Yasuda T, Araki A, Kubota T, Ito J, Mikami Y, Fromont J, Kobayashi J (2009) Bromopyrrole alkaloids from marine sponges of the genus Agelas. J Nat Prod 72:488 1256. Araki A, Kubota T, Aoyama K, Mikami Y, Fromont J, Kobayashi J (2009) Nagelamides Q and R, novel dimeric bromopyrrole alkaloids from sponges Agelas sp. Org Lett 11:1785 1257. Tanaka N, Kusama T, Takahashi-Nakaguchi A, Gonoi T, Fromont J, Kobayashi J (2013) Nagelamides U-W, bromopyrrole alkaloids from a marine sponge Agelas sp. Tetrahedron Lett 54:3794 1258. Tanaka N, Kusama T, Takahashi-Nakaguichi A, Gonoi T, Fromont J, Kobayashi J (2013) Nagelamides X-Z, dimeric bromopyrrole alkaloids from a marine sponge Agelas sp. Org Lett 15:3262 1259. Iwai T, Kubota T, Fromont J, Kobayashi J (2014) Nagelamide I and 2,2 didebromonagelamide B, new dimeric bromopyrrole-imidazole alkaloids from a marine sponge Agelas sp. Chem Pharm Bull 62:213 1260. Appenzeller J, Tilvi S, Martin M-T, Gallard J-F, El-Bitar H, Dau ETH, Debitus C, Laurent D, Moriou C, Al-Mourabit A (2009) Benzosceptrins A and B with a unique benzocyclobutane skeleton and nagelamide S and T from Pacific sponges. Org Lett 11:4874 1261. Nakamura K, Kusama T, Tanaka N, Sakai K, Gonoi T, Fromont J, Kobayashi J (2015) 2Debromonagelamide U, 2-debromomukanadin G, and 2-debromonagelamide P from marine sponge Agelas sp. Heterocycles 90:425

Naturally Occurring Organohalogen Compounds …

467

1262. Northrop BH, O’Malley DP, Zografos AL, Baran PS, Houk KN (2006) Mechanism of the vinylcyclobutane rearrangement of sceptrin to ageliferin and nagelamide E. Angew Chem Int Ed 45:4126 1263. O’Malley DP, Li K, Maue M, Zografos AL, Baran PS (2007) Total synthesis of dimeric pyrrole-imidazole alkaloids: sceptrin, ageliferin, nagelamide E, oxysceptrin, nakamuric acid, and the axinellamine carbon skeleton. J Am Chem Soc 129:4762 1264. Kubota T, Araki A, Yasuda T, Tsuda M, Fromont J, Aoyama K, Mikami Y, Wälchli MR, Kobayashi J (2009) Benzosceptrin C, a new dimeric bromopyrrole alkaloid from sponge Agelas sp. Tetrahedron Lett 50:7268 1265. Tilvi S, Moriou C, Martin M-T, Gallard J-F, Sorres J, Patel K, Petek S, Debitus C, Ermolenko L, Al-Mourabit A (2010) Agelastatin E, agelastatin F, and benzosceptrin C from the marine sponge Agelas dendromorpha. J Nat Prod 73:720 1266. Stout EP, Morinaka BI, Wang Y-G, Romo D, Molinski TF (2012) De novo synthesis of benzosceptrin C and nagelamide H from 7–15 N-oroidin: implications for pyrroleaminoimidazole alkaloid biosynthesis. J Nat Prod 75:527 1267. Muñoz J, Köck M (2016) Hybrid pyrrole-imidazole alkaloids from the sponge Agelas sceptrum. J Nat Prod 79:434 1268. Sun Y-T, Lin B, Li S-G, Liu M, Zhou Y-J, Xu Y, Hua H-M, Lin H-W (2017) New bromopyrrole alkaloids from the marine sponge Agelas sp. Tetrahedron 73:2786 1269. Kwon O-S, Kim D, Kim H, Lee Y-J, Lee H-S, Sim CJ, Oh D-C, Lee SK, Oh K-B, Shin J (2018) Bromopyrrole alkaloids from the sponge Agelas kosrae. Mar Drugs 16:513 1270. Hughes CC, Prieto-Davo A, Jensen PR, Fenical W (2008) The marinopyrroles, antibiotics of an unprecedented structure class from a marine Streptomyces sp. Org Lett 10:629 1271. Hughes CC, Kauffman CA, Jensen PR, Fenical W (2010) Structures, reactivities, and antibiotic properties of the marinopyrroles A-F. J Org Chem 75:3240 1272. Cheng C, Pan L, Chen Y, Song H, Qin Y, Li R (2010) Total synthesis of (±)-marinopyrrole A and its library as potential antibiotic and anticancer agents. J Comb Chem 12:541 1273. Kanakis AA, Sarli V (2010) Total synthesis of (±)-marinopyrrole A via copper-mediated N-arylation. Org Lett 12:4872 1274. Nicolaou KC, Simmons NL, Chen JS, Haste NM, Nizet V (2011) Total synthesis and biological evaluation of marinopyrrole A and analogs. Tetrahedron Lett 52:2041 1275. Cheng P, Clive DLJ, Fernandopulle S, Chen Z (2013) Racemic marinopyrrole B by total synthesis. Chem Commun 49:558 1276. Stodulski M, Kohlhepp SV, Raabe G, Gulder T (2016) Exploration of the bis(thio)ureacatalyzed atropselective synthesis of marinopyrrole A. Eur J Org Chem, 2170 1277. Yamanaka K, Ryan KS, Gulder TAM, Hughes CC, Moore BS (2012) Flavoenzyme-catalyzed atropo-selective N, C-bipyrrole homocoupling in marinopyrrole biosynthesis. J Am Chem Soc 134:12434 1278. Clive DLJ, Cheng P (2013) The marinopyrroles. Tetrahedron 69:5067 1279. Sultan MZ, Park K, Lee SY, Park JK, Varughese T, Moon S-S (2008) Novel oxidized derivatives of antifungal pyrrolnitrin from the bacterium Burkholderia cepacia K87. J Antibiot 61:420 1280. Vázquez AB, Bernès S, Ortíz A, Quintero L, Meza-León RL (2009) A contribution to the elucidation of the biosynthesis of 3-chloro-4-(3 -chloro-2 -nitrophenyl)-1H-pyrrole (pyrrolnitrin). Tetrahedron Lett 50:1539 1281. Yang Y-L, Liao W-Y, Liu W-Y, Liaw C-C, Shen C-N, Huang Z-Y, Wu S-H (2009) Discovery of new natural products by intact-cell mass spectrometry and LC-SPE-NMR: malbranpyrroles, novel polyketides from thermophilic fungus Malbranchea sulfurea. Chem Eur J 15:11573 1282. Hopp DC, Rhea J, Jacobsen D, Romari K, Smith C, Rabenstein J, Irigoyen M, Clarke M, Francis L, Luche M, Carr GJ, Mocek U (2009) Neopyrrolomycins with broad spectrum antibacterial activity. J Nat Prod 72:276 1283. Ebada SS, Edrada-Ebel R, de Voogd NJ, Wray V, Proksch P (2009) Dibromopyrrole alkaloids from the marine sponge Acanthostylotella sp. Nat Prod Commun 4:47

468

G. W. Gribble

1284. Guella G, Frassanito R, Mancini I, Sandron T, Modeo L, Verni F, Dini F, Petroni G (2010) Keronopsamides, a new class of pigments from marine ciliates. Eur J Org Chem, 427 1285. Kwon HC, Epsindola APDM, Park J-S, Prieto-Davó A, Rose M, Jensen PR, Fenical W (2010) Nitropyrrolins A-E, cytotoxic farnesyl-α-nitropyrroles from a marine-derived bacterium within the actinomycete family Streptomycetaceae. J Nat Prod 73:2047 1286. Ding X-B, Brimble MA, Furkert DP (2016) Nitropyrrole natural products: isolation, biosynthesis and total synthesis. Org Biomol Chem 14:5390 1287. Ebada SS, Linh MH, Longeon A, de Voogd NJ, Durieu E, Meijer L, Bourguet-Kondracki M-L, Singab ANB, Müller WEG, Proksch P (2015) Dispacamide E and other bioactive bromopyrrole alkaloids from two Indonesian marine sponges of the genus Stylissa. Nat Prod Res 29:231 1288. Hertiani T, Edrada-Ebel R, Ortlepp S, van Soest RWM, de Voogd NJ, Wray V, Hentschel U, Kozytska S, Müller WEG, Proksch P (2010) From anti-fouling to biofilm inhibition: new cytotoxic secondary metabolites from two Indonesian Agelas sponges. Bioorg Med Chem 18:1297 1289. Fehér D, Barlow R, McAtee J, Hemscheidt TK (2010) Highly brominated antimicrobial metabolites from a marine Pseudoalteromonas sp. J Nat Prod 73:1963 1290. Patel K, Laville R, Martin M-T, Tilvi S, Moriou C, Gallard J-F, Ermolenko L, Debitus C, Al-Mourabit A (2010) Unprecedented stylissazoles A-C from Stylissa carteri: another dimension for marine pyrrole-2-aminoimidazole metabolite diversity. Angew Chem Int Ed 49:4775 1291. Regalado EL, Laguna A, Mendiola J, Thomas OP, Nogueiras C (2011) Bromopyrrole alkaloids from the Caribbean sponge Agelas cerebrum. Quim Nova 34:289 1292. Sauleau P, Retailleau P, Nogues S, Carletti I, Marcourt L, Raux R, Al Mourabit A, Debitus C (2011) Dihydrohymenialdisines, new pyrrole-2-aminoimidazole alkaloids from the marine sponge Cymbastela cantharella. Tetrahedron Lett 52:2676 1293. Fouad MA, Debbab A, Wray V, Müller WEG, Proksch P (2012) New bioactive alkaloids from the marine sponge Stylissa sp. Tetrahedron 68:10176 1294. Tebben J, Motti C, Tapiolas D, Thomas-Hall P, Harder T (2014) A coralline algal-associated bacterium, Pseudoalteromonas strain J010, yields five new korormicins and a bromopyrrole. Mar Drugs 12:2802 1295. Alvarez-Mico X, Jensen PR, Fenical W, Hughes CC (2013) Chlorizidine, a cytotoxic 5Hpyrrolo[2,1-a]isoindol-5-one-containing alkaloid from a marine Streptomyces sp. Org Lett 15:988 1296. Nuzzo G, Ciavatta ML, Kiss R, Mathieu V, Leclercqz H, Manzo E, Villani G, Mollo E, Lefranc F, D’Souza L, Gavagnin M, Cimino G (2012) Chemistry of the nudibranch Aldisa andersoni: structure and biological activity of phorbazole metabolites. Mar Drugs 10:1799 1297. Dufour C, Wink J, Kurz M, Kogler H, Olivan H, Sablé S, Heyse W, Gerlitz M, Toti L, Nußer A, Rey A, Couturier C, Bauer A, Brönstrup M (2012) Isolation and structural elucidation of armeniaspirols A-C: potent antibiotics against Gram-positive pathogens. Chem Eur J 18:16123 1298. Jansen R, Sood S, Huch V, Kunze B, Stadler M, Müller R (2014) Pyrronazols, metabolites from the myxobacteria Nannocystis pusilla and N. exedens, are unusual chlorinated pyroneoxazole-pyrroles. J Nat Prod 77:320 1299. Witte SNR, Hug JJ, Géraldy MNE, Müller R, Kalesse M (2017) Biosynthesis and total synthesis of pyrronazol B: a secondary metabolite from Nannocystis pusilla. Chem Eur J 23:15917 1300. Yang F, Hamann MT, Zou Y, Zhang M-Y, Gong X-B, Xiao J-R, Chen W-S, Lin H-W (2012) Antimicrobial metabolites from the Paracel Islands sponge Agelas mauritiana. J Nat Prod 75:774 1301. Kusama T, Tanaka N, Sakai K, Gonoi T, Fromont J, Kashiwada Y, Kobayashi J (2014) Agelamadins A and B, dimeric bromopyrrole alkaloids from a marine sponge Agelas sp. Org Lett 16:3916

Naturally Occurring Organohalogen Compounds …

469

1302. Kusama T, Tanaka N, Sakai K, Gonoi T, Fromont J, Kashiwada Y, Kobayashi J (2014) Agelamadins C-E, bromopyrrole alkaloids comprising oroidin and 3-hydroxykynurenine from a marine sponge Agelas sp. Org Lett 16:5176 1303. Muñoz J, Moriou C, Gallard J-F, Marie PD, Al-Mourabit A (2012) Donnazoles A and B from Axinella donnani sponge: very close derivatives from the postulated intermediate ‘pre-axinellamine.’ Tetrahedron Lett 53:5828 1304. Zhang H, Khalil Z, Conte MM, Plisson F, Capon RJ (2012) A search for kinase inhibitors and antibacterial agents: bromopyrrolo-2-aminoimidazoles from a deep-water Great Australian Bight sponge, Axinella sp. Tetrahedron Lett 53:3784 1305. Plisson F, Prasad P, Xiao X, Piggott AM, Huang X, Khalil Z, Capon RJ (2014) Callyspongisines A-D: bromopyrrole alkaloids from an Australian marine sponge, Callyspongia sp. Org Biomol Chem 12:1579 1306. Patiño CLP, Muniain C, Knott ME, Puricelli L, Palermo JA (2014) Bromopyrrole alkaloids isolated from the Patagonian bryozoan Aspidostoma giganteum. J Nat Prod 77:1170 1307. Kusama T, Tanaka N, Takahashi-Nakaguchi A, Gonoi T, Fromont J, Kobayashi J (2014) Bromopyrrole alkaloids from a marine sponge Agelas sp. Chem Pharm Bull 62:499 1308. Kusama T, Tanaka N, Kashiwada Y, Kobayashi J (2015) Agelamadin F and tauroacidin E, bromopyrrole alkaloids from an Okinawan marine sponge Agelas sp. Tetrahedron Lett 56:4502 1309. Cychon C, Lichte E, Köck M (2015) The marine sponge Agelas citrina as a source of the new pyrrole-imidazole alkaloids citrinamines A-D and N-methylagelongine. Beilstein J Org Chem 11:2029 1310. Zhu Y, Wang Y, Gu B-B, Yang F, Jiao W-H, Hu G-H, Yu H-B, Han B-N, Zhang W, Shen Y, Lin H-W (2016) Antifungal bromopyrrole alkaloids from the South China Sea sponge Agelas sp. Tetrahedron 72:2964 1311. Abdjul DB, Yamazaki H, Kanno S, Tomizawa A, Rotinsulu H, Wewengkang DS, Sumilat DA, Ukai K, Kapojos MM, Namikoshi M (2017) An anti-mycobacterial bisfunctionalized sphingolipid and new bromopyrrole alkaloid from the Indonesian marine sponge Agelas sp. J Nat Med 71:531 1312. Xu W-G, Xu J-J, Wang J, Xing G-S, Qiao W, Duan H-Q, Zhao C, Tang S-A (2017) Axinellin A and B: two new pyrrolactam alkaloids from Axinella sp. Chem Nat Compd 53:325 1313. Sauleau P, Moriou C, Al Mourabit A (2017) Metabolomics approach to chemical diversity of the Mediterranean marine sponge Agelas oroides. Nat Prod Res 31:1625 1314. Woo S-Y, Win NN, Wong CP, Ito T, Hoshino S, Ngwe H, Aye AA, Han NM, Zhang H, Hayashi F, Abe I, Morita H (2018) Two new pyrrolo-2-aminoimidazoles from a Myanmarese marine sponge, Clathria prolifera. J Nat Med 72:803 1315. de Souza RTMP, Freire VF, Gubiani JR, Ferreira RO, Trivella DBB, Moraes FC, Paradas WC, Salgado LT, Pereira RC, Filho GMA, Ferreira AG, Williams DE, Andersen RJ, Molinski TF, Berlinck RGS (2018) Bromopyrrole alkaloid inhibitors of the proteasome isolated from a Dictyonella sp. marine sponge collected at the Amazon River mouth. J Nat Prod 81:2296 1316. Parra LLL, Bertonha AF, Severo IRM, Aguiar ACC, de Souza GE, Oliva G, Guido RVC, Grazzia N, Costa TB, Miguel DC, Gadelha FR, Ferreira AG, Hajdu E, Romo D, Berlinck RGS (2018) Isolation, derivative synthesis, and structure–activity relationships of antiparasitic bromopyrrole alkaloids from the marine sponge Tedania brasiliensis. J Nat Prod 81:188 1317. Sun J, Wu J, An B, de Voogd NJ, Cheng W, Lin W (2018) Bromopyrrole alkaloids with the inhibitory effects against the biofilm formation of Gram negative bacteria. Mar Drugs 16:9 1318. Katsuki A, Kato H, Ise Y, Losung F, Mangindaan REP, Tsukamoto S (2019) Agesamines A and B, new dibromopyrrole alkaloids from the sponge Agelas sp. Heterocycles 98:558 1319. Li T, Li P-L, Luo X-C, Tang X-L, Li G-Q (2019) Three new dibromopyrrole alkaloids from the South China Sea sponge Agelas nemoechinata. Tetrahedron Lett 60:1996 1320. Li T, Tang X, Luo X, Wang Q, Liu K, Zhang Y, de Voogd NJ, Yang J, Li P, Li G (2019) Agelanemoechine, a dimeric bromopyrrole alkaloid with a pro-angiogenic effect from the South China Sea sponge Agelas nemoechinata. Org Lett 21:9483

470

G. W. Gribble

1321. Lee S, Tanaka N, Takahashi S, Tsuji D, Kim S-Y, Kojoma M, Itoh K, Kobayashi J, Kashiwada Y (2020) Agesasines A and B, bromopyrrole alkaloids from marine sponges Agelas spp. Mar Drugs 18:455 1322. Kovalerchik D, Singh RP, Schlesinger P, Mahajni A, Shefer S, Fridman M, Ilan M, Carmeli S (2020) Bromopyrrole alkaloids of the sponge Agelas oroides collected near the Israeli Mediterranean coastline. J Nat Prod 83:374 1323. Miguel-Gordo M, Gegunde S, Jennings LK, Genta-Jouve G, Calabro K, Alfonso A, Botana LM, Thomas OP (2020) Futunamine, a pyrrole-imidazole alkaloid from the sponge Stylissa aff. carteri collected off the Futuna Islands. J Nat Prod 83:2299 1324. Lacerna NM II, Miller BW, Lim AL, Tun JO, Robes JMD, Cleofas MJB, Lin Z, SalvadorReyes LA, Haygood MG, Schmidt EW, Concepcion GP (2019) Mindapyrroles A-C, pyoluteorin analogues from a shipworm-associated bacterium. J Nat Prod 82:1024 1325. Mevers E, Sauri J, Helfrich EJN, Henke M, Barns KJ, Bugni TS, Andes D, Currie CR, Clardy J (2019) Pyonitrins A-D: chimeric natural products produced by Pseudomonas protegens. J Am Chem Soc 141:17098 1326. Shingare RD, Aniebok V, Lee H-W, MacMillan JB (2020) Synthesis and investigation of the abiotic formation of pyonitrins A-D. Org Lett 22:1516 1327. Zhang F, Braun DR, Chanana S, Rajski SR, Bugni TS (2019) Phallusialides A–E, pyrrolederived alkaloids discovered from a marine-derived Micromonospora sp. bacterium using MS-based metabolomics approaches. J Nat Prod 82:3432 1328. Tohyama S, Takahashi Y, Akamatsu Y (2010) Biosynthesis of amycolamicin: the biosynthetic origin of a branched α-aminoethyl moiety in the unusual sugar amycolose. J Antibiot 63:147 1329. Sawa R, Takahashi Y, Hashizume H, Sasaki K, Ishizaki Y, Umekita M, Hatano M, Abe H, Watanabe T, Kinoshita N, Homma Y, Hayashi C, Inoue K, Ohba S, Masuda T, Arakawa M, Kobayashi Y, Hamada M, Igarashi M, Adachi H, Nishimura Y, Akamatsu Y (2012) Amycolamicin: a novel broad-spectrum antibiotic inhibiting bacterial topoisomerase. Chem Eur J 18:15772 1330. Phillips JW, Goetz MA, Smith SK, Zink DL, Polishook J, Onishi R, Salowe S, Wiltsie J, Allocco J, Sigmund J, Dorso K, Lee S, Skwish S, de la Cruz M, Martín J, Vicente F, Genilloud O, Lu J, Painter RE, Young K, Overbye K, Donald RGK, Singh SB (2011) Discovery of kibdelomycin, a potent new class of bacterial type II topoisomerase inhibitor by chemical-genetic profiling in Staphylococcus aureus. Chem Biol 18:955 1331. Singh SB, Goetz MA, Smith SK, Zink DL, Polishook J, Onishi R, Salowe S, Wiltsie J, Allocco J, Sigmund J, Dorso K, de la Cruz M, Martín J, Vicente F, Genilloud O, Donald RGK, Phillips JW (2012) Kibdelomycin A, a congener of kibdelomycin, derivatives and their antibacterial activities. Bioorg Med Chem Lett 22:7127 1332. Yang S, Chen C, Chen J, Li C (2021) Total synthesis of the potent and broad-spectrum antibiotics amycolamicin and kibdelomycin. J Am Chem Soc 143:21258 1333. Meguro Y, Ito J, Nakagawa K, Kuwahara S (2022) Total synthesis of the broad-spectrum antibiotic amycolamicin. J Am Chem Soc 144:5253 1334. Singh SB (2016) Discovery and development of kibdelomycin, a new class of broad-spectrum antibiotics targeting the clinically proven bacterial type II topoisomerase. Bioorg Med Chem 24:6291 1335. Mazzetti C, Ornaghi M, Gaspari E, Parapini S, Maffioli S, Sosio M, Donadio S (2012) Halogenated spirotetronates from Actinoallomurus. J Nat Prod 75:1044 1336. Vetter W (2012) Polyhalogenated alkaloids in environmental and food samples. In: The alkaloids, vol 71. Elsevier, p 211 1337. Pangallo K, Nelson RK, Teuten EL, Pedler BE, Reddy CM (2008) Expanding the range of halogenated 1 -methyl-1,2 -bipyrroles (MBPs) using GC/ECNI-MS and GC × GC/TOFMS. Chemosphere 71:1557 1338. Unger MA, Harvey E, Vadas GG, Vecchione M (2008) Persistent pollutants in nine species of deep-sea cephalopods. Mar Pollut Bull 56:1498

Naturally Occurring Organohalogen Compounds …

471

1339. Haraguchi K, Hisamichi Y, Kotaki Y, Kato Y, Endo T (2009) Halogenated bipyrroles and methoxylated tetrabromodiphenyl ethers in tiger shark (Galeocerdo cuvier) from the southern coast of Japan. Environ Sci Technol 43:2288 1340. Haraguchi K, Hisamichi Y, Endo T (2009) Accumulation and mother-to-calf transfer of anthropogenic and natural organohalogens in killer whales (Orcinus orca) stranded on the Pacific coast of Japan. Sci Total Environ 407:2853 1341. Gaul S, Bendig P, Olbrich D, Rosenfelder N, Ruff P, Gaus C, Mueller JF, Vetter W (2011) Identification of the natural product 2,3,4,5-tetrabromo-1-methylpyrrole in Pacific biota, passive samplers and seagrass from Queensland, Australia. Mar Pollut Bull 62:2463 1342. Pena-Abaurrea M, Weijs L, Ramos L, Borghesi N, Corsolini S, Neels H, Blust R, Covaci A (2009) Anthropogenic and naturally-produced organobrominated compounds in bluefin tuna from the Mediterranean Sea. Chemosphere 76:1477 1343. Rosenfelder N, Lehnert K, Kaffarnik S, Torres JPM, Vianna M, Vetter W (2012) Thorough analysis of polyhalogenated compounds in ray liver samples off the coast of Rio de Janeiro, Brazil. Environ Sci Pollut Res 19:379 1344. Bendig P, Rosenfelder N, Mueller JF, Vetter W (2012) Halogenated natural products (HNPs) in fish, sea cucumber and sediment from the Great Barrier Reef (Australia). Organohalogen Comp 74:915 1345. Hauler C, Martin R, Knölker H-J, Gaus C, Mueller JF, Vetter W (2013) Discovery and widespread occurrence of polyhalogenated 1,1 dimethyl-2,2 -bipyrroles (PDBPs) in marine biota. Environ Pollut 178:329 1346. Hauler C, Vetter W (2017) Synthesis, structure elucidation, and determination of polyhalogenarted N-methylpyrroles (PMPs) in blue mussels. Environ Sci Pollut Res 24:26029 1347. Stapleton HM, Dodder NG, Kucklick JR, Reddy CM, Schantz MM, Becker PR, Gulland F, Porter BJ, Wise SA (2006) Determination of HBCD, PBDEs and MeO-BDEs in California sea lions (Zalophus californianus) stranded between 1993 and 2003. Mar Pollut Bull 52:522 1348. Mello FV, Kasper D, Alonso MB, Torres JPM (2020) Halogenated natural products in birds associated with the marine environment: a review. Sci Total Environ 717:137000 1349. Vetter W, Schlabach M, Kallenborn R (2002) Evidence for the presence of natural halogenated hydrocarbons in southern Norwegian and polar air. Fresenius Environ Bull 11:170 1350. Pangallo KC, Reddy CM (2009) Distribution patterns suggest biomagnification of halogenated 1 -methyl-1,2 -bipyrroles (MBPs). Environ Sci Technol 43:122 1351. Pangallo KC, Reddy CM (2010) Marine natural products, the halogenated 1 -methyl-1,2 bipyrroles, biomagnify in a northwestern Atlantic food web. Environ Sci Technol 44:5741 1352. Pangallo KC, Reddy CM, Poyton M, Bolotin J, Hofstetter TB (2012) δ15 N enrichment suggests possible source for halogenated 1 -methyl-1,2 -bipyrroles (MBPs). Environ Sci Technol 46:2064 1353. Kumar A, Borgen M, Aluwihare LI, Fenical W (2017) Ozone-activated halogenation of mono- and dimethylbipyrrole in seawater. Environ Sci Technol 51:589 1354. Gaul S, Vetter W (2008) Photolytic dehalogenation of the marine halogenated natural product Q1. Chemosphere 70:1721 1355. Gaul S, Vetter W (2009) Production of mixed halogenated congeners of the natural product heptachloro-1 -methyl-1,2 -bipyrrole (Q1) by photolysis in the presence of bromine. J Chromatogr A 1216:6433 1356. Gamal AE, Agarwal V, Rahman I, Moore BS (2016) Enzymatic reductive dehalogenation controls the biosynthesis of marine bacterial pyrroles. J Am Chem Soc 138:13167 1357. Rosenfelder N, Ostrowicz P, Fu L, Gribble GW, Tittlemier SA, Frey W, Vetter W (2010) Enantioseparation and absolute configuration of the atropisomers of a naturally produced hexahalogenated 1,1 -dimethyl-2,2 -bipyrrole. J Chromatogr A 1217:2050 1358. Fu L, Gribble GW (2008) A short synthesis of the naturally occurring 2,3,3 ,4,4 ,5,5 heptachloro- (“Q1”) and heptabromo-1 -methyl-1,2 -bipyrroles. Org Prep Proc Int 40:561 1359. Martin R, Jäger A, Knölker H-J (2011) Transition metals in organic synthesis, Part 97: silver-catalyzed synthesis of hexahalogenated 2,2 -bipyrroles. Synlett:2795

472

G. W. Gribble

1360. Kennedy JP, Brogan JT, Lindsley CW (2008) Total synthesis and biological evaluation of the marine bromopyrrole alkaloid dispyrin: elucidation of discrete molecular targets with therapeutic potential. J Nat Prod 71:1783 1361. Han S, Siegel DS, Morrison KC, Hergenrother PJ, Movassaghi M (2013) Synthesis and anticancer activity of all known (–)-agelastatin alkaloids. J Org Chem 78:11970 1362. Mahajan JP, Mhaske SB (2017) Synthesis of methyl-protected (±)-chlorizidine A. Org Lett 19:2774 1363. Mantovani SM, Moore BS (2013) Flavin-linked oxidase catalyzes pyrrolizine formation of dichloropyrrole-containing polyketide extender unit in chlorizidine A. J Am Chem Soc 135:18032 1364. Qiao Y, Yan J, Jia J, Xue J, Qu X, Hu Y, Deng Z, Bi H, Zhu D (2019) Characterization of the biosynthetic gene cluster for the antibiotic armeniaspirols in Streptomyces armeniacus. J Nat Prod 82:318 1365. van Rensburg M, Copp BR, Barker D (2018) Synthesis and absolute stereochemical reassignment of mukanadin F: a study of isomerization of bromopyrrole alkaloids with implications on marine natural product isolation. Eur J Org Chem:3065 1366. Bhandari MR, Sivappa R, Lovely CJ (2009) Total synthesis of the putative structure of nagelamide D. Org Lett 11:1535 1367. Kikuchi H, Sekiya M, Katou Y, Ueda K, Kabeya T, Kurata S, Oshima Y (2009) Revised structure and synthesis of celastramycin A, a potent innate immune suppressor. Org Lett 11:1693 1368. Al-Mourabit A, Zancanella MA, Tilvi S, Romo D (2011) Biosynthesis, asymmetric synthesis, and pharmacology, including cellular targets, of the pyrrole-2-aminoimidazole marine alkaloids. Nat Prod Rep 28:1229 1369. Beniddir MA, Evanno L, Joseph D, Skiredj A, Poupon E (2016) Emergence of diversity and stereochemical outcomes in the biosynthetic pathways of cyclobutane-centered marine alkaloid dimers. Nat Prod Rep 33:820 1370. Seiple IB, Su S, Young IS, Lewis CA, Yamaguchi J, Baran PS (2010) Total synthesis of palau’amine. Angew Chem Int Ed 49:1095 1371. Seiple IB, Su S, Young IS, Nakamura A, Yamaguchi J, Jørgensen L, Rodriguez RA, O’Malley DP, Gaich T, Köck M, Baran PS (2011) Enantioselective total syntheses of (–)-palau’amine, (–)-axinellamines, and (–)-massadines. J Am Chem Soc 133:14710 1372. Jessen HJ, Gademann K (2010) Total synthesis of the marine alkaloid palau’amine. Angew Chem Int Ed 49:2972 1373. Grube A, Köck M (2007) Structural assignment of tetrabromostyloguanidine: does the relative configuration of the palau’amines need revision? Angew Chem Int Ed 46:2320 1374. Buchanan MS, Carroll AR, Quinn RJ (2007) Revised structure of palau’amine. Tetrahedron Lett 48:4573 1375. Köck M, Grube A, Seiple IB, Baran PS (2007) The pursuit of palau’amine. Angew Chem Int Ed 46:6586 1376. Lanman BA, Overman LE, Paulini R, White NS (2007) On the structure of palau’amine: evidence for the revised relative configuration from chemical synthesis. J Am Chem Soc 129:12896 1377. Lindel T, Jacquot DEN, Zöllinger M, Kinnel RB, McHugh S, Köck M (2010) Study on the absolute configuration of (–)-palau’amine. Tetrahedron Lett 51:6353 1378. Reinscheid UM, Köck M, Cychon C, Schmidts V, Thiele CM, Griesinger C (2010) The absolute configuration of dibromopalau’amine. Eur J Org Chem:6900 1379. Su S, Rodriguez RA, Baran PS (2011) Scalable, stereocontrolled total syntheses of (±)axinellamines A and B. J Am Chem Soc 133:13922 1380. Feldman KS, Nuriye AY, Li J (2011) Extending Pummerer reaction chemistry: studies in the palau’amine synthesis area. J Org Chem 76:5042 1381. Stout EP, Wang Y-G, Romo D, Molinski TF (2012) Pyrrole aminoimidazole alkaloid metabiosynthesis with marine sponges Agelas conifera and Stylissa caribica. Angew Chem Int Ed 51:4877

Naturally Occurring Organohalogen Compounds …

473

1382. Wang X, Wang X, Tan X, Lu J, Cormier KW, Ma Z, Chen C (2012) A biomimetic route for construction of the [4+2] and [3+2] core skeletons of dimeric pyrrole-imidazole alkaloids and asymmetric synthesis of ageliferins. J Am Chem Soc 134:18834 1383. Köck M, Schmidt G, Seiple IB, Baran PS (2012) Configurational analysis of tetracyclic dimeric pyrrole-imidazole alkaloids using a floating chirality approach. J Nat Prod 75:127 1384. Rodriguez RA, Steed DB, Kawamata Y, Su S, Smith PA, Steed TC, Romesberg FE, Baran PS (2014) Axinellamines as broad-spectrum antibacterial agents: scalable synthesis and biology. J Am Chem Soc 136:15403 1385. Ma Z, Wang X, Ma Y, Chen C (2016) Asymmetric synthesis of axinellamines A and B. Angew Chem Int Ed 55:4763 1386. Grube A, Immel S, Baran PS, Köck M (2007) Massadine chloride: a biosynthetic precursor of massadine and stylissadine. Angew Chem Int Ed 46:6721 1387. Su H, Yuan ZH, Li J, Guo SJ, Deng LP, Han LJ, Zhu XB, Shi DY (2009) Two new bromoindoles from red alga Laurencia similis. Chin Chem Lett 20:456 1388. Woolner VH, Jones CM, Field JJ, Fadzilah NH, Munkacsi AB, Miller JH, Keyzers RA, Northcote PT (2016) Polyhalogenated indoles from the red alga Rhodophyllis membranacea: the first isolation of bromo-chloro-iodo secondary metabolites. J Nat Prod 79:463 1389. Bao B, Zhang P, Lee Y, Hong J, Lee C-O, Jung JH (2007) Monoindole alkaloids from a marine sponge Spongosorites sp. Mar Drugs 5:31 1390. Li L, Deng Z, Fu H, Li J, Proksch P, Lin W (2003) Chemical constituents from the marine sponge Iotrochoto birotulata. Pharmazie 58:680 1391. Santalova EA, Denisenko VA, Berdyshev DV, Aminin DL, Sanamyan KE (2008) 6-Bromo5-hydroxyindolyl-3-glyoxylate from the Far Eastern ascidian Syncarpa oviformis. Nat Prod Commun 3:1617 1392. Wang R-P, Lin H-W, Li L-Z, Gao P-Y, Xu Y, Song S-J (2012) Monoindole alkaloids from a marine sponge Mycale fibrexilis. Biochem Syst Ecol 43:210 1393. Longeon A, Copp BR, Quévrain E, Roué M, Kientz B, Cresteil T, Petek S, Debitus C, Bourguet-Kondracki M-L (2011) Bioactive indole derivatives from the South Pacific marine sponges Rhopaloeides odorabile and Hyrtios sp. Mar Drugs 9:879 1394. Maltseva AL, Kotenko ON, Shabalin KA, Shavarda AL, Winson MK, Ostrovsky AN (2014) Novel brominated fungicidal alkaloid isolated from the marine bryozoan Chartella membranacea truncata (Smitt, 1868). Studi Trent Sci Nat 94:163 1395. Maltseva AL, Kotenko ON, Kutyumov VA, Matvienko DA, Shavarda AL, Winson MK, Ostrovsky AN (2017) Novel brominated metabolites from Bryozoa: a functional analysis. Nat Prod Res 31:1840 1396. Takahashi Y, Tanaka N, Kubota T, Ishiyama H, Shibazaki A, Gonoi T, Fromont J, Kobayashi J (2012) Heteroaromatic alkaloids, nakijinamines, from a sponge Suberites sp. Tetrahedron 68:8545 1397. Takahashi Y, Kubota T, Shibazaki A, Gonoi T, Fromont J, Kobayashi J (2011) Nakijinamines C-E, new heteroaromatic alkaloids from the sponge Suberites species. Org Lett 13:3016 1398. Olsen EK, Hansen E, Moodie LWK, Isaksson J, Sepˇci´c K, Cergolj M, Svenson J, Andersen JH (2016) Marine AChE inhibitors isolated from Geodia barretti: natural compounds and their synthetic analogs. Org Biomol Chem 14:1629 1399. Lorig-Roach N, Hamkins-Indik F, Johnson TA, Tenney K, Valeriote FA, Crews P (2018) The potential of achiral sponge-derived and synthetic bromoindoles as selective cytotoxins against PANC-1 tumor cells. Tetrahedron 74:217 1400. dos Santos LAH, Clavico EEG, Parra LLL, Berlinck RGS, Ferreira AG, Paul VJ, Pereira RC (2017) Evaluation of chemical defense and chemical diversity in the exotic bryozoan Amathia verticillata. J Braz Chem Soc 28:435 1401. Wang D, Feng Y, Murtaza M, Wood S, Mellick G, Hooper JNA, Quinn RJ (2016) A grand challenge: unbiased phenotypic function of metabolites from Jaspis splendens against Parkinson’s disease. J Nat Prod 79:353 1402. Bagalagel AA, Bogari HA, Ahmed SA, Diri RM, Elhady SS (2018) New bromoindole alkaloid isolated from the marine sponge Hyrtios erectus. Heterocycles 96:749

474

G. W. Gribble

1403. Miguel-Gordon M, Gegunde S, Calabro K, Jennings LK, Alfonso A, Genta-Jouve G, Vacelet J, Botana LM, Thomas OP (2019) Bromotryptamine and bromotyramine derivatives from the tropical southwestern Pacific sponge Narrabeena nigra. Mar Drugs 17:319 1404. Kleks G, Holland DC, Kennedy EK, Avery VM, Carroll AR (2020) Antiplasmodial alkaloids from the Australian bryozoan Amathia lamourouxi. J Nat Prod 83:3435 1405. Li C-S, Li X-M, Cui C-M, Wang B-G (2010) Brominated metabolites from the marine red alga Laurencia similis. Z Naturforsch 65b:87 1406. Fang H-Y, Chiou S-F, Uvarani C, Wen Z-H, Hsu C-H, Wu Y-C, Wang W-L, Liaw C-C, Sheu J-H (2014) Cytotoxic, anti-inflammatory, and antibacterial sulfur-containing polybromoindoles from the Formosan red alga Laurencia brongniartii. Bull Chem Soc Jpn 87:1278 1407. Steinmetz H, Mohr KI, Zander W, Jansen R, Gerth K, Müller R (2012) Indiacens A and B: prenyl indoles from the myxobacterium Sandaracinus amylolyticus. J Nat Prod 75:1803 1408. El-Hawary SS, Sayed AM, Mohammed R, Khanfar MA, Rateb ME, Mohammed TA, Hajjar D, Hassan HM, Gulder TAM, Abdelmohsen UR (2018) New Pim-1 kinase inhibitor from the co-culture of two sponge-associated actinomycetes. Front Chem 6:538 1409. da Silva AB, Pinto FCL, Silveira ER, Costa-Lotufo LV, Costa WS, Ayala AP, Canuto KM, Barros AB, Araújo AJ, Filho JDBM, Pessoa ODL (2019) 4-Hydroxy-pyran-2-one and 3hydroxy-N-methyl-2-oxindole derivatives of Salinispora arenicola from Brazilian marine sediments. Fitoterapia 138:104357 1410. Ragini K, Piggott AM, Karuso P (2019) Bisindole alkaloids from a New Zealand deep-sea marine sponge Lamellomorpha strongylata. Mar Drugs 17:683 1411. Campos P-E, Pichon E, Moriou C, Clerc P, Trépos R, Frederich M, De Voogd N, Hellio C, Gauvin-Bialecki A, Al-Mourabit A (2019) New antimalarial and antimicrobial tryptamine derivatives from the marine sponge Fascaplysinopsis reticulata. Mar Drugs 17:167 1412. Shaker KH, Göhl M, Müller T, Seifert K (2015) Indole alkaloids from the sea anemone Heteractis aurora and homarine from Octopus cyanea. Chem Biodivers 12:1746 1413. Carroll AR, Wild SJ, Duffy S, Avery VM (2012) Kororamide A, a new tribrominated indole alkaloid from the Australian bryozoan Amathia tortuosa. Tetrahedron Lett 53:2873 1414. Dashti Y, Vial M-L, Wood SA, Mellick GD, Roullier C, Quinn RJ (2015) Kororamide B, a brominated alkaloid from the bryozoan Amathia tortuosa and its effects on Parkinson’s disease cells. Tetrahedron 71:7879 1415. Pénez N, Culioli G, Pérez T, Briand J-F, Thomas OP, Blache Y (2011) Antifouling properties of simple indole and purine alkaloids from the Mediterranean gorgonian Paramuricea clavata. J Nat Prod 74:2304 1416. Shen S, Liu D, Wei C, Proksch P, Lin W (2012) Purpuroines A-J, halogenated alkaloids from the sponge Iotrochota purpurea with antibiotic activity and regulation of tyrosine kinases. Bioorg Med Chem 20:6924 1417. Cachet N, Loffredo L, Vicente OO, Thomas OP (2013) Chemical diversity in the scleractinian coral Astroides calycularis. Phytochem Lett 6:205 1418. Volk R-B, Girreser U, Al-Refai M, Laatsch H (2009) Bromoanaindolone, a novel antimicrobial exometabolite from the cyanobacterium Anabaena constricta. Nat Prod Res 23:607 1419. Shin HJ, Jeong HS, Lee H-S, Park S-K, Kim HM, Kwon HJ (2007) Isolation and structure determination of streptochlorin, an antiproliferative agent from a marine-derived Streptomyces sp. 04DH110. J Microbiol Biotechnol 17:1403 1420. Watanabe H, Amano S, Yoshida J, Takase Y, Miyadoh S, Sasaki T, Hatsu M, Takeuchi Y, Komada Y (1988) A new antibiotic SF2583A, 4-chloro-5-(3 -indolyl)oxazole, produced by Streptomyces. Meiji Seika Kenkyu Nenpo 27:55 1421. Capon RJ, Peng C, Dooms C (2008) Trachycladindoles A-G: cytotoxic heterocycles from an Australian marine sponge, Trachycladus laevispirulifer. Org Biomol Chem 6:2765 1422. Zaharenko AJ, Picolo G, Ferreira WA Jr, Murakami T, Kazuma K, Hashimoto M, Cury Y, de Freitas JC, Satake M, Konno K (2011) Bunodosine 391: an analgesic acylamino acid from the venom of the sea anemone Bunodosoma cangicum. J Nat Prod 74:378

Naturally Occurring Organohalogen Compounds …

475

1423. Hu J, Zhang W-D, Shen Y-H, Zhang C, Liu R-H, Xu X-K, Wang B (2007) Two novel alkaloids from Zanthoxylum nitidum. Helv Chim Acta 90:720 1424. Wang W-L, Lu Z-Y, Tao H-W, Zhu T-J, Fang Y-C, Gu Q-Q, Zhu W-M (2007) Isoechinulintype alkaloids, variecolorins A-L, from halotolerant Aspergillus variecolor. J Nat Prod 70:1558 ˇ 1425. Rezanka T, Hanuš LO, Dembitsky VM, Sigler K (2008) Identification of the eight-membered heterocycles hicksoanes A–C from the gorgonian Subergorgia hicksoni. Eur J Org Chem: 1265 1426. Tapiolas DM, Bowden BF, Abou-Mansour E, Willis RH, Doyle JR, Muirhead AN, Liptrot C, Llewellyn LE, Wolff CWW, Wright AD, Motti CA (2009) Eusynstyelamides A, B, and C, nNOS inhibitors, from the ascidian Eusynstyela latericius. J Nat Prod 72:1115 1427. Swersey JC, Ireland CM, Cornell LM, Peterson RW (1994) Eusynstyelamide, a highly modified dimer peptide from the ascidian Eusynstyela misakiensis. J Nat Prod 57:842 1428. Tadesse M, Tabudravu JN, Jaspars M, Strøm MB, Hansen E, Andersen JH, Kristiansen PE, Haug T (2011) The antibacterial ent-eusynstyelamide B and eusynstyelamide D, E, and F from the Arctic bryozoan Tegella cf. spitzbergensis. J Nat Prod 74:837 1429. McArthur KA, Mitchell SS, Tsueng G, Rheingold A, White DJ, Grodberg J, Lam KS, Potts BCM (2008) Lynamicins A-E, chlorinated bisindole pyrrole antibiotics from a novel marine actinomycete. J Nat Prod 71:1732 1430. Dai J, Jiménez JI, Kelly M, Barnes S, Lorenzo P, Williams P (2008) Dictazolines A and B, bisspiroimidazolidinones from the marine sponge Smenospongia cerebriformis. J Nat Prod 71:1287 1431. Dai J, Jiménez JI, Kelly M, Williams PG (2010) Dictazoles: potential vinyl cyclobutane biosynthetic precursors to the dictazolines. J Org Chem 75:2399 1432. Iwagawa T, Miyazaki M, Yokogawa Y, Okamura H, Nakatani M, Doe M, Morimoto Y, Takemura K (2008) Aplysinopsin dimers from a stony coral, Tubastraea aurea. Heterocycles 75:2023 1433. Carroll AR, Avery VM (2009) Leptoclinidamines A-C, indole alkaloids from the Australian ascidian Leptoclinides durus. J Nat Prod 72:696 1434. Zhang H, Conte MM, Khalil Z, Huang X-C, Capon RJ (2012) New dictyodendrins as BACE inhibitors from a Southern Australian marine sponge, Ianthella sp. RSC Adv 2:4209 1435. Feng T, Li Y, Cai X-H, Gong X, Liu Y-P, Zhang R-T, Zhang X-Y, Tan Q-G, Luo X-D (2009) Monoterpenoid indole alkaloids from Alstonia yunnanensis. J Nat Prod 72:1836 1436. Mo S, Krunic A, Chlipala G, Orjala J (2009) Antimicrobial ambiguine isonitriles from the cyanobacterium Fischerella ambigua. J Nat Prod 72:894 1437. Mo S, Krunic A, Santarsiero BD, Franzblau SG, Orjala J (2010) Hapalindole-related alkaloids from the cultured cyanobacterium Fischerella ambigua. Phytochemistry 71:2116 1438. Wang G-C, Zhong X-Z, Zhang D-M, Wang Y, Zhang X-Q, Jiang R-W, Li Y-L, Wang J, Yao X-S, Ye W-C (2011) Two pairs of epimeric indole alkaloids from Catharanthus roseus. Planta Med 77:1739 1439. Rochfort SJ, Moore S, Craft C, Martin NH, Van Wagoner RM, Wright JLC (2009) Further studies on the chemistry of the Flustra alkaloids from the bryozoan Flustra foliacea. J Nat Prod 72:1773 1440. Morales-Ríos MS, Suárez-Castillo OR (2008) Synthesis of marine indole alkaloids from Flustra foliacea. Nat Prod Commun 3:629 1441. Kim J-S, Padnya A, Weltzin M, Edmonds BW, Schulte MK, Glennon RA (2007) Synthesis of desformylflustrabromine and its evaluation as an α4β2 and α7 nACh receptor modulator. Bioorg Med Chem Lett 17:4855 1442. Isaji H, Nakazaki A, Isobe M, Nishikawa T (2011) Concise synthesis of deformylflustrabromine, a marine indole alkaloid, through a 2-propynyl dicobalt hexacarbonyl complex. Chem Lett 40:1079 1443. Kawasaki T, Shinada M, Ohzono M, Ogawa A, Terashima R, Sakamoto M (2008) Total synthesis of (±)-flustramines A and C, (±)-flustramide A, and (–)- and (+)debromoflustramines A. J Org Chem 73:5959

476

G. W. Gribble

1444. Adla SK, Sasse F, Kelter G, Fiebig H-H, Lindel T (2013) Doubly prenylated tryptamines: cytotoxicity, antimicrobial activity and cyclisation to the marine natural product flustramine A. Org Biomol Chem 11:6119 1445. Hirano T, Iwakiri K, Miyamoto H, Nakazaki A, Kobayashi S (2009) Total synthesis of (– )-flustramine B via one-pot intramolecular Ullmann coupling and Claisen rearrangement. Heterocycles 79:805 1446. Cordero-Rivera RE, Meléndez-Rodríguez M, Suárez-Castillo OR, Bautista-Hernández CI, Trejo-Carbajal N, Cruz-Borbolla J, Castelán-Duarte LE, Morales-Ríos MS, Joseph-Nathan P (2015) Formal synthesis of (–)-flustramine B and its absolute configuration assignment by vibrational circular dichroism exciton chirality. Tetrahedron: Asymmetry 26:710 1447. Rivera-Becerril E, Joseph-Nathan P, Pérez-Álvarez VM, Morales-Ríos MS (2008) Synthesis and biological evaluation of (–)- and (+)-debromoflustramine B and its analogues as selective butyrylcholinesterase inhibitors. J Med Chem 51:5271 1448. Liberio MS, Sooraj D, Williams ED, Feng Y, Davis RA (2011) Kingamide A, a new indole alkaloid from the ascidian Leptoclinides kingi. Tetrahedron Lett 52:6729 1449. Hughes CC, MacMillan JB, Gaudêncio SP, Jensen PR, Fenical W (2009) The ammosamides: structures of cell cycle modulators from a marine-derived Streptomyces species. Angew Chem Int Ed 48:725 1450. Hughes CC, MacMillan JB, Gaudêncio SP, Fenical W, La Clair JJ (2009) Ammosamides A and B target myosin. Angew Chem Int Ed 48:728 1451. Hughes CC, Fenical W (2010) Total synthesis of the ammosamides. J Am Chem Soc 132:2528 1452. Wu Q, Jiao X, Wang L, Xiao Q, Liu X, Xie P (2010) Short and straightforward total synthesis of ammosamide B. Tetrahedron Lett 51:4806 1453. Reddy PVN, Banerjee B, Cushman M (2010) Efficient total synthesis of ammosamide B. Org Lett 12:3112 1454. Takayama Y, Yamada T, Tatekabe S, Nagasawa K (2013) A tandem Friedel-Crafts based method for the construction of a tricyclic pyrroloquinoline skeleton and its application in the synthesis of ammosamide B. Chem Commun 49:6519 1455. Yang S-W, Wang C-M, Tang K-X, Wang J-X, Sun L-P (2016) An efficient approach to the total synthesis of ammosamide B. Eur J Org Chem: 1050 1456. Zurwerra D, Wullschleger CW, Altmann K-H (2010) Treasures from the sea: discovery and total synthesis of ammosamides. Angew Chem Int Ed 49:6936 1457. Reimer D, Hughes CC (2017) Thiol-based probe for electrophilic natural products reveals that most of the ammosamides are artifacts. J Nat Prod 80:126 1458. Genta-Jouve G, Francezon N, Puissant A, Auberger P, Vacelet J, Pérez T, Fontana A, Al Mourabit A, Thomas OP (2011) Structure elucidation of the new citharoxazole from the Mediterranean deep-sea sponge Latrunculia (Biannulata) citharistae. Magn Reson Chem 49:533 1459. Carbone M, Li Y, Irace C, Mollo E, Castelluccio F, Di Pascale A, Cimino G, Santamaria R, Guo Y-W, Gavagnin M (2011) Structure and cytotoxicity of phidianidines A and B: first finding of 1,2,4-oxadiazole system in a marine natural product. Org Lett 13:2516 1460. Labriere C, Elumalai V, Staffansson J, Cervin G, Le Norcy T, Denardou H, Réhel K, Moodie LWK, Hellio C, Pavia H, Hansen JH, Svenson J (2020) Phidianidine A and synthetic analogues as naturally inspired marine antifoulants. J Nat Prod 83:3413 1461. Liu J, Li H, Chen K-X, Zuo J-P, Guo Y-W, Tang W, Li X-W (2018) Design and synthesis of marine phidianidine derivatives as potential immunosuppressive agents. J Med Chem 61:11298 1462. Brogan JT, Stoops SL, Lindsley CW (2012) Total synthesis and biological evaluation of phidianidines A and B uncovers unique pharmacological profiles at CNS targets. ACS Chem Neurosci 3:658 1463. Finlayson R, Pearce AN, Page MJ, Kaiser M, Bourguet-Kondracki M-L, Harper JL, Webb VL, Copp BR (2011) Didemnidines A and B, indole spermidine alkaloids from the New Zealand ascidian Didemnum sp. J Nat Prod 74:888

Naturally Occurring Organohalogen Compounds …

477

1464. Wei X, Henriksen NM, Skalicky JJ, Harper MK, Cheatham TE III, Ireland CM, Van Wagoner RM (2011) Araiosamines A-D: tris-bromoindole cyclic guanidine alkaloids from the marine sponge Clathria (Thalysias) araiosa. J Org Chem 76:5515 1465. Tian M, Yan M, Baran PS (2016) 11-Step total synthesis of araiosamines. J Am Chem Soc 138:14234 1466. Li JL, Han SC, Yoo ES, Shin S, Hong J, Cui Z, Li H, Jung JH (2011) Anti-inflammatory amino acid derivatives from the ascidian Herdmania momus. J Nat Prod 74:1792 1467. Tsukamoto S, Kawabata T, Kato H, Greshock TJ, Hirota H, Ohta T, Williams RM (2009) Isolation of antipodal (–)-versicolamide B and notoamides L-N from a marine-derived Aspergillus sp. Org Lett 11:1297 1468. Tsukamoto S, Umaoka H, Yoshikawa K, Ikeda T, Hirota H (2010) Notoamide O, a structurally unprecedented prenylated indole alkaloid, and notoamides P-R from a marine-derived fungus, Aspergillus sp.. J Nat Prod 73:1438 1469. Figueroa M, González MDC, Mata R (2008) Malbrancheamide B, a novel compound from the fungus Malbranchea aurantiaca. Nat Prod Res 22:709 1470. Ding Y, Greshock TJ, Miller KA, Sherman DH, Williams RM (2008) Premalbrancheamide: synthesis, isotopic labeling, biosynthetic incorporation, and detection in cultures of Malbranchea aurantiaca. Org Lett 10:4863 1471. Figueroa M, González-Andrade M, Sosa-Peinado A, Madariaga-Mazón A, Del Río-Portilla F, Del Carmen GM, Mata R (2011) Fluorescence, circular dichroism, NMR, and docking studies of the interaction of the alkaloid malbrancheamide with calmodulin. J Enzyme Inhibit Med Chem 26:378 1472. Watts KR, Loveridge ST, Tenney K, Media J, Valeriote FA, Crews P (2011) Utilizing DART mass spectrometry to pinpoint halogenated metabolites from a marine invertebrate-derived fungus. J Org Chem 76:6201 1473. Miller KA, Welch TR, Greshock TJ, Ding Y, Sherman DH, Williams RM (2008) Biomimetic total synthesis of malbrancheamide and malbrancheamide B. J Org Chem 73:3116 1474. Miller KA, Figueroa M, Valente MWN, Greshock TJ, Mata R, Williams RM (2008) Calmodulin inhibitory activity of the malbrancheamides and various analogs. Bioorg Med Chem Lett 18:6479 1475. Frebault F, Simpkins NS, Fenwick A (2009) Concise enantioselective synthesis of entmalbrancheamide B. J Am Chem Soc 131:4214 1476. Miller KA, Williams RM (2009) Synthetic approaches to the bicyclo[2.2.2]diazaoctane ring system common to the paraherquamides, stephacidins and related prenylated indole alkaloids. Chem Soc Rev 38:3160 1477. Miller KA, Tsukamoto S, Williams RM (2009) Asymmetric total syntheses of (+)- and (–)-versicolamide B and biosynthetic implications. Nat Chem 1:63 1478. Frebault FC, Simpkins NS (2010) A cationic cyclisation route to prenylated indole alkaloids: synthesis of malbrancheamide B and brevianamide B, and progress towards stephacidin A. Tetrahedron 66:6585 1479. Fraley AE, Garcia-Borràs M, Tripathi A, Khare D, Mercado-Marin EV, Tran H, Dan Q, Webb GP, Watts KR, Crews P, Sarpong R, Williams RM, Smith JL, Houk KN, Sherman DH (2017) Function and structure of MalA/MalA , iterative halogenases for late-stage C-H functionalization of indole alkaloids. J Am Chem Soc 139:12060 1480. Dan Q, Newmister SA, Klas KR, Fraley AE, McAfoos TJ, Somoza AD, Sunderhaus JD, Ye Y, Shende VV, Yu F, Sanders JN, Brown WC, Zhao L, Paton RS, Houk KN, Smith JL, Sherman DH, Williams RM (2019) Fungal indole alkaloid biogenesis through evolution of a bifunctional reductase/Diels-Alderase. Nature Chem 11:972 1481. Harayama Y, Kita Y (2005) Pyrroloiminoquinone alkaloids: discorhabdins and makaluvamines. Curr Org Chem 9:1567 1482. Wada Y, Harayama Y, Kamimura D, Yoshida M, Shibata T, Fujiwara K, Morimoto K, Fujioka H, Kita Y (2011) The synthetic and biological studies of discorhabdins and related compounds. Org Biomol Chem 9:4959

478

G. W. Gribble

1483. Kalinski J-CJ, Krause RWM, Parker-Nance S, Waterworth SC, Dorrington RA (2021) Unlocking the diversity of pyrroloiminoquinones produced by latrunculid sponge species. Mar Drugs 19:68 1484. El-Naggar M, Capon RJ (2009) Discorhabdins revisited: cytotoxic alkaloids from Southern Australian marine sponges of the genera Higginsia and Spongosorites. J Nat Prod 72:460 1485. El-Naggar M, Capon RJ (2009) Correction to discorabdins revisited: cytotoxic alkaloids from Southern Australian marine sponges of the genera Higginsia and Spongosorites. J Nat Prod 72:1368 1486. Grkovic T, Copp BR (2009) New natural products in the discorhabdin A- and B-series from New Zealand-sourced Latrunculia spp. sponges. Tetrahedron 65:6335 1487. Na M, Ding Y, Wang B, Tekwani BL, Schinazi RF, Franzblau S, Kelly M, Stone R, Li X-C, Ferreira D, Hamann MT (2010) Anti-infective discorhabdins from a deep-water Alaskan sponge of the genus Latrunculia. J Nat Prod 73:383 1488. Grdovic T, Pearce AN, Munro MHG, Blunt JW, Davies-Coleman MT, Copp BR (2010) Isolation and characterization of diastereomers of discorhabdins H and K and assignment of absolute configuration to discorhabdins D, N, Q, S, T, and U. J Nat Prod 73:1686 1489. Lam CFC, Grkovic T, Pearce AN, Copp BR (2012) Investigation of the electrophilic reactivity of the cytotoxic marine alkaloid discorhabdin B. Org Biomol Chem 10:3092 1490. Boti´c T, Defant A, Zanini P, Žužek MC, Frangež R, Janussen D, Kersken D, Knez Ž, Mancini I, Sepˇci´c K (2017) Discorhabdin alkaloids from Antarctic Latrunculia spp. sponges as a new class of cholinesterase inhibitors. Eur J Med Chem 136:294 1491. Li F, Peifer C, Janussen D, Tasdemir D (2019) New discorhabdin alkaloids from the Antarctic deep-sea sponge Latrunculia biformis. Mar Drugs 17:439 1492. Li F, Pandey P, Janussen D, Chittiboyina AG, Ferreira D, Tasdemir D (2020) Tridiscorhabdin and didiscorhabdin, the first discorhabdin oligomers linked with a direct C-N bridge from the sponge Latrunculia biformis collected from the deep sea in Antarctica. J Nat Prod 83:706 1493. Li F, Janussen D, Tasdemir D (2020) New discorhabdin B dimers with anticancer activity from the Antarctic deep-sea sponge Latrunculia biformis. Mar Drugs 18:107 1494. Lam CFC, Cadelis MM, Copp BR (2020) Exploration of the electrophilic reactivity of the cytotoxic marine alkaloid discorhabdin C and subsequent discovery of a new dimeric C-1/ N13-linked discorhabdin natural product. Mar Drugs 18:404 1495. Zou Y, Hamann MT (2013) Atkamine: a new pyrroloiminoquinone scaffold from the cold water Aleutian Islands Latrunculia sponge. Org Lett 15:1516 1496. Zou Y, Wang X, Sims J, Wang B, Pandey P, Welsh CL, Stone RP, Avery MA, Doerksen RJ, Ferreira D, Anklin C, Valeriote FA, Kelly M, Hamann MT (2019) Computationally assisted discovery and assignment of a highly strained and PANC-1 selective alkaloid from Alaska’s Deep Ocean. J Am Chem Soc 141:4338 1497. Taufa T, Gordon RMA, Hashmi MA, Hira K, Miller JH, Lein M, Fromont J, Northcote PT, Keyzers RA (2019) Pyrroloquinoline derivatives from a Tongan specimen of the marine sponge Strongylodesma tongaensis. Tetrahedron Lett 60:1825 1498. Kalinski J-CJ, Waterworth SC, Noundou XS, Jiwaji M, Parker-Nance S, Krause RWM, McPhail KL, Dorrington RA (2019) Molecular networking reveals two distinct chemotypes in pyrroloiminoquinone-producing Tsitsikamma favus sponges. Mar Drugs 17:60 1499. Wada Y, Otani K, Endo N, Harayama Y, Kamimura D, Yoshida M, Fujioka H, Kita Y (2009) The first total synthesis of prianosin B. Tetrahedron 65:1059 1500. Oshiyama T, Satoh T, Okano K, Tokuyama H (2012) Total synthesis of batzelline C and isobatzelline C. RSC Adv 2:5147 1501. Oshiyama T, Satoh T, Okano K, Tokuyama H (2012) Total synthesis of makaluvamine A/ D, damirone B, batzelline C, makaluvone, and isobatzelline C featuring one-pot benzynemediated cyclization–functionalization. Tetrahedron 68:9376 1502. Yamashita Y, Poignant L, Sakata J, Tokuyama H (2020) Divergent total syntheses of isobatzellines A/B and batzelline A. Org Lett 22:6239 1503. Alonso E, Alvariño R, Leirós M, Tabudravu JN, Feussner K, Dam MA, Rateb ME, Jaspars M, Botana LM (2016) Evaluation of the antioxidant activity of the marine pyrroloiminoquinone makaluvamines. Mar Drugs 14:197

Naturally Occurring Organohalogen Compounds …

479

1504. Wright AE, Killday KB, Chakrabarti D, Guzmán EA, Harmody D, McCarthy PJ, Pitts T, Pomponi SA, Reed JK, Roberts BF, Felix CR, Rohde KH (2017) Dragmacidin G, a bioactive bis-indole alkaloid from a deep-water sponge of the genus Spongosorites. Mar Drugs 15:16 1505. Hitora Y, Takada K, Ise Y, Okada S, Matsunaga S (2016) Dragmacidins G and H, bisindole alkaloids tethered by a guanidino ethylthiopyrazine moiety, from a Lipastrotethya sp. marine sponge. J Nat Prod 79:2973 1506. Cruz PG, Leal JFM, Duranas AH, Pérez M, Cuevas C (2018) On the mechanism of action of dragmacidins I and J, two new representatives of a new class of protein phosphatase 1 and 2A inhibitors. ACS Omega 3:3760 1507. Mandal D, Yamaguchi AD, Yamaguchi J, Itami K (2011) Synthesis of dragmacidin D via direct C-H couplings. J Am Chem Soc 133:19660 1508. Jackson JJ, Kobayashi H, Steffens SD, Zakarian A (2015) 10-Step asymmetric total synthesis and stereochemical elucidation of (+)-dragmacidin D. Angew Chem Int Ed 54:9971 1509. Zhang F, Wang B, Prasad P, Capon RJ, Jia Y (2015) Asymmetric total synthesis of (+)dragmacidin D reveals unexpected stereocomplexity. Org Lett 17:1529 1510. Feldman KS, Ngernmeesri P (2012) Total synthesis of (±)-dragmacidin E; problems solved and lessons learned. Synlett 23:1882 1511. Liu D-Q, Mao S-C, Yu X-Q, Feng L-H, Lai X-P (2012) Caulerchlorin, a novel chlorinated bisindole alkaloid with antifungal activity from the Chinese green alga Caulerpa racemosa. Heterocycles 85:661 1512. Feng Y, Davis RA, Sykes ML, Avery VM, Quinn RJ (2012) Iotrochamides A and B, antitrypanosomal compounds from the Australian marine sponge Iotrochota sp. Bioorg Med Chem Lett 22:4873 1513. Zhang W, Liu Z, Li S, Yang T, Zhang Q, Ma L, Tian X, Zhang H, Huang C, Zhang S, Ju J, Shen Y, Zhang C (2012) Spiroindimicins A-D: new bisindole alkaloids from a deep-sea-derived actinomycete. Org Lett 14:3364 1514. Di X, Rouger C, Hardardottir I, Freysdottir J, Molinski TF, Tasdemir D, Omarsdottir S (2018) 6-Bromoindole derivatives from the Icelandic marine sponge Geodia barretti: isolation and anti-inflammatory activity. Mar Drugs 16:437 1515. Kelley EW, Norman SG, Scheerer JR (2017) Synthesis of monoalkylidene diketopiperazines and application to the synthesis of barettin. Org Biomol Chem 15:8634 1516. Kim H, Krunic A, Lantvit D, Shen Q, Kroll DJ, Swanson SM, Orjala J (2012) Nitrilecontaining fischerindoles from the cultured cyanobacterium Fischerella sp. Tetrahedron 68:3205 1517. Brown LE, Konopelski JP (2008) Turning the corner: recent advances in the synthesis of the welwitindolinones. Org Prep Proc Int 40:411 1518. Li JL, Kim EL, Wang H, Hong J, Shin S, Lee C-K, Jung JH (2013) Epimeric methylsulfinyladenosine derivatives from the marine ascidian Herdmania momus. Bioorg Med Chem Lett 23:4701 1519. Rudolph KE, Liberio MS, Davis RA, Carroll AR (2013) Pteridine-, thymidine-, choline- and imidazole-derived alkaloids from the Australian ascidian, Leptoclinides durus. Org Biomol Chem 11:261 1520. Sun W-S, Su S, Zhu R-X, Tu G-Z, Cheng W, Liang H, Guo X-Y, Zhao Y-Y, Zhang Q-Y (2013) A pair of unprecedented spiro-trisindole enantiomers fused through a five-member ring from Laurencia similis. Tetrahedron Lett 54:3617 1521. Shi L, Li L, Wang J, Huang B, Zeng K, Jin H, Zhang Q, Jia Y (2017) Total synthesis of natural spiro-trisindole enantiomers similisines A, B and their stereoisomers. Tetrahedron Lett 58:1934 1522. Li M-C, Sun W-S, Cheng W, Liu D, Liang H, Zhang Q-Y, Lin W-H (2016) Four new minor brominated indole related alkaloids with antibacterial activities from Laurencia similis. Bioorg Med Chem Lett 26:3590 1523. Geng C-A, Liu X-K (2013) Five new indole alkaloids from the leaves of Rauvolfia yunnanensis. Fitoterapia 89:42

480

G. W. Gribble

1524. Zeng J, Zhang D-B, Zhou P-P, Zhang Q-L, Zhao L, Chen J-J, Gao K (2017) Rauvomines A and B, two monoterpenoid indole alkaloids from Rauvolfia vomitoria. Org Lett 19:3998 1525. de Medeiros LS, da Silva JV, Abreu LM, Pfenning LH, Silva CL, Thomasi SS, Venâncio T, van Pée K-H, Nielsen KF, Rodrigues-Filho E (2015) Dichlorinated and brominated rugulovasines, ergot alkaloids produced by Talaromyces wortmannii. Molecules 20:17627 1526. Fu P, Jamison M, La S, MacMillan JB (2014) Inducamides A-C, chlorinated alkaloids from an RNA polymerase mutant strain of Streptomyces sp. Org Lett 16:5656 1527. Murcia C, Coello L, Fernández R, Martín MJ, Reyes F, Francesch A, Munt S, Cuevas C (2014) Tanjungides A and B: new antitumoral bromoindole derived compounds from Diazona cf. formosa. Isolation and total synthesis. Mar Drugs 12:1116 1528. Hahn D, Kim GJ, Choi H, Kang H (2015) A novel bromoindole alkaloid from a Korean colonial tunicate Didemnum sp. Nat Prod Sci 21:278 1529. Liu H-B, Lauro G, O’Connor RD, Lohith K, Kelly M, Colin P, Bifulco G, Bewley CA (2017) Tulongicin, an antibacterial tri-indole alkaloid from a deep-water Topsentia sp. sponge. J Nat Prod 80:2556 1530. Kwon J, Lee H, Ko W, Kim D-C, Kim K-W, Kwon HC, Guo Y, Sohn JH, Yim JH, Kim Y-C, Oh H, Lee D (2017) Chemical constituents isolated from Antarctic marine-derived Aspergillus sp. SF-5976 and their anti-inflammatory effects in LPS-stimulated RAW 264.7 and BV2 cells. Tetrahedron 73:3905 1531. Hansen KØ, Isaksson J, Bayer A, Johansen JA, Andersen JH, Hansen E (2017) Securamine derivatives from the Arctic bryozoan Securiflustra securifrons. J Nat Prod 80:3276 1532. Guo C, Wang P, Lin X, Salendra L, Kong F, Liao S, Yang B, Zhou X, Wang J, Liu Y (2019) Phloroglucinol heterodimers and bis-indolyl alkaloids from the sponge-derived fungus Aspergillus sp. SCSIO 41018. Org Chem Front 6:3053 1533. Zhang P, Li X-M, Li X, Wang B-G (2015) New indole-diterpenoids from the algal-associated fungus Aspergillus nidulans. Phytochem Lett 12:182 1534. Ivanets EV, Yurchenko AN, Smetanina OF, Rasin AB, Zhuravleva OI, Pivkin MV, Popov RS, von Amsberg G, Afiyatullov SS, Dyshlovoy SA (2018) Asperindoles A–D and a p-terphenyl derivative from the ascidian-derived fungus Aspergillus sp. KMM 4676. Mar Drugs 16:232 1535. Gao S-S, Li X-M, Williams K, Proksch P, Ji N-Y, Wang B-G (2016) Rhizovarins A-F, indolediterpenes from the mangrove-derived endophytic fungus Mucor irregularis QEN-189. J Nat Prod 79:2066 1536. Zhou G, Sun C, Hou X, Che Q, Zhang G, Gu Q, Liu C, Zhu T, Li D (2021) Ascandinines AD, indole diterpenoids, from the sponge-derived fungus Aspergillus candidus HDN15-152. J Org Chem 86:2431 1537. Hanssen KØ, Schuler B, Williams AJ, Demissie TB, Hansen E, Andersen JH, Svenson J, Blinov K, Repisky M, Mohn F, Meyer G, Svendsen J-S, Ruud K, Elyashberg M, Gross L, Jaspars M, Isaksson J (2012) A combined atomic force microscopy and computational approach for the structural elucidation of breitfussin A and B: highly modified halogenated dipeptides from Thuiaria breitfussi. Angew Chem Int Ed 51:12238 1538. Hansen KØ, Andersen JH, Bayer A, Pandey SK, Lorentzen M, Jørgensen KB, Sydnes MO, Guttormsen Y, Baumann M, Koch U, Klebl B, Eickhoff J, Haug BE, Isaksson J, Hansen EH (2019) Kinase chemodiversity from the Arctic: the breitfussins. J Med Chem 62:10167 1539. Pandey SK, Guttormsen Y, Haug BE, Hedberg C, Bayer A (2015) A concise total synthesis of breitfussin A and B. Org Lett 17:122 1540. Khan AH, Chen JS (2015) Synthesis of breitfussin B by late-stage bromination. Org Lett 17:3718 1541. Nabi AA, Liyu J, Lindsay AC, Sperry J (2018) C4–H alkoxylation of 6-bromoindole and its application to the synthesis of breitfussin B. Tetrahedron 74:1199 1542. Yun K, Khong TT, Leutou AS, Kim G-D, Hong J, Lee C-H, Son BW (2016) Cristazine, a new cytotoxic dioxopiperazine alkaloid from the mudflat-sediment-derived fungus Chaetomium cristatum. Chem Pharm Bull 64:59 1543. Ruiz-Sanchis P, Savina SA, Albericio F, Álvarez M (2011) Structure, bioactivity and synthesis of natural products with hexahydropyrrolo[2,3-b]indole. Chem Eur J 17:1388

Naturally Occurring Organohalogen Compounds …

481

1544. Hirota-Takahata Y, Kobayshi H, Kizuka M, Ohyama T, Kitamura-Miyazaki M, Suzuki Y, Fujiwara M, Nakajima M, Ando O (2016) Studies on novel HIF activators, A-503451s. I. Producing organism, fermentation, isolation and structural elucidation. J Antibiot 69:747 1545. Park HB, Lam YC, Gaffney JP, Weaver JC, Krivoshik SR, Hamchand R, Pieribone V, Gruber DF, Crawford JM (2019) Bright green biofluorescence in sharks derives from bromo-kynurenine metabolism. iScience 19:1291 1546. El-Hawary SS, Sayed AM, Mohammed R, Hassan HM, Rateb ME, Amin E, Mohammed TA, El-Mesery M, Muhsinah AB, Alsayari A, Wajant H, Anany MA, Abdelmohsen UR (2019) Bioactive brominated oxindole alkaloids from the Red Sea sponge Callyspongia siphonella. Mar Drugs 17:465 1547. Sayed AM, Alhadrami HA, El-Hawary SS, Mohammed R, Hassan HM, Rateb ME, Abdelmohsen UR, Bakeer W (2020) Discovery of two brominated oxindole alkaloids as staphylococcal DNA gyrase and pyruvate kinase inhibitors via inverse virtual screening. Microorganisms 8:293 1548. Jennings LK, Khan NMD, Kaur N, Rodrigues D, Morrow C, Boyd A, Thomas OP (2019) Brominated bisindole alkaloids from the Celtic Sea sponge Spongosorites calcicola. Molecules 24:3890 1549. Park JS, Cho E, Hwang J-Y, Park SC, Chung B, Kwon O-S, Sim CJ, Oh D-C, Oh K-B, Shin J (2021) Bioactive bis(indole) alkaloids from a Spongosorites sp. sponge. Mar Drugs 19:3 1550. Khushi S, Nahar L, Salim AA, Capon RJ (2020) Trachycladindoles H-M: molecular networking guided exploration of a library of Southern Australian marine sponges. Aust J Chem 73:338 1551. Maeyama Y, Nakashima Y, Kato H, Hitora Y, Maki K, Inada N, Murakami S, Inazumi T, Ise Y, Sugimoto Y, Ishikawa H, Tsukamoto S (2021) Amakusamine from a Psammocinia sp. sponge: Isolation, synthesis, and SAR study on the inhibition of RANKL-induced formation of multinuclear osteoclasts. J Nat Prod 84:2738 1552. Di X, Wang S, Oskarsson JT, Rouger C, Tasdemir D, Hardardottir I, Freysdottir J, Wang X, Molinski TF, Omarsdottir S (2020) Bromotryptamine and imidazole alkaloids with antiinflammatory activity from the Bryozoan Flustra foliacea. J Nat Prod 83:2854 1553. Paulus C, Rebets Y, Tokovenko B, Nadmid S, Terekhova LP, Myronovskyi M, Zotchev SB, Rückert C, Braig S, Zahler S, Kalinowski J, Luzhetskyy A (2017) New natural products identified by combined genomics-metabolomics profiling of marine Streptomyces sp. MP131-18. Sci Rep 7:42382 1554. Blair LM, Sperry J (2016) Total syntheses of (±)-spiroindimicins B and C enabled by a late-stage Schöllkopf-Magnus-Barton-Zard (SMBZ) reaction. Chem Commun 52:800 1555. Song Y, Yang J, Yu J, Li J, Yuan J, Wong N-K, Ju J (2020) Chlorinated bis-indole alkaloids from deep-sea derived Streptomyces sp. SCSIO 11791 with antibacterial and cytotoxic activities. J Antibiot 73:542 1556. Du Y-L, Ryan KS (2015) Expansion of bisindole biosynthetic pathways by combinatorial construction. ACS Synth Biol 4:682 1557. Breinlinger S, Phillips TJ, Haram BN, Mareš J, Yerena JAM, Hrouzek P, Sobotka R, Henderson WM, Schmieder P, Williams SM, Lauderdale JD, Wilde HD, Gerrin W, Kust A, Washington JW, Wagner C, Geier B, Liebeke M, Enke H, Niedermeyer THJ, Wilde SB (2021) Hunting the eagle killer: a cyanobacterial neurotoxin causes vacuolar myelinopathy. Science 371:1335 1558. Adak S, Lukowski AL, Schäfer RJB, Moore BS (2022) From tryptophan to toxin: nature’s convergent biosynthetic strategy to aetokthonotoxin. J Am Chem Soc 144:2861 1559. Lebar MD, Baker BJ (2010) Synthesis and structure reassessment of psammopemmin A. Aust J Chem 63:862 1560. Sala S, Nealon GL, Sobolev AN, Fromont J, Gomez O, Flematti GR (2020) Structure reassignment of echinosulfone A and the echinosulfonic acids A-D supported by single-crystal X-ray diffraction and density functional theory analysis. J Nat Prod 83:105 1561. Holland DC, Kiefel MJ, Carroll AR (2020) Structure revisions of the sponge-derived dibrominated bis-indole alkaloids, echinosulfone A and the echinosulfonic acids A to D. J Org Chem 85:3490

482

G. W. Gribble

1562. Neupane P, Salim AA, Capon RJ (2020) Structure revision of the rare sponge metabolite echinosulfone A, and biosynthetically related echinosulfonic acids A-D. Tetrahedron Lett 61:151651 1563. Anantoju KK, Mohd BS, Maringanti TC (2017) An efficient and concise synthesis of indiacen A and indiacen B. Tetrahedron Lett 58:1499 1564. Barykina OV, Snider BB (2010) Synthesis of (±)-eusynstyelamide A. Org Lett 12:2664 1565. Skiredj A, Beniddir MA, Joseph D, Leblanc K, Bernadat G, Evanno L, Poupon E (2014) Spontaneous biomimetic formation of (±)-dictazole B under irradiation with artificial sunlight. Angew Chem Int Ed 53:6419 1566. Scott LM, Sperry J (2016) Synthesis of inducamides A and B. J Nat Prod 79:519 1567. Zhang X, King-Smith E, Renata H (2018) Total synthesis of tambromycin by combining chemocatalytic and biocatalytic C-H functionalization. Angew Chem Int Ed 57:5037 1568. Hussain MA, Khan FA (2019) Total synthesis of (±) aspidostomide B, C, regioisomeric N-methyl aspidostomide D and their derivatives. Tetrahedron Lett 60:151040 1569. Zhang H, Hong L, Kang H, Wang R (2013) Construction of vicinal all-carbon quaternary stereocenters by catalytic asymmetric alkylation reaction of 3-bromooxindoles with 3-substituted indoles: total synthesis of (+)-perophoramidine. J Am Chem Soc 135:14098 1570. Fuchs JR, Funk RL (2004) Total synthesis of (±)-perophoramidine. J Am Chem Soc 126:5068 1571. Šíša M, Pla D, Altuna M, Francesch A, Cuevas C, Albericio F, Álvarez M (2009) Total synthesis and antiproliferative activity screening of (±)-aplicyanins A, B and E and related analogues. J Med Chem 52:6217 1572. Douki K, Ono H, Taniguchi T, Shimokawa J, Kitamura M, Fukuyama T (2016) Enantioselective total synthesis of (+)-hinckdentine A via a catalytic dearomatization approach. J Am Chem Soc 138:14578 1573. Higuchi K, Sato Y, Tsuchimochi M, Sugiura K, Hatori M, Kawasaki T (2009) First total synthesis of hinckdentine A. Org Lett 11:197 1574. Boyd EM, Sperry J (2015) Biomimetic synthesis of dendridine A. Org Lett 17:1344 1575. Parsons TB, Spencer N, Tsang CW, Grainger RS (2013) Total synthesis of kottamide E. Chem Commun 49:2296 1576. Ma Y, Yakushijin K, Miyake F, Horne D (2009) A concise synthesis of indolic enamides: coscinamide A, coscinamide B, and igzamide. Tetrahedron Lett 50:4343 1577. Sperry J (2011) Concise syntheses of 5,6-dibromotryptamine and 5,6-dibromo-N,Ndimethyltryptamine en route to the antibiotic alternatamide D. Tetrahedron Lett 52:4042 1578. Ansari NH, Taylor MC, Söderberg BCG (2017) Syntheses of three naturally occurring polybrominated 3,3 -bi-1H-indoles. Tetrahedron Lett 58:1053 1579. Walker SR, Czyz ML, Morris JC (2014) Concise syntheses of meridianins and meriolins using a catalytic domino amino-palladation reaction. Org Lett 16:708 1580. Gao D, Sand R, Fu H, Sharmin N, Gallin WJ, Hall DG (2013) Synthesis of the nonpeptidic snail toxin 6-bromo-2-mercaptotryptamine dimer (BrMT)2 , its lower and higher thio homologs and their ability to modulate potassium ion channels. Bioorg Med Chem Lett 23:5503 1581. Golantsov NE, Festa AA, Varlamov AV, Voskressensky LG (2017) Revision of the structure and total synthesis of topsentin C. Synthesis 49:2562 1582. Chandra A, Johnston JN (2011) Total synthesis of the chlorine-containing hapalindoles K, A, and G. Angew Chem Int Ed 50:7641 1583. Hu L, Rawal VH (2021) Total synthesis of the chlorinated pentacyclic indole alkaloid (+)ambiguine G. J Am Chem Soc 143:10872 1584. Wolk JL, Frimer AA (2010) A simple, safe and efficient synthesis of tyrian purple (6,6 dibromoindigo). Molecules 15:5561 1585. Reisman SE, Ready JM, Weiss MM, Hasuoka A, Hirata M, Tamaki K, Ovaska TV, Smith CJ, Wood JL (2008) Evolution of a synthetic strategy: total synthesis of (±)-welwitindolinone A isonitrile. J Am Chem Soc 130:2087

Naturally Occurring Organohalogen Compounds …

483

1586. Tian X, Huters AD, Douglas CJ, Garg NK (2009) Concise synthesis of the bicyclic scaffold of N-methylwelwitindolinone C isothiocyanate via an indolyne cyclization. Org Lett 11:2349 1587. Quasdorf KW, Huters AD, Lodewyk MW, Tantillo DJ, Garg NK (2012) Total synthesis of oxidized welwitindolinones and (–)-N-methylwelwitindolinone C isonitrile. J Am Chem Soc 134:1396 1588. Huters AD, Quasdorf KW, Styduhar ED, Garg NK (2011) Total synthesis of (–)-Nmethylwelwitindolinone C isothiocyanate. J Am Chem Soc 133:15797 1589. Bhat V, Allan KM, Rawal VH (2011) Total synthesis of N-methylwelwitindolinone D isonitrile. J Am Chem Soc 133:5798 1590. Bhat V, Rawal VH (2011) Stereocontrolled synthesis of 20,21-dihydro N-methylwelwitindolinone B isothiocyanate. Chem Commun 47:9705 1591. Allan KM, Kobayashi K, Rawal VH (2012) A unified route to the welwitindolinone alkaloids: total syntheses of (–)-N-methylwelwitindolinone C isothiocyanate, (–)-Nmethylwelwitindolinone C isonitrile, and (–)-3-hydroxy-N-methylwelwitindolinone C isothiocyanate. J Am Chem Soc 134:1392 1592. Fu T, McElroy WT, Shamszad M, Martin SF (2012) Formal syntheses of naturally occurring welwitindolinones. Org Lett 14:3834 1593. Huters AD, Styduhar ED, Garg NK (2012) Total syntheses of the elusive welwitindolinones with bicyclo[4.3.1] cores. Angew Chem Int Ed 51:3758 1594. Fu T, McElroy WT, Shamszad M, Heidebrecht RW Jr, Gulledge B, Martin SF (2013) Studies toward welwitindolinones: formal syntheses of N-methylwelwitindolinone C isothiocyanate and related natural products. Tetrahedron 69:5588 1595. Weires NA, Styduhar ED, Baker EL, Garg NK (2014) Total synthesis of (–)-Nmethylwelwitindolinone B isothiocyanate via a chlorinative oxabicycle ring-opening strategy. J Am Chem Soc 136:14710 1596. Komine K, Nomura Y, Ishihara J, Hatakeyama S (2015) Total synthesis of (–)-Nmethylwelwitindolinone C isothiocyanate based on a Pd-catalyzed tandem enolate coupling strategy. Org Lett 17:3918 1597. Reyes JR, Xu J, Kobayashi K, Bhat V, Rawal VH (2017) Total synthesis of (–)-Nmethylwelwitindolinone B isothiocyanate. Angew Chem Int Ed 56:9962 1598. Baran PS, Ambhaikar NB, Guerrero CA, Hafensteiner BD, Lin DW, Richter JM (2006) Oxidative C–C bond formation in heterocyclic chemistry. ARKIVOC vii:310 1599. Richter JM, Whitefield BW, Maimone TJ, Lin DW, Castroviejo MP, Baran PS (2007) Scope and mechanism of direct indole and pyrrole couplings adjacent to carbonyl compounds: total synthesis of acremoauxin A and oxazinin 3. J Am Chem Soc 129:12857 1600. Richter JM, Ishihara Y, Masuda T, Whitefield BW, Llamas T, Pohjakallio A, Baran PS (2008) Enantiospecific total synthesis of the hapalindoles, fischerindoles, and welwitindolinones via a redox economic approach. J Am Chem Soc 130:17938 1601. Maimone TJ, Ishihara Y, Baran PS (2015) Scalable total syntheses of (–)-hapalindole U and (+)-ambiguine H. Tetrahedron 71:3652 1602. Sahu S, Das B, Maji MS (2018) Stereodivergent total synthesis of hapalindoles, fischerindoles, hapalonamide H, and ambiguine H alkaloids by developing a biomimetic, redox-neutral, cascade Prins-type cyclization. Org Lett 20:6485 1603. Hohlman RM, Sherman DH (2021) Recent advances in hapalindole-type cyanobacterial alkaloids: biosynthesis, synthesis, and biological activity. Nat Prod Rep 38:1567 1604. Lee S-C, Williams GA, Brown GD (1999) Maculalactone L and three halogenated carbazole alkaloids from Kyrtuthrix maculans. Phytochemistry 52:537 1605. Zhu L, Hites RA (2005) Identification of brominated carbazoles in sediment cores from Lake Michigan. Environ Sci Technol 39:9446 1606. Kuehl DW, Durhan E, Butterworth BC, Linn D (1984) Tetrachloro-9H-carbazole, a previously unrecognized contaminant in sediments of the Buffalo River. J Great Lakes Res 10:210 1607. Tröbs L, Henkelmann B, Lenoir D, Reischl A, Schramm K-W (2011) Degradative fate of 3-chlorocarbazole and 3,6-dichlorocarbazole in soil. Environ Sci Pollut Res 18:547

484

G. W. Gribble

1608. Mumbo J, Lenoir D, Henkelmann B, Schramm K-W (2013) Enzymatic synthesis of bromoand chlorocarbazoles and elucidation of their structures by molecular modeling. Environ Sci Pollut Res 20:8996 1609. Guo J, Chen D, Potter D, Rockne KJ, Sturchio NC, Giesy JP, Li A (2014) Polyhalogenated carbazoles in sediments of Lake Michigan: a new discovery. Environ Sci Technol 48:12807 1610. Parette R, McCrindle R, McMahon KS, Pena-Abaurrea M, Reiner E, Chittim B, Riddell N, Voss G, Dorman FL, Pearson WN (2015) Halogenated indigo dyes: a likely source of 1,3,6,8-tetrabromocarbazole and some other halogenated carbazoles in the environment. Chemosphere 127:18 1611. Parette R, McCrindle R, McMahon KS, Pena-Abaurrea M, Reiner E, Chittim B, Riddell N, Voss G, Dorman FL, Pearson WN, Robson M (2016) Response to the comment on “Halogenated indigo dyes: a likely source of 1,3,6,8-tetrabromocarbazole and some other halogenated carbazoles in the environment.” Chemosphere 150:414 1612. Peverly AA, Hites RA (2016) Comment on “Halogenated indigo dyes: a likely source of 1,3,6,8-tetrabromocarbazole and some other halogenated carbazoles in the environment.” Chemosphere 144:273 1613. Riddell N, Jin U-H, Safe S, Cheng Y, Chittim B, Konstantinov A, Parette R, Pena-Abaurrea M, Reiner EJ, Poirier D, Stefanac T, McAlees AJ, McCrindle R (2015) Characterization and biological potency of mono- to tetra-halogenated carbazoles. Environ Sci Technol 49:10658 1614. Peng H, Chen C, Cantin J, Saunders DMV, Sun J, Tang S, Codling G, Hecker M, Wiseman S, Jones PD, Li A, Rockne KJ, Sturchio NC, Cai M, Giesy JP (2016) Untargeted screening and distribution of organo-iodine compounds in sediments from Lake Michigan and the Arctic Ocean. Environ Sci Technol 50:10097 1615. Yue S, Zhang T, Shen Q, Song Q, Ji C, Chen Y, Mao M, Kong Y, Chen D, Liu J, Sun Z, Zhao M (2020) Assessment of endocrine-disrupting effects of emerging polyhalogenated carbazoles (PHCZs): in vitro, in silico, and in vivo evidence. Environ Inte 140:105729 1616. Britton R, de Oliveira JHHL, Andersen RJ, Berlinck RGS (2001) Granulatimide and 6bromogranulatimide, minor alkaloids of the Brazilian ascidian Didemnum granulatum. J Nat Prod 64:254 1617. Lyakhova EG, Kolesnikova SA, Kalinovsky AI, Afiyatullov SS, Dyshlovoy SA, Krasokhin VB, Minh CV, Stonik VA (2012) Bromine-containing alkaloids from the marine sponge Penares sp. Tetrahedron Lett 53:6119 1618. Zhang Q, Mándi A, Li S, Chen Y, Zhang W, Tian X, Zhang H, Li H, Zhang W, Zhang S, Ju J, Kurtán T, Zhang C (2012) N–N-Coupled indolo-sesquiterpene atropo-diastereomers from a marine-derived actinomycete. Eur J Org Chem, 5256 1619. Kim S-H, Ha T-K-Q, Oh WK, Shin J, Oh D-C (2016) Antiviral indolosesquiterpenoid xiamycins C-E from a halophilic actinomycete. J Nat Prod 79:51 1620. Sánchez C, Méndez C, Salas JA (2006) Indolocarbazole natural products: occurrence, biosynthesis, and biological activity. Nat Prod Rep 23:1007 ¯ 1621. Nakano H, Omura S (2009) Chemical biology of natural indolocarbazole products: 30 years since the discovery of staurosporine. J Antibiot 62:17 1622. Chambers GE, Sayan AE, Brown RCD (2021) The synthesis of biologically active indolocarbazole natural products. Nat Prod Rep 38:1794 1623. Williams DE, Davies J, Patrick BO, Bottriell H, Tarling T, Roberge M, Andersen RJ (2008) Cladoniamides A-G, tryptophan-derived alkaloids produced in culture by Streptomyces uncialis. Org Lett 10:3501 1624. Loosley BC, Andersen RJ, Dake GR (2013) Total synthesis of cladoniamide G. Org Lett 15:1152 1625. Ngernmeesri P, Soonkit S, Konkhum A, Kongkathip B (2014) Formal synthesis of (±)cladoniamide G. Tetrahedron Lett 55:1621 1626. Schütte J, Kilgenstein F, Fischer M, Koert U (2014) Unsymmetrical vic-tricarbonyl compounds for the total syntheses of cladoniamide G and cladoniamide F. Eur J Org Chem: 5302

Naturally Occurring Organohalogen Compounds …

485

1627. Kimura T, Kanagaki S, Matsui Y, Imoto M, Watanabe T, Shibasaki M (2012) Synthesis and assignment of the absolute configuration of indenotryptoline bisindole alkaloid BE-54017. Org Lett 14:4418 1628. Russell F, Harmody D, McCarthy PJ, Pomponi SA, Wright AE (2013) Indolo[3,2a]carbazoles from a deep-water sponge of the genus Asteropus. J Nat Prod 76:1989 1629. Chang F-Y, Brady SF (2013) Discovery of indolotryptoline antiproliferative agents by homology-guided metagenomic screening. Proc Natl Acad Sci USA 110:2478 1630. Zhang W, Ma L, Li S, Liu Z, Chen Y, Zhang H, Zhang G, Zhang Q, Tian X, Yuan C, Zhang S, Zhang W, Zhang C (2014) Indimicins A–E, bisindole alkaloids from the deep-sea-derived Streptomyces sp. SCSIO 03032. J Nat Prod 77:1887 1631. Sigala I, Ganidis G, Thysiadis S, Zografos AL, Giannakouros T, Sarli V, Nikolakaki E (2017) Lynamicin D an antimicrobial natural product affects splicing by inducing the expression of SR protein kinase 1. Bioorg Med Chem 25:1622 1632. Shaaban KA, Elshahawi SI, Wang X, Horn J, Kharel MK, Leggas M, Thorson JS (2015) Cytotoxic indolocarbazoles from Actinomadura melliaura ATCC 39691. J Nat Prod 78:1723 1633. Yang CL, Zhang B, Xue WW, Li W, Xu ZF, Shi J, Shen Y, Jiao RH, Tan RX, Ge HM (2020) Discovery, biosynthesis, and heterologous production of loonamycin, a potent anticancer indolocarbazole alkaloid. Org Lett 22:4665 1634. Ankietty S, Kelly M, Slattery M (2007) Alkaloids from an undescribed thorectid sponge (Porifera: Dictyoceratida) from the Northern Marianas. Nat Prod Commun 2:1145 1635. Kuzmich AS, Fedorov SN, Shastina VV, Shubina LK, Radchenko OS, Balaneva NN, Zhidkov ME, Park J-I, Kwak JY, Stonik VA (2010) The anticancer activity of 3- and 10bromofascaplysins is mediated by caspase-8, -9, -3-dependent apoptosis. Bioorg Med Chem 18:3834 1636. Wang W, Nam S-J, Lee B-C, Kang H (2008) β-Carboline alkaloids from a Korean tunicate Eudistoma sp. J Nat Prod 71:163 1637. Till M, Prinsep MR (2009) 5-Bromo-8-methoxy-1-methyl-β-carboline, an alkaloid from the New Zealand marine bryozoan Pterocella vesiculosa. J Nat Prod 72:796 1638. Takahashi Y, Ishiyama H, Kubota T, Kobayashi J (2010) Eudistomidin G, a new β-carboline alkaloid from the Okinawan marine tunicate Eudistoma glaucus and structure revision of eudistomidin B. Bioorg Med Chem Lett 20:4100 1639. Suzuki T, Kubota T, Kobayashi J (2011) Eudistomidins H-K, new β-carboline alkaloids from the Okinawan marine tunicate Eudistoma glaucus. Bioorg Med Chem Lett 21:4220 1640. Davis RA, Duffy S, Avery VM, Camp D, Hooper JNA, Quinn RJ (2010) (+)-7Bromotrypargine: an antimalarial β-carboline from the Australian marine sponge Ancorina sp. Tetrahedron Lett 51:583 1641. Chan STS, Pearce AN, Page MJ, Kaiser M, Copp BR (2011) Antimalarial β-carbolines from the New Zealand ascidian Pseudodistoma opacum. J Nat Prod 74:1972 1642. Lu Z, Ding Y, Li X-C, Djigbenou DR, Grimberg BT, Ferreira D, Ireland CM, Van Wagoner RM (2011) 3-Bromohomofascaplysin A, a fascaplysin analogue from a Fijian Didemnum sp. ascidian. Bioorg Med Chem 19:6604 1643. Prinsep MR, Dumté M (2013) 7-Bromo-1-ethyl-β-carboline, an alkaloid from the New Zealand marine bryozoan Pterocella vesiculosa. Nat Prod Commun 8:693 1644. Du Y-L, Ding T, Patrick BO, Ryan KS (2013) Xenocladoniamide F, minimal indolotryptoline from the cladoniamide pathway. Tetrahedron Lett 54:5635 1645. Wang J, Pearce AN, Chan STS, Taylor RB, Page MJ, Valentin A, Bourguet-Kondracki ML, Dalton JP, Wiles S, Copp BR (2016) Biologically active acetylenic amino alcohol and N-hydroxylated 1,2,3,4-tetrahydro-β-carboline constituents of the New Zealand ascidian Pseudodistoma opacum. J Nat Prod 79:607 1646. Tadokoro Y, Nishikawa T, Ichimori T, Matsunaga S, Fujita MJ, Sakai R (2017) N-Methyl-βcarbolinium salts and an N-methylated 8-oxoisoguanine as acetylcholinesterase inhibitors from a solitary ascidian, Cnemidocarpa irene. ACS Omega 2:1074 1647. Tabudravu JN, Pellissier L, Smith AJ, Subko K, Autréau C, Feussner K, Hardy D, Butler D, Kidd R, Milton EJ, Deng H, Ebel R, Salonna M, Gissi C, Montesanto F, Kelly SM,

486

1648. 1649. 1650.

1651.

1652. 1653. 1654.

1655.

1656.

1657.

1658. 1659. 1660. 1661. 1662. 1663.

1664.

1665. 1666. 1667.

G. W. Gribble Milne BF, Cimpan G, Jaspars M (2019) LC-HRMS-Database screening metrics for rapid prioritization of samples to accelerate the discovery of structurally new natural products. J Nat Prod 82:211 Pohl B, Luchterhandt T, Bracher F (2007) Total syntheses of the chlorinated β-carboline alkaloids bauerine A, B, and C. Synth Commun 37:1273 Lingam Y, Rao DM, Bhowmik DR, Islam A (2007) First total synthesis of bauerine C. Synth Commun 37:4313 Zhidkov ME, Baranova OV, Balaneva NN, Fedorov SN, Radchenko OS, Dubovitskii SV (2007) The first syntheses of 3-bromofascaplysin, 10-bromofascaplysin and 3,10dibromofascaplysin—marine alkaloids from Fascaplysinopsis reticulata and Didemnum sp. by application of a simple and effective approach to the pyrido[1,2-a:3,4-b’]diindole system. Tetrahedron Lett 48:7998 Yamagishi H, Matsumoto K, Iwasaki K, Miyazaki T, Yokoshima S, Tokuyama H, Fukuyama T (2008) Synthesis of eudistomin C and E: improved preparation of the indole unit. Org Lett 10:2369 Ishiyama H, Ohshita K, Abe T, Nakata H, Kobayashi J (2008) Synthesis of eudistomin D analogues and its effects on adenosine receptors. Bioorg Med Chem 16:3825 Kennedy JP, Breininger ML, Lindsley CW (2009) Total synthesis of eudistomins Y1 –Y6 . Tetrahedron Lett 50:7067 Finlayson R, Brackovic A, Simon-Levert A, Banaigs B, O’Toole RF, Miller CH, Copp BR (2011) Establishment of the absolute configuration of the bioactive marine alkaloid eudistomin X by stereospecific synthesis. Tetrahedron Lett 52:837 Jin H, Zhang P, Bijian K, Ren S, Wan S, Alaoui-Jamali MA, Jiang T (2013) Total synthesis and biological activity of marine alkaloid eudistomins Y1 –Y7 and their analogues. Mar Drugs 11:1427 Trieu TH, Dong J, Zhang Q, Zheng B, Meng T-Z, Lu X, Shi X-X (2013) Total syntheses of eudistomins Y1 –Y7 by an efficient one-pot process of tandem benzylic oxidation and aromatization of 1-benzyl-3,4-dihydro-β-carbolines. Eur J Org Chem, 3271 Bonazzi S, Barbaras D, Patiny L, Scopelliti R, Schneider P, Cole ST, Kaiser M, Brun R, Gademann K (2010) Antimalarial and antitubercular nostocarboline and eudistomin derivatives: synthesis, in vitro and in vivo biological evaluation. Bioorg Med Chem 18:1464 Panarese JD, Waters SP (2013) Tandem iodine-mediated oxidations of tetrahydro-ßcarbolines: total synthesis of eudistomins Y1 –Y7 . Org Biomol Chem 11:3428 Ito T, Kitajima M, Takayama H (2009) Asymmetric total synthesis of reported structure of eudistomidin B, an indole alkaloid isolated from a marine tunicate. Tetrahedron Lett 50:4506 Ishiyama H, Yoshizawa K, Kobayashi J (2012) Enantioselective total synthesis of eudistomidins G, H, and I. Tetrahedron 68:6186 Ibrahim SRM, Mohamed GA (2016) Marine pyridoacridine alkaloids: biosynthesis and biological activities. Chem Biodiversity 13:37 Li G-H, Yu Z-F, Li X, Wang X-B, Zheng L-J, Zhang K-Q (2007) Nematicidal metabolites produced by the endophytic fungus Geotrichum sp. AL4. Chem Biodivers 4:1520 Cao S, Al-Rehaily AJ, Brodie P, Wisse JH, Moniz E, Malone S, Kingston DGI (2008) Furoquinoline alkaloids of Ertela (Monnieria) trifolia (L.) Kuntze from the Suriname rainforest. Phytochemistry 69:553 Boyd DR, Sharma ND, Loke PL, Malone JF, McRoberts WC, Hamilton JTG (2007) Synthesis, structure and stereochemistry of quinoline alkaloids from Choisya ternata. Org Biomol Chem 5:2983 Kawada M, Momose I, Someno T, Tsujiuchi G, Ikeda D (2009) New atpenins, NBR123477 A and B, inhibit the growth of human prostate cancer cells. J Antibiot 62:243 ¯ Ohtawa M, Ogihara S, Sugiyama K, Shiomi K, Harigaya Y, Nagamitsu T, Omura S (2009) Enantioselective total synthesis of atpenin A5. J Antibiot 62:289 Ohtawa M, Sugiyama K, Hiura T, Izawa S, Shiomi K, Omura S, Nagamitsu T (2012) Stereoselective total synthesis of atpenins A4 and B, harzianopyridone, and NBRI23477 B. Chem Pharm Bull 60:898

Naturally Occurring Organohalogen Compounds …

487

1668. Lee D, Kondo H, Kuwayama Y, Takahashi K, Arima S, Omur S, Ohtawa M, Nagamitsu T (2019) Total synthesis of 4-epi-atpenin A5 as a potent nematode complex II inhibitor. Tetrahedron 75:3178 1669. Margiastuti P, Ogi T, Teruya T, Taira J, Suenaga K, Ueda K (2008) An unusual iodinated 5 -deoxyxyrofuranosyl nucleoside from an Okinawan ascidian, Diplosoma sp. Chem Lett 37:448 1670. Maloney KN, MacMillan JB, Kauffman CA, Jensen PR, DiPasquale AG, Rheingold AL, Fenical W (2009) Lodopyridone, a structurally unprecedented alkaloid from a marine actinomycete. Org Lett 11:5422 1671. George IR, Lewis W, Moody CJ (2013) Synthesis of lodopyridone. Tetrahedron 69:8209 1672. Hawas UW, Shaaban M, Shaaban KA, Speitling M, Maier A, Kelter G, Fiebig HH, Meiners M, Helmke E, Laatsch H (2009) Mansouramycins A-D, cytotoxic isoquinolinequinones from a marine streptomycete. J Nat Prod 72:2120 1673. Sorek H, Rudi A, Goldberg I, Aknin M, Kashman Y (2009) Saldedines A and B, dibromo proaporphine alkaloids from a Madagascan tunicate. J Nat Prod 72:784 1674. Yin S, Boyle GM, Carroll AR, Kotiw M, Dearnaley J, Quinn RJ, Davis RA (2010) Caelestines A-D, brominated quinolinecarboxylic acids from the Australian ascidian Aplidium caelestis. J Nat Prod 73:1586 1675. Possner ST, Schroeder FC, Rapp HT, Sinnwell V, Franke S, Francke W (2017) 3,7Isoquinoline quinones from the ascidian tunicate Ascidia virginea. Z Naturforsch 72c:259 1676. Davis RA, Carroll AR, Andrews KT, Boyle GM, Tran TL, Healy PC, Kalaitzis JA, Shivas RG (2010) Pestalactams A-C: novel caprolactams from the endophytic fungus Pestalotiopsis sp. Org Biomol Chem 8:1785 1677. Beattie KD, Ellwood N, Kumar R, Yang X, Healy PC, Choomuenwai V, Quinn RJ, Elliott AG, Huang JX, Chitty JL, Fraser JA, Cooper MA, Davis RA (2016) Antibacterial and antifungal screening of natural products sourced from Australian fungi and characterisation of pestalactams D-F. Phytochemistry 124:79 1678. Conda-Sheridan M, Marler L, Park E-J, Kondratyuk TP, Jermihov K, Mesecar AD, Pezzuto JM, Asolkar RN, Fenical W, Cushman M (2010) Potential chemopreventive agents based on the structure of the lead compound 2-bromo-1-hydroxyphenazine, isolated from Streptomyces species, strain CNS284. J Med Chem 53:8688 1679. Kondratyuk TP, Park E-J, Yu R, van Breemen RB, Asolkar RN, Murphy BT, Fenical W, Pezzuto JM (2012) Novel marine phenazines as potential cancer chemopreventive and antiinflammatory agents. Mar Drugs 10:451 1680. Asolkar RN, Singh A, Jensen PR, Aalbersberg W, Carté BK, Feussner K-D, Subramani R, DiPasquale A, Rheingold AL, Fenical W (2017) Marinocyanins, cytotoxic bromophenazinone meroterpenoids from a marine bacterium from the streptomycete clade MAR4. Tetrahedron 73:2234 1681. Nakayama O, Shigematsu N, Katayama A, Takase S, Kiyoto S, Hashimoto M, Kohsaka M (1989) WS-9659 A and B, novel testosterone 5α-reductase inhibitors isolated from a Streptomyces. II. Structural elucidation of WS-9659 A and B. J Antibiot 42:1230 1682. Milanowski DJ, Oku N, Cartner LK, Bokesch HR, Williamson RT, Sauri J, Liu Y, Blinov KA, Ding Y, Li X-C, Ferreira D, Walker LA, Khan S, Davies-Coleman MT, Kelley JA, McMahon JB, Martin GE, Gustafson KR (2018) Unequivocal determination of calamidines A and B: application and validation of new tools in the structure elucidation tool box. Chem Sci 9:307 1683. Tian X-R, Tang H-F, Li Y-S, Lin H-W, Zhang X-Y, Feng J-T, Zhang X (2014) Studies on the chemical constituents from marine bryozoan Cryptosula pallasiana. Rec Nat Prod 9:628 1684. AlTarabeen M, Aly AH, Hemphill CFP, Rasheed M, Wray V, Proksch P (2015) New nitrogenous compounds from a Red Sea sponge from the Gulf of Aqaba. Z Naturforsch 70:75 1685. Pan E, Jamison M, Yousufuddin M, MacMillan JB (2012) Ammosamide D, an oxidatively ring opened ammosamide analog from a marine-derived Streptomyces variabilis. Org Lett 14:2390

488

G. W. Gribble

1686. Soares AR, Engene N, Gunasekera SP, Sneed JM, Paul VJ (2015) Carriebowlinol, an antimicrobial tetrahydroquinolinol from an assemblage of marine cyanobacteria containing a novel taxon. J Nat Prod 78:534 1687. Cheng C, Othman EM, Reimer A, Grüne M, Kozjak-Pavlovic V, Stopper H, Hentschel U, Abdelmohsen UR (2016) Ageloline A, new antioxidant and antichlamydial quinolone from the marine sponge-derived bacterium Streptomyces sp. SBT345. Tetrahedron Lett 57:2786 1688. Le TC, Yim C-Y, Park S, Katila N, Yang I, Song MC, Yoon YJ, Choi D-Y, Choi H, Nam S-J, Fenical W (2017) Lodopyridones B and C from a marine sediment-derived bacterium Saccharomonospora sp. Bioorg Med Chem Lett 27:3123 1689. Liu N, Song F, Shang F, Huang Y (2015) Mycemycins A-E, new dibenzoxazepinones isolated from two different streptomycetes. Mar Drugs 13:6247 1690. Song F, Liu N, Liu M, Chen Y, Huang Y (2018) Identification and characterization of mycemycin biosynthetic gene clusters in Streptomyces olivaceus FXJ8.012 and Streptomyces sp. FXJ1.235. Mar Drugs 16:98 1691. Zhang C, Yang Z, Qin X, Ma J, Sun C, Huang H, Li Q, Ju J (2018) Geonome mining for mycemycin: discovery and elucidation of related methylation and chlorination biosynthetic chemistries. Org Lett 20:7633 1692. Olivon F, Apel C, Retailleau P, Allard PM, Wolfender JL, Touboul D, Roussi F, Litaudon M, Desrat S (2018) Searching for original natural products by molecular networking: detection, isolation and total synthesis of chloroaustralasines. Org Chem Front 5:2171 1693. Umetsu S, Kanda M, Imai I, Sakai R, Fujita MJ (2019) Questiomycins, algicidal compounds produced by the marine bacterium Alteromonas sp. D and their production cue. Molecules 24:4522 1694. Neupane JB, Neupane RP, Luo Y, Yoshida WY, Sun R, Williams PG (2019) Characterization of leptazolines A–D, polar oxazolines from the cyanobacterium Leptolyngbya sp., reveals a glitch with the “Willoughby–Hoye” scripts for calculating NMR chemical shifts. Org Lett 21:8449 1695. Kochanowska-Karamyan AJ, Araujo HC, Zhang X, El-Alfy A, Carvalho P, Avery MA, Holmbo SD, Magolan J, Hamann MT (2020) Isolation and synthesis of veranamine, an antidepressant lead from the marine sponge Verongula rigida. J Nat Prod 83:1092 1696. Miyako K, Yasuno Y, Shinada T, Fujita MJ, Sakai R (2020) Diverse aromatic metabolites in the solitary tunicate Cnemidocarpa irene. J Nat Prod 83:3156 1697. Feng X, Bello D, Lowe PT, Clark J, O’Hagan D (2019) Two 3 -O-β-glucosylated nucleoside fluorometabolites related to nucleocidin in Streptomyces calvus. Chem Sci 10:9501 1698. Pan E, Oswald NW, Legako AG, Life JM, Posner BA, MacMillan JB (2013) Precursordirected generation of amidine containing ammosamide analogs: ammosamides E-P. Chem Sci 4:482 1699. Wildmann J, Möhler H, Vetter W, Ranalder U, Schmidt K, Maurer R (1987) Diazepam and N-desmethyldiazepam are found in rat brain and adrenal and may be of plant origin. J Neural Transm 70:383 1700. Unseld E, Fischer C, Rothemund E, Klotz U (1990) Occurrence of ‘natural’ diazepam in human brain. Biochem Pharmacol 39:210 1701. Unseld E, Kirshna DR, Fischer C, Klotz U (1989) Detection of desmethyldiazepam and diazepam in brain of different species and plants. Biochem Pharmacol 38:2473 1702. Piva MA, Medina JH, de Blas AL, Peña C (1991) Formation of benzodiazepine-like molecules in rat brain. Biochem Biophys Res Commun 180:972 1703. De Blas AL (1993) Benzodiazepines and benzodiazepine-like molecules are present in brain. In: Izquierdo I, Medina JH (eds) Naturally occurring benzodiazepines. Ellis Horwood, Chichester, UK, p 1 1704. Medina JH, de Stein ML, Wolfman C, Wasowski C, De Blas A, Paladini AC (1993) In vivo formation of benzodiazepine-like molecules in mammalian brain. Biochem Biophys Res Commun 195:1111 1705. De Blas AL, Park D, Friedrich P (1987) Endogenous benzodiazepine-like molecules in the human, rat and bovine brains studied with a monoclonal antibody to benzodiazepines. Brain Res 413:275

Naturally Occurring Organohalogen Compounds …

489

1706. De Blas AL, Sotelo C (1987) Localization of benzodiazepine-like molecules in the rat brain. A light and electron microscopy immunocytochemistry study with an anti-benzodiazepine monoclonal antibody. Brain Res 413:285 1707. Basile AS, Pannell L, Jaouni T, Gammal SH, Fales HM, Jones EA, Skolnick P (1990) Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy. Proc Natl Acad Sci USA 87:5263 1708. Unseld E, Klotz U (1989) Benzodiazepines: are they of natural origin? Pharm Res 6:1 1709. Baraldi M, Avallone R, Corsi L, Venturini I, Baraldi C, Zeneroli ML (2009) Natural endogenous ligands for benzodiazepine receptors in hepatic encephalopathy. Metab Brain Dis 24:81 1710. Coppola A, Sucunza D, Burgos C, Vaquero JJ (2015) Isoquinoline synthesis by heterocyclization of tosylmethyl isocyanide derivatives: total synthesis of mansouramycin B. Org Lett 17:78 ¯ 1711. Krautwald S, Nilewski C, Mori M, Shiomi K, Omura S, Carreira EM (2016) Bioisosteric exchange of Csp 3 -chloro and methyl substituents: synthesis and initial biological studies of atpenin A5 analogues. Angew Chem Int Ed 55:4049 1712. Song Y, Ding H, Dou Y, Yang R, Sun Q, Xiao Q, Ju Y (2011) Efficient and practical synthesis of 5 -deoxytubercidin and its analogues via Vorbrüggen glycosylation. Synthesis:1442 1713. Naciuk FF, Milan JC, Andreão A, Miranda PCML (2013) Exploitation of a tuned oxidation with N-haloimides in the synthesis of caulibugulones A-D. J Org Chem 78:5026 1714. Peitsinis ZV, Melidou DA, Stefanakis JG, Evgenidou H, Koumbis AE (2014) A versatile total synthesis of trachycladines A and B and their analogues. Eur J Org Chem, 8160 1715. Huber SG, Wunderlich S, Scholer HF, Williams J (2010) Natural abiotic formation of furans in soil. Environ Sci Technol 44:5799 1716. Krause T, Tubbesing C, Benzing K, Schöler HF (2014) Model reactions and natural occurrence of furans from hypersaline environments. Biogeosciences 11:2871 1717. Greve H, Meis S, Kassack MU, Kehraus S, Krick A, Wright AD, König GM (2007) New iantherans from the marine sponge Ianthella quadrangulata: novel agonists of the P2Y11 receptor. J Med Chem 50:5600 1718. Yan D-F, Lan W-J, Wang K-T, Huang L, Jiang C-W, Li H-J (2015) Two chlorinated benzofuran derivatives from the marine fungus Pseudallescheria boydii. Nat Prod Commun 10:621 1719. Masi M, Cimmino A, Boari A, Tuzi A, Zonno MC, Baroncelli R, Vurro M, Evidente A (2017) Colletochlorins E and F, new phytotoxic tetrasubstituted pyran-2-one and dihydrobenzofuran, isolated from Colletotrichum higginsianum with potential herbicidal activity. J Agric Food Chem 65:1124 1720. Scopel M, Mothes B, Lerner CB, Henriques AT, Macedo AJ, Abraham W-R (2017) Arvoredol—an unusual chlorinated and biofilm inhibiting polyketide from a marine Penicillium sp. of the Brazilian coast. Phytochem Lett 20:73 1721. Chokpaiboon S, Unagul P, Nithithanasilp S, Komwijit S, Somyong W, Ratiarpakul T, Isaka M, Bunyapaiboonsri T (2018) Salicylaldehyde and dihydroisobenzofuran derivatives from the marine fungus Zopfiella marina. Nat Prod Res 32:149 1722. Zhang D, Yang X, Kang JS, Choi HD, Son BW (2008) Chlorohydroaspyrones A and B, antibacterial aspyrone derivatives from the marine-derived fungus Exophiala sp. J Nat Prod 71:1458 1723. Shintani A, Ohtsuki T, Yamamoto Y, Hakamatsuka T, Kawahara N, Goda Y, Ishibashi M (2009) Fuligoic acid, a new yellow pigment with a chlorinated polyene-pyrone acid structure isolated from the myxomycete Fuligo septica f. flava. Tetrahedron Lett 50:3189 1724. Shintani A, Toume K, Yamamoto Y, Ishibashi M (2010) Dehydrofuligoic acid, a new yellow pigment isolated from the myxomycete Fuligo septica f. flava. Heterocycles 82:839 1725. Nenkep V, Yun K, Zhang D, Choi HD, Kang JS, Son BW (2010) Induced production of bromomethylchlamydosporols A and B from the marine-derived fungus Fusarium tricinctum. J Nat Prod 73:2061

490

G. W. Gribble

1726. Rukachaisirikul V, Kannai S, Klaiklay S, Phongpaichit S, Sakayaroj J (2013) Rare 2phenylpyran-4-ones from the seagrass-derived fungi polyporales PSU-ES44 and PSU-ES83. Tetrahedron 69:6981 1727. Wyche TP, Standiford M, Hou Y, Braun D, Johnson DA, Johnson JA, Bugni TS (2013) Activation of the nuclear factor E2-related factor 2 pathway by novel natural products halomadurones A-D and a synthetic analogue. Mar Drugs 11:5089 1728. Liou J-R, Wu T-Y, Thang TD, Hwang T-L, Wu C-C, Cheng Y-B, Chiang MY, Lan Y-H, El-Shazly M, Wu S-L, Beerhues L, Yuan S-S, Hou M-F, Chen S-L, Chang F-R, Wu Y-C (2014) Bioactive 6S-styryllactone constituents of Polyalthia parviflora. J Nat Prod 77:2626 1729. Song R, Shi H, Zhu J, Wang H, Shen Y (2019) A single-component flavoenzyme catalyzed regioselective halogenation of pyrone in the biosynthesis of venemycins. ACS Chem Biol 14:2533 1730. Schäberle TF (2016) Biosynthesis of α-pyrones. Beilstein J Org Chem 12:571 1731. Ramesh P, Reddy YN, Reddy TN, Srinivasu N (2017) First total synthesis of the highly potent antitumor lactones 8-chlorogoniodiol and parvistone A: exploiting a bioinspired late-stage epoxide ring-opening. Tetrahedron: Asymmetry 28:246 1732. Sharada A, Rao KLS, Yadav JS, Rao TP, Nagaiah K (2017) First stereoselective synthesis of (6R,7R,8S)-8-chlorogoniodiol. Synthesis 49:2483 1733. Reddy KM, Shashidhar J, Ghosh S (2014) A concise approach for the synthesis of bitungolides: total syntheses of (–)-bitungolide B & E. Org Biomol Chem 12:4002 1734. Mantle PG (2000) Uptake of radiolabelled ochratoxin A from soil by coffee plants. Phytochemistry 53:377 1735. Romani S, Pinnavaia GG, Dalla Rosa M (2003) Influence of roasting levels on ochratoxin A content in coffee. J Agric Food Chem 51:5168 1736. Batista LR, Chalfoun SM, Prado G, Schwan RF, Wheals AE (2003) Toxigenic fungi associated with processed (green) coffee beans (Coffea arabica L.). Int J Food Microbiol 85:293 1737. Napolitano A, Fogliano V, Tafuri A, Ritieni A (2007) Natural occurrence of ochratoxin A and antioxidant activities of green and roasted coffees and corresponding byproducts. J Agric Food Chem 55:10499 1738. Cramer B, Königs M, Humpf H-U (2008) Identification and in vitro cytotoxicity of ochratoxin A degradation products formed during coffee roasting. J Agric Food Chem 56:5673 1739. Leong SL, Hocking AD, Varelis P, Giannikopoulos G, Scott ES (2006) Fate of ochratoxin A during vinification of Semillon and Shiraz grapes. J Agric Food Chem 54:6460 1740. Perrone G, Nicoletti I, Pascale M, De Rossi A, De Girolamo A, Visconti A (2007) Positive correlation between high levels of ochratoxin A and resveratrol-related compounds in red wines. J Agric Food Chem 55:6807 1741. Kurtbay HM, Bekçi Z, Merdivan M, Yurdakoç K (2008) Reduction of ochratoxin A levels in red wine by bentonite, modified bentonites, and chitosan. J Agric Food Chem 56:2541 1742. Hierro JMH, Garcia-Villanova RJ, Torrero PR, Fonseca IMT (2008) Aflatoxins and ochratoxin A in red paprika for retail sale in Spain: occurrence and evaluation of a simultaneous analytical method. J Agric Food Chem 56:751 1743. El-Sayed YS, Khalil RH, Saad TT (2009) Acute toxicity of ochratoxin-A in marine waterreared sea bass (Dicentrarchus labrax L.). Chemosphere 75:878 1744. Sun XD, Su P, Shan H (2017) Mycotoxin contamination of rice in China. J Food Sci 82:573 1745. Gabriele B, Attya M, Fazio A, Di Donna L, Plastina P, Sindona G (2009) A new and expedient total synthesis of ochratoxin A and d 5 -ochratoxin A. Synthesis:1815 1746. Bouisseau A, Roland A, Reillon F, Schneider R, Cavelier F (2013) First synthesis of a stable isotope of ochratoxin A metabolite for a reliable detoxification monitoring. Org Lett 15:3888 1747. Cramer B, Harrer H, Nakamura K, Uemura D, Humpf H-U (2010) Total synthesis and cytotoxicity evaluation of all ochratoxin A stereoisomers. Bioorg Med Chem 18:343 1748. Li T, Jo E-J, Kim M-G (2012) A label-free fluorescence immunoassay system for the sensitive detection of the mycotoxin, ochratoxin A. Chem Commun 48:2304

Naturally Occurring Organohalogen Compounds …

491

1749. Gan F, Zhou Y, Hou L, Qjan G, Chen X, Huang K (2017) Ochratoxin A induces nephrotoxicity and immunotoxicity through different MAPK signaling pathways in PK15 cells and porcine primary splenocytes. Chemosphere 182:630 1750. Hou L, Gan F, Zhou X, Zhou Y, Qian G, Liu Z, Huang K (2018) Immunotoxicity of ochratoxin A and aflatoxin B1 in combination is associated with the nuclear factor kappa B signaling pathway in 3D4/21 cells. Chemosphere 199:718 1751. Lenz CA, Rychlik M (2013) Efficient synthesis of (R)-ochratoxin alpha, the key precursor to the mycotoxin ochratoxin A. Tetrahedron Lett 54:883 1752. Xu X, He F, Zhang X, Bao J, Qi S (2013) New mycotoxins from marine-derived fungus Aspergillus sp. SCSGAF0093. Food Chem Toxicol 53:46 1753. Liu J-T, Wu W, Cao M-J, Yang F, Lin H-W (2018) Trienic α-pyrone and ochratoxin derivatives from a sponge-derived fungus Aspergillus ochraceopetaliformis. Nat Prod Res 32:1791 1754. Stadler M, Anke H, Sterner O (1995) Metabolites with nematicidal and antimicrobial activities from the ascomycete Lachnum papyraceum (Karst.) Karst. III. Production of novel isocoumarin derivatives, isolation, and biological activities. J Antibiot 48:261 1755. Anderle C, Li S-M, Kammerer B, Gust B, Heide L (2007) New aminocoumarin antibiotics derived from 4-hydroxycinnamic acid are formed after heterologous expression of a modified clorobiocin biosynthetic gene cluster. J Antibiot 60:504 1756. Kihampa C, Nkunya MHH, Joseph CC, Magesa SM, Hassanali A, Heydenreich M, Kleinpeter E (2009) Anti-mosquito and antimicrobial nor-halimanoids, isocoumarins and an anilinoid from Tessmannia densiflora. Phytochemistry 70:1233 1757. Matumoto T, Hosoya T, Shigemori H (2010) Palmariols A and B, two new chlorinated dibenzo-α-pyrones from discomycete Lachnum palmae. Heterocycles 81:1231 1758. Tanabe Y, Matsumoto T, Hosoya T, Sato H, Shigemori H (2013) Palmaerins A-D, new chlorinated and brominated dihydroisocoumarins with antimicrobial and plant growth regulating activities from discomycete Lachnum palmae. Heterocycles 87:1481 1759. Thongbai B, Surup F, Mohr K, Kuhnert E, Hyde KD, Stadler M (2013) Gymnopalynes A and B, chloropropynyl-isocoumarin antibiotics from cultures of the basidiomycete Gymnopus sp. J Nat Prod 76:2141 1760. Hwang CH, Jaki BU, Klein LL, Lankin DC, McAlpine JB, Napolitano JG, Fryling NA, Franzblau SG, Cho SH, Stamets PE, Wang Y, Pauli GF (2013) Chlorinated coumarins from the polypore mushroom Fomitopsis officinalis and their activity against Mycobacterium tuberculosis. J Nat Prod 76:1916 1761. Lu C-H, Liu S-S, Wang J-Y, Wang M-Z, Shen Y-M (2014) Characterization of eight new secondary metabolites from the mutant strain G-444 of Tubercularia sp. TF 5. Helv Chim Acta 97:334 1762. Elsebai MF, Ghabbour HA (2016) Isocoumarin derivatives from the marine-derived fungus Phoma sp. 135. Tetrahedron Lett 57:354 1763. Zhao Y, Liu D, Proksch P, Yu S, Lin W (2016) Isocoumarin derivatives from the spongeassociated fungus Peyronellaea glomerata with antioxidant activities. Chem Biodivers 13:1186 1764. Darsih C, Prachyawarakorn V, Wiyakrutta S, Mahidol C, Ruchirawat S, Kittakoop P (2015) Cytotoxic metabolites from the endophytic fungus Penicillium chermesinum: discovery of a cysteine-targeted Michael acceptor as a pharmacophore for fragment-based drug discovery, bioconjugation and click reactions. RSC Adv 5:70595 1765. Tatsuta K, Furuyama A, Yano T, Suzuki Y, Ogura T, Hosokawa S (2008) The first total synthesis and structural determination of TMC-264. Tetrahedron Lett 49:4036 1766. Niu S, Liu D, Shao Z, Huang J, Fan A, Lin W (2021) Chlorinated metabolites with antibacterial activities from a deep-sea-derived Spiromastix fungus. RSC Adv 11:29661 1767. Schmidt W, Schulze TM, Brasse G, Nagrodzka E, Maczka M, Zettel J, Jones PG, Grunenberg J, Hilker M, Trauer-Kizilelma U, Braun U, Schulz S (2015) Sigillin A, a unique polychlorinated arthropod deterrent from the snow flea Ceratophysella sigillata. Angew Chem Int Ed 54:7698

492

G. W. Gribble

1768. Yamaoka Y, Nakayama T, Kawai S, Takasu K (2020) Total synthesis of (–)-sigillin A: a polychlorinated and polyoxygenated natural product. Org Lett 22:7721 1769. Fang N, Casida JE (1999) Cubé resin insecticide: identification and biological activity of 29 rotenoid constituents. J Agric Food Chem 47:2130 1770. Ondeyka JG, Zink D, Basilio A, Vicente F, Bills G, Diez MT, Motyl M, Dezeny G, Byrne K, Singh SB (2007) Coniothyrione, a chlorocyclopentandienylbenzopyrone as a bacterial protein synthesis inhibitor discovered by antisense technology. J Nat Prod 70:668 1771. Andrianasolo EH, Haramaty L, Rosario-Passapera R, Bidle K, White E, Vetriani C, Falkowski P, Lutz R (2009) Ammonificins A and B, hydroxyethylamine chroman derivatives from a cultured marine hydrothermal vent bacterium, Thermovibrio ammonificans. J Nat Prod 72:1216 1772. Andrianasolo EH, Haramaty L, Rosario-Passapera R, Vetriani C, Falkowski P, White E, Lutz R (2012) Ammonificins C and D, hydroxyethylamine chromene derivatives from a cultured marine hydrothermal vent bacterium, Thermovibrio ammonificans. Mar Drugs 10:2300 1773. Klaiklay S, Rukachaisirikul V, Tadpetch K, Sukpondma Y, Phongpaichit S, Buatong J, Sakayaroj J (2012) Chlorinated chromone and diphenyl ether derivatives from the mangrove-derived fungus Pestalotiopsis sp. PSU-MA69. Tetrahedron 68:2299 1774. Liu S, Lu C, Huang J, Shen Y (2012) Three new compounds from the marine fungal strain Aspergillus sp. AF119. Rec Nat Prod 6:334 1775. Yang X-W, Huang M-Z, Jin Y-S, Sun L-N, Song Y, Chen H-S (2012) Phenolics from Bidens bipinnata and their amylase inhibitory properties. Fitoterapia 83:1169 1776. Wu B, Kwon SW, Hwang GS, Park JH (2012) Eight new 2-(2-phenylethyl)chromone (=2-(2phenylethyl)-4H-1-benzopyran-4-one) derivatives from Aquilaria malaccensis agarwood. Helv Chim Acta 95:1657 1777. Gao Y-H, Liu J-M, Lu H-X, Wei Z-X (2012) Two new 2-(2-phenylethyl)chromen-4-ones from Aquilaria sinensis (Lour.) Gilg. Helv Chim Acta 95:951 1778. Liao G, Mei W-L, Dong W, Li W, Wang P, Kong F-D, Gai C-J, Song X-Q, Dai HF (2016) 2-(2-Phenylethyl)chromone derivatives in artificial agarwood from Aquilaria sinensis. Fitoterapia 110:38 1779. Huo H-X, Gu Y-F, Sun H, Zhang Y-F, Liu W-J, Zhu Z-X, Shi S-P, Song Y-L, Jin H-W, Zhao Y-F, Tu P-F, Li J (2017) Anti-inflammatory 2-(2-phenylethyl)chromone derivatives from Chinese agarwood. Fitoterapia 118:49 1780. Huo H-X, Gu Y-F, Zhu Z-X, Zhang Y-F, Chen X-N, Guan P-W, Shi S-P, Song YL, Zhao Y-F, Tu P-F, Li J (2019) LC-MS-guided isolation of anti-inflammatory 2-(2phenylethyl)chromone dimers from Chinese agarwood (Aquilaria sinensis). Phytochemistry 158:46 1781. Li J, Jiang Z, Li X, Hou Y, Liu F, Li N, Liu X, Yang L, Chen G (2015) Natural therapeutic agents for neurodegenerative diseases from a traditional herbal medicine Pongamia pinnata (L.) Pierre. Bioorg Med Chem Lett 25:53 1782. Ma J, Zhang X-L, Wang Y, Zheng J-Y, Wang C-Y, Shao C-L (2017) Aspergivones A and B, two new flavones isolated from a gorgonian-derived Aspergillus candidus fungus. Nat Prod Res 31:32 1783. Masi M, Meyer S, Clement S, Pescitelli G, Cimmino A, Cristofaro M, Evidente A (2017) Chloromonilinic acids C and D, phytotoxic tetrasubstituted 3-chromanonacrylic acids isolated from Cochliobolus australiensis with potential herbicidal activity against buffelgrass (Cenchrus ciliaris). J Nat Prod 80:2771 1784. Bashiri S, Abdollahzadeh J, Di Lecce R, Alioto D, Górecki M, Pescitelli G, Masi M, Evidente A (2020) Rabenchromenone and rabenzophenone, phytotoxic tetrasubstituted chromenone and hexasubstituted benzophenone constituents produced by the oak-decline-associated fungus Fimetariella rabenhorstii. J Nat Prod 83:447 1785. Lee SR, Schalk F, Schwitalla JW, Benndorf R, Vollmers J, Kaster A-K, de Beer ZW, Park M, Ahn M-J, Jung WH, Beemelmanns C, Kim KH (2020) Polyhalogenation of isoflavonoids by the termite-associated Actinomadura sp. RB99. J Nat Prod 83:3102

Naturally Occurring Organohalogen Compounds …

493

1786. Siddiq A, Dembitsky V (2008) Acetylenic anticancer agents. Anti-Cancer Agents Med Chem 8:132 1787. Tian Y, Wei X, Xu H (2006) Photoactivated insecticidal thiophene derivatives from Xanthopappus subacaulis. J Nat Prod 69:1241 1788. Casu L, Bonsignore L, Pinna M, Casu M, Floris C, Gertsch J, Cottiglia F (2006) Cytotoxic diacetylenic spiroketal enol ethers from Plagius flosculosus. J Nat Prod 69:295 1789. Wang KDG, Wang J, Xie S-S, Li Z-R, Kong L-Y, Luo J (2016) New naturally occurring diacetylenic spiroacetal enol ethers from Artemisia selengensis. Tetrahedron Lett 57:32 1790. Ma L, Ge F, Tang C-P, Ke C-Q, Li X-Q, Althammer A, Ye Y (2011) The absolute configuration determination of naturally occurring diacetylenic spiroacetal enol ethers from Artemisia lactiflora. Tetrahedron 67:3533 1791. Liu H-L, Guo Y-W (2008) Three new thiophene acetylenes from Rhaponticum uniflorum (L.) DC. Helv Chim Acta 91:130 1792. Lai W-C, Wu Y-C, Dankó B, Cheng Y-B, Hsieh T-J, Hsieh C-T, Tsai Y-C, El-Shazly M, Martins A, Hohmann J, Hunyadi A, Chang F-R (2014) Bioactive constituents of Cirsium japonicum var. australe. J Nat Prod 77:1624 1793. Margl L, Eisenreich W, Adam P, Bacher A, Zenk MH (2001) Biosynthesis of thiophenes in Tagetes patula. Phytochemistry 58:875 1794. Cahoon EB, Schnurr JA, Huffman EA, Minto RE (2003) Fungal responsive fatty acid acetylenases occur widely in evolutionarily distant plant families. Plant J 34:671 1795. Lane AL, Nam S-J, Fukuda T, Yamanaka K, Kauffman CA, Jensen PR, Fenical W, Moore BS (2013) Structures and comparative characterization of biosynthetic gene clusters for cyanosporasides, enediyne-derived natural products from marine actinomycetes. J Am Chem Soc 135:4171 1796. Ma SY, Xiao YS, Zhang B, Shao FL, Guo ZK, Zhang JJ, Jiao RH, Sun Y, Xu Q, Tan RX, Ge HM (2017) Amycolamycins A and B, two enediyne-derived compounds from a locust-associated actinomycete. Org Lett 19:6208 1797. Cohen DR, Townsend CA (2018) Characterization of an anthracene intermediate in dynemicin biosynthesis. Angew Chem Int Ed 57:5650 1798. Van Lanen SG, Shen B (2008) Biosynthesis of enediyne antitumor antibiotics. Curr Top Med Chem 8:448 1799. Liang Z-X (2010) Complexity and simplicity in the biosynthesis of enediyne natural products. Nat Prod Rep 27:499 1800. Chen Y, Yin M, Horsman GP, Huang S, Shen B (2010) Manipulation of pathway regulation in Streptomyces globisporus for overproduction of the enediyne antitumor antibiotic C-1027. J Antibiot 63:482 1801. Chen Y, Yin M, Horsman GP, Shen B (2011) Improvement of the enediyne antitumor antibiotic C-1027 production by manipulating its biosynthetic pathway regulation in Streptomyces globisporus. J Nat Prod 74:420 1802. Grediˇcak M, Jeriˇc I (2007) Enediyne compounds—new promises in anticancer therapy. Acta Pharm 57:133 1803. Nicolaou KC, Chen JS, Dalby SM (2009) From nature to the laboratory and into the clinic. Bioorg Med Chem 17:2290 1804. Komano K, Shimamura S, Inoue M, Hirama M (2007) Total synthesis of the maduropeptin chromophore aglycon. J Am Chem Soc 129:14184 1805. Komano K, Shimamura S, Norizuki Y, Zhao D, Kabuto C, Sato I, Hirama M (2009) Total synthesis and structure revision of the (–)-maduropeptin chromophore. J Am Chem Soc 131:12072 1806. Inoue M, Ohashi I, Kawaguchi T, Hirama M (2008) Total synthesis of the C-1027 chromophore core: extremely facile enediyne formation through SmI2 -mediated 1,2-elimination. Angew Chem Int Ed 47:1777 1807. Ren F, Hogan PC, Anderson AJ, Myers AG (2007) Kedarcidin chromophore: synthesis of its proposed structure and evidence for a stereochemical revision. J Am Chem Soc 129:5381

494

G. W. Gribble

1808. Yoshimura F, Lear MJ, Ohashi I, Koyama Y, Hirama M (2007) Synthesis of the entire carbon framework of the kedarcidin chromophore aglycon. Chem Commun, 3057 1809. Ogawa K, Koyama Y, Ohashi I, Sato I, Hirama M (2009) Total synthesis of a protected aglycon of the kedarcidin chromophore. Angew Chem Int Ed 48:1110 1810. Levenfors JJ, Hedman R, Thaning C, Gerhardson B, Welch CJ (2004) Broad-spectrum antifungal metabolites produced by the soil bacterium Serratia plymuthica A 153. Soil Biol Biochem 36:677 1811. Schomaker JM, Borhan B (2008) Total synthesis of haterumalides NA and NC via a chromium-mediated macrocyclization. J Am Chem Soc 130:12228 1812. Ueda M, Yamaura M, Ikeda Y, Suzuki Y, Yoshizato K, Hayakawa I, Kigoshi H (2009) Total synthesis and cytotoxicity of haterumalides NA and B and their artificial analogues. J Org Chem 74:3370 1813. Williams DE, Keyzers RA, Warabi K, Desjardine K, Riffell JL, Roberge M, Andersen RJ (2007) Spirastrellolides C to G: macrolides obtained from the marine sponge Spirastrella coccinea. J Org Chem 72:9842 1814. Paterson I, Anderson EA, Dalby SM, Lim JH, Maltas P (2012) The stereocontrolled total synthesis of spirastrellolide A methyl ester. Fragment coupling studies and completion of the synthesis. Org Biomol Chem 10:5873 1815. Paterson I, Anderson EA, Dalby SM, Lim JH, Maltas P, Loiseleur O, Genovino J, Moessner C (2012) The stereocontrolled total synthesis of spirastrellolide A methyl ester. Expedient construction of the key fragments. Org Biomol Chem 10:5861 1816. Arlt A, Benson S, Schulthoff S, Gabor B, Fürstner A (2013) A total synthesis of spirastrellolide A methyl ester. Chem Eur J 19:3596 1817. Benson S, Collin M-P, O’Neil GW, Ceccon J, Fasching B, Fenster MDB, Godbout C, Radkowski K, Goddard R, Fürstner A (2009) Total synthesis of spirastrellolide F methyl ester—part 2: macrocyclization and completion of the synthesis. Angew Chem Int Ed 48:9946 1818. Benson S, Collin M-P, Arlt A, Gabor B, Goddard R, Fürstner A (2011) Second-generation total synthesis of spirastrellolide F methyl ester: the alkyne route. Angew Chem Int Ed 50:8739 1819. MacMillan JB, Xiong-Zhou G, Skepper CK, Molinski TF (2008) Phorbasides A-E, cytotoxic chlorocyclopropane macrolide glycosides from the marine sponge Phorbas sp. CD determination of C-methyl sugar configurations. J Org Chem 73:3699 1820. Dalisay DS, Molinski TF (2010) Structure elucidation at the nanomole scale. 3. Phorbasides G–I from Phorbas sp. J Nat Prod 73:679 1821. Paterson I, Paquet T (2010) Total synthesis and configurational validation of (+)-phorbaside A. Org Lett 12:2158 1822. Gerth K, Steinmetz H, Höfle G, Jansen R (2008) Chlorotonil A, a macrolide with a unique gem-dichloro-1,3-dione functionality from Sorangium cellulosum, So ce1525. Angew Chem Int Ed 47:600 1823. Rahn N, Kalesse M (2008) The total synthesis of chlorotonil A. Angew Chem Int Ed 47:597 1824. Greve H, Schupp PJ, Eguereva E, Kehraus S, König GM (2008) Ten-membered lactones from the marine-derived fungus Curvularia sp. J Nat Prod 71:1651 1825. Erkel G, Belahmer H, Serwe A, Anke T, Kunz H, Kolshorn H, Liermann J, Opatz T (2008) Oxacyclododecindione, a novel inhibitor of IL-4 signaling from Exserohilum rostratum. J Antibiot 61:285 1826. Shinonaga H, Kawamura Y, Ikeda A, Aoki M, Sakai N, Fujimoto N, Kawashima A (2009) The search for a hair-growth stimulant: new radicicol analogues as WNT-5A expression inhibitors from Pochonia chlamydosporia var. chlamydosporia. Tetrahedron Lett 50:108 1827. Shinonaga H, Kawamura Y, Ikeda A, Aoki M, Sakai N, Fujimoto N, Kawashima A (2009) Pochonins K-P: new radicicol analogues from Pochonia chlamydosporia var. chlamydosporia and their WNT-5A expression inhibitory activities. Tetrahedron 65:3446 1828. Shinonaga H, Sakai N, Nozawa Y, Ikeda A, Aoki M, Kawashima A (2009) 13Bromomonocillin I: a new WNT-5A expression inhibitor produced by Pochonia chlamydosporia var. chlamydosporia. Heterocycles 78:2855

Naturally Occurring Organohalogen Compounds …

495

1829. Choe H, Cho H, Ko H-J, Lee J (2017) Total synthesis of (+)-pochonin D and (+)-monocillin II via chemo- and regioselective intramolecular nitrile oxide cycloaddition. Org Lett 19:6004 1830. Karthikeyan G, Zambaldo C, Barluenga S, Zoete V, Karplus M, Winssinger N (2012) Asymmetric synthesis of pochonin E and F, revision of their proposed structure, and their conversion to potent Hsp90 inhibitors. Chem Eur J 18:8978 1831. El-Elimat T, Raja HA, Day CS, Chen W-L, Swanson SM, Oberlies NH (2014) Greensporones: resorcylic acid lactones from an aquatic Halenospora sp. J Nat Prod 77:2088 1832. Gaddam J, Reddy AVV, Sarma AVS, Yadav JS, Mohapatra DK (2020) Total synthesis and structural revision of greensporone F and dechlorogreensporone F. J Org Chem 85:12418 1833. Zhang W, Shao C-L, Chen M, Liu Q-A, Wang C-Y (2014) Brominated resorcylic acid lactones from the marine-derived fungus Cochliobolus lunatus induced by histone deacetylase inhibitors. Tetrahedron Lett 55:4888 1834. Mejia EJ, Loveridge ST, Stepan G, Tsai A, Jones GS, Barnes T, White KN, Draškovi´c M, Tenney K, Tsiang M, Geleziunas R, Cihlar T, Pagratis N, Tian Y, Yu H, Crews P (2014) Study of marine natural products including resorcyclic acid lactones from Humicola fuscoatra that reactivate latent HIV-1 expression in an in vitro model of central memory CD4+ T cells. J Nat Prod 77:618 1835. Bashyal BP, Wijeratne EMK, Tillotson J, Arnold AE, Chapman E, Gunatilaka AAL (2017) Chlorinated dehydrocurvularins and alterperylenepoxide A from Alternaria sp. AST0039, a fungal endophyte of Astragalus lentiginosus. J Nat Prod 80:427 1836. Shao C-L, Wu H-X, Wang C-Y, Liu Q-A, Xu Y, Wei M-Y, Qian P-Y, Gu Y-C, Zheng C-J, She Z-G, Lin Y-C (2011) Potent antifouling resorcylic acid lactones from the gorgonian-derived fungus Cochliobolus lunatus. J Nat Prod 74:629 1837. Shao C-L, Wu H-X, Wang C-Y, Liu Q-A, Xu Y, Wei M-Y, Qian P-Y, Gu Y-C, Zheng C-J, She Z-G, Lin Y-C (2013) Correction to potent antifouling resorcylic acid lactones from the gorgonian-derived fungus Cochliobolus lunatus. J Nat Prod 76:302 1838. Liu Q-A, Shao C-L, Gu Y-C, Blum M, Gan L-S, Wang K-L, Chen M, Wang C-Y (2014) Antifouling and fungicidal resorcylic acid lactones from the sea anemone-derived fungus Cochliobolus lunatus. J Agric Food Chem 62:3183 1839. Mahankali B, Srihari P (2015) A carbohydrate approach for the first total synthesis of cochliomycin C: stereoselective total synthesis of paecilomycin E, paecilomycin F and 6 -epi-cochliomycin C. Eur J Org Chem:3983 1840. Pal P, Jana N, Nanda S (2014) Asymmetric total synthesis of paecilomycin E, 10 epipaecilomycin E and 6 -epi-cochliomycin C. Org Biomol Chem 12:8257 1841. Banwell MG, Ma X, Bolte B, Zhang Y, Dlugosch M (2017) Chemical syntheses of the cochliomycins and certain related resorcylic acid lactones. Tetrahedron Lett 58:4025 1842. Zhou J, Gao Y, Chang J-L, Yu H-Y, Chen J, Zhou M, Meng X-G, Ruan H-L (2020) Resorcylic acid lactones from an Ilyonectria sp. J Nat Prod 83:1505 1843. Hickford SJH, Blunt JW, Munro MHG (2009) Antitumour polyether macrolides: four new halichondrins from the New Zealand deep-water marine sponge Lissodendoryx sp. Bioorg Med Chem 17:2199 1844. Dalisay DS, Morinaka BI, Skepper CK, Molinski TF (2009) A tetrachloro polyketide hexahydro-1H-isoindolone, muironolide A, from the marine sponge Phorbas sp. natural products at the nanomole scale. J Am Chem Soc 131:7552 1845. Xiao Q, Young K, Zakarian A (2015) Total synthesis and structural revision of (+)muironolide A. J Am Chem Soc 137:5907 1846. Lu C, Liu X, Li Y, Shen Y (2010) Two 18-membered epothilones from Sorangium cellulosum So0157-2. J Antibiot 63:571 1847. Matthew S, Salvador LA, Schupp PJ, Paul VJ, Luesch H (2010) Cytotoxic halogenated macrolides and modified peptides from the apratoxin-producing marine cyanobacterium Lyngbya bouillonii from Guam. J Nat Prod 73:1544 1848. Yan P, Lv Y, van Ofwegen L, Proksch P, Lin W (2010) Lobophytones A-G, new isobiscembranoids from the soft coral Lobophytum pauciflorum. Org Lett 12:2484

496

G. W. Gribble

1849. Yan P, Deng Z, van Ofwegen L, Proksch P, Lin W (2010) Lobophytones O-T, new biscembranoids and cembranoid from soft coral Lobophytum pauciflorum. Mar Drugs 8:2837 1850. Chlipala GE, Tri PH, Hung NV, Krunic A, Shim SH, Soejarto DD, Orjala J (2010) Nhatrangins A and B, aplysiatoxin-related metabolites from the marine cyanobacterium Lyngbya majuscula from Vietnam. J Nat Prod 73:784 1851. Nam S-J, Gaudencio SP, Kauffman CA, Jensen PR, Kondratyuk TP, Marler LE, Pezzuto JM, Fenical W (2010) Fijiolides A and B, inhibitors of TNF-α-induced NFαB activation, from a marine-derived sediment bacterium of the genus Nocardiopsis. J Nat Prod 73:1080 1852. Heinz C, Cramer N (2015) Synthesis of fijiolide A via an atropselective paracyclophane formation. J Am Chem Soc 137:11278 1853. Lin A-S, Stout EP, Prudhomme J, Le Roch K, Fairchild CR, Franzblau SG, Aalbersberg W, Hay ME, Kubanek J (2010) Bioactive bromophycolides R-U from the Fijian red alga Callophycus serratus. J Nat Prod 73:275 1854. Bishara A, Rudi A, Aknin M, Neumann D, Ben-Califa N, Kashman Y (2010) Salarins D-J, seven new nitrogenous macrolides from the Madagascar sponge Fascaplysinopsis sp. Tetrahedron 66:4339 1855. Fukuda T, Takahashi M, Kasai H, Nagai K, Tomoda H (2017) Chlokamycin, a new chloride from the marine-derived Streptomyces sp. MA2-12. Nat Prod Commun 12:1223 1856. Talontsi FM, Facey P, Tatong MDK, Islam MT, Frauendorf H, Draeger S, von Tiedemann A, Laatsch H (2012) Zoosporicidal metabolites from an endophytic fungus Cryptosporiopsis sp. of Zanthoxylum leprieurii. Phytochemistry 83:87 1857. Choi H, Mevers E, Byrum T, Valeriote FA, Gerwick WH (2012) Lyngbyabellins K–N from two Palmyra Atoll collections of the marine cyanobacterium Moorea bouillonii. Eur J Org Chem: 5141 1858. Pham C-D, Hartmann R, Böhler P, Stork B, Wesselborg S, Lin W, Lai D, Proksch P (2014) Callyspongiolide a cytotoxic macrolide from the marine sponge Callyspongia sp. Org Lett 16:266 1859. Ma J, Shen Y-M, Zeng Y, Zhao P-J (2012) Two new N-(O)-carbamoylglucopyranosyl)-Ndimethylansamitocins from Actinosynnema pretiosum. Helv Chim Acta 95:1630 1860. Mao S, Chen H, Chen L, Wang C, Jia W, Chen X, Yang H, Huang W, Zheng W (2013) Two novel ansamitocin analogs from Actinosynnema pretiosum. Nat Prod Res 27:1532 1861. Wyche TP, Piotrowski JS, Hou Y, Braun D, Deshpande R, McIlwain S, Ong IM, Myers CL, Guzei IA, Westler WM, Andes DR, Bugni TS (2014) Forazoline A: marine-derived polyketide with antifungal in vivo efficacy. Angew Chem Int Ed 53:11583 1862. Gira S, Kindo AJ (2012) A review of Candida species causing blood stream infection. Indian J Med Microbiol 30:270 1863. Gupta DK, Kaur P, Leong ST, Tan LT, Prinsep MR, Chu JJH (2014) Anti-chikungunya viral activities of aplysiatoxin-related compounds from the marine cyanobacterium Trichodesmium erythraeum. Mar Drugs 12:115 1864. Lorente A, Gil A, Fernández R, Cuevas C, Albericio F, Álvarez M (2015) Phormidolides B and C, cytotoxic agents from the sea: enantioselective synthesis of the macrocyclic core. Chem Eur J 21:150 1865. Moon K, Ahn C-H, Shin Y, Won TH, Ko K, Lee SK, Oh K-B, Shin J, Nam S-I, Oh D-C (2014) New benzoxazine secondary metabolites from an Arctic actinomycete. Mar Drugs 12:2526 1866. Perrin CL, Rodgers BL, O’Connor JM (2007) Nucleophilic addition to a p-benzyne derived from an enediyne: a new mechanism for halide incorporation into biomolecules. J Am Chem Soc 129:4795 1867. Richter J, Sandjo LP, Liermann JC, Opatz T, Erkel G (2015) 4-Dechloro-14-deoxyoxacyclododecindione and 14-deoxy-oxacylododecindione, two inhibitors of inducible connective tissue growth factor expression from the imperfect fungus Exserohilum rostratum. Bioorg Med Chem 23:556 1868. Tauber J, Rohr M, Walter T, Schollmeyer D, Rahn-Hotze K, Erkel G, Opatz T (2016) A surprising switch in absolute configuration of anti-inflammatory macrolactones. Org Biomol Chem 14:3695

Naturally Occurring Organohalogen Compounds …

497

1869. Rasmussen SA, Meier S, Andersen NG, Blossom HE, Duus JØ, Nielsen KF, Hansen PJ, Larsen TO (2016) Chemodiversity of ladder-frame prymnesin polyethers in Prymnesium parvum. J Nat Prod 79:2250 1870. Nagai H, Sato S, Iida K, Hayashi K, Kawaguchi M, Uchida H, Satake M (2019) Oscillatoxin I. A new aplysiatoxin derivative from a marine cyanobacterium. Toxins 11:366 1871. Nagai H, Watanabe M, Sato S, Kawaguchi M, Xiao Y-Y, Hayashi K, Watanabe R, Uchida H, Satake M (2019) New aplysiatoxin derivatives from the Okinawan cyanobacterium Moorea producens. Tetrahedron 75:2486 1872. Kawaguchi M, Satake M, Zhang B-T, Xiao Y-Y, Fukuoka M, Uchida H, Nagai H (2020) Neo-aplysiatoxin A isolated from Okinawan cyanobacterium Moorea producens. Molecules 25:457 1873. Fogarty S, Ouyang Y, Li L, Chen Y, Rane H, Manoni F, Parra KJ, Rutter J, Harran PG (2020) Callyspongiolide is a potent inhibitor of the vacuolar ATPase. J Nat Prod 83:3381 1874. Ghosh AK, Kassekert LA, Bungard JD (2016) Enantioselective total synthesis and structural assignment of callyspongiolide. Org Biomol Chem 14:11357 1875. Manoni F, Rumo C, Li L, Harran PG (2018) Unconventional fragment usage enables a concise total synthesis of (–)-callyspongiolide. J Am Chem Soc 140:1280 1876. Igarashi Y, Matsuoka N, In Y, Kataura T, Tashiro E, Saiki I, Sudoh Y, Duangmal K, Thamchaipenet A (2017) Nonthmicin, a polyether polyketide bearing a halogen-modified tetronate with neuroprotective and antiinvasive activity from Actinomadura sp. Org Lett 19:1406 1877. Ochoa JL, Sanchez LM, Koo B-M, Doherty JS, Rajendram M, Huang KC, Gross CA, Linington RG (2018) Marine mammal microbiota yields novel antibiotic with potent activity against Clostridium difficile. ACS Infect Dis 4:59 1878. Pérez-Bonilla M, Oves-Costales D, de la Cruz M, Kokkini M, Martín J, Vicente F, Genilloud O, Reyes F (2018) Phocoenamicins B and C, new antibacterial spirotetronates isolated from a marine Micromonospora sp. Mar Drugs 16:95 1879. Xiao Y, Li S, Niu S, Ma L, Zhang G, Zhang H, Zhang G, Ju J, Zhang C (2011) Characterization of tiacumicin B biosynthetic gene cluster affording diversified tiacumicin analogues and revealing a tailoring dihalogenase. J Am Chem Soc 133:1092 1880. Niu S, Hu T, Li S, Xiao Y, Ma L, Zhang G, Zhang H, Yang X, Ju J, Zhang C (2011) Characterization of a sugar-O-methyltransferase TiaS5 affords new tiacumicin analogues with improved antibacterial properties and reveals substrate promiscuity. ChemBioChem 12:1740 1881. Zhang H, Tian X, Pu X, Zhang Q, Zhang W, Zhang C (2018) Tiacumicin congeners with improved antibacterial activity from a halogenase-inactivated mutant. J Nat Prod 81:1219 1882. Erb W, Zhu J (2013) From natural product to marketed drug: the tiacumicin odyssey. Nat Prod Rep 30:161 1883. Dorst A, Gademann K (2020) Chemistry and biology of the clinically used macrolactone antibiotic fidaxomicin. Helv Chim Acta 103:e2000038 1884. Dorst A, Shchelik IS, Schäfle D, Sander P, Gademann K (2020) Synthesis and biological evaluation of iodinated fidaxomicin antibiotics. Helv Chim Acta 103:e2000130 1885. Yu Z, Zhang H, Yuan C, Zhang Q, Khan I, Zhu Y, Zhang C (2019) Characterizing two cytochrome P450s in tiacumicin biosynthesis reveals reaction timing for tailoring modifications. Org Lett 21:7679 1886. Erg W, Grassot J-M, Linder D, Neuville L, Zhu J (2015) Enantioselective synthesis of putative lipiarmycin aglycon related to fidaxomicin/tiacumicin B. Angew Chem Int Ed 54:1929 1887. Miyatake-Ondozabal H, Kaufmann E, Gademann K (2015) Total synthesis of the protected aglycon of fidaxomicin (tiacumicin B, lipiarmycin A3). Angew Chem Int Ed 54:1933 1888. Glaus F, Altmann K-H (2015) Total synthesis of the tiacumicin B (lipiarmycin A3/ fidaxomicin) aglycone. Angew Chem Int Ed 54:1937 1889. Kaufmann E, Hattori H, Miyatake-Ondozabal H, Gademann K (2015) Total synthesis of the glycosylated macrolide antibiotic fidaxomicin. Org Lett 17:3514 1890. Cui C, Dai W-M (2018) Total synthesis of laingolide B stereoisomers and assignment of absolute configuration. Org Lett 20:3358

498

G. W. Gribble

1891. Hayakawa I, Suzuki K, Okamura M, Funakubo S, Onozaki Y, Kawamura D, Ohyoshi T, Kigoshi H (2017) Total synthesis of biselide E, a marine polyketide. Org Lett 19:5713 1892. Roulland E (2008) Total synthesis of (+)-oocydin A: application of the Suzuki-Miyaura cross-coupling of 1,1-dichloro-1-alkenes with 9-alkyl 9-BBN. Angew Chem Int Ed 47:3762 1893. Nicolaou KC, Tang Y, Wang J (2009) Total synthesis of sporolide B. Angew Chem Int Ed 48:3449 1894. Smith III AB, Sfouggatakis C, Risatti CA, Sperry JB, Zhu W, Doughty VA, Tomioka T, Gotchev DB, Bennett CS, Sakamoto S, Atasoylu O, Shirakami S, Bauer D, Takeuchi M, Koyanagi J, Sakamoto Y (2009) Spongipyran synthetic studies. Evolution of a scalable total synthesis of (+)-spongistatin 1. Tetrahedron 65:6489 1895. O’Brien M, Diéguez-Vázquez A, Hsu D-S, Kraus H, Sumino Y, Ley SV (2008) Azeotropic reflux chromatography: an efficient solution to a difficult separation in the scale-up synthesis of spongistatin 1. Org Biomol Chem 6:1159 1896. Smith AB III, Razler TM, Ciavarri JP, Hirose T, Ishikawa T, Meis RM (2008) A secondgeneration total synthesis of (+)-phorboxazole A. J Org Chem 73:1192 1897. Hoye TR, Danielson ME, May AE, Zhao H (2010) Total synthesis of (–)-callipeltoside A. J Org Chem 75:7052 1898. Frost JR, Pearson CM, Snaddon TN, Booth RA, Turner RM, Gold J, Shaw DM, Gaunt MJ, Ley SV (2015) Callipeltosides A, B and C: total syntheses and structural confirmation. Chem Eur J 21:13261 1899. Lam NYS, Muir G, Challa VR, Britton R, Paterson I (2019) A counterintuitive stereochemical outcome from a chelation-controlled vinylmetal aldehyde addition leads to the configurational reassignment of phormidolide A. Chem Commun 55:9717 1900. Larivée A, Unger JB, Thomas M, Wirtz C, Dubost C, Handa S, Fürstner A (2011) The leiodolide B puzzle. Angew Chem Int Ed 50:304 1901. Heinrich M, Murphy JJ, Ilg MK, Letort A, Flasz JT, Philipps P, Fürstner A (2020) Chagosensine: a riddle wrapped in a mystery inside an enigma. J Am Chem Soc 142:6409 1902. Klüppel A, Gille A, Karayel CE, Hiersemann M (2019) Synthesis of a diastereomer of the marine macrolide lytophilippine A. Org Lett 21:2421 1903. Fuwa H, Okuaki Y, Yamagata N, Sasaki M (2015) Total synthesis, stereochemical reassignment, and biological evaluation of (–)-lyngbyaloside B. Angew Chem Int Ed 54:868 1904. Fuwa H, Yamagata N, Okuaki Y, Ogata Y, Saito A, Sasaki M (2016) Total synthesis and complete stereostructure of a marine macrolide glycoside, (–)-lyngbyaloside B. Chem Eur J 22:6815 1905. Chang C-F, Stefan E, Taylor RE (2015) Total synthesis and structural reassignment of lyngbyaloside C highlighted by intermolecular ketene esterification. Chem Eur J 21:10681 1906. Nicolaou KC, Frederick MO, Aversa RJ (2008) The continuing saga of the marine polyether biotoxins. Angew Chem Int Ed 47:7182 1907. Lorente A, Lamariano-Merketegi J, Albericio F, Álvarez M (2013) Tetrahydrofurancontaining macrolides: a fascinating gift from the deep sea. Chem Rev 113:4567 1908. Shen W, Mao H, Huang Q, Dong J (2015) Benzenediol lactones: a class of fungal metabolites with diverse structural features and biological activities. Eur J Med Chem 97:747 1909. Kitson RRA, Moody CJ (2013) Learning from nature: advances in geldanamycin- and radicicol-based inhibitors of Hsp90. J Org Chem 78:5117 1910. Gallimore AR (2009) The biosynthesis of polyketide-derived polycyclic ethers. Nat Prod Rep 26:266 1911. Paterson I, Findlay AD (2009) Recent advances in the total synthesis of polyketide natural products as promising anticancer agents. Aust J Chem 62:624 1912. Chu M, Patel MG, Pai J-K, Das PR, Puar MS (1996) SCH 53823 and SCH 53825, novel fungal metabolites with phospholipase D inhibitory activity. Bioorg Med Chem Lett 6:579 1913. Cai Y-S, Kurtán T, Miao Z-H, Mándi A, Komáromi I, Liu H-L, Ding J, Guo Y-W (2011) Palmarumycins BG1–BG7 and preussomerin BG1: establishment of their absolute configurations using theoretical calculations of electronic circular dichroism spectra. J Org Chem 76:1821

Naturally Occurring Organohalogen Compounds …

499

1914. Ai W, Wei X, Lin X, Sheng L, Wang Z, Tu Z, Yang X, Zhou X, Li J, Liu Y (2014) Guignardins A–F, spirodioxynaphthalenes from the endophytic fungus Guignardia sp. KcF8 as a new class of PTP1B and SIRT1 inhibitors. Tetrahedron 70:5806 1915. Chen S, Chen D, Cai R, Cui H, Long Y, Lu Y, Li C, She Z (2016) Cytotoxic and antibacterial preussomerins from the mangrove endophytic fungus Lasiodiplodia theobromae ZJ-HQ1. J Nat Prod 79:2397 1916. Ding H, Zhang D, Zhou B, Ma Z (2017) Inhibitors of BRD4 protein from a marine-derived fungus Alternaria sp. NH-F6. Mar Drugs 15:76 1917. Yamazaki H, Yagi A, Akaishi M, Kirikoshi R, Takahashi O, Abe T, Chiba S, Takahashi K, Iwakura N, Namikoshi M, Uchida R (2018) Halogenated cladosporols produced by the sodium halide-supplemented fermentation of the plant-associated fungus Cladosporium sp. TMPU1621. Tetrahedron Lett 59:1913 1918. Liu X, Wang W, Zhao Y, Lai D, Zhou L, Liu Z, Wang M (2018) Total synthesis and structure revision of palmarumycin B6 . J Nat Prod 81:1803 1919. Cai Y-S, Guo Y-W, Krohn K (2010) Structure, bioactivities, biosynthetic relationships and chemical synthesis of the spirodioxynaphthalenes. Nat Prod Rep 27:1840 1920. Motohashi K, Sue M, Furihata K, Ito S, Seto H (2008) Terpenoids produced by actinomycetes: napyradiomycins from Streptomyces antimycoticus NT17. J Nat Prod 71:595 1921. Yamamoto K, Tashiro E, Motohashi K, Seto H, Imoto M (2012) Napyradiomycin A1, an inhibitor of mitochondrial complexes I and II. J Antibiot 65:211 1922. Winter JM, Jansma AL, Handel TM, Moore BS (2009) Formation of the pyridazine natural product azamerone by biosynthetic rearrangement of an aryl diazoketone. Angew Chem Int Ed 48:767 1923. Nawrat CC, Moody CJ (2011) Natural products containing a diazo group. Nat Prod Rep 28:1426 1924. Wu Z, Li S, Li J, Chen Y, Saurav K, Zhang Q, Zhang H, Zhang W, Zhang W, Zhang S, Zhang C (2013) Antibacterial and cytotoxic new napyradiomycins from the marine-derived Streptomyces sp. SCSIO 10428. Mar Drugs 11:2113 1925. Cheng Y-B, Jensen PR, Fenical W (2013) Cytotoxic and antimicrobial napyradiomycins from two marine-derived Streptomyces strains. Eur J Org Chem: 3751 1926. Farnaes L, Coufal NG, Kauffman CA, Rheingold AL, DiPasquale AG, Jensen PR, Fenical W (2014) Napyradiomycin derivatives, produced by a marine-derived actinomycete, illustrate cytotoxicity by induction of apoptosis. J Nat Prod 77:15 1927. Farnaes L, La Clair JJ, Fenical W (2014) Napyradiomycins CNQ525.510B and A80915C target the Hsp90 paralogue Grp94. Org Biomol Chem 12:418 1928. Lacret R, Pérez-Victoria I, Oves-Costales D, de la Cruz M, Domingo E, Martín J, Díaz C, Vicente F, Genilloud O, Reyes F (2016) MDN-0170, a new napyradiomycin from Streptomyces sp. strain CA-271078. Mar Drugs 14:188 1929. Carretero-Molina D, Ortiz-López FJ, Martín J, Oves-Costales D, Díaz C, de la Cruz M, Cautain B, Vicente F, Genilloud O, Reyes F (2020) New napyradiomycin analogues from Streptomyces sp. strain CA-271078. Mar Drugs 18:22 1930. Hwang JS, Kim GJ, Choi HG, Kim MC, Hahn D, Nam J-W, Nam S-J, Kwon HC, Chin J, Cho SJ, Hwang H, Choi H (2017) Identification of antiangiogenic potential and cellular mechanisms of napyradiomycin A1 isolated from the marine-derived Streptomyces sp. YP127. J Nat Prod 80:2269 1931. Pereira F, Almeida JR, Paulino M, Grilo IR, Macedo H, Cunha I, Sobral RG, Vasconcelos V, Gaudêncio SP (2020) Antifoling napyradiomycins from marine-derived actinomycetes Streptomyces aculeolatus. Mar Drugs 18:63 1932. Snyder SA, Tang Z-Y, Gupta R (2009) Enantioselective total synthesis of (–)-napyradiomycin A1 via asymmetric chlorination of an isolated olefin. J Am Chem Soc 131:5744 1933. McKinnie SMK, Miles ZD, Jordan PA, Awakawa T, Pepper HP, Murray LAM, George JH, Moore BS (2018) Total enzyme syntheses of napyradiomycins A1 and B1. J Am Chem Soc 140:17840

500

G. W. Gribble

1934. Feng Z, Chakraborty D, Dewell SB, Reddy BVB, Brady SF (2012) Environmental DNAencoded antibiotics fasamycins A and B inhibit FabF in type II fatty acid biosynthesis. J Am Chem Soc 134:2981 1935. Qin Z, Munnoch JT, Devine R, Holmes NA, Seipke RF, Wilkinson KA, Wilkinson B, Hutchings MI (2017) Formicamycins, antibacterial polyketides produced by Streptomyces formicae isolated from African Tetraponera plant-ants. Chem Sci 8:3218 1936. Qin Z, Devine R, Booth TJ, Farrar EHE, Grayson MN, Hutchings MI, Wilkinson B (2020) Formicamycin biosynthesis involves a unique reductive ring contraction. Chem Sci 11:8125 ¯ 1937. Fukumoto A, Kim Y-P, Iwatsuki M, Hirose T, Sunazuka T, Hanaki H, Omura S, Shiomi K (2017) Naphthacemycins, novel circumventors of β-lactam resistance in MRSA, produced by Streptomyces sp. KB-3346-5. II. Structure elucidation. J Antibiot 70:568 1938. Huo C, Zheng Z, Xu Y, Ding Y, Zheng H, Mu Y, Niu Y, Gao J, Lu X (2020) Naphthacemycins from a Streptomyces sp. as protein-tyrosine phosphatase inhibitors. J Nat Prod 83:1394 1939. Yuan J, Wang L, Ren J, Huang J-P, Yu M, Tang J, Yan Y, Yang J, Huang S-X (2020) Antibacterial pentacyclic polyketides from a soil-derived Streptomyces. J Nat Prod 83:1919 1940. Qin Z, Devine R, Hutchings MI, Wilkinson B (2019) A role for antibiotic biosynthesis monooxygenase domain proteins in fidelity control during aromatic polyketide biosynthesis. Nature Commun 10:3611 1941. Sakoulas G, Nam S-J, Loesgen S, Fenical W, Jensen PR, Nizet V, Hensler M (2012) Novel bacterial metabolite merochlorin A demonstrates in vitro activity against multi-drug resistant methicillin-resistant Staphylococcus aureus. PLoS One 7:e29439 1942. Kaysser L, Bernhardt P, Nam S-J, Loesgen S, Ruby JG, Skewes-Cox P, Jensen PR, Fenical W, Moore BS (2012) Merochlorins A-D, cyclic meroterpenoid antibiotics biosynthesized in divergent pathways with vanadium-dependent chloroperoxidases. J Am Chem Soc 134:11988 1943. Kaysser L, Bernhardt P, Nam S-J, Loesgen S, Ruby JG, Skewes-Cox P, Jensen PR, Fenical W, Moore BS (2014) Correction to “Merochlorins A-D, cyclic meroterpenoid antibiotics biosynthesized in divergent pathways with vanadium-dependent chloroperoxidases.” J Am Chem Soc 136:14626 1944. Ryu M-J, Hwang S, Kim S, Yang I, Oh D-C, Nam S-J, Fenical W (2019) Meroindenon and merochlorins E and F, antibacterial meroterpenoids from a marine-derived sediment bacterium of the genus Streptomyces. Org Lett 21:5779 1945. Miles ZD, Diethelm S, Pepper HP, Huang DM, George JH, Moore BS (2017) A unifying paradigm for naphthoquinone-based meroterpenoid (bio)synthesis. Nature Chem 9:1235 1946. Pepper HP, George JH (2013) Biomimetic total synthesis of (±)-merochlorin A. Angew Chem Int Ed 52:12170 1947. Meier R, Strych S, Trauner D (2014) Biomimetic synthesis of (±)-merochlorin B. Org Lett 16:2634 1948. Pepper HP, George JH (2015) The biosynthesis and biomimetic synthesis of merochlorins A and B. Synlett 26:2485 1949. Yang H, Liu X, Li Q, Li L, Zhang J-R, Tang Y (2016) Total synthesis and preliminary SAR study of (±)-merochlorins A and B. Org Biomol Chem 14:198 1950. Brandstätter M, Freis M, Huwyler N, Carreira EM (2019) Total synthesis of (–)-merochlorin A. Angew Chem Int Ed 58:2490 1951. Sloman DL, Bacon JW, Porco JA Jr (2011) Total synthesis and absolute stereochemical assignment of kibdelone C. J Am Chem Soc 133:9952 1952. Butler JR, Wang C, Bian J, Ready JM (2011) Enantioselective total synthesis of (–)-kibdelone C. J Am Chem Soc 133:9956 1953. Dai Y, Ma F, Shen Y, Xie T, Gao S (2018) Convergent synthesis of kibdelone C. Org Lett 20:2872 1954. Winter DK, Endoma-Arias MA, Hudlicky T, Beutler JA, Porco JA Jr (2013) Enantioselective total synthesis and biological evaluation of (+)-kibdelone A and a tetrahydroxanthone analogue. J Org Chem 78:7617

Naturally Occurring Organohalogen Compounds …

501

1955. Chlipala GE, Sturdy M, Krunic A, Lantvit DD, Shen Q, Porter K, Swanson SM, Orjala J (2010) Cylindrocyclophanes with proteasome inhibitory activity from the cyanobacterium Nostoc sp. J Nat Prod 73:1529 1956. Kang H-S, Santarsiero BD, Kim H, Krunic A, Shen Q, Swanson SM, Chai H, Kinghorn AD, Orjala J (2012) Merocyclophanes A and B, antiproliferative cyclophanes from the cultured terrestrial cyanobacterium Nostoc sp. Phytochemistry 79:109 1957. Luo S, Kang H-S, Krunic A, Chlipala GE, Cai G, Chen W-L, Franzblau SG, Swanson SM, Orjala J (2014) Carbamidocyclophanes F and G with anti-Mycobacterium tuberculosis activity from the cultured freshwater cyanobacterium Nostoc sp. Tetrahedron Lett 55:686 1958. Preisitsch M, Harmrolfs K, Pham HTL, Heiden SE, Füssel A, Wiesner C, Pretsch A, Swiatecka-Hagenbruch M, Niedermeyer THJ, Müller R, Mundt S (2015) Anti-MRSA-acting carbamidocyclophanes H–L from the Vietnamese cyanobacterium Nostoc sp. CAVN2. J Antibiot 68:165 1959. Preisitsch M, Niedermeyer THJ, Heiden SE, Neidhardt I, Kumpfmüller J, Wurster M, Harmrolfs K, Wiesner C, Enke H, Müller R, Mundt S (2016) Cylindrofridins A-C, linear cylindrocyclophane-related alkylresorcinols from the cyanobacterium Cylindrospermum stagnale. J Nat Prod 79:106 1960. Nakamura H, Hamer HA, Sirasani G, Balskus EP (2012) Cylindrocyclophane biosynthesis involves functionalization of an unactivated carbon center. J Am Chem Soc 134:18518 1961. Nakamura H, Balskus EP (2013) Using chemical knowledge to uncover new biological function: discovery of the cylindrocyclophane biosynthetic pathway. Synlett 24:1464 1962. Nakamura H, Wang JX, Balskus EP (2015) Assembly line termination in cylindrocyclophane biosynthesis: discovery of an editing type II thioesterase domain in a type I polyketide synthase. Chem Sci 6:3816 1963. Preisitsch M, Heiden SE, Beerbaum M, Niedermeyer THJ, Schneefeld M, Herrmann J, Kumpfmüller J, Thürmer A, Neidhardt I, Wiesner C, Daniel R, Müller R, Bange F-C, Schmieder P, Schweder T, Mundt S (2016) Effects of halide ions on the carbamidocyclophane biosynthesis in Nostoc sp. CAVN2. Mar Drugs 14:21 1964. Nakamura H, Schultz EE, Balskus EP (2017) A new strategy for aromatic ring alkylation in cylindrocyclophane biosynthesis. Nat Chem Biol 13:916 1965. Hoye TR, Humpal PE, Moon B (2000) Total synthesis of (–)-cylindrocyclophane A via a double Horner-Emmons macrocyclic dimerization event. J Am Chem Soc 122:4982 1966. Smith III AB, Adams CM, Kozmin SA, Paone DV (2001) Total synthesis of (–)cylindrocyclophanes A and F exploiting the reversible nature of the olefin cross metathesis reaction. J Am Chem Soc 123:5925 1967. Yamakoshi H, Ikarashi F, Minami M, Shibuya M, Sugahara T, Kanoh N, Ohori H, Shibata H, Iwabuchi Y (2009) Syntheses of naturally occurring cytotoxic [7.7]paracyclophanes, (– )-cyclindrocyclophane A and its enantiomer, and implications for biological activity. Org Biomol Chem 7:3772 1968. Nicolaou KC, Sun Y-P, Korman H, Sarlah D (2010) Asymmetric total synthesis of cylindrocyclophanes A and F through cyclodimerization and a Ramberg-Bäcklund reaction. Angew Chem Int Ed 49:5875 1969. Qin J, Su H, Zhang Y, Gao J, Zhu L, Wu X, Pan H, Li X (2010) Highly brominated metabolites from marine red alga Laurencia similis inhibit protein tyrosine phosphatase 1B. Bioorg Med Chem Lett 20:7152 1970. Murakami S, Takahashi Y, Naganawa H, Takeuchi T, Aoyagi T (1995) Belactins A and B, new serine carboxypeptidase inhibitors produced by actinomycete. II. Physico-chemical properties, structure determinations and enzymatic inhibitory activities compared with other ß-lactone containing inhibitors. J Enzym Inhibit 9:277 1971. Murakami S, Takahashi Y, Takeuchi T, Kodama Y, Aoyagi T (1999) The absolute configuration of belactin A, a ß-lactone-containing serine carboxypeptidase inhibitor: importance of the ß-lactone structure for serine carboxypeptidase inhibition. J Enzym Inhibit 14:437 1972. Rehman NU, Rafiq K, Khan A, Halim SA, Ali L, Al-Saady N, Al-Balushi AH, Al-Busaidi HK, Al-Harrasi A (2019) α-Glucosidase inhibition and molecular docking studies of natural

502

1973. 1974.

1975. 1976. 1977. 1978.

1979.

1980.

1981.

1982.

1983. 1984.

1985.

1986.

1987. 1988. 1989.

1990.

1991.

G. W. Gribble brominated metabolites from marine macro brown alga Dictyopteris hoytii. Mar Drugs 17:666 Baumeister TUH, Staudinger M, Wirgenings M, Pohnert G (2019) Halogenated anilines as novel natural products from a marine biofilm forming microalga. Chem Commun 55:11948 Felder S, Dreisigacker S, Kehraus S, Neu E, Bierbaum G, Wright PR, Menche D, Schäberle TF, König GM (2013) Salimabromide: unexpected chemistry from the obligate marine myxobacterium Enhygromxya salina. Chem Eur J 19:9319 Schmid M, Grossmann AS, Wurst K, Magauer T (2018) Total synthesis of salimabromide: a tetracyclic polyketide from a marine myxobacterium. J Am Chem Soc 140:8444 Schmid M, Grossmann AS, Mayer P, Müller T, Magauer T (2019) Ring-expansion approaches for the total synthesis of salimabromide. Tetrahedron 75:3195 Palm A, Knopf C, Schmalzbauer B, Menche D (2019) Enantioselective total synthesis of (+)-salimabromide reveals almost racemic nature of natural salimabromide. Org Lett 21:1939 Cartagena E, Marcinkevicius K, Luciardi C, Rodríguez G, Bardón A, Arena ME (2014) Activity of a novel compound produced by Aspergillus parasiticus in the presence of red flour beetle Tribolium castaneum against Pseudomonas aeruginosa and coleopteran insects. J Pest Sci 87:521 Chan QHS, Zolensky ME, Kebukawa Y, Fries M, Ito M, Steele A, Rahman Z, Nakato A, Kilcoyne ALD, Suga H, Takahashi Y, Takeichi Y, Mase K (2018) Organic matter in extraterrestrial water-bearing salt crystals. Sci Adv 4:eaao3521 Eigenrode JL, Summons RE, Steele A, Freissinet C, Millan M, Navarro-González R, Sutter B, McAdam AC, Franz HB, Glavin DP, Archer PD Jr, Mahaffy PR, Conrad PG, Hurowitz JA, Grotzinger JP, Gupta S, Ming DW, Sumner DY, Szopa C, Malespin C, Buch H, Coll P (2018) Organic matter preserved in 3-billion-year-old mudstones at Gale crater, Mars. Science 360:1096 Führer U, Deißler A, Ballschmiter K (1996) Determination of biogenic halogenated methylphenyl ethers (halogenated anisoles) in the picogram m-3 range in air. Fresenius J Anal Chem 354:333 Bouman EAP, Dusbábek F, Šimek P, Zahradníèková H (2003) Methyl 3-chloro-4methoxybenzoate, a new candidate semiochemical inhibiting copulation behaviour of Ixodes ricinus (L.) males. Physiol Entomol 28:276 Chen J-J, Lin W-J, Liao C-H, Shieh P-C (2007) Anti-inflammatory benzenoids from Antrodia camphorata. J Nat Prod 70:989 Morris HR, Masento MS, Taylor GW, Jermyn KA, Kay RR (1988) Structure elucidation of two differentiation inducing factors (DIF-2 and DIF-3) from the cellular slime mold Dictyostelium discoideum. Biochem J 249:903 Omata W, Shibata H, Nagasawa M, Kojima I, Kikuchi H, Oshima Y, Hosaka K, Kubohara Y (2007) Dictyostelium differentiation-inducing factor-1 induces glucose transporter 1 translocation and promotes glucose uptake in mammalian cells. FEBS J 274:3392 Kubohara Y, Kikuchi H, Oshima Y (2008) Exploitation of the derivatives of Dictyostelium differentiation-inducing factor-1, which promote glucose consumption in mammalian cells. Life Sci 83:608 Labbé C, Faini F, Villagrán C, Coll J, Rycroft DS (2007) Bioactive polychlorinated bibenzyls from the liverwort Riccardia polyclada. J Nat Prod 70:2019 Chen X-Q, Li Y, He J, Wang K, Li M-M, Pan Z-H, Peng L-Y, Cheng X, Zhao Q-S (2009) Four new lignans from Viburnum foetidum var. foedidum. Chem Pharm Bull 57:1129 Ziaratnia SM, Ohyama K, Hussein AB-F, Muranaka T, Lall N, Kunert KJ, Meyer JJM (2009) Isolation and identification of a novel chlorophenol from a cell suspension culture of Helichrysum aureonitens. Chem Pharm Bull 57:1282 Al-Zereini W, Schuhmann I, Laatsch H, Helmke E, Anke H (2007) New aromatic nitro compounds from Salegentibacter sp. T436, an Arctic Sea ice bacterium: taxonomy, fermentation, isolation and biological activities. J Antibiot 60:301 Schuhmann I, Yao CBF-F, Al-Zereini W, Anke H, Helmke E, Laatsch H (2009) Nitro derivatives from the Arctic ice bacterium Salegentibacter sp. isolate T436. J Antibiot 62:453

Naturally Occurring Organohalogen Compounds …

503

1992. Klausmeyer P, Howard OMZ, Shipley SM, McCloud TG (2009) An inhibitor of CCL2induced chemotaxis from the fungus Leptoxyphium sp. J Nat Prod 72:1369 1993. Hosono K, Ogihara J, Ohdake T, Masuda S (2009) LL-Z1272α epoxide, a precursor of ascochlorin produced by a mutant of Ascochyta viciae. J Antibiot 62:571 1994. Kikuchi H, Ishiko S, Nakamura K, Kubohara Y, Oshima Y (2010) Novel prenylated and geranylated aromatic compounds isolated from Polysphondylium cellular slime molds. Tetrahedron 66:6000 1995. Hiebl J, Lehnert K, Vetter W (2011) Identification of a fungi-derived terrestrial halogenated natural product in wild boar (Sus scrofa). J Agric Food Chem 59:6188 1996. Wang T, Rabe P, Citron CA, Dickschat JS (2013) Halogenated volatiles from the fungus Geniculosporium and the actinomycete Streptomyces chartreusis. Beilstein J Org Chem 9:2767 1997. Wang Z-H, Huang J, Ma X-C, Li G-Y, Ma Y-P, Li N, Wang J-H (2013) Phenolic glycosides from Curculigo orchioides Gaertn. Fitoterapia 86:64 1998. Chen X, Zuo A, Deng Z, Huang X, Zhang X, Geng C, Li T, Chen J (2017) New phenolic glycosides from Curculigo orchioides and their xanthine oxidase inhibitory activities. Fitoterapia 122:144 1999. Zhao M, Da-Wa Z-M, Gu Y-C, Guo D-L, Ye Y, Ding L-S, Zhou Y (2017) Three new chlorinated phenolic glycosides from Przewalskia tangutica. Phytochem Lett 20:168 2000. Lou L-L, Li L-G, Liu Q-B, Li D-Q, Liu Z-X, Huang X-X, Song S-J (2016) 3,3 -Neolignans from Pithecellobium clypearia Benth. and their anti-inflammatory activity. Fitoterapia 112:16 2001. Shang S-Z, Yan J-M, Zhang H-B, Shi Y-M, Gao Z-H, Du X, Li Y, Xiao W-L, Sun H-D (2012) Two new neolignans from Manglietia insignis. Nat Prod Bioprospect 2:227 2002. Shiono Y, Miyazaki N, Murayama T, Koseki T, Harizon KDG, Supratman U, Nakata J, Kakihara Y, Saeki M, Yoshida J, Uesugi S, Kimura K (2016) GSK-3β inhibitory activities of novel dichroloresorcinol derivatives from Cosmospora vilior isolated from a mangrove plant. Phytochem Lett 18:122 2003. Shiono Y, Muslihah NI, Suzuki T, Arefta NR, Anwar C, Nurjanto HH, Aboshi T, Murayama T, Tawaraya K, Koseki T, Yoshida J, Usukhbayar N, Uesugi S, Kimura K (2017) New eremophilane and dichlororesorcinol derivatives produced by endophytes isolated from Ficus ampelas. J Antibiot 70:1133 2004. Masi M, Cimmino A, Boari A, Zonno MC, Górecki M, Pescitelli G, Tuzi A, Vurro M, Evidente A (2017) Colletopyrandione, a new phytotoxic tetrasubstituted indolylidenepyran2,4-dione, and colletochlorins G and H, new tetrasubstituted chroman- and isochroman-3,5diols isolated from Colletotrichum higginsianum. Tetrahedron 73:6644 2005. Verastegui-Omaña B, Rebollar-Ramos D, Pérez-Vásquez A, Martínez AL, MadariagaMazón A, Flores-Bocanegra L, Mata R (2017) α-Glucosidase inhibitors from Malbranchea flavorosea. J Nat Prod 80:190 2006. Hassan AR, El-Kousy SM, El-Toumy SA, Frydenvang K, Tung TT, Olsen J, Nielsen J, Christensen SB (2017) Metformin, an anthropogenic contaminant of Seidlitzia rosmarinus collected in a desert region near the Gulf of Aqaba, Sinai Peninsula. J Nat Prod 80:2830 2007. Kikuchi H, Ito I, Takahashi K, Ishigaki H, Iizumi K, Kubohara Y, Oshima Y (2017) Isolation, synthesis, and biological activity of chlorinated alkylresorcinols from Dictyostelium cellular slime molds. J Nat Prod 80:2716 2008. Joulain D, Tabacchi R (2009) Lichen extracts as raw materials in perfumery. Part 1: oakmoss. Flavour Fragr J 24:49 2009. Garvie LAJ, Wilkens B, Groy TL, Glaeser JA (2015) Substantial production of drosophilin A methyl ether (tetrachloro-1,4-dimethoxybenzene) by the lignicolous basidiomycete Phellinus badius in the heartwood of mesquite (Prosopis juliflora) trees. Sci Nat 102:18 2010. Sefton MA, Simpson RF (2005) Compounds causing cork taint and the factors affecting their transfer from natural cork closures to wine—a review. Aust J Grape Wine Res 11:226 2011. Jönsson S, Hagberg J, van Bavel B (2008) Determination of 2,4,6-trichloroanisole and 2,4,6tribromoanisole in wine using microextraction in packed syringe and gas chromatographymass spectrometry. J Agric Food Chem 56:4962

504

G. W. Gribble

2012. Siegmund B, Pöllinger-Zierler B (2007) Growth behavior of off-flavor-forming microorganisms in apple juice. J Agric Food Chem 55:6692 2013. Schroeder M, Pöllinger-Zierler B, Aichernig N, Siegmund B, Guebitz GM (2008) Enzymatic removal of off-flavors from apple juice. J Agric Food Chem 56:2485 2014. Perez-Cacho PR, Rouseff R (2008) Processing and storage effects on orange juice aroma: a review. J Agric Food Chem 56:9785 2015. Wells, D (2007) Organohalogen taints in foods. Australian Food Grocery Council, 1 2016. Li K, Li X-M, Ji N-Y, Wang B-G (2007) Natural bromophenols from the marine red alga Polysiphonia urceolata (Rhodomelaceae): structural elucidation and DPPH radicalscavenging activity. Bioorg Med Chem 15:6627 2017. Hodgkin JH, Craigie JS, McInnes AG (1966) The occurrence of 2,3-dibromobenzyl alcohol 4,5-disulfate, dipotassium salt, in Polysiphonia lanosa. Can J Chem 44:74 2018. Kurata K, Amiya T, Yabe K (1973) Studies on the constituents of a red marine alga, Odonthalia corymbifera. Bull Jpn Soc Sci Fish 39:973 2019. Duan X-J, Li X-M, Wang B-G (2007) Highly brominated mono- and bis-phenols from the marine red alga Symphyocladia latiuscula with radical-scavenging activity. J Nat Prod 70:1210 2020. Chen L, Fang Y, Zhu T, Gu Q, Zhu W (2008) Gentisyl alcohol derivatives from the marinederived fungus Penicillium terrestre. J Nat Prod 71:66 2021. Pontius A, Mohamed I, Krick A, Kehraus S, König GM (2008) Aromatic polyketides from marine algicolous fungi. J Nat Prod 71:272 2022. Buchanan MS, Carroll AR, Wessling D, Jobling M, Avery VM, Davis RA, Feng Y, Xue Y, Öster L, Fex T, Deinum J, Hooper JNA, Quinn RJ (2008) Clavatadine A, a natural product with selective recognition and irreversible inhibition of factor XIa. J Med Chem 51:3583 2023. Conn SJ, Vreeland SM, Wexler AN, Pouwer RN, Quinn RJ, Chamberland S (2015) Total synthesis of clavatadine A. J Nat Prod 78:120 2024. Jin HJ, Oh MY, Jin DH, Hong YK (2008) Identification of a Taq DNA polymerase inhibitor from the red seaweed Symphyocladia latiuscula. J Environ Biol 29:475 2025. Lim C-W, Lee J-S, Cho Y-J (2000) Structures and some properties of the antimicrobial compounds in the red alga, Symphyocladia latiuscula. Korean Fish Soc 33:280 2026. Badr JM, Shaala LA, Abou-Shoer MI, Tawfik MK, Habib A-AM (2008) Bioactive brominated metabolites from the red sea sponge Pseudoceratina arabica. J Nat Prod 71:1472 2027. Liu Q-W, Qiao Q-A, Zhang T, Sun L-X, Wang M-S (2009) The structure elucidation of a new bromophenol metabolite from Polysiphonia urceolata by experimental and DFT theoretical methods. J Mol Struct 929:1 2028. Zhang P, Bao B, Dang HT, Hong J, Lee HJ, Yoo ES, Bae KS, Jung JH (2009) Antiinflammatory sesquiterpenoids from a sponge-derived fungus Acremonium sp. J Nat Prod 72:270 2029. Xu X, Song F, Fan X, Fang N, Shi J (2009) A novel bromophenol from marine red alga Symphyocladia latiuscula. Chem Nat Compd 45:811 2030. Kim J-K, Noh JH, Lee S, Choi JS, Suh H, Chung HY, Song Y-O, Choi WC (2002) The first total synthesis of 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (TDB) and its antioxidant activity. Bull Korean Chem Soc 23:661 2031. Popplewell WL, Northcote PT (2009) Colensolide A: a new nitrogenous bromophenol from the New Zealand marine red alga Osmundaria colensoi. Tetrahedron Lett 50:6814 2032. Plaza A, Keffer JL, Bifulco G, Lloyd JR, Bewley CA (2010) Chrysophaentins A-H, antibacterial bisdiarylbutene macrocycles that inhibit the bacterial cell division protein FtsZ. J Am Chem Soc 132:9069 2033. Li K, Li X-M, Gloer JB, Wang B-G (2011) Isolation, characterization, and antioxidant activity of bromophenols of the marine red alga Rhodomela confervoides. J Agric Food Chem 59:9916 2034. Rob T, Ogi T, Maarisit W, Taira J, Ueda K (2011) Isolation of C11 compounds and a cyclopropane fatty acid from an Okinawan ascidian, Diplosoma sp. Molecules 16:9972

Naturally Occurring Organohalogen Compounds …

505

2035. Feng Y, Bowden BF, Kapoor V (2012) Ianthellamide A, a selective kynurenine-3hydroxylase inhibitor from the Australian marine sponge Ianthella quadrangulata. Bioorg Med Chem Lett 22:3398 2036. Li K, Li X-M, Gloer JB, Wang B-G (2012) New nitrogen-containing bromophenols from the marine red alga Rhodomela confervoides and their radical scavenging activity. Food Chem 135:868 2037. Xu X, Piggott AM, Yin L, Capon RJ, Song F (2012) Symphyocladins A-G: bromophenol adducts from a Chinese marine red alga, Symphyocladia latiuscula. Tetrahedron Lett 53:2103 2038. Xu X, Yin L, Fang N, Fan X, Song F (2012) Bromophenol coupled with diketopiperazine from marine red alga Symphyocladia latiuscula. Chem Nat Compd 48:622 2039. Xu X, Yin L, Gao L, Gao J, Chen J, Li J, Song F (2013) Two new bromophenols with radical scavenging activity from marine red alga Symphyocladia latiuscula. Mar Drugs 11:842 2040. Xu X, Yin L, Wang Y, Wang S, Song F (2013) A new bromobenzyl methyl sulphoxide from marine red alga Symphyocladia latiuscula. Nat Prod Res 27:723 2041. Xu X, Yang H, Khalil ZG, Yin L, Xiao X, Neupane P, Bernhardt PV, Salim AA, Song F, Capon RJ (2017) Chemical diversity from a Chinese marine red alga, Symphyocladia latiuscula. Mar Drugs 15:374 2042. Xu X, Yang H, Khalil ZG, Yin L, Xiao X, Salim AA, Song F, Capon RJ (2019) Bromocatechol conjugates from a Chinese marine red alga, Symphyocladia latiuscula. Phytochemistry 158:20 2043. Fu P, Kong F, Wang Y, Wang Y, Liu P, Zuo G, Zhu W (2013) Antibiotic metabolites from the coral-associated actinomycete Streptomyces sp. OUCMDZ-1703. Chin J Chem 31:100 2044. Moore SL, Berthomier L, Braganza CD, MacKichan JK, Ryan JL, Visnovsky G, Keyzer RA (2016) Identification, library synthesis and anti-vibriosis activity of 2-benzyl-4-chlorophenol from cultures of the marine bacterium Shewanella halifaxensis. Bioorg Med Chem Lett 26:3086 2045. Mikami D, Kurihara H, Ono M, Kim SM, Takahashi K (2016) Inhibition of algal bromophenols and their related phenols against glucose 6-phosphate dehydrogenase. Fitoterapia 108:20 2046. Michael P, Hansen KØ, Isaksson J, Andersen JH, Hansen E (2017) A novel brominated alkaloid securidine A, isolated from the marine bryozoan Securiflustra securifrons. Molecules 22:1236 2047. Tadesse M, Strøm MB, Svenson J, Jaspars M, Milne BF, Tørfoss V, Andersen JH, Hansen E, Stensvåg K, Haug T (2010) Synoxazolidinones A and B: novel bioactive alkaloids from the ascidian Synoicum pulmonaria. Org Lett 12:4752 2048. Tadesse M, Svenson J, Sepˇci´c K, Trembleau L, Engqvist M, Andersen JH, Jaspars M, Stensvåg K, Haug T (2014) Isolation and synthesis of pulmonarins A and B, acetylcholinesterase inhibitors from the colonial ascidian Synoicum pulmonaria. J Nat Prod 77:364 2049. Cheng C, Balasubramanian S, Fekete A, Krischke M, Mueller MJ, Hentschel U, Oelschlaeger TA, Abdelmohsen UR (2017) Inhibitory potential of strepthonium A against Shiga toxin production in enterohemorrhagic Escherichia coli (EHEC) strain EDL933. Nat Prod Res 31:2818 2050. Islam MR, Mikami D, Kurihara H (2017) Two new algal bromophenols from Odonthalia corymbifera. Tetrahedron Lett 58:4119 2051. Han Z, Li Y-X, Liu L-L, Lu L, Guo X-R, Zhang X-X, Zhang X-Y, Qi S-H, Xu Y, Qian P-Y (2017) Thielavins W–Z7 , new antifouling thielavins from the marine-derived fungus Thielavia sp. UST030930-004. Mar Drugs 15:128 2052. Wang W, Li S, Chen Z, Li Z, Liao Y, Chen J (2017) Secondary metabolites produced by the deep-sea-derived fungus Engyodontium album. Chem Nat Compd 53:224 2053. Wu Z, Li Y, Liu D, Ma M, Chen J, Lin W (2017) New resorcinol derivatives from a spongederived fungus Hansfordia sinuosae. Chem Biodivers 14:e1700059 2054. Suzuki T, Yoshida S, Koseki T, Aboshi T, Murayama T, Supratman U, Shiono Y (2018) New metabolites produced by Cylindrocarpon sp. SY-39 from a driftwood. Chem Biodivers 15:e1700493

506

G. W. Gribble

2055. Costa M, Sampaio-Dias IE, Castelo-Branco R, Scharfenstein H, de Castro RR, Silva A, Schneider MPC, Araújo MJ, Martins R, Domingues VF, Nogueira F, Camões V, Vasconcelos VM, Leão PN (2019) Structure of hierridin C, synthesis of hierridins B and C, and evidence for prevalent alkylresorcinol biosynthesis in picocyanobacteria. J Nat Prod 82:393 2056. Cao D-T, Nguyen T-L, Tran V-H, Doan-Thi-Mai H, Vu-Thi Q, Nguyen M-A, Le-Thi HM, Chau V-M, Pham V-C (2019) Synthesis, structure and antimicrobial activity of novel metabolites from a marine actinomycete in Vietnam’s East Sea. Nat Prod Commun 14:121 2057. Niu S, Liu Q, Xia J-M, Xie C-L, Luo Z-H, Shao Z, Liu G, Yang X-W (2018) Polyketides from the deep-sea-derived fungus Graphostroma sp. MCCC 3A00421 showed potent antifood allergic activities. J Agric Food Chem 66:1369 2058. Hofer S, Hartmann A, Orfanoudaki M, Ngoc HN, Nagl M, Karsten U, Heesch S, Ganzera M (2019) Development and validation of an HPLC method for the quantitative analysis of bromophenolic compounds in the red alga Vertebrata lanosa. Mar Drugs 17:675 2059. Shaala LA, Youssef DTA, Alzughaibi TA, Elhady SS (2020) Antimicrobial chlorinated 3-phenylpropanoic acid derivatives from the Red Sea marine actinomycete Streptomyces coelicolor LY001. Mar Drugs 18:450 2060. Afonso TB, Costa MS, de Castro RR, Freitas S, Silva A, Schneider MPC, Martins R, Leão PN (2016) Bartolosides E-K from a marine coccoid cyanobacterium. J Nat Prod 79:2504 2061. Davison JR, Bewley CA (2019) Antimicrobial chrysophaentin analogs identified from laboratory cultures of the marine microalga Chrysophaeum taylorii. J Nat Prod 82:148 2062. Abou-Shoer MI, Shaala LA, Youssef DTA, Badr JM, Habib A-AM (2008) Bioactive brominated metabolites from the Red Sea sponge Suberea mollis. J Nat Prod 71:1464 2063. Shaker KH, Zinecker H, Ghani MA, Imhoff JF, Schneider B (2010) Bioactive metabolites from the sponge Suberea sp. Chem Biodivers 7:2880 2064. Shaala LA, Khalifa SI, Mesbah MK, van Soest RWM, Youssef DTA (2008) Subereaphenol A, a new cytotoxic and antimicrobial dibrominated phenol from the Red Sea sponge Suberea mollis. Nat Prod Commun 3:219 2065. Yun K, Kondempudi CM, Choi HD, Kang JS, Son BW (2011) Microbial mannosidation of bioactive chlorogentisyl alcohol by the marine-derived fungus Chrysosporium synchronum. Chem Pharm Bull 59:499 2066. Agarwal V, El Gamal AA, Yamanaka K, Poth D, Kersten RD, Schorn M, Allen EE, Moore BS (2014) Biosynthesis of polybrominated aromatic organic compounds by marine bacteria. Nat Chem Biol 10:640 2067. Oh K-B, Lee JH, Chung S-C, Shin J, Shin HJ, Kim H-K, Lee H-S (2008) Antimicrobial activities of the bromophenols from the red alga Odonthalia corymbifera and some synthetic derivatives. Bioorg Med Chem Lett 18:104 2068. Barrett TN, Braddock DC, Monta A, Webb MR, White AJP (2011) Total synthesis of the marine metabolite (±)-polysiphenol via highly regioselective intramolecular oxidative coupling. J Nat Prod 74:1980 2069. Bayrak Ç, Taslimi P, Gülçin ˙I, Menzek A (2017) The first synthesis of 4-phenylbutenone derivative bromophenols including natural products and their inhibition profiles for carbonic anhydrase, acetylcholinesterase and butyrylcholinesterase enzymes. Bioorg Chem 72:359 2070. Rezai M, Bayrak Ç, Taslimi P, Gülçin ˙I, Menzek A (2018) The first synthesis and antioxidant and anticholinergic activities of 1-(4,5-dihydroxybenzyl)pyrrolidin-2-one derivative bromophenols including natural products. Turk J Chem 43:808 2071. Bayrak C, Taslimi P, Karaman HS, Gulcin I, Menzek A (2019) The first synthesis, carbonic anhydrase inhibition and anticholinergic activities of some bromophenol derivatives with S including natural products. Bioorg Chem 85:128 2072. Bayrak C, Menzek A (2020) The first synthesis of phenylpropanoid derivative bromophenols including natural products: formation of an indene derivative compound. Tetrahedron 76:131016 2073. Cordes J, Wessel C, Harms K, Koert U (2008) meta-Selective aromatic borylation as key step in the synthesis of poipuol. Synthesis, 2217

Naturally Occurring Organohalogen Compounds …

507

2074. Balaydin HT, Sentürk ¸ M, Menzek A (2012) Synthesis and carbonic anhydrase inhibitory properties of novel cyclohexanonyl bromophenol derivatives. Bioorg Med Chem Lett 22:1352 2075. Balaydin HT, Sentürk ¸ M, Göksu S, Menzek A (2012) Synthesis and carbonic anhydrase inhibitory properties of novel bromophenols and their derivatives including natural products: vidalol B. Eur J Med Chem 54:423 2076. Matulja D, Vranješevi´c F, Markovic MK, Paveli´c SK, Markovi´c D (2022) Anticancer activities of marine-derived phenolic compounds and their derivatives. Molecules 27:1449 2077. Dong H, Dong S, Hansen PE, Stagos D, Lin X, Liu M (2020) Progress of bromophenols in marine algae from 2011 to 2020: structure, bioactivities, and applications. Mar Drugs 18:411 2078. Liu M, Hansen PE, Lin X (2011) Bromophenols in marine algae and their bioactivities. Mar Drugs 9:1273 2079. Boyle JL, Lindsay RC, Stuiber DA (1992) Contributions of bromophenols to marineassociated flavors of fish and seafoods. J Aquatic Food Prod Technol 1:43 2080. Boyle JL, Lindsay RC, Stuiber DA (1993) Occurrence and properties of flavor-related bromophenols found in the marine environment: a review. J Aquatic Food Prod Technol 2:75 2081. Malleret L, Bruchet A (2002) A taste and odor episode caused by 2,4,6-tribromoanisole. J Am Water Works Assn 94:84 2082. Whitfield FB, Hill JL, Shaw KJ (1997) 2,4,6-Tribromoanisole: a potential case of mustiness in packaged food. J Agric Food Chem 45:889 2083. Acero JL, Piriou P, von Gunten U (2005) Kinetics and mechanisms of formation of bromophenols during drinking water chlorination: assessment of taste and odor development. Water Res 39:2979 2084. Bendig P, Lehnert K, Vetter W (2014) Quantification of bromophenols in Islay whiskies. J Agric Food Chem 62:2767 2085. Bidleman TF, Agosta K, Andersson A, Haglund P, Liljelind P, Hegmans A, Jantunen LM, Nygren O, Poole J, Ripszam M, Tysklind M (2016) Sea-air exchange of bromoanisoles and methoxylated bromodiphenyl ethers in the Northern Baltic. Mar Pollut Bull 112:58 2086. Bidleman TF, Brorström-Lundén E, Hansson K, Laudon H, Nygren O, Tysklind M (2017) Atmospheric transport and deposition of bromoanisoles along a temperate to Arctic gradient. Environ Sci Technol 51:10974 2087. Bidleman TF, Andersson A, Brugel S, Ericson L, Haglund P, Kupryianchyk D, Lau DCP, Liljelind P, Lundin L, Tysklind A, Tysklind M (2019) Bromoanisoles and methoxylated bromodiphenyl ethers in macroalgae from Nordic coastal regions. Environ Sci Processes Impacts 21:881 2088. Löfstrand K, Malmvärn A, Haglund P, Bignert A, Bergman Å, Asplund L (2010) Brominated phenols, anisoles, and dioxins present in blue mussels from the Swedish coastline. Environ Sci Pollut Res 17:1460 2089. Carrizo D, Unger M, Holmstrand H, Andersson P, Gustafsson Ö, Sylva SP, Reddy CM (2011) Compound-specific bromine isotope compositions of one natural and six industrially synthesised organobromine substances. Environ Chem 8:127 2090. Gribble GW, Leese RM, Evans BE (1977) Reactions of sodium borohydride in acidic media. IV. Reduction of diarylmethanols and triarylmethanols in trifluoroacetic acid. Synthesis, 172 2091. Gribble GW, Nutaitis CF (1985) [1.1.1.1.1]Paracyclophane and [1.1.1.1.1.1]paracyclophane. Tetrahedron Lett 26:6023 2092. Fan X, Xu NJ, Shi JG (2003) Two new bromophenols from red alga Rhodomela confervoides. Chin Chem Lett 14:939 2093. Xu NJ, Fan X, Yang YC, Shi JG (2003) A new poly brominated dibenzylphenol from Rhodomela confervoides. Chin Chem Lett 14:807 2094. Li K, Li X-M, Ji N-Y, Wang B-G (2008) Bromophenols from the marine red alga Polysiphonia urceolata with DPPH radical scavenging activity. J Nat Prod 71:28 2095. Vetter W, Turek C, Marsh G, Gaus C (2008) Identification and quantification of new polybrominated dimethoxybiphenyls (PBDMBs) in marine mammals from Australia. Chemosphere 73:580

508

G. W. Gribble

2096. Olsen EK, Hansen E, Isaksson J, Andersen JH (2013) Cellular antioxidant effect of four bromophenols from the red algae, Vertebrata lanosa. Mar Drugs 11:2769 2097. Xu X, Yin L, Gao J, Gao L, Song F (2014) Antifungal bromophenols from marine red alga Symphyocladia latiuscula. Chem Biodivers 11:807 2098. Choi YK, Ye B-R, Kim E-A, Kim J, Kim M-S, Lee WW, Ahn G-N, Kang N, Jung W-K, Heo S-J (2018) Bis (3-bromo-4,5-dihydroxybenzyl) ether, a novel bromophenol from the marine red alga Polysiphonia morrowii that suppresses LPS-induced inflammatory response by inhibiting ROS-mediated ERK signaling pathway in RAW 264.7 macrophages. Biomed Pharmacother 103:1170 2099. Lever J, Curtis G, Brkljaˇca R, Urban S (2019) Bromophenolics from the red alga Polysiphonia decipiens. Mar Drugs 17:497 2100. Song R-Y, Liu Y, Liu R-H, Wang X-B, Li T-X, Kong L-Y, Yang M-H (2017) Benzophenone derivatives from the plant endophytic fungus, Pestalotiopsis sp. Phytochem Lett 22:189 2101. Shi D, Li J, Guo S, Su H, Fan X (2009) The antitumor effect of bromophenol derivative in vitro and Leathesia nana extract in vivo. Chin J Oceanol Limnol 27:277 2102. Wu N, Luo J, Jiang B, Wang L, Wang S, Wang C, Fu C, Li J, Shi D (2015) Marine bromophenol bis (2,3-dibromo-4,5-dihydroxy-phenyl)-methane inhibits the proliferation, migration, and invasion of heptocellular carcinoma cells via modulating β1-integrin/FAK signaling. Mar Drugs 13:1010 2103. Oh K-B, Lee JH, Lee JW, Yoon K-M, Chung S-C, Jeon HB, Shin J, Lee H-S (2009) Synthesis and antimicrobial activities of halogenated bis(hydroxyphenyl)methanes. Bioorg Med Chem Lett 19:945 2104. Oh K-B, Jeon HB, Han Y-R, Lee Y-J, Park J, Lee S-H, Yang D, Kwon M, Shin J, Lee H-S (2010) Bromophenols as Candida albicans isocitrate lyase inhibitors. Bioorg Med Chem Lett 20:6644 2105. Liu M, Wang G, Xiao L, Xu X, Liu X, Xu P, Lin X (2014) Bis(2,3-dibromo-4,5dihydroxybenzyl) ether, a marine algae derived bromophenol, inhibits the growth of Botrytis cinerea and interacts with DNA molecules. Mar Drugs 12:3838 2106. Taslimi P, Aslan HE, Demir Y, Oztaskin N, Mara¸s A, Gulçin I, Beydemir S, Goksu S (2018) Diarylmethanon, bromophenol and diarylmethane compounds: discovery of potent aldose reductase, α-amylase and α-glycosidase inhibitors as new therapeutic approach in diabetes and functional hyperglycemia. Int J Biol Macromol 119:857 2107. Luo J, Wu N, Jiang B, Wang L, Wang S, Li X, Wang B, Wang C, Shi D (2015) Marine bromophenol derivative 3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6isopropoxymethyl benzyl)benzene-1,2-diol protects hepatocytes from lipid-induced cell damage and insulin resistance via PTP1B inhibition. Mar Drugs 13:4452 2108. Luo J, Hou Y, Xie M, Ma W, Shi D, Jiang B (2020) CYC31, a natural bromophenol PTP1B inhibitor, activates insulin signaling and improves long chain-fatty acid oxidation in C2C12 myotubes. Mar Drugs 18:267 2109. Balaydin HT, Gülçin Ï, Menzek A, Göksu S, Sahin ¸ E (2010) Synthesis and antioxidant properties of diphenylmethane derivative bromophenols including a natural product. J Enzym Inhib Med Chem 25:685 2110. Akbaba Y, Balaydm HT, Göksu S, Sahin E, Menzek A (2010) Total synthesis of the biologically active, naturally occurring 3,4-dibromo-5-[2-bromo-3,4-dihydroxy6-(methoxymethyl)benzyl]benzene-1,2-diol and regioselective O-demethylation of aryl methyl ethers. Helv Chim Acta 93:1127 2111. Balaydin HT, Soyut H, Ekinci D, Göksu S, Beydemir S, ¸ Menzek A, Sahin ¸ E (2012) Synthesis and carbonic anhydrase inhibitory properties of novel bromophenols including natural products. J Enzym Inhib Med Chem 27:43 2112. Wegener A, Miller KA (2017) Total synthesis of avrainvilleol. J Org Chem 82:11655 2113. Balaydin HT, Akbaba Y, Menzek A, Sahin E, Göksu S (2009) First and short syntheses of biologically active, naturally occurring brominated mono- and dibenzyl phenols. Arkivoc 14:75

Naturally Occurring Organohalogen Compounds …

509

2114. Bultel-Poncé V, Debitus C, Berge J-P, Cerceau C, Guyot M (1998) Metabolites from the sponge-associated bacterium Micrococcus luteus. J Mar Biotechnol 6:233 2115. Nishina A, Kihara H, Uchibori T, Oi T (1991) Antimicrobial substances in “DF-100”, extract of grapefruit seeds. Bokin Bobai 19:401 2116. Zinkernagel R, Koenig M (1967) 2,4,4 -Trichloro-2 -hydroxydiphenyl ether, a new antimicrobial agent. Seifen Oele Fette Wachse 93:670 2117. Cameron GM, Stapleton BL, Simonsen SM, Brecknell DJ, Garson MJ (2000) New sesquiterpene and brominated metabolites from the tropical marine sponge Dysidea sp. Tetrahedron 56:5247 2118. Shimada A, Takahashi I, Kawano T, Kimura Y (2001) Chloroisosulochrin, chloroisosulochrin dehydrate, and pestheic acid, plant growth regulators, produced by Pestalotiopsis theae. Z Naturforsch 56b:797 2119. Utkina NK, Denisenko VA (2006) New polybrominated diphenyl ether from the marine sponge Dysidea herbacea. Chem Nat Compd 42:606 2120. Xu N, Fan X, Yan X, Li X, Niu R, Tseng CK (2003) Antibacterial bromophenols from the marine red alga Rhodomela confervoides. Phytochemistry 62:1221 2121. Lee I-K, Lee J-H, Yin B-S (2008) Polychlorinated compounds with PPAR-γ agonistic effect from the medicinal fungus Phellinus ribis. Bioorg Med Chem Lett 18:4566 2122. Zhang H, Skildum A, Stromquist E, Rose-Hellekant T, Chang LC (2008) Bioactive polybrominated diphenyl ethers from the marine sponge Dysidea sp. J Nat Prod 71:262 2123. Li K, Li X-M, Ji N-Y, Gloer JB, Wang B-G (2008) Urceolatin, a structurally unique bromophenol from Polysiphonia urceolata. Org Lett 10:1429 2124. Calcul L, Chow R, Oliver AG, Tenney K, White KN, Wood AW, Fiorilla C, Crews P (2009) NMR strategy for unraveling structures of bioactive sponge-derived oxy-polyhalogenated diphenyl ethers. J Nat Prod 72:443 2125. Millot M, Tomasi S, Studzinska E, Rouaud I, Boustie J (2009) Cytotoxic constituents of the lichen Diploicia canescens. J Nat Prod 72:2177 2126. Wang J-F, Zhou L-M, Chen S-T, Yang B, Liao S-R, Kong F-D, Lin X-P, Wang F-Z, Zhou XF, Liu Y-H (2018) New chlorinated diphenyl ethers and xanthones from a deep-sea-derived fungus Penicillium chrysogenum SCSIO 41001. Fitoterapia 125:49 2127. Choi H, Engene N, Smith JE, Preskitt LB, Gerwick WH (2010) Crossbyanols A-D, toxic brominated polyphenyl ethers from the Hawai’ian bloom-forming cyanobacterium Leptolyngbya crossbyana. J Nat Prod 73:517 2128. Unger M, Asplund L, Marsh G, Gustafsson Ö (2010) Characterization of an abundant and novel methyl- and methoxy-substituted brominated diphenyl ether isolated from whale blubber. Chemosphere 79:408 2129. Keffer JL, Hammill JT, Lloyd JR, Plaza A, Wipf P, Bewley CA (2012) Geographic variability and anti-staphylococcal activity of the chrysophaentins and their synthetic fragments. Mar Drugs 10:1103 2130. Schreiber D, Jung M, Sandjo LP, Liermann JC, Opatz T, Erkel G (2012) 3 Demethyldihydromaldoxin and dihydromaldoxin, two anti-inflammatory diaryl ethers from a Steganospora species. J Antibiot 65:473 2131. Zhan F, Yang T, Han Y, Li G (2013) A new chlorinated diphenyl ether and five known polyketide metabolites from Penicillium griseofulvum Cib-119. Nat Prod Res 27:1393 2132. Rukachaisirikul V, Satpradit S, Klaiklay S, Phongpaichit S, Borwornwiriyapan K, Sakayaroj J (2014) Polyketide anthraquinone, diphenyl ether, and xanthone derivatives from the soil fungus Penicillium sp. PSU-RSPG99. Tetrahedron 70:5148 2133. Niu S, Liu D, Proksch P, Shao Z, Lin W (2015) New polyphenols from a deep sea Spiromastix sp. fungus, and their antibacterial activities. Mar Drugs 13:2526 2134. Hussain H, Root N, Jabeen F, Al-Harrasi A, Ahmad M, Mabood F, Hassan Z, Shah A, Green IR, Schulz B, Krohn K (2015) Microsphaerol and seimatorone: two new compounds isolated from the endophytic fungi, Microsphaeropsis sp. and Seimatosporium sp. Chem Biodivers 12:289

510

G. W. Gribble

2135. Liu H, Lohith K, Rosario M, Pulliam TH, O’Connor RD, Bell LJ, Bewley CA (2016) Polybrominated diphenyl ethers: structure determination and trends in antibacterial activity. J Nat Prod 79:1872 2136. Dewi AS, Cheney KL, Urquhart HH, Blanchfield JT, Garson MJ (2016) The sesquestration of oxy-polybrominated diphenyl ethers in the nudibranchs Miamira magnifica and Miamira miamirana. Mar Drugs 14:198 2137. Phainuphong P, Rukachaisirikul V, Phongpaichit S, Preedanon S, Sakayaroj J (2017) Diphenyl ethers and indanones from the soil-derived fungus Aspergillus unguis PSURSPG204. Tetrahedron 73:5920 2138. Ki D-W, Awouafack MD, Wong CP, Nguyen HM, Thai QM, Nu LHT, Morita H (2019) Brominated diphenyl ethers including a new tribromoiododiphenyl ether from the Vietnamese marine sponge Arenosclera sp. and their antibacterial activities. Chem Biodivers 16:e1800593 2139. Yamaoka Y, Ohta S, Carmona ML, Oclarit JM (2006) Content and composition of brominated compounds in marine sponges. Bull Soc Sea Water Sci Jpn 60:195 2140. Chilczuk T, Monson R, Schmieder P, Christov V, Enke H, Salmond G, Niedermeyer THJ (2020) Ambigols from the cyanobacterium Fischerella ambigua increase prodigiosin production in Serratia spp. ACS Chem Biol 15:2929 2141. Kresna IDM, Linares-Otoya L, Milzarek T, Duell ER, Mohseni MM, Mettal U, König GM, Gulder TAM, Schäberle TF (2021) In vitro characterization of 3-chloro-4-hydroxybenzoic acid building block formation in ambigol biosynthesis. Org Biomol Chem 19:2302 2142. Shridhar DMP, Mahajan GB, Kamat VP, Naik CG, Parab RR, Thakur NR, Mishra PD (2009) Antibacterial activity of 2-(2 ,4 -dibromophenoxy)-4,6-dibromophenol from Dysidea granulosa. Mar Drugs 7:464 2143. Sun S, Canning CB, Bhargava K, Sun X, Zhu W, Zhou N, Zhang Y, Zhou K (2015) Polybrominated diphenyl ethers with potent and broad spectrum antimicrobial activity from the marine sponge Dysidea. Bioorg Med Chem Lett 25:2181 2144. Hanif N, Ardan MS, Tohir D, Setiawan A, de Voogd NJ, Farid M, Murni A, Tanaka J (2019) Polybrominated diphenyl ethers with broad spectrum antibacterial activity from the Indonesian marine sponge Lamellodysidea herbacea. J Appl Pharm Sci 9:001 2145. Keffer JL, Huecas S, Hammill JT, Wipf P, Andreu JM, Bewley CA (2013) Chrysophaentins are competitive inhibitors of FtsZ and inhibit Z-ring formation in live bacteria. Bioorg Med Chem 21:5673 2146. Schmitt L, Hinxlage I, Cea PA, Gohlke H, Wesselborg S (2021) 40 years of research on polybrominated diphenyl ethers (PBDEs)—a historical overview and newest data of a promising anticancer drug. Molecules 26:995 2147. Legradi J, van Pomeren M, Dahlberg A-K, Legler J (2017) Effects of hydroxylated polybrominated diphenyl ethers in developing zebrafish are indicative of disruption of oxidative phosphorylation. Int J Mol Sci 18:970 2148. Singh KS, Singh A (2022) Chemical diversities, biological activities and chemical synthesis of marine diphenyl ether and their derivatives. J Mol Struct 1265:133302 2149. Wan Y, Wiseman S, Chang H, Zhang X, Jones PD, Hecker M, Kannan K, Tanabe S, Hu J, Lam MHW, Giesy JP (2009) Origin of hydroxylated brominated diphenyl ethers: natural compounds or man-made flame retardants? Environ Sci Technol 43:7536 2150. Alonso MB, Azevedo A, Torres JPM, Dorneles PR, Eljarrat E, Barceló D, Lailson-Brito J Jr, Malm O (2014) Anthropogenic (PBDE) and naturally-produced (MeO-PBDE) brominated compounds in cetaceans—a review. Sci Total Environ 481:619 2151. Lindqvist D, Dahlgren E, Asplund L (2017) Biosynthesis of hydroxylated polybrominated diphenyl ethers and the correlation with photosynthetic pigments in the red alga Ceramium tenuicorne. Phytochemistry 133:51 2152. Losada S, Roach A, Roosens L, Santos FJ, Galceran MT, Vetter W, Neels H, Covaci A (2009) Biomagnification of anthropogenic and naturally-produced organobrominated compounds in a marine food web from Sydney Harbour, Australia. Environ Int 35:1142

Naturally Occurring Organohalogen Compounds …

511

2153. Kim U-J, Jo H, Lee I-S, Joo G-J, Oh J-E (2015) Investigation of bioaccumulation and biotransformation of polybrominated diphenyl ethers, hydroxylated and methoxylated derivatives in varying trophic level freshwater fishes. Chemosphere 137:108 2154. Bendig P, Vetter W (2013) UV-induced formation of bromophenols from polybrominated diphenyl ethers. Environ Sci Technol 47:3665 2155. Lin K, Gan J, Liu W (2014) Production of hydroxylated polybrominated diphenyl ethers from bromophenols by bromoperoxidase-catalyzed dimerization. Environ Sci Technol 48:11977 2156. Solano G, Motti CA, Jaspars M (2009) New iodotyramine derivatives from Didemnum rubeum. Tetrahedron 65:7482 2157. Aiella A, Fattorusso E, Imperatore C, Menna M, Müller WEG (2010) Iodocionin, a cytotoxic iodinated metabolite from the Mediterranean ascidian Ciona edwardsii. Mar Drugs 8:285 2158. Tian L-W, Feng Y, Shimizu Y, Pfeifer TA, Wellington C, Hooper JNA, Quinn RJ (2014) ApoE secretion modulating bromotyrosine derivative from the Australian marine sponge Callyspongia sp. Bioorg Med Chem Lett 24:3537 2159. Tarazona G, Santamaría G, Cruz PG, Fernández R, Pérez M, Martínez-Leal JF, Rodríguez J, Jiménez C, Cuevas C (2017) Cytotoxic anomoian B and aplyzanzine B, new bromotyrosine alkaloids from Indonesian sponges. ACS Omega 2:3494 2160. Bromley CL, Raab A, Parker-Nance S, Beukes DR, Jaspars M, Davies-Coleman MT (2018) Hyphenated LC-ICP-MS/ESI-MS identification of halogenated metabolites in South African marine ascidian extracts. Afr J Chem 71:111 2161. Guillen PO, Jaramillo KB, Jennings L, Genta-Jouve G, de la Cruz M, Cautain B, Reyes F, Rodríguez J, Thomas OP (2019) Halogenated tyrosine derivatives from the tropical Eastern Pacific zoantharians Antipathozoanthus hickmani and Parazoanthus darwini. J Nat Prod 82:1354 2162. Scanlan TS, Suchland KL, Hart ME, Chiellini G, Huang Y, Kruzich PJ, Frascarelli S, Crossley DA II, Bunzow JR, Ronca-Testoni S, Lin ET, Hatton D, Zucchi R, Grandy DK (2004) 3Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Nat Med 10:638 2163. Tan ES, Miyakawa M, Bunzow JR, Grandy DK, Scanlan TS (2007) Exploring the structure– activity relationship of the ethylamine portion of 3-iodothyronamine for rat and mouse trace amine-associated receptor 1. J Med Chem 50:2787 2164. Chemburkar SR, Deming KC, Reddy RE (2010) Chemistry of thyroxine: an historical perspective and recent progress on its synthesis. Tetrahedron 66:1955 2165. Joharapurkar AA, Dhote VV, Jain MR (2012) Selective thyromimetics using receptor and tissue selectivity approaches: prospects for dyslipidemia. J Med Chem 55:5649 2166. Ueberlein S, Machill S, Niemann H, Proksch P, Brunner E (2014) The skeletal amino acid composition of the marine demosponge Aplysina cavernicola. Mar Drugs 12:4417 2167. Ueberlein S, Machill S, Schupp PJ, Brunner E (2017) Determination of the halogenated skeleton constituents of the marine demosponge Ianthella basta. Mar Drugs 15:34 2168. de Lira TO, Berlinck RGS, Nascimento GGF, Hajdu E (2006) Further dibromotyrosinederived metabolites from the marine sponge Aplysina caissara. J Braz Chem Soc 17:1233 2169. Hernández-Guerrero CJ, Zubía E, Ortega MJ, Carballo JL (2007) Cytotoxic dibromotyrosine-derived metabolites from the sponge Aplysina gerardogreeni. Bioorg Med Chem 15:5275 2170. Peng J, Li J, Hamann MT (2005) The marine bromotyrosine derivatives. Alkaloids 61:59 2171. Rogers EW, Molinski TF (2007) Highly polar spiroisoxazolines from the sponge Aplysina fulva. J Nat Prod 70:1191 2172. Motti CA, Freckelton ML, Tapiolas DM, Willis RH (2009) FTICR-MS and LC-UV/MSSPE-NMR applications for the rapid dereplication of a crude extract from the sponge Ianthella flabelliformis. J Nat Prod 72:290 2173. Kalaitzis JA, Leone PDA, Hooper JNA, Quinn RJ (2008) Ianthesine E, a new bromotyrosinederived metabolite from the Great Barrier Reef sponge Pseudoceratina sp. Nat Prod Res 22:1257

512

G. W. Gribble

2174. Ma K, Yang Y, Deng Z, de Voogd NJ, Proksch P, Lin W (2008) Two new bromotyrosine derivatives from the marine sponge Pseudoceratina sp. Chem Biodivers 5:1313 2175. Buchanan MS, Carroll AR, Fechner GA, Boyle A, Simpson MM, Addepalli R, Avery VM, Hooper JNA, Su N, Chen H, Quinn RJ (2007) Spermatinamine, the first natural product inhibitor of isoprenylcysteine carboxyl methyltransferase, a new cancer target. Bioorg Med Chem Lett 17:6860 2176. Yin S, Davis RA, Shelper T, Sykes ML, Avery VM, Elofsson M, Sundin C, Quinn RJ (2011) Pseudoceramines A-D, new antibacterial bromotyrosine alkaloids from the marine sponge Pseudoceratina sp. Org Biomol Chem 9:6755 2177. Buchanan MS, Carroll AR, Addepalli R, Avery VM, Hooper JNA, Quinn RJ (2007) Psammaplysenes C and D, cytotoxic alkaloids from Psammoclemma sp. J Nat Prod 70:1827 2178. Buchanan MS, Carroll AR, Fechner GA, Boyle A, Simpson M, Addepalli R, Avery VM, Hooper JNA, Cheung T, Chen H, Quinn RJ (2008) Aplysamine 6, an alkaloidal inhibitor of isoprenylcysteine carboxyl methyltransferase from the sponge Pseudoceratina sp. J Nat Prod 71:1066 2179. Ullah N, Arafeh KM (2009) The first total synthesis of aplysamine 6, an inhibitor of isoprenylcysteine carboxy methyltransferase. Tetrahedron Lett 50:158 2180. Teruya T, Iwasaki A, Suenaga K (2008) 20-N-Methylpurpuramine E: new bromotyrosinedrived metabolite from Okinawan marine sponge Pseudoceratina purpurea. Bull Chem Soc Jpn 81:1026 2181. Shinde PB, Lee YM, Dang HT, Hong J, Lee C-O, Jung JH (2008) Cytotoxic bromotyrosine derivatives from a two-sponge association of Jaspis sp. and Poecillastra sp. Bioorg Med Chem Lett 18:6414 2182. Buchanan MS, Carroll AR, Wessling D, Jobling M, Avery VM, Davis RA, Feng Y, Hooper JNA, Quinn RJ (2009) Clavatadines C-E, guanidine alkaloids from the Australian sponge Suberea clavata. J Nat Prod 72:973 2183. Nuñez CV, de Almeida EVR, Granato AC, Marques SO, Santos KO, Pereira FR, Macedo ML, Ferreira AG, Hajdu E, Pinheiro US, Muricy G, Peixinho S, Freeman CJ, Gleason DF, Berlinck RGS (2008) Chemical variability within the marine sponge Aplysina fulva. Biochem Syst Ecol 36:283 2184. Mukai H, Kubota T, Aoyama K, Mikami Y, Fromont J, Kobayashi J (2009) Tyrokeradines A and B, new bromotyrosine alkaloids with an imidazolyl-quinolinone moiety from a Verongid sponge. Bioorg Med Chem Lett 19:1337 2185. Fujiwara T, Hwang J-H, Kanamoto A, Nagai H, Takagi M, Shin-ya K (2009) JBIR-44, a new bromotyrosine compound from a marine sponge Psammaplysilla purpurea. J Antibiot 62:393 2186. Cachet N, Genta-Jouve G, Regalado EL, Mokrini R, Amade P, Culioli G, Thomas OP (2009) Parazoanthines A-E, hydantoin alkaloids from the Mediterranean Sea anemone Parazoanthus axinellae. J Nat Prod 72:1612 2187. Yin S, Cullinane C, Carroll AR, Quinn RJ, Davis RA (2010) Botryllamides K and L, new tyrosine derivatives from the Australian ascidian Aplidium altarium. Tetrahedron Lett 51:3403 2188. Henrich CJ, Robey RW, Takada K, Bokesch HR, Bates SE, Shukla S, Ambudkar SV, McMahon JB, Gustafson KR (2009) Botryllamides: natural product inhibitors of ABCG2. ACS Chem Biol 4:637 2189. Wright AE, Roth GP, Hoffman JK, Divlianska DB, Pechter D, Sennett SH, Guzmán EA, Linley P, McCarthy PJ, Pitts TP, Pomponi SA, Reed JK (2009) Isolation, synthesis, and biological activity of aphrocallistin, an adenine-substituted bromotyramine metabolite from the Hexactinellida sponge Aphrocallistes beatrix. J Nat Prod 72:1178 2190. Takada N, Watanabe R, Suenaga K, Yamada K, Ueda K, Kita M, Uemura D (2001) Zamamistatin, a significant antibacterial bromotyrosine derivative, from the Okinawan sponge Pseudoceratina purpurea. Tetrahedron Lett 42:5265 2191. Kita M, Tsunematsu Y, Hayakawa I, Kigoshi H (2008) Structure of zamamistatin—a correction. Tetrahedron Lett 49:5383

Naturally Occurring Organohalogen Compounds …

513

2192. Maru N, Koyama T, Ohno O, Yamada K, Uemura D (2010) Sunabedine, a novel toxic bromotyrosine-derivative alkaloid from Okinawan sponge, order Verongida. Heterocycles 82:371 2193. Feng Y, Davis RA, Sykes ML, Avery VM, Camp D, Quinn RJ (2010) Pseudoceratinazole A: a novel bromotyrosine alkaloid from the Australian sponge Pseudoceratina sp. Tetrahedron Lett 51:4847 2194. Kon Y, Kubota T, Shibazaki A, Gonoi T, Kobayashi J (2010) Ceratinadins A-C, new bromotyrosine alkaloids from an Okinawan marine sponge Pseudoceratina sp. Bioorg Med Chem Lett 20:4569 2195. Yang X, Davis RA, Buchanan MS, Duffy S, Avery VM, Camp D, Quinn RJ (2010) Antimalarial bromotyrosine derivatives from the Australian marine sponge Hyattella sp. J Nat Prod 73:985 2196. Xu M, Andrews KT, Birrell GW, Tran TL, Camp D, Davis RA, Quinn RJ (2011) Psammaplysin H, a new antimalarial bromotyrosine alkaloid from a marine sponge of the genus Pseudoceratina. Bioorg Med Chem Lett 21:846 2197. Graham SK, Lambert LK, Pierens GK, Hooper JNA, Garson MJ (2010) Psammaplin metabolites new and old: an NMR study involving chiral sulfur chemistry. Aust J Chem 63:867 2198. Shaala LA, Bamane FH, Badr JM, Youssef DTA (2011) Brominated arginine-derived alkaloids from the Red Sea sponge Suberea mollis. J Nat Prod 74:1517 2199. Davis RA, Sykes M, Avery VM, Camp D, Quinn RJ (2011) Convolutamines I and J, antitrypanosomal alkaloids from the bryozoan Amathia tortusa. Bioorg Med Chem 19:6615 2200. Mudianta IW, Skinner-Adams T, Andrews KT, Davis RA, Hadi TA, Hayes PY, Garson MJ (2012) Psammaplysin derivatives from the Balinese marine sponge Aplysinella strongylata. J Nat Prod 75:2132 2201. Wright AD, Schupp PJ, Schrör J-P, Engemann A, Rohde S, Kelman D, de Voogd N, Carroll A, Motti CA (2012) Twilight zone sponges from Guam yield theonellin isocyanate and psammaplysins I and J. J Nat Prod 75:502 2202. Lee Y-J, Han S, Lee H-S, Kang JS, Yun J, Sim CJ, Shin HJ, Lee JS (2013) Cytotoxic psammaplysin analogues from a Suberea sp. marine sponge and the role of the spirooxepinisoxazoline in their activity J Nat Prod 76:1731 2203. Carroll AR, Duffy S, Sykes M, Avery VM (2011) Wilsoniamines A and B: novel alkaloids from the temperate Australian bryozoan, Amathia wilsoni. Org Biomol Chem 9:604 2204. Salim AA, Khalil ZG, Capon RJ (2012) Structural and stereochemical investigations into bromotyrosine-derived metabolites from southern Australian marine sponges, Pseudoceratina spp. Tetrahedron 68:9802 2205. Shaala LA, Youssef DTA, Sulaiman M, Behery FA, Foudah AI, El Sayed KA (2012) Subereamolline A as a potent breast cancer migration, invasion and proliferation inhibitor and bioactive dibrominated alkaloids from the Red Sea sponge Pseudoceratina arabica. Mar Drugs 10:2492 2206. Xu M, Davis RA, Feng Y, Sykes ML, Shelper T, Avery VM, Camp D, Quinn RJ (2012) Ianthelliformisamines A-C, antibacterial bromotyrosine-derived metabolites from the marine sponge Suberea ianthelliformis. J Nat Prod 75:1001 2207. Mani L, Jullian V, Mourkazel B, Valentin A, Dubois J, Cresteil T, Folcher E, Hooper JNA, Erpenbeck D, Aalbersberg W, Debitus C (2012) New antiplasmodial bromotyrosine derivatives from Suberea ianthelliformis Lendenfeld, 1888. Chem Biodivers 9:1436 2208. Tran TD, Pham NB, Fechner G, Hooper JNA, Quinn RJ (2013) Bromotyrosine alkaloids from the Australian marine sponge Pseudoceratina verrucosa. J Nat Prod 76:516 2209. Gotsbacher MP, Karuso P (2015) New antimicrobial bromotyrosine analogues from the sponge Pseudoceratina purpurea and its predator Tylodina corticalis. Mar Drugs 13:1389 2210. Tian L-W, Feng Y, Shimizu Y, Pfeifer T, Wellington C, Hooper JNA, Quinn RJ (2014) Aplysinellamides A–C, bromotyrosine-derived metabolites from an Australian Aplysinella sp. marine sponge. J Nat Prod 77:1210

514

G. W. Gribble

2211. Audoin C, Cocandeau V, Thomas OP, Bruschini A, Holderith S, Genta-Jouve G (2014) Metabolome consistency: additional parazoanthines from the Mediterranean zoanthid Parazoanthus axinellae. Metabolites 4:421 2212. Göthel Q, Sirirak T, Köck M (2015) Bromotyrosine-derived alkaloids from the Caribbean sponge Aplysina lacunosa. Beilstein J Org Chem 11:2334 2213. Shaala LA, Youssef DTA, Badr JM, Sulaiman M, Khedr A, El Sayed KA (2015) Bioactive alkaloids from the Red Sea marine verongid sponge Pseudoceratina arabica. Tetrahedron 71:7837 2214. Sirimangkalakitti N, Olatunji OJ, Changwichit K, Saesong T, Chamni S, Chanvorachote P, Ingkaninan K, Plubrukarn A, Suwanborirux K (2015) Bromotyrosine alkaloids with acetylcholinesterase inhibitory activity from the Thai sponge Acanthodendrilla sp. Nat Prod Commun 10:1945 2215. Shaala LA, Youssef DTA, Badr JM, Sulaiman M, Khedr A (2015) Bioactive secondary metabolites from the Red Sea marine verongid sponge Suberea species. Mar Drugs 13:1621 2216. Dai J, Parrish SM, Yoshida WY, Yip MLR, Turkson J, Kelly M, Williams P (2016) Bromotyrosine-derived metabolites from an Indonesian marine sponge in the family Aplysinellidae (Order Verongiida). Bioorg Med Chem Lett 26:499 2217. Sirimangkalakitti N, Yokoya M, Chamni S, Chanvorachote P, Plubrukrn A, Saito N, Suwanborirux K (2016) Synthesis and absolute configuration of acanthodendrilline, a new cytotoxic bromotyrosine alkaloid from the Thai marine sponge Acanthodendrilla sp. Chem Pharm Bull 64:258 2218. McCauley EP, Lam H, Lorig-Roach N, Luu J, Lloyd C, Tenney K, Pietraszkiewicz H, Diaz C, Valeriote FA, Auerbuch V, Crews P (2017) Investigation of the physical and bioactive properties of bromo- and iodo-containing sponge-derived compounds possessing an oxyphenylethanamine core. J Nat Prod 80:3255 ¯ 2219. Kuromoto S, Ohno T, Hokari R, Ishiyama A, Iwatsuki M, Omura S, Kobayashi J, Kubota T (2018) Ceratinadins E and F, new bromotyrosine alkaloids from an Okinawan marine sponge Pseudoceratina sp. Mar Drugs 16:463 2220. Campos P-E, Wolfender J-L, Queiroz EF, Marcourt L, Al-Mourabit A, De Voogd N, Illien B, Gauvin-Bialecki A (2017) Amphimedonoic acid and psammaplysene E, novel brominated alkaloids from Amphimedon sp. Tetrahedron Lett 58:3901 2221. Huang X-P, Deng Z-W, van Soest RWM, Lin W-H (2008) Brominated derivatives from the Chinese sponge Pseudoceratina sp. J Asian Nat Prod Res 10:239 2222. Shaala LA, Khalifa SI, Mesbah MK, van Soest RWM, Youssef DTA (2008) Subereaphenol A, a new cytotoxic and antimicrobial dibrominated phenol from the Red Sea sponge Suberea mollis. Nat Prod Commun 3:219 2223. Jiao W-H, Li J, Zhang M-M, Cui J, Gui Y-H, Zhang Y, Li J-Y, Liu K-C, Lin H-W (2019) Frondoplysins A and B, unprecedented terpene-alkaloid bioconjugates from Dysidea frondosa. Org Lett 21:6190 2224. Shaala LA, Youssef DTA (2019) Cytotoxic psammaplysin analogues from the verongid Red Sea sponge Aplysinella species. Biomolecules 9:841 2225. Kurimoto S, Seino S, Fromont J, Kobayashi J, Kubota T (2019) Ma’edamines C and D, new bromotyrosine alkaloids possessing a unique tetrasubstituted pyridinium moiety from an Okinawan marine sponge Suberea sp. Org Lett 21:8824 2226. Salib MN, Jamison MT, Molinski TF (2020) Bromo-spiroisoxazoline alkaloids, including an isoserine peptide, from the Caribbean marine sponge Aplysina lacunosa. J Nat Prod 83:1532 2227. Tintillier F, Moriou C, Petek S, Fauchon M, Hellio C, Saulnier D, Ekins M, Hooper JNA, AlMourabit A, Debitus C (2020) Quorum sensing inhibitory and antifouling activities of new bromotyrosine metabolites from the Polynesian sponge Pseudoceratina n. sp. Mar Drugs 18:272 2228. Youssef DTA, Asfour HZ, Shaala LA (2021) Psammaceratin A: A cytotoxic psammaplysin dimer featuring an unprecedented (2Z,3Z)-2,3-bis(aminomethylene)succinamide backbone from the Red Sea sponge Pseudoceratina arabica. Mar Drugs 19:433

Naturally Occurring Organohalogen Compounds …

515

2229. Moriou C, Lacroix D, Petek S, El-Demerdash A, Trepos R, Leu TM, Florean C, Diederich M, Hellio C, Debitus C, Al-Mourabit A (2021) Bioactive bromotyrosine derivatives from the Pacific marine sponge Suberea clavata (Pulitzer-Finali, 1982). Mar Drugs 19:143 2230. El-Demerdash A, Moriou C, Toullec J, Besson M, Soulet S, Schmitt N, Petek S, Lecchini D, Debitus C, Al-Mourabit A (2018) Bioactive bromotyrosine-derived alkaloids fom the Polynesian sponge Suberea ianthelliformis. Mar Drugs 16:146 2231. Kubota T, Watase S, Mukai H, Fromont J, Kobayashi J (2012) Tyrokeradines C-F, new bromotyrosine alkaloids from the Verongid sponges. Chem Pharm Bull 60:1599 2232. Kubota T, Watase S, Sakai K, Fromont J, Gonoi T, Kobayashi J (2015) Tyrokeradines G and H, new bromotyrosine alkaloids from an Okinawan verongid sponge. Bioorg Med Chem Lett 25:5221 2233. Ragini K, Fromont J, Piggott AM, Karuso P (2017) Enantiodivergence in the biosynthesis of bromotyrosine alkaloids from sponges? J Nat Prod 80:215 2234. Tadesse M, Svenson J, Jaspars M, Strøm MB, Abdelrahman MH, Andersen JH, Hansen E, Kristiansen PE, Stensvåg K, Haug T (2011) Synoxazolidinone C; a bicyclic member of the synoxazolidinone family with antibacterial and anticancer activities. Tetrahedron Lett 52:1804 2235. Trepos R, Cervin G, Hellio C, Pavia H, Stensen W, Stensvåg K, Svendsen J-S, Haug T, Svenson J (2014) Antifouling compounds from the Sub-Arctic ascidian Synoicum pulmonaria: synoxazolidinones A and C, pulmonarins A and B, and synthetic analogues. J Nat Prod 77:2105 2236. Hopmann KH, Šebestík J, Novotná J, Stensen W, Urbanová M, Svenson J, Svendsen JS, Bouˇr P, Ruud K (2012) Determining the absolute configuration of two marine compounds using vibrational chiroptical spectroscopy. J Org Chem 77:858 2237. Pick N, Rawat M, Arad D, Lan J, Fan J, Kende AS, Av-Gay Y (2006) In vitro properties of antimicrobial bromotyrosine alkaloids. J Med Microbiol 55:407 2238. Galeano E, Thomas OP, Robledo S, Munoz D, Martinez A (2011) Antiparasitic bromotyrosine derivatives from the marine sponge Verongula rigida. Mar Drugs 9:1902 2239. Galeano E, Martínez A, Thomas OP, Robledo S, Munoz D (2012) Antiparasitic bromotyrosine derivatives from the Caribbean marine sponge Aiolochroia crassa. Quim Nova 35:1189 2240. Gómez-Archila LG, Zapata W, Galeano E, Martínez A, Díaz FJ, Rugeles MT (2014) Bromotyrosine derivatives from marine sponges inhibit the HIV-1 replication in vitro. Vitae 21:114 2241. Garcia-Vilas JA, Martínez-Poveda B, Quesada AR, Medina MÁ (2016) Aeroplysinin-1, a sponge-derived multi-targeted bioactive marine drug. Mar Drugs 14:1 2242. Barbero H, Díez-Poza C, Barbero A (2017) The oxepane motif in marine drugs. Mar Drugs 15:361 2243. Santalova EA, Denisenko VA, Glazunov VP, Kalinovskii AI, Anastyuk SD, Stonik VA (2011) Dibromotyrosine derivatives from the ethanol extract of the marine sponge Aplysina sp.: structures, transformations, and origin. Russ Chem Bull Int Ed 60:570 2244. Santalova EA (2012) Base-mediated transformations of 3,5-dibromoverongiaquinol from the sponge Aplysina sp. to cavernicolins-1, -2 and a subereatensin analogue. Nat Prod Commun 7:617 2245. Mándi A, Mudianta IW, Kurtán T, Garson MJ (2015) Absolute configuration and conformational study of psammaplysins A and B from the Balinese marine sponge Aplysinella strongylata. J Nat Prod 78:2051 2246. Florean C, Kim KR, Schnekenburger M, Kim H-J, Moriou C, Debitus C, Dicato M, AlMourabit A, Han BW, Diederich M (2018) Synergistic AML cell death induction by marine cytotoxin (+)-(1R,6S,1 R,6 S,11R,17S)-fistularin-3 and Bcl-2 inhibitor venetoclax. Mar Drugs 16:518 2247. Nicacio KJ, Ióca LP, Fróes AM, Leomil L, Appolinario LR, Thompson CC, Thompson FL, Ferreira AG, Williams DE, Andersen RJ, Eustaquio AS, Berlinck RGS (2017) Cultures of the marine bacterium Pseudovibrio denitrificans Ab134 produce bromotyrosine-derived alkaloids previously only isolated from marine sponges. J Nat Prod 80:235

516

G. W. Gribble

2248. Ullah N (2009) The first total synthesis of racemic hydroxymoloka’iamine. Z Naturforsch 64b:879 2249. Yoshida M, Yamaguchi K (2009) Total synthesis of the marine bromotyrosine alkaloid moloka’iakitamide. Chem Pharm Bull 57:1147 2250. Yang Q, Liu D, Sun D, Yang S, Hu G, Wu Z, Zhao L (2010) Synthesis of the marine bromotyrosine psammaplin F and crystal structure of a psammaplin A analogue. Molecules 15:8784 2251. Kumar R, Bidgood CL, Levrier C, Gunter JH, Nelson CC, Sadowski MC, Davis RA (2020) Synthesis of a unique psammaplysin F library and functional evaluation in prostate cancer cells by multiparametric quantitative single cell imaging. J Nat Prod 83:2357 2252. Mujumdar P, Teruya K, Tonissen KF, Vullo D, Supuran CT, Peat TS, Poulsen S-A (2016) An unusual natural product primary sulfonamide: synthesis, carbonic anhydrase inhibition, and protein X-ray structures of psammaplin C. J Med Chem 59:5462 2253. Hentschel F, Lindel T (2010) Synthesis of oximinotyrosine-derived marine natural products. Synthesis:181 2254. Shearman JW, Myers RM, Beale TM, Brenton JD, Ley SV (2010) Total syntheses of the bromotyrosine-derived natural products ianthelline, 5-bromoverongamine and JBIR-44. Tetrahedron Lett 51:4812 2255. Ullah N, Haladu SA, Mosa BA (2011) An improved total synthesis of spermatinamine, an inhibitor of isoprenylcysteine carboxy methyltransferase. Tetrahedron Lett 52:212 2256. Hillgren JM, Öberg CT, Elofsson M (2012) Syntheses of pseudoceramines A-D and a new synthesis of spermatinamine, bromotyrosine natural products from marine sponges. Org Biomol Chem 10:1246 2257. Shearman JW, Myers RM, Brenton JD, Ley SV (2011) Total syntheses of subereamollines A and B. Org Biomol Chem 9:62 2258. Kottakota SK, Evangelopoulos D, Alnimr A, Bhakta S, McHugh TD, Gray M, Groundwater PW, Marrs ECL, Perry JD, Spilling CD, Harburn JJ (2012) Synthesis and biological evaluation of purpurealidin E-derived marine sponge metabolites: aplysamine-2, aplyzanzine A, and suberedamines A and B. J Nat Prod 75:1090 2259. Chiyoda K, Shimokawa J, Fukuyama T (2012) Total syntheses of all the amathaspiramides. Angew Chem Int Ed 51:2505 2260. Soheili A, Tambar UK (2013) Synthesis of (±)-amathaspiramide F and discovery of an unusual stereocontrolling element for the [2,3]-Stevens rearrangement. Org Lett 15:5138 2261. Cho H, Shin JE, Lee S, Jeon H, Park S, Kim S (2018) Asymmetric Cα-alkylation of proline via chirality transfers of conformationally restricted proline derivative: application to the total synthesis of (–)-amathaspiramide F. Org Lett 20:6121 2262. O’Connor M, Sun C, Lee D (2015) Synthesis of amathaspiramides by aminocyanation of enoates. Angew Chem Int Ed 54:9963 2263. Cai S-L, Song R, Dong H-Q, Lin G-Q, Sun X-W (2016) Practical asymmetric synthesis of amathaspiramides B, D, and F. Org Lett 18:1996 2264. Ahmad S, Choudhury S, Khan FA (2015) Synthesis of marine brominated alkaloid amathamide F: a palladium-catalyzed enamide synthesis. Tetrahedron 71:4192 2265. Khan FA, Ahmad S (2012) Synthesis of reported and revised structures of amathamide D and synthesis of convolutamine F, H and lutamide A. C. J Org Chem 77:2389 2266. Khan FA, Ahmad S (2013) Synthesis of wilsoniamines A and B. Tetrahedron Lett 54:2996 2267. Kubo H, Matsui K, Saitoh T, Nishiyama S (2014) Synthesis and assignment of the absolute stereochemistry of (+)-hemifistularin 3. Tetrahedron 70:6392 2268. Xu J, Wang K, Wu J (2018) A short and efficient total synthesis of the bromotyrosine-derived alkaloid psammaplysene A. RSC Adv 8:13747 2269. Bhat C, Ilina P, Tilli I, Voráˇcová M, Bruun T, Barba V, Hribernik N, Lillsunde K-E, MäkiLohiluoma E, Rüffer T, Lang H, Yli-Kauhaluoma J, Kiuru P, Tammela P (2018) Synthesis and antiproliferative activity of marine bromotyrosine purpurealidin I and its derivatives. Mar Drugs 16:481

Naturally Occurring Organohalogen Compounds …

517

2270. Wu W-J, Wu Y, Liu B (2017) Synthesis of purpuroine A, nakirodin A and MDN-0104: The hidden puzzles and risk of error in their configurational assignments. Tetrahedron 73:1265 2271. Cheng Z-Q, Song J-L, Zhu K, Zhang J, Jiang C-S, Zhang H (2018) Total synthesis of pulmonarin B and design of brominated phenylacetic acid/tacrine hybrids: marine pharmacophore inspired discovery of new ChE and Aβ aggregation inhibitors. Mar Drugs 16:293 2272. Davenport MT, Dickson JA, Johnson MR, Chamberland S (2019) Total synthesis of clavatadine B. J Nat Prod 82:3191 2273. Badart MP, Squires CML, Baird SK, Hawkins BC (2016) The synthesis of clavatadine C. Tetrahedron Lett 57:5108 2274. Wefer J, Lindel T (2015) Total synthesis of the marine natural product parazoanthine F by copper-mediated C–N coupling. Eur J Org Chem 6370 2275. Pieri C, Borselli D, Di Giorgio C, De Méo M, Bolla J-M, Vidal N, Combes S, Brunel JM (2014) New ianthelliformisamine derivatives as antibiotic enhancers against resistant Gram-negative bacteria. J Med Chem 57:4263 2276. Khan FA, Ahmad S, Kodipelli N, Shivange G, Anindya R (2014) Syntheses of a library of molecules on the marine natural product ianthelliformisamines platform and their biological evaluation. Org Biomol Chem 12:3847 2277. Saha S, Reddy CVR, Chiranjeevi T, Addepally U, Rao TSC, Patro B (2013) The first total synthesis and biological evaluation of marine natural products ma’edamines A and B. Bioorg Med Chem Lett 23:1013 2278. Saha S, Reddy CVR, Xu S, Sankar S, Neamati N, Patro B (2013) Synthesis and SAR studies of marine natural products ma’edamines A, B and their analogues. Bioorg Med Chem Lett 23:5135 2279. Shymanska NV, An IH, Pierce JG (2014) A rapid synthesis of 4-oxazolidinones: total synthesis of synoxazolidinones A and B. Angew Chem Int Ed 53:5401 2280. Greve H, Kehraus S, Krick A, Kelter G, Maier A, Fiebig H-H, Wright AD, König GM (2008) Cytotoxic bastadin 24 from the Australian sponge Ianthella quadrangulata. J Nat Prod 71:309 2281. Carroll AR, Kaiser SM, Davis RA, Moni RW, Hooper JNA, Quinn RJ (2010) A bastadin with potent and selective δ-opioid receptor binding affinity from the Australian sponge Ianthella flabelliformis. J Nat Prod 73:1173 2282. Calcul L, Inman WD, Morris AA, Tenney K, Ratnam J, McKerrow JH, Valeriote FA, Crews P (2010) Additional insights on the bastadins: isolation of analogues from the sponge Ianthella cf. reticulata and exploration of the oxime configurations. J Nat Prod 73:365 2283. Pérez-Rodríguez S, Pereira-Cameselle R, de Lera AR (2012) First total synthesis of dioxepine bastadin 3. Org Biomol Chem 10:6945 2284. Van Wyk AWW, Zuck KM, McKee TC (2011) Lithothamnin A, the first bastadin-like metabolite from the red alga Lithothamnion fragilissimum. J Nat Prod 74:1275 2285. Eguchi K, Kato H, Fujiwara Y, Losung F, Mangindaan REP, de Voogd NJ, Takeya M, Tsukamoto S (2015) Bastadins, brominated-tyrosine derivatives, suppress accumulation of cholesterol ester in macrophages. Bioorg Med Chem Lett 25:5389 2286. Niemann H, Lin W, Müller WEG, Kubbutat M, Lai D, Proksch P (2013) Trimeric hemibastadin congener from the marine sponge Ianthella basta. J Nat Prod 76:121 2287. Gartshore CJ, Salib MN, Renshaw AA, Molinski TF (2018) Isolation of bastadin-6-Osulfate and expedient purifications of bastadins-4, -5 and -6 from extracts of Ianthella basta. Fitoterapia 126:16 2288. Guo Z, Machiya K, Salamonczyk GM, Sih CJ (1998) Total synthesis of bastadins 2, 3, and 6. J Org Chem 63:4269 2289. Zieminska E, Lazarewicz JW, Couladouros EA, Moutsos VI, Pitsinos EN (2008) Openchain half-bastadins mimic the effects of cyclic bastadins on calcium homeostasis in cultured neurons. Bioorg Med Chem Lett 18:5734 2290. Inman WD, Crews P (2011) Unraveling the bastarane and isobastarane oximo amide configurations and associated macrocycle conformations: implications of their influence on bioactivities. J Nat Prod 74:402

518

G. W. Gribble

2291. Le Norcy T, Niemann H, Proksch P, Tait K, Linossier I, Réhel K, Hellio C, Faÿ F (2017) Sponge-inspired dibromohemibastadin prevents and disrupts bacterial biofilms without toxicity. Mar Drugs 15:222 2292. Elix JA, Wardlaw JH (2000) A new chloro-depside from the lichen Hypotrachyna leiophylla. Aust J Chem 53:1007 2293. Li E, Jiang L, Guo L, Zhang H, Che Y (2008) Pestalachlorides A-C, antifungal metabolites from the plant endophytic fungus Pestalotiopsis adusta. Bioorg Med Chem 16:7894 2294. Zhu C-C, Wang T-M, Wang K-J, Li N (2009) A new chlorine-containing glucosyl-fused compound from Curculigo glabrescens. Z Naturforsch 64b:1077 2295. Millot M, Tomasi S, Articus K, Rouaud I, Bernard A, Boustie J (2007) Metabolites from the lichen Ochrolechia parella growing under two different heliotropic conditions. J Nat Prod 70:316 2296. Li G-Y, Li B-G, Yang T, Liu G-Y, Zhang G-L (2008) Secondary metabolites from the fungus Chaetomium brasiliense. Helv Chim Acta 91:124 2297. Khumkomkhet P, Kanokmedhakul S, Kanokmedhakul K, Hahnvajanawong C, Soytong K (2009) Antimalarial and cytotoxic depsidones from the fungus Chaetomium brasiliense. J Nat Prod 72:1487 2298. Sureram S, Wiyakrutta S, Ngamrojanavanich N, Mahidol C, Ruchirawat S, Kittakoop P (2012) Depsidones, aromatase inhibitors and radical scavenging agents from the marinederived fungus Aspergillus unguis CRI282-03. Planta Med 78:582 2299. Niu S, Liu D, Hu X, Proksch P, Shao Z, Lin W (2014) Spiromastixones A–O, antibacterial chlorodepsidones from a deep-sea-derived Spiromastix sp. fungus. J Nat Prod 77:1021 2300. Klaiklay S, Rukachaisirikul V, Aungphao W, Phongpaichit S, Sakayaroj J (2016) Depsidone and phthalide derivatives from the soil-derived fungus Aspergillus unguis PSU-RSPG199. Tetrahedron Lett 57:4348 2301. Uchida R, Nakajyo K, Kobayashi K, Ohshiro T, Terahara T, Imada C, Tomoda H (2016) 7-Chlorofolipastatin, an inhibitor of sterol O-acyltransferase, produced by marine-derived Aspergillus ungui NKH-007. J Antibiot 69:647 2302. Liu D, Li Y, Li X, Cheng Z, Huang J, Proksch P, Lin W (2017) Chartarolides A-C, novel meroterpenoids with antitumor activities. Tetrahedron Lett 58:1826 2303. Liu H, Tan H, Chen Y, Guo X, Wang W, Guo H, Liu Z, Zhang W (2019) Cytorhizins AD, four highly structure-combined benzophenones from the endophytic fungus Cytospora rhizophorae. Org Lett 21:1063 2304. Ibrahim SRM, Mohamed GA, Al Haidari RA, El-Kholy AA, Zayed MF, Khayat MT (2018) Biologically active fungal depsidones: chemistry, biosynthesis, structural characterization, and bioactivities. Fitoterapia 129:317 2305. Lösgen S, Magull J, Schulz B, Draeger S, Zeeck A (2008) Isofusidienols: novel chromone3-oxepines produced by the endophytic fungus Chalara sp. Eur J Org Chem: 698 2306. Leet JE, Liu X, Drexler DM, Cantone JL, Huang S, Mamber SW, Fairchild CR, Hussain R, Newman DJ, Kingston DGI (2008) Cytotoxic xanthones from Psorospermum molluscum from the Madagascar rain forest. J Nat Prod 71:460 2307. Pontius A, Krick A, Kehraus S, Brun R, König GM (2008) Antiprotozoal activities of heterocyclic-substituted xanthones from the marine-derived fungus Chaetomium sp. J Nat Prod 71:1579 2308. Huang L, Lei T, Lin C, Kuang X, Chen H, Zhou H (2010) Blumeaxanthene II, a novel xanthene from Blumea riparia DC. Fitoterapia 81:389 2309. Fredimoses M, Zhou X, Lin X, Tian X, Ai W, Wang J, Liao S, Liu J, Yang B, Yang X, Liu Y (2014) New prenylxanthones from the deep-sea derived fungus Emericella sp. SCSIO 05240. Mar Drugs 12:3190 2310. Yao Q, Wang J, Zhang X, Nong X, Xu X, Qi S (2014) Cytotoxic polyketides from the deep-sea-derived fungus Engyodontium album DFFSCS021. Mar Drugs 12:5902 2311. Qin C, Lin X, Lu X, Wan J, Zhou X, Liao S, Tu Z, Xu S, Liu Y (2015) Sesquiterpenoids and xanthones derivatives produced by sponge-derived fungus Stachybotrys sp. HH1 ZSDS1F12. J Antibiot 68:121

Naturally Occurring Organohalogen Compounds …

519

2312. Wang J, Ding W, Wang R, Du Y, Liu H, Kong X, Li C (2015) Identification and bioactivity of compounds from the mangrove endophytic fungus Alternaria sp. Mar Drugs 13:4492 2313. He K-Y, Zhang C, Duan Y-R, Huang G-L, Yang C-Y, Lu X-R, Zheng C-J, Chen G-Y (2017) New chlorinated xanthone and anthraquinone produced by a mangrove-derived fungus Penicillium citrinum HL-5126. J Antibiot 70:823 2314. Han J, Zhang J, Song Z, Liu M, Hu J, Hou C, Zhu G, Jiang L, Xia X, Quinn RJ, Feng Y, Zhang L, Hsiang T, Liu X (2019) Genome- and MS-based mining of antibacterial chlorinated chromones and xanthones from the phytopathogenic fungus Bipolaris sorokiniana strain 11134. Appl Microbiol Biotechnol 103:5167 2315. Winter DK, Sloman DL, Porco JA Jr (2013) Polycyclic xanthone natural products: structure, biological activity and chemical synthesis. Nat Prod Rep 30:382 2316. Potterat O, Puder C, Wagner K, Bolek W, Vettermann R, Kauschke SG (2007) Chlorocyclinones A-D, chlorinated angucyclinones from Streptomyces sp. strongly antagonizing rosiglitazone-induced PPAR-γ activation. J Nat Prod 70:1934 2317. Karmakar R, Mal D (2012) Total synthesis of chlorocyclinone A, a PPAR-γ antagonist. J Org Chem 77:10235 2318. Wolkenstein K, Schoefberger W, Müller N, Oji T (2009) Proisocrinins A-F, brominated anthraquinone pigments from the stalked crinoid Proisocrinus ruberrimus. J Nat Prod 72:2036 2319. Wangun HVK, Wood A, Fiorilla C, Reed JK, McCarthy PJ, Wright AE (2010) Gymnochromes E and F, cytotoxic phenanthroperylenequinones from a deep-water crinoid, Holopus rangii. J Nat Prod 73:712 2320. Murphy BT, Narender T, Kauffman CA, Woolery M, Jensen PR, Fenical W (2010) Saliniquinones A-F, new members of the highly cytotoxic anthraquinone-γ-pyrones from the marine actinomycete Salinispora arenicola. Aust J Chem 63:929 2321. Motohashi K, Takagi M, Yamamura H, Hayakawa M, Shin-ya K (2010) A new angucycline and a new butenolide isolated from lichen-derived Streptomyces spp. J Antibiot 63:545 2322. Aly AH, Debbab A, Clements C, Edrada-Ebel R, Orlikova B, Diederich M, Wray V, Lin WH, Proksch P (2011) NF kappa B inhibitors and antitrypanosomal metabolites from endophytic fungus Penicillium sp. isolated from Limonium tubiflorum. Bioorg Med Chem 19:414 2323. Huang H, Wang F, Luo M, Chen Y, Song Y, Zhang W, Zhang S, Ju J (2012) Halogenated anthraquinones from the marine-derived fungus Aspergillus sp. SCSIO F063. J Nat Prod 75:1346 2324. Isaka M, Chinthanom P, Rachtawee P, Srichomthong K, Srikitikulchai P, Kongsaeree P, Prabpai S (2015) Cytotoxic hydroanthraquinones from the mangrove-derived fungus Paradictyoarthrinium diffractum BCC 8704. J Antibiot 68:334 2325. Lü Y, Yue C, Shao M, Qian S, Liu N, Bao Y, Wang M, Liu M, Li X, Wang Y, Huang Y (2016) Molecular genetic characterization of an anthrabenzoxocinones gene cluster in Streptomyces sp. FJS31-2 for the biosynthesis of BE-24566B and zunyimycin ale. Molecules 21:711 2326. Lü Y, Shao M, Wang Y, Qian S, Wang M, Wang Y, Li X, Bao Y, Deng C, Yue C, Liu D, Liu N, Liu M, Huang Y, Chen Z, Hu Y (2017) Zunyimycins B and C, new chloroanthrabenzoxocinones antibiotics against methicillin-resistant Staphylococcus aureus and Enterococci from Streptomyces sp. FJS31–2. Molecules 22:251 2327. Mei X, Yan X, Zhang H, Yu M, Shen G, Zhou L, Deng Z, Lei C, Qu X (2018) Expanding the bioactive chemical space of anthrabenzoxocinones through engineering the highly promiscuous biosynthetic modification steps. ACS Chem Biol 13:200 2328. Khokhar S, Pierens GK, Hooper JNA, Ekins MG, Feng Y, Davis RA (2016) Rhodocomatulintype anthraquinones from the Australian marine invertebrates Clathria hirsuta and Comatula rotalaria. J Nat Prod 79:946 2329. Cruz JCS, Maffioli SI, Bernasconi A, Brunati C, Gaspari E, Sosio M, Wellington E, Donadio S (2017) Allocyclinones, hyperchlorinated angucyclinones from Actinoallomurus. J Antibiot 70:73 2330. Luo M, Cui Z, Huang H, Song X, Sun A, Dang Y, Lu L, Ju J (2017) Amino acid conjugated anthraquinones from the marine-derived fungus Penicillium sp. SCSIO sof101. J Nat Prod 80:1668

520

G. W. Gribble

2331. Mandelare PE, Adpressa DA, Kaweesa EN, Zakharov LN, Loesgen S (2018) Coculture of two developmental stages of a marine-derived Aspergillus alliaceus results in the production of the cytotoxic bianthrone allianthrone A. J Nat Prod 81:1014 2332. Zhang D, Jiang Y, Li J, Zhang H, Ding W, Ma Z (2018) Alokicenones A–H, eight tetrahydroanthracenes from the mangrove-derived Streptomyces sp. HN-A101. Tetrahedron 74:6667 2333. Wolkenstein K, Fuentes-Monteverde JC, Nath N, Oji T, Griesinger C (2019) Hypalocrinins, taurine-conjugated anthraquinone and biaryl pigments from the deep sea crinoid Hypalocrinus naresianus. J Nat Prod 82:163 2334. Ge X, Sun C, Feng Y, Wang L, Peng J, Che Q, Gu Q, Zhu T, Li D, Zhang G (2019) Anthraquinone derivatives from a marine-derived fungus Sporendonema casei HDN16-802. Mar Drugs 17:334 2335. Stevanovi´c D, Damljanovi´c I, Vuki´cevi´c M, Manojlovi´c N, Radulovi´c NS, Vuki´cevi´c RD (2011) Electrochemical chlorination of physcion—an approach to naturally occurring chlorinated secondary metabolites of lichens. Helv Chim Acta 94:1406 2336. Zaleski PA, Maini R, Leiris SJ, Elban MA, Hecht SM (2012) Synthesis and biological activities of topopyrones. J Nat Prod 75:577 2337. Stocker-Wörgötter E (2008) Metabolic diversity of lichen-forming ascomycetous fungi: culturing, polyketide and shikimate metabolite production, and PKS genes. Nat Prod Rep 25:188 2338. Falk H (1999) From the photosensitizer hypericin to the photoreceptor stentorin—the chemistry of phenanthroperylene quinones. Angew Chem Int Ed 38:3116 2339. Greco G, Turrini E, Catanzaro E, Fimognari C (2021) Marine anthraquinones: pharmacological and toxicological issues. Mar Drugs 19:272 2340. Rønnest MH, Rebacz B, Markworth L, Terp AH, Larsen TO, Krämer A, Clausen MH (2009) Synthesis and structure–activity relationship of griseofulvin analogues as inhibitors of centrosomal clustering in cancer cells. J Med Chem 52:3342 2341. Rønnest MH, Raab MS, Anderhub S, Boesen S, Krämer A, Larsen TO, Clausen MH (2012) Disparate SAR data of griseofulvin analogues for the dermatophytes Trichophyton mentagrophytes, T. rubrum, and MDA-MB-231 cancer cells. J Med Chem 55:652 2342. Rønnest MH, Harris P, Gotfredsen CH, Larsen TO, Clausen MH (2010) Synthesis and single crystal X-ray analysis of two griseofulvin metabolites. Tetrahedron Lett 51:5881 2343. Wen L, Guo Z, Li Q, Zhang D, She Z, Vrijmoed LLP (2010) A new griseofulvin derivative from the mangrove endophytic fungus Sporothrix sp. Chem Nat Compd 46:363 2344. Shang Z, Li X-M, Li C-S, Wang B-G (2012) Diverse secondary metabolites produced by marine-derived fungus Nigrospora sp. MA75 on various culture media. Chem Biodivers 9:1338 2345. Xia X, Li Q, Li J, Shao C, Zhang J, Zhang Y, Liu X, Lin Y, Liu C, She Z (2011) Two new derivatives of griseofulvin from the mangrove endophytic fungus Nigrospora sp. (strain No. 1403) from Kandelia candel (L.) Druce. Planta Med 77:1735 2346. Wei M-Y, Xu R-F, Du S-Y, Wang C-Y, Xu T-Y, Shao C-L (2016) A new griseofulvin derivative from the marine-derived Arthrinium sp. fungus and its biological activity. Chem Nat Compd 52:1011 2347. Roullier C, Guitton Y, Valery M, Amand S, Prado S, du Pont TR, Grovel O, Pouchus YF (2016) Automated detection of natural halogenated compounds from LC-MS profiles— application to the isolation of bioactive chlorinated compounds from marine-derived fungi. Anal Chem 88:9143 2348. Zhang D, Zhao L, Wang L, Fang X, Zhao J, Wang X, Li L, Liu H, Wei Y, You X, Cen S, Yu L (2017) Griseofulvin derivative and indole alkaloids from Penicillium griseofulvum CPCC 400528. J Nat Prod 80:371 2349. Cacho RA, Chooi Y-H, Zhou H, Tang Y (2013) Complexity generation in fungal polyketide biosynthesis: a spirocycle-forming P450 in the concise pathway to the antifungal drug griseofulvin. ACS Chem Biol 8:2322

Naturally Occurring Organohalogen Compounds …

521

2350. Petersen AB, Rønnest MH, Larsen TO, Clausen MH (2014) The chemistry of griseofulvin. Chem Rev 114:12088 2351. Liu L, Liu S, Jiang L, Chen X, Guo L, Che Y (2008) Chloropupukeananin, the first chlorinated pupukeanane derivative, and its precursors from Pestalotiopsis fici. Org Lett 10:1397 2352. Liu L, Li Y, Liu S, Zheng Z, Chen X, Zhang H, Guo L, Che Y (2009) Chloropestolide A, an antitumor metabolite with an unprecedented spiroketal skeleton from Pestalotiopsis fici. Org Lett 11:2836 2353. Liu L, Niu S, Lu X, Chen X, Zhang H, Guo L, Che Y (2010) Unique metabolites of Pestalotiopsis fici suggest a biosynthetic hypothesis involving a Diels-Alder reaction and then mechanistic diversification. Chem Commun 46:460 2354. Liu L, Bruhn T, Guo L, Götz DCG, Brun R, Stich A, Che Y, Bringmann G (2011) Chloropupukeanolides C-E: cytotoxic pupukeanane chlorides with a spiroketal skeleton from Pestalotiopsis fici. Chem Eur J 17:2604 2355. Liu L, Li Y, Li L, Cao Y, Guo L, Liu G, Che Y (2013) Spiroketals of Pestalotiopsis fici provide evidence for a biosynthetic hypothesis involving diversified Diels-Alder reaction cascades. J Org Chem 78:2992 2356. Wei M-Y, Li D, Shao C-L, Deng D-S, Wang C-Y (2013) (±)-Pestalachloride D, an antibacterial racemate of chlorinated benzophenone derivative from a soft coral-derived fungus Pestalotiopsis sp. Mar Drugs 11:1050 2357. Arredondo V, Roa DE, Yan S, Liu-Smith F, Van Vranken DL (2019) Total synthesis of (±)-pestalachloride C and (±)-pestalachloride D through a biomimetic Knoevenagel/heteroDiels–Alder cascade. Org Lett 21:1755 2358. Slavov N, Cvengros J, Neudörfl J-M, Schmalz H-G (2010) Total synthesis of the marine antibiotic pestalone and its surprisingly facile conversion into pestalalactone and pestalachloride A. Angew Chem Int Ed 49:7588 2359. Xing Q, Gan L-S, Mou X-F, Wang W, Wang C-Y, Wei M-Y, Shao C-L (2016) Isolation, resolution and biological evaluation of pestalachlorides E and F containing both point and axial chirality. RSC Adv 6:22653 2360. Misiek M, Williams J, Schmich K, Hüttel W, Merfort I, Salomon CE, Aldrich CC, Hoffmeister D (2009) Structure and cytotoxicity of arnamial and related fungal sesquiterpene aryl esters. J Nat Prod 72:1888 2361. Kobori H, Sekiya A, Suzuki T, Choi J-H, Hirai H, Kawagishi H (2015) Bioactive sesquiterpene aryl esters from the culture broth of Armillaria sp. J Nat Prod 78:163 2362. Bohnert M, Miethbauer S, Dahse H-M, Ziemen J, Nett M, Hoffmeister D (2011) In vitro cytotoxicity of melleolide antibiotics: structural and mechanistic aspects. Bioorg Med Chem Lett 21:2003 2363. Kornsakulkarn J, Thongpanchang C, Chainoy R, Choowong W, Nithithanasilp S, Thongpanchang T (2010) Bioactive metabolites from cultures of basidiomycete Favolaschia tonkinensis. J Nat Prod 73:759 2364. Kornsakulkarn J, Palasarn S, Choowong W, Thongpanchang T, Boonyuen N, Choeyklin R, Boonpratuang T, Isaka M, Thongpanchang C (2020) Antimalarial 9-methoxystrobilurins, oudemansins, and related polyketides from cultures of basidiomycete Favolaschia species. J Nat Prod 83:905 2365. Guimarães DO, Lopes NP, Pupo MT (2012) Meroterpenes isolated from the endophytic fungus Guignardia mangiferae. Phytochem Lett 5:519 2366. Kim S-H, Kwon SH, Park S-H, Lee JK, Bang H-S, Nam S-J, Kwon HC, Shin J, Oh D-C (2013) Tripartin, a histone demethylase inhibitor from a bacterium associated with a dung beetle larva. Org Lett 15:1834 2367. Asai T, Otsuki S, Sakurai H, Yamashita K, Ozeki T, Oshima Y (2013) Benzophenones from an endophytic fungus, Graphiopsis chlorocephala, from Paeonia lactiflora cultivated in the presence of an NAD+ -dependent HDAC inhibitor. Org Lett 15:2058 2368. Kawaguchi M, Fukuda T, Uchida R, Nonaka K, Masuma R, Tomoda H (2013) A new ascochlorin derivative from Cylindrocarpon sp. FKI-4602. J Antibiot 66:23

522

G. W. Gribble

2369. Wanigesekara WMAP, Wijeratne EMK, Arnold AE, Gunatilaka AAL (2013) 10 -Deoxy10 α-hydroxyascochlorin, a new cell migration inhibitor and other metabolites from Acremonium sp., a fungal endophyte in Ephedra trifurca. Nat Prod Commun 8:601 2370. Isaka M, Yangchum A, Supothina S, Laksanacharoen P, Luangsa-ard JJ, Hywel-Jones NL (2015) Ascochlorin derivatives from the leafhopper pathogenic fungus Microcera sp. BCC 17074. J Antibiot 68:47 2371. Nirma C, Eparvier V, Stien D (2015) Antibacterial ilicicolinic acids C and D and ilicicolinal from Neonectria discophora SNB-CN63 isolated from a termite nest. J Nat Prod 78:159 2372. Sorres J, Sabri A, Brel O, Stien D, Eparvier V (2018) Ilicicolinic acids and ilicicolinal derivatives from the fungus Neonectria discophora SNB-CN63 isolated from the nest of the termite Nasutitermes corniger found in French Guiana show antimicrobial activity. Phytochemistry 151:69 2373. Wu J, Tokunaga T, Kondo M, Ishigami K, Tokuyama S, Suzuki T, Choi J-H, Hirai H, Kawagishi H (2015) Erinaceolactones A to C, from the culture broth of Hericium erinaceus. J Nat Prod 78:155 2374. Fu Y, Wu P, Xue J, Wei X (2014) Cytotoxic and antibacterial quinone sesquiterpenes from a Myrothecium fungus. J Nat Prod 77:1791 2375. Hammerschmidt L, Debbab A, Ngoc TD, Wray V, Hemphil CP, Lin WH, Broetz-Oesterhelt H, Kassack MU, Proksch P, Aly AH (2014) Polyketides from the mangrove-derived endophytic fungus Acremonium strictum. Tetrahedron Lett 55:3463 2376. Bunyapaiboonsri T, Yoiprommarat S, Lapanun S, Balram U, Chanthaket R, Klaysuban A, Suetrong S (2016) Trichothecenes from the fungus Acremonium crotocinigenum BCC 20012. Phytochem Lett 18:39 2377. Du L, King JB, Cichewicz RH (2014) Chlorinated polyketide obtained from a Daldina sp. treated with the epigenetic modifier suberoylanilide hydroxamic acid. J Nat Prod 77:2454 2378. Daengrot C, Rukachaisirikul V, Tansakul C, Thongpanchang T, Phongpaichit S, Bowornwiriyapan K, Sakayaroj J (2015) Eremophilane sesquiterpenes and diphenyl thioesters from the soil fungus Penicillium copticola PSU-RSPG138. J Nat Prod 78:615 2379. Bu Y-Y, Yamazaki H, Ukai K, Namikoshi M (2015) Penicillimide, an open-chain hemisuccinimide from Okinawan marine-derived Penicillium copticola. J Antibiot 68:537 2380. Cardoso-Martínez F, de la Rosa JM, Díaz-Marrero AR, Darias J, Cerella C, Diederich M, Cueto M (2015) Tanzawaic acids isolated from a marine-derived fungus of the genus Penicillium with cytotoxic activities. Org Biomol Chem 13:7248 2381. Zhao Y, Si L, Liu D, Proksch P, Zhou D, Lin W (2015) Truncateols A-N, new isoprenylated cyclohexanols from the sponge-associated fungus Truncatella angustata with anti-H1 N1 virus activities. Tetrahedron 71:2708 2382. Niu S, Si L, Liu D, Zhou A, Zhang Z, Shao Z, Wang S, Zhang L, Zhou D, Lin W (2016) Spiromastilactones: a new class of influenza virus inhibitors from deep-sea fungus. Eur J Med Chem 108:229 2383. Ren X, Chen C, Ye Y, Xu Z, Zhao Q, Luo X, Liu Y, Guo P (2022) Anti-inflammatory compounds from the mangrove endophytic fungus Amorosia sp. SCSIO 41026. Front Microbiol 13:976399 2384. Tanaka S, Honmura Y, Uesugi S, Fukushi E, Tanaka K, Maeda H, Kimura K, Nehira T, Hashimoto M (2017) Cyclohelminthol X, a hexa-substituted spirocyclopropane from Helminthosporium velutinum yone96: structural elucidation, electronic circular dichroism analysis, and biological properties. J Org Chem 82:5574 2385. Tanaka S, Tanaka K, Maeda H, Hashimoto M (2018) Cyclohelminthols Y1–Y4 metabolites possessing two spirocyclopropanes in their structure. J Org Chem 83:5688 2386. Subko K, Kildgaard S, Vicente F, Reyes F, Genilloud O, Larsen TO (2021) Bioactive ascochlorin analogues from the marine-derived fungus Stilbella fimetaria. Mar Drugs 19:46 2387. Bogdanov A, Papu A, Kehraus S, Cruesemann M, Wägele H, König GM (2020) Metabolome of the Phyllidiella pustulosa species complex (Nudibranchia, Heterobranchia, Gastropoda) reveals rare dichloroimidic sesquiterpene derivatives from a phylogenetically distinct and undescribed clade. J Nat Prod 83:2785

Naturally Occurring Organohalogen Compounds …

523

2388. Iqbal Z, Han L-C, Soares-Sello AM, Nofiani R, Thormann G, Zeeck A, Cox RJ, Willis CL, Simpson TJ (2018) Investigations into the biosynthesis of the antifungal strobilurins. Org Biomol Chem 16:5524 2389. Nofiani R, de Mattos-Shipley K, Lebe KE, Han L-C, Iqbal Z, Bailey AM, Willis CL, Simpson TJ, Cox RJ (2018) Strobilurin biosynthesis in basidiomycete fungi. Nature Commun 9:3940 2390. Chankhamjon P, Boettger-Schmidt D, Scherlach K, Urbansky B, Lackner G, Kalb D, Dahse H-M, Hoffmeister D, Hertweck C (2014) Biosynthesis of the halogenated mycotoxin aspirochlorine in Koji mold involves a cryptic amino acid conversion. Angew Chem Int Ed 53:13409 2391. Quan Z, Awakawa T, Wang D, Hu Y, Abe I (2019) Multidomain P450 epoxidase and a terpene cyclase from the ascochlorin biosynthetic pathway in Fusarium sp. Org Lett 21:2330 2392. Tsunematsu Y, Maeda N, Sato M, Hara K, Hashimoto H, Watanabe K, Hertweck C (2021) Specialized flavoprotein promotes sulfur migration and spiroaminal formation in aspirochlorine biosynthesis. J Am Chem Soc 143:206 2393. Haga Y, Tonoi T, Anbiru Y, Takahashi Y, Tamura S, Yamamoto M, Ifuku S, Morimoto M, Saimoto H (2010) A short and efficient total synthesis of (±)-ascofuranone. Chem Lett 39:622 2394. Grabovyi GA, Mohr JT (2016) Total synthesis of grifolin, grifolic acid, LL-Z1272α, LLZ1272α, and ilicicolinic acid A. Org Lett 18:5010 2395. Hovey MT, Cohen DT, Walden DM, Cheong PH-Y, Scheidt KA (2017) A carbene catalysis strategy for the synthesis of protoilludane natural products. Angew Chem Int Ed 56:9864 2396. Marsico G, Pignataro BA, Masi M, Evidente A, Casella F, Zonno MC, Tak J-H, Bloomquist JR, Superchi S, Scafato P (2018) Asymmetric synthesis and structure-activity studies of the fungal metabolites colletorin A, colletochlorin A and their halogenated analogues. Tetrahedron 74:3912 2397. Pinchman JR, Boger DL (2013) Investigation into the functional impact of the vancomycin C-ring aryl chloride. Bioorg Med Chem Lett 23:4817 2398. Pinchman JR, Boger DL (2013) Probing the role of the vancomycin E-ring aryl chloride: selective divergent synthesis and evaluation of alternatively substituted E-ring analogues. J Med Chem 56:4116 2399. Zhanel GG, Calic D, Schweizer F, Zelenitsky S, Adam H, Lagacé-Wiens PRS, Rubinstein E, Gin AS, Hoban DJ, Karlowsky JA (2010) New lipoglycopeptides. A comparative review of dalbavancin, oritavancin and telavancin. Drugs 70:859 2400. Wright GD (2011) Molecular mechanisms of antibiotic resistance. Chem Commun 47:4055 2401. Jia ZG, O’Mara ML, Zuegg J, Cooper MA, Mark AE (2013) Vancomycin: ligand recognition, dimerization and super-complex formation. FEBS J 280:1294 2402. Butler MS, Hansford KA, Blaskovich MAT, Halai R, Cooper MA (2014) Glycopeptide antibiotics: back to the future. J Antibiot 67:631 2403. Okano A, Isley NA, Boger DL (2017) Total syntheses of vancomycin-related glycopeptide antibiotics and key analogues. Chem Rev 117:11952 2404. Moore MJ, Qu S, Tan C, Cai Y, Mogi Y, Keith DJ, Boger DL (2020) Next-generation total synthesis of vancomycin. J Am Chem Soc 142:16039 2405. Crane CM, Boger DL (2009) Synthesis and evaluation of vancomycin aglycon analogues that bear modifications in the N-terminal d-leucyl amino acid. J Med Chem 52:1471 2406. Leung SSF, Tirado-Rives J, Jorgensen WL (2009) Vancomycin analogs: seeking improved binding of d-ala-d- ala and d-ala-d- lac peptides by side-chain and backbone modifications. Bioorg Med Chem 17:5874 2407. Quinn RK, Cianci AL, Beaudoin JA, Sculimbrene BR (2010) Synthesis of a d-ala-d-ala peptide isostere via olefin cross-metathesis and evaluation of vancomycin binding. Bioorg Med Chem Lett 20:4382 2408. Wu Z-C, Boger DL (2019) Exploration of the site-specific nature and generalizability of a trimethylammonium salt modification on vancomycin: A-ring derivatives. Tetrahedron 75:3160

524

G. W. Gribble

2409. Gu W, Chen B, Ge M (2014) Design and synthesis of new vancomycin derivatives. Bioorg Med Chem Lett 24:2305 2410. Crane CM, Pierce JG, Leung SSF, Tirado-Rives J, Jorgensen WL, Boger DL (2010) Synthesis and evaluation of selected key methyl ether derivatives of vancomycin aglycon. J Med Chem 53:7229 2411. Oh T-J, Kim DH, Kang SY, Yamaguchi T, Sohng JK (2011) Enzymatic synthesis of vancomycin derivatives using galactosyltransferase and sialyltransferase. J Antibiot 64:103 2412. Kitamura K, Shigeta M, Maezawa Y, Watanabe Y, Hsu D-S, Ando Y, Matsumoto T, Suzuki K (2013) Preparation of l-vancosamine-related glycosyl donors. J Antibiot 66:131 2413. Guan D, Chen F, Xiong L, Tang F, Faridoon QY, Zhang N, Gong L, Li J, Lan L, Huang W (2018) Extra sugar on vancomycin: new analogues for combating multidrug-resistant Staphylococcus aureus and vancomycin-resistant Enterococci. J Med Chem 61:286 2414. Peltier-Pain P, Marchillo K, Zhou M, Andes DR, Thorson JS (2012) Natural product disaccharide engineering through tandem glycosyltransferase catalysis reversibility and neoglycosylation. Org Lett 14:5086 2415. Pathak TP, Miller SJ (2012) Site-selective bromination of vancomycin. J Am Chem Soc 134:6120 2416. Choi K-H, Lee H-J, Park BJ, Wang K-K, Shin EP, Park J-C, Kim YK, Oh M-K, Kim Y-R (2012) Photosensitizer and vancomycin-conjugated novel multifunctional magnetic particles as photoinactivation agents for selective killing of pathogenic bacteria. Chem Commun 48:4591 2417. Zhang S-J, Yang Q, Xu L, Chang J, Sun X (2012) Synthesis and antibacterial activity against Clostridium difficile of novel demethylvancomycin derivatives. Bioorg Med Chem Lett 22:4942 2418. Fowler BS, Laemmerhold KM, Miller SJ (2012) Catalytic site-selective thiocarbonylations and deoxygenations of vancomycin reveal hydroxyl-dependent conformational effects. J Am Chem Soc 134:9755 2419. Yarlagadda V, Sarkar P, Manjunath GB, Haldar J (2015) Lipophilic vancomycin aglycon dimer with high activity against vancomycin-resistant bacteria. Bioorg Med Chem Lett 25:5477 2420. Mishra NM, Briers Y, Lamberigts C, Steenackers H, Robijns S, Landuyt B, Vanderleyden J, Schoofs L, Lavigne R, Luyten W, Van der Eycken EV (2015) Evaluation of the antibacterial and antibiofilm activities of novel CRAMP–vancomycin conjugates with diverse linkers. Org Biomol Chem 13:7477 2421. Yarlagadda V, Sarkar P, Samaddar S, Haldar J (2016) A vancomycin derivative with a pyrophosphate-binding group: a strategy to combat vancomycin-resistant bacteria. Angew Chem Int Ed 55:7836 2422. Silverman SM, Moses JE, Sharpless KB (2017) Reengineering antibiotics to combat bacterial resistance: click chemistry [1,2,3]-triazole vancomycin dimers with potent activity against MRSA and VRE. Chem Eur J 23:79 2423. Yoganathan S, Miller SJ (2015) Structure diversification of vancomycin through peptidecatalyzed, site-selective lipidation: a catalysis-based approach to combat glycopeptideresistant pathogens. J Med Chem 58:2367 2424. Tanaka KSE, Dietrich E, Ciblat S, Métayer C, Arhin FF, Sarmiento I, Moeck G, Parr TR Jr, Far AR (2010) Synthesis and in vitro evaluation of bisphosphonated glycopeptide prodrugs for the treatment of osteomyelitis. Bioorg Med Chem Lett 20:1355 2425. Wadzinski TJ, Gea KD, Miller SJ (2016) A stepwise dechlorination/cross-coupling strategy to diversify the vancomycin ‘in-chloride.’ Bioorg Med Chem Lett 26:1025 2426. Nakama Y, Yoshida O, Yoda M, Araki K, Sawada Y, Nakamura J, Xu S, Miura K, Maki H, Arimoto H (2010) Discovery of a novel series of semisynthetic vancomycin derivatives effective against vancomycin-resistant bacteria. J Med Chem 53:2528 2427. Pintér G, Batta G, Kéki S, Mándi A, Komáromi I, Takács-Novák K, Sztaricskai F, Roth E, Ostorházi E, Rozgonyi F, Naesens L, Herczegh P (2009) Diazo transfer—click reaction route to new, lipophilic teicoplanin and ristocetin aglycon derivatives with high antibacterial

Naturally Occurring Organohalogen Compounds …

2428. 2429. 2430.

2431.

2432.

2433. 2434. 2435.

2436.

2437.

2438. 2439. 2440. 2441. 2442. 2443.

2444. 2445.

2446. 2447.

525

and anti-influenza virus activity: an aggregation and receptor binding study. J Med Chem 52:6053 Pathak TP, Miller SJ (2013) Chemical tailoring of teicoplanin with site-selective reactions. J Am Chem Soc 135:8415 Han S, Miller SJ (2013) Asymmetric catalysis at a distance: catalytic, site-selective phosphorylation of teicoplanin. J Am Chem Soc 135:12414 Bereczki I, Kicsák M, Dobray L, Borbás A, Batta G, Kéki S, Nikodém EN, Ostorházi E, Rozgonyi F, Vanderlinden E, Naesens L, Herczegh P (2014) Semisynthetic teicoplanin derivatives as new influenza virus binding inhibitors: synthesis and antiviral studies. Bioorg Med Chem Lett 24:3251 Sz˝ucs Z, Csávás M, R˝oth E, Borbás A, Batta G, Perret F, Ostorházi E, Szatmári R, Vanderlinden E, Naesens L, Herczegh P (2017) Synthesis and biological evaluation of lipophilic teicoplanin pseudoaglycon derivatives containing a substituted triazole function. J Antibiot 70:152 Sz˝ucs Z, Bereczki I, Csávás M, R˝oth E, Borbás A, Batta G, Ostorházi E, Szatmári R, Herczegh P (2017) Lipophilic teicoplanin pseudoaglycon derivatives are active against vancomycinand teicoplanin-resistant enterococci. J Antibiot 70:664 Fang X, Nam J, Shin D, Rew Y, Boger DL, Walker S (2009) Functional and biochemical analysis of a key series of ramoplanin analogues. Bioorg Med Chem Lett 19:6189 Yim G, Thaker MN, Koteva K, Wright G (2014) Glycopeptide antibiotic biosynthesis. J Antibiot 67:31 Schmartz PC, Zerbe K, Abou-Hadeed K, Robinson JA (2014) Bis-chlorination of a hexapeptide–PCP conjugate by the halogenase involved in vancomycin biosynthesis. Org Biomol Chem 12:5574 Brieke C, Yim G, Peschke M, Wright GD, Cryle MJ (2016) Catalytic promiscuity of glycopeptide N-methyltransferases enables bio-orthogonal labelling of biosynthetic intermediates. Chem Commun 52:13679 Ozturk S, Forneris CC, Nguy AKL, Sorensen EJ, Seyedsayamdost MR (2018) Modulating OxyB-catalyzed cross-coupling reactions in vancomycin biosynthesis by incorporation of diverse d-Tyr analogues. J Org Chem 83:7309 McCranie EK, Bachmann BO (2014) Bioactive oligosaccharide natural products. Nat Prod Rep 31:1026 Mertz JL, Peloso JS, Barker BJ, Babbitt GE, Occolowitz JL, Simson VL, Kline RM (1986) Isolation and structural identification of nine avilamycins. J Antibiot 39:877 Alcock RE, Jones KC (1996) Dioxins in the environment: a review of trend data. Environ Sci Technol 30:3133 Huwe JK (2002) Dioxins in food: a modern agricultural perspective. J Agric Food Chem 50:1739 Millot M, Dieu A, Tomasi S (2016) Dibenzofurans and derivatives from lichens and ascomycetes. Nat Prod Rep 33:801 Zhou Y, Liu J (2018) Emissions, environmental levels, sources, formation pathways, and analysis of polybrominated dibenzo-p-dioxins and dibenzofurans: a review. Environ Sci Pollut Res 25:33082 Fernandes AR, Falandysz J (2021) Polybrominated dibenzo-p-dioxins and furans (PBDD/ Fs): contamination in food, humans and dietary exposure. Sci Total Environ 761:143191 Kikuchi H, Kubohara Y, Nguyen VH, Katou Y, Oshima Y (2013) Novel chlorinated dibenzofurans isolated from the cellular slime mold, Polysphondylium filamentosum, and their biological activities. Bioorg Med Chem 21:4628 Beekman AM, Wossa SW, Kevo O, Ma P, Barrow RA (2015) Discovery and synthesis of boletopsins 13 and 14, brominated fungal metabolites of terrestrial origin. J Nat Prod 78:2133 Haglund P, Lindkvist K, Malmvärn A, Wiberg K, Bignert A, Nakano T, Asplund L (2005) High levels of potentially biogenic dibromo and tribromo dibenzo-p-dioxins in Swedish fish. Organohalogen Compd 67:1267

526

G. W. Gribble

2448. Malmvärn A, Zebühr Y, Kautsky L, Bergman Å, Nakano T, Asplund L (2006) Hydroxylatedand methoxylated-polybrominated diphenyl ethers and polybrominated dibenzo-p-dioxins in red alga from the Baltic Sea. Organohalogen Compd 68:1004 2449. Haglund P, Malmvärn A, Bergek S, Bignert A, Kautsky L, Nakano T, Wiberg K, Asplund L (2007) Brominated dibenzo-p-dioxins: a new class of marine toxins? Environ Sci Technol 41:3069 2450. Unger M, Malmvärn A, Gustafsson Ö, Asplund L (2008) Aquatic sponge—a producer of brominated dioxins in the Baltic? Organohalogen Compd 70:1744 2451. Unger M, Asplund L, Haglund P, Malmvärn A, Arnoldsson K, Gustafsson O (2009) Polybrominated and mixed brominated/chlorinated dibenzo-p-dioxins in sponge (Ephydatia fluviatilis) from the Baltic Sea. Environ Sci Technol 43:8245 2452. Malmvärn A, Zebühr Y, Kautsky L, Bergman Å, Asplund L (2008) Hydroxylated and methoxylated polybrominated diphenyl ethers and polybrominated dibenzo-p-dioxins in red alga and cyanobacteria living in the Baltic Sea. Chemosphere 72:910 2453. Haglund P (2010) On the identity and formation routes of environmentally abundant tri- and tetrabromodibenzo-p-dioxins. Chemosphere 78:724 2454. Haglund P, Löfstrand K, Malmvärn A, Bignert A, Asplund L (2010) Temporal variations of polybrominated dibenzo-p-dioxin and methoxylated diphenyl ether concentrations in fish revealing large differences in exposure and metabolic stability. Environ Sci Technol 44:2466 2455. Löfstrand K, Liu X, Lindqvist D, Jensen S, Asplund L (2011) Seasonal variations of hydroxylated and methoxylated brominated diphenyl ethers in blue mussels from the Baltic Sea. Chemosphere 84:527 2456. Goto A, Tue NM, Someya M, Isobe T, Takahashi S, Tanabe S, Kunisue T (2017) Occurrence of natural mixed halogenated dibenzo-p-dioxins: specific distribution and profiles in mussels from Seto Inland Sea. Japan. Environ Sci Technol 51:11771 2457. Bjurlid F, Dam M, Hoydal K, Hagberg J (2018) Occurrence of polybrominated dibenzop-dioxins, dibenzofurans (PBDD/Fs) and polybrominated diphenyl ethers (PBDEs) in pilot whales (Globicephala melas) caught around the Faroe Islands. Chemosphere 195:11 2458. Falandysz J, Smith F, Fernandes AR (2020) Polybrominated dibenzo-p-dioxins (PBDDs) and dibenzofurans (PBDFs) in cod (Gadus morhua) liver-derived products from 1972 to 2017. Sci Total Environ 722:137840 2459. Wu Q, Eisenhardt N, Holbert SS, Pawlik JR, Kucklick JR, Vetter W (2021) Naturally occurring organobromine compounds (OBCs) including polybrominated dibenzo-p-dioxins in the marine sponge Hyrtios proteus from The Bahamas. Mar Pollut Bull 172:112872 2460. Steen PO, Grandbois M, McNeill K, Arnold WA (2009) Photochemical formation of halogenated dioxins from hydroxylated polybrominated diphenyl ethers (OH-PBDEs) and chlorinated derivatives (OH-PBCDEs). Environ Sci Technol 43:4405 2461. Arnoldsson K, Andersson PL, Haglund P (2012) Photochemical formation of polybrominated dibenzo-p-dioxins from environmentally abundant hydroxylated polybrominated diphenyl ethers. Environ Sci Technol 46:7567 2462. Arnoldsson K, Andersson PL, Haglund P (2012) Formation of environmentally relevant brominated dioxins from 2,4,6-tribromophenol via bromoperoxidase-catalyzed dimerization. Environ Sci Technol 46:7239 2463. Truce WE, Kreider EM, Brand WW (1970) The Smiles and related rearrangements of aromatic systems. Org React 18:99 2464. Agarwal V, Moore BS (2014) Enzymatic synthesis of polybrominated dioxins from the marine environment. ACS Chem Biol 9:1980 2465. Vollmuth S, Zajc A, Niessner R (1994) Formation of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans during the photolysis of pentachlorophenol-containing water. Environ Sci Technol 28:1145 2466. Bastos PM, Eriksson J, Bergman A (2009) Photochemical decomposition of dissolved hydroxylated polybrominated diphenyl ethers under various aqueous conditions. Chemosphere 77:791

Naturally Occurring Organohalogen Compounds …

527

2467. Vallejo M, Fernández-Castro P, San Román MF, Ortiz I (2015) Assessment of PCDD/Fs formation in the Fenton oxidation of 2-chlorophenol: influence of the iron dose applied. Chemosphere 137:135 2468. Dimmel DR, Riggs KB, Pitts G, White J, Lucas S (1993) Formation mechanisms of polychlorinated dibenzo-p-dioxins and dibenzofurans during pulp chlorination. Environ Sci Technol 27:2553 2469. Wichmann H, Dettmer FT, Bahadir M (2002) Thermal formation of PBDD/F from tetrabromobisphenol A—a comparison of polymer linked TBBP A with its additive incorporation in thermoplastics. Chemosphere 47:349 2470. Weber R, Kuch B (2003) Relevance of BFRs and thermal conditions on the formation pathways of brominated and brominated–chlorinated dibenzodioxins and dibenzofurans. Environ Int 29:699 2471. Carroll WF Jr (2001) The relative contribution of wood and poly(vinyl chloride) to emissions of PCDD and PCDF from house fires. Chemosphere 45:1173 2472. Gullett BK, Touati A (2003) PCDD/F Emissions from forest fire simulations. Atmos Environ 37:803 2473. Denys S, Gombert D, Tack K (2012) Combined approaches to determine the impact of wood fire on PCDD/F and PCB contamination of the environment: a case study. Chemosphere 88:806 2474. Holmstrand H, Gadomski D, Mandalakis M, Tysklind M, Irvine R, Andersson P, Gustafsson O (2006) Origin of PCDDs in ball clay assessed with compound-specific chlorine isotope analysis and radiocarbon dating. Environ Sci Technol 40:3730 2475. Horii Y, van Bavel B, Kannan K, Petrick G, Nachtigall K, Yamashita N (2008) Novel evidence for natural formation of dioxins in ball clay. Chemosphere 70:1280 2476. Gu C, Li H, Teppen BJ, Boyd SA (2008) Octachlorodibenzodioxin formation on Fe(III)montmorillonite clay. Environ Sci Technol 42:4758 2477. Moon H-B, Choi M, Choi H-G, Ok G, Kannan K (2009) Historical trends of PCDDs, PCDFs, dioxin-like PCBs and nonylphenols in dated sediment cores from a semi-enclosed bay in Korea: tracking the sources. Chemosphere 75:565 2478. Kishida M, Imamura K, Takenaka N, Maeda Y, Viet PH, Kondo A, Bandow H (2010) Characteristics of the abundance of polychlorinated dibenzo-p-dioxin and dibenzofurans, and dioxin-like polychlorinated biphenyls in sediment samples from selected Asian regions in Can Gio, Southern Vietnam and Osaka, Japan. Chemosphere 78:127 2479. Horii Y, Ohtsuka N, Minomo K, Nojiri K, Kannan K, Lam PKS, Yamashita N (2011) Distribution, characteristics, and worldwide inventory of dioxins in kaolin ball clays. Environ Sci Technol 45:7517 2480. Gu C, Liu C, Ding Y, Li H, Teppen BJ, Johnston CT, Boyd SA (2011) Clay mediated route to natural formation of polychlorodibenzo-p-dioxins. Environ Sci Technol 45:3445 2481. Tondeur Y, Vining B, Mace K, Mills W, Hart J (2012) Environmental release of dioxins from reservoir sources during beach nourishment programs. Chemosphere 88:358 2482. Alawi MA, Najjar AA, Khoury HN (2014) Analytical method development for the screening and determination of dioxins in clay matrices. Clean: Soil, Air, Water 42:979 2483. Grant S, Stevenson G, Malcolm D, Zennegg M, Gaus C (2015) Isomer-specific investigation of PCDD/F mobility and other fate processes in deep soil cores. Chemosphere 137:87 2484. Hayward DG, Bolger PM (2005) Tetrachlorodibenzo-p-dioxin in baby food made from chicken produced before and after the termination of ball clay use in chicken feed in the United States. Environ Res 99:307 2485. Hoogenboom R, Zeilmaker M, van Eijkeren J, Kan K, Mengelers M, Luykx D, Traag W (2010) Kaolinic clay derived PCDD/Fs in the feed chain from a sorting process for potatoes. Chemosphere 78:99 2486. Ghabbour AA, Davis G (eds) (2001). Humic substances: structures, models and functions, Royal Society of Chemistry, Cambridge, UK 2487. Hatcher PG, Bortlatynski JM, Minard RD, Dec J, Bollag J-M (1993) Use of high-resolution 13 C NMR to examine the enzymatic covalent binding of 13 C-labeled 2,4-dichlorophenol to humic substances. Environ Sci Technol 27:2098

528

G. W. Gribble

2488. Lassen P, Randall A, Jørgensen O, Warwick P, Carlsen L (1994) Enzymatically mediated incorporation of 2-chlorophenol and 4-chlorophenol into humic acids. Chemosphere 28:703 2489. Breider F, Hunkeler D (2014) Investigating chloroperoxidase-catalyzed formation of chloroform from humic substances using stable chlorine isotope analysis. Environ Sci Technol 48:1592 2490. Saunders RW, Kumar R, MacDonald SM, Plane JMC (2012) Insights into the photochemical transformation of iodine in aqueous systems: humic acid photosensitized reduction of iodate. Environ Sci Technol 46:11854 2491. Fujimori DG, Walsh CT (2007) What’s new in enzymatic halogenations. Curr Opin Chem Biol 11:553 2492. Blasiak LC, Drennan CL (2009) Structural perspective on enzymatic halogenation. Acc Chem Res 42:147 2493. Butler A, Sandy M (2009) Mechanistic considerations of halogenating enzymes. Nature 460:848 2494. Senn HM (2014) Insights into enzymatic halogenation from computational studies. Front Chem 2:1 2495. Winter JM, Moore BS (2009) Exploring the chemistry and biology of vanadium-dependent haloperoxidases. J Biol Chem 284:18577 2496. Leblanc C, Vilter H, Fournier J-B, Delage L, Potin P, Rebuffet E, Michel G, Solari PL, Feiters MC, Czjzek M (2015) Vanadium haloperoxidases: from the discovery 30 years ago to X-ray crystallographic and V K-edge absorption spectroscopic studies. Coord Chem Rev 301–302:134 2497. Groves JT (2003) The bioinorganic chemistry of iron in oxygenases and supramolecular assemblies. Proc Natl Acad Sci USA 100:3569 2498. Emmerich M, Bhansali A, Lösekann-Behrens T, Schröder C, Kappler A, Behrens S (2012) Abundance, distribution, and activity of Fe(II)-oxidizing and Fe(III)-reducing microorganisms in hypersaline sediments of Lake Kasin, southern Russia. Appl Environ Microbiol 78:4386 2499. Yang Y, Pignatello JJ (2017) Participation of the halogens in photochemical reactions in natural and treated waters. Molecules 22:1684 2500. Atashgahi S, Liebensteiner MG, Janssen DB, Smidt H, Stams AJM, Sipkema D (2018) Microbial synthesis and transformation of inorganic and organic chlorine compounds. Front Microbiol 9:3079 2501. Bengtson P, Bastviken D, Öberg G (2013) Possible roles of reactive chlorine II: assessing biotic chlorination as a way for organisms to handle oxygen stress. Environ Microbiol 15:991 2502. Öberg G, Bastviken D (2012) Transformation of chloride to organic chlorine in terrestrial environments: variability, extent, and implications. Crit Rev Environ Sci Technol 42:2526 2503. Wagner C, Omari ME, König GM (2009) Biohalogenation: nature’s way to synthesize halogenated metabolites. J Nat Prod 72:540 2504. van Pée K-H (2012) Halogenation. In: Drauz K, Gröger H, May O (eds) Enzyme catalysis in organic synthesis, 3rd edn. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, p 1569 2505. Chung W, Vanderwal CD (2016) Stereoselective halogenation in natural product synthesis. Angew Chem Int Ed 55:4396 2506. Weichold V, Milbredt D, van Pée K-H (2016) Specific enzymatic halogenation—from the discovery of halogenated enzymes to their applications in vitro and in vivo. Angew Chem Int Ed 55:6374 2507. Latham J, Brandenburger E, Shepherd SA, Menon BRK, Micklefield J (2018) Development of halogenase enzymes for use in synthesis. Chem Rev 118:232 2508. Herrera-Rodriguez LN, Khan F, Robins KT, Meyer H-P (2011) Perspectives on biotechnological halogenation. Chim Oggi 29:31 2509. Jit˘areanu A, T˘at˘arîng˘a G, Zbancioc A-M, Trifan A (2018) Bromination-A versatile tool for drugs optimization. Med Surg J Rev Med Chir Soc Med Nat, Ia¸si 122:614

Naturally Occurring Organohalogen Compounds …

529

2510. Fraley AE, Sherman DH (2018) Halogenase engineering and its utility in medicinal chemistry. Bioorg Med Chem Lett 28:1992 2511. Jit˘areanu A, Caba IC, Agoroaei L (2019) Halogenation—a versatile tool for drug synthesis— the importance of developing effective and eco-friendly reaction protocols. Curr Anal Biotechnol 2:11 2512. Fejzagi´c AV, Gebauer J, Huwa N, Classen T (2019) Halogenating enzymes for active agent synthesis: first steps are done and many have to follow. Molecules 24:4008 2513. Minges H, Sewald N (2020) Recent advances in synthetic application and engineering of halogenases. ChemCatChem 12:4450 2514. Agarwal V, Miles ZD, Winter JM, Eustáquio AS, El Gamal AA, Moore BS (2017) Enzymatic halogenation and dehalogenation reactions: pervasive and mechanistically diverse. Chem Rev 117:5619 2515. Field JA (2016) Natural production of organohalide compounds in the environment. In: Adrian L, Löffler FE (eds) Organohalide-respiring bacteria. Springer, Berlin, Heidelberg, p7 2516. Chen X, van Pée K-H (2008) Catalytic mechanisms, basic roles, and biotechnological and environmental significance of halogenating enzymes. Acta Biochim Biophys Sin 40:183 2517. Walz I, Schwack W (2007) Cutinase inhibition by means of insecticidal organophosphates and carbamates. 3. Oxidation of phosphorothionates by chloroperoxidase from Caldariomyces fumago. J Agric Food Chem 55:8177 2518. Renirie R, Dewilde A, Pierlot C, Wever R, Hober D, Aubry J-M (2008) Bactericidal and virucidal activity of the alkalophilic P395D/L241V/T343A mutant of vanadium chloroperoxidase. J Appl Microbiol 105:264 2519. Perez DI, Grau MM, Arends IWCE, Hollmann F (2009) Visible light-driven and chloroperoxidase-catalyzed oxygenation reactions. Chem Commun 45:6848 2520. de Hoog HM, Nallani M, Cornelissen JJLM, Rowan AE, Nolte RJM, Arends IWCE (2009) Biocatalytic oxidation by chloroperoxidase from Caldariomyces fumago in polymersome nanoreactors. Org Biomol Chem 7:4604 2521. Natalio F, Wiese S, Brandt W, Wessjohann L (2017) Reconstitution of vanadium haloperoxidase’s catalytic activity by boric acid—towards a potential biocatalytic role of boron. Chem Eur J 23:4973 2522. Wang K, Huang X, Lin K (2019) Multiple catalytic roles of chloroperoxidase in the transformation of phenol: products and pathways. Ecotoxicol Environ Safety 179:96 2523. Dong JJ, Fernández-Fueyo E, Li J, Guo Z, Renirie R, Wever R, Hollmann F (2017) Halofunctionalization of alkenes by vanadium chloroperoxidase from Curvularia inaequalis. Chem Commun 53:6207 2524. Winter JM, Moffitt MC, Zazopoulos E, McAlpine JB, Dorrestein PC, Moore BS (2007) Molecular basis for chloronium-mediated meroterpene cyclization. J Biol Chem 282:16362 2525. Bernhardt P, Okino T, Winter JM, Miyanaga A, Moore BS (2011) A stereoselective vanadium-dependent chloroperoxidase in bacterial antibiotic biosynthesis. J Am Chem Soc 133:4268 2526. Runguphan W, Qu X, O’Connor SE (2010) Integrating carbon-halogen bond formation into medicinal plant metabolism. Nature 468:461 2527. Diethelm S, Teufel R, Kaysser L, Moore BS (2014) A multitasking vanadium-dependent chloroperoxidase as an inspiration for the chemical synthesis of the merochlorins. Angew Chem Int Ed 53:11023 2528. Wever R, Barnett P (2017) Vanadium chloroperoxidases: the missing link in the formation of chlorinated compounds and chloroform in the terrestrial environment? Chem Asian J 12:1997 2529. Mubarak MQE, Gérard EF, Blanford CF, Hay S, de Visser SP (2020) How do vanadium chloroperoxidases generate hypochlorite from hydrogen peroxide and chloride? A computational study. ACS Catal 10:14067 2530. Aeppli C, Bastviken D, Andersson P, Gustafsson Ö (2013) Chlorine isotope effects and composition of naturally produced organochlorines from chloroperoxidases, flavindependent halogenases, and in forest soil. Environ Sci Technol 47:6864

530

G. W. Gribble

2531. Izumi Y, Ohshiro T, Wever R (1997) Bromoperoxidase from a marine red macro-alga, Corallina pilulifera. Verh-Kned Akad Tweede Reeks 98:69 2532. Wever R, van der Horst MA (2013) The role of vanadium haloperoxidases in the formation of volatile brominated compounds and their impact on the environment. Dalton Trans 42:11778 2533. Wischang D, Brücher O, Hartung J (2011) Bromoperoxidases and functional enzyme mimics as catalysts for oxidative bromination—a sustainable synthetic approach. Coord Chem Rev 255:2204 2534. Wischang D, Hartung J (2011) Parameters for bromination of pyrroles in bromoperoxidasecatalyzed oxidations. Tetrahedron 67:4048 2535. Wischang D, Hartung J (2012) Bromination of phenols in bromoperoxidase-catalyzed oxidations. Tetrahedron 68:9456 2536. Hartung J, Brücher O, Hach D, Schulz H, Vilter H, Ruick G (2008) Bromoperoxidase activity and vanadium level of the brown alga Ascophyllum nodosum. Phytochemistry 69:2826 2537. Wischang D, Radlow M, Schulz H, Vilter H, Viehweger L, Altmeyer MO, Kegler C, Herrmann J, Müller R, Gaillard F, Delage L, Leblanc C, Hartung J (2012) Molecular cloning, structure, and reactivity of the second bromoperoxidase from Ascophyllum nodosum. Bioorg Chem 44:25 2538. Littlechild J, Rodriguez EG, Isupov M (2009) Vanadium containing bromoperoxidase— insights into the enzymatic mechanism using X-ray crystallography. J Inorg Biochem 103:617 2539. Sandy M, Carter-Franklin JN, Martin JD, Butler A (2011) Vanadium bromoperoxidase from Delisea pulchra: enzyme-catalyzed formation of bromofuranone and attendant disruption of quorum sensing. Chem Commun 47:12086 2540. Kaneko K, Washio K, Umezawa T, Matsuda F, Morikawa M, Okino T (2014) cDNA cloning and characterization of vanadium-dependent bromoperoxidases from the red alga Laurencia nipponica. Biosci Biotechnol Biochem 78:1310 2541. Belal M, Sarkar S, Subramanian R, Khan AT (2022) Synthetic utility of biomimicking vanadium bromoperoxidase and n-tetrabutylammonium tribromide (TBATB) in organic synthesis. Org Biomol Chem 20:2562 2542. Küpper FC, Carpenter LJ, Leblanc C, Toyama C, Uchida Y, Maskrey BH, Robinson J, Verhaeghe EF, Malin G, Luther GW III, Kroneck PMH, Kloareg B, Meyer-Klaucke W, Muramatsu Y, Megson IL, Potin P, Feiters MC (2013) In vivo speciation studies and antioxidant properties of bromine in Laminaria digitata reinforce the significance of iodine accumulation for kelps. J Exp Bot 64:2653 2543. Leri AC, Mayer LM, Thornton KR, Ravel B (2014) Bromination of marine particulate organic matter through oxidative mechanisms. Geochem Cosmochim Acta 142:53 2544. McCall AS, Cummings CF, Bhave G, Vanacore R, Page-McCaw A, Hudson BG (2014) Bromine is an essential trace element for assembly of collagen IV scaffolds in tissue development and architecture. Cells 157:1380 2545. Maurya A, Mahato AK, Chaudhary N, Kesharwani N, Kachhap P, Mishra VK, Haldar C (2020) Synthesis and characterization of dimeric μ-oxidovanadium complexes as the functional model of vanadium bromoperoxidase. Appl Organometal Chem 34:e5508 2546. Franssen MCR (1994) Haloperoxidases: useful catalysts for halogenation and oxidation reactions. Catal Today 22:441 2547. Gkotsi DS, Dhaliwal J, McLachlan MMW, Mulholand KR, Goss RJM (2018) Halogenases: powerful tools for biocatalysis (mechanisms applications and scope). Curr Opin Chem Biol 43:119 2548. Menon BRK, Richmond D, Menon N (2022) Halogenases for biosynthetic pathway engineering: toward new routes to naturals and non-naturals. Catal Rev 64:533 2549. Zeng J, Zhan J (2019) Chlorinated natural products and related halogenases. Isr J Chem 59:387 2550. Schnepel C, Sewald N (2017) Enzymatic halogenation: a timely strategy for regioselective C-H activation. Chem Eur J 23:12064 2551. Goss RJM, Grüschow S (2014) A radical finding. Nat Chem Biol 10:878

Naturally Occurring Organohalogen Compounds …

531

2552. Leblanc C, Colin C, Cosse A, Delage L, La Barre S, Morin P, Fiévet B, Voiseux C, Ambroise Y, Verhaeghe E, Amouroux D, Donard O, Tessier E, Potin P (2006) Iodine transfers in the coastal marine environment: the key role of brown algae and of their vanadium-dependent haloperoxidases. Biochimie 88:1773 2553. Frank A, Seel CJ, Groll M, Gulder T (2016) Characterization of a cyanobacterial haloperoxidase and evaluation of its biocatalytic halogenation potential. ChemBioChem 17:2028 2554. Vardhaman AK, Barman P, Kumar S, Sastri CV, Kumar D, de Visser SP (2013) Mechanistic insight into halide oxidation by non-heme iron complexes. Haloperoxidase versus halogenase activity. Chem Commun 49:10926 2555. Hillwig ML, Liu X (2014) A new family of iron-dependent halogenases acts on freestanding substrates. Nat Chem Biol 10:921 2556. Timmins A, Quesne MG, Borowski T, de Visser SP (2018) Group transfer to an aliphatic bond: a biomimetic study inspired by nonheme iron halogenases. ACS Catal 8:8685 2557. Yeh E, Blasiak LC, Koglin A, Drennan CL, Walsh CT (2007) Chlorination by a long-lived intermediate in the mechanism of flavin-dependent halogenases. Biochemistry 46:1284 2558. Heemstra JR Jr, Walsh CT (2008) Tandem action of the O2 - and FADH2 -dependent halogenases KtzQ and KtzR produce 6,7-dichlorotryptophan for kutzneride assembly. J Am Chem Soc 130:14024 2559. Flecks S, Patallo EP, Zhu X, Ernyei AJ, Seifert G, Schneider A, Dong C, Naismith JH, van Pée K-H (2008) New insights into the mechanism of enzymatic chlorination of tryptophan. Angew Chem Int Ed 47:9533 2560. Zhu X, De Laurentis W, Leang K, Herrmann J, Ihlefeld K, van Pée K-H, Naismith JH (2009) Structural insights into regioselectivity in the enzymatic chlorination of tryptophan. J Mol Biol 391:74 2561. Lang A, Polnick S, Nicke T, William P, Patallo EP, Naismith JH, van Pée K-H (2011) Changing the regioselectivity of the tryptophan 7-halogenase PrnA by site-directed mutagenesis. Angew Chem Int Ed 50:2951 2562. Gutleben J, Koehorst JJ, McPherson K, Pomponi S, Wijffels RH, Smidt H, Sipkema D (2019) Diversity of tryptophan halogenases in sponges of the genus Aplysina. FEMS Microbiol Ecol 95:fiz108 2563. Veldmann KH, Dachwitz S, Risse JM, Lee J-H, Sewald N, Wendisch VF (2019) Bromination of l-tryptophan in a fermentative process with Corynebacterium glutamicum. Front Bioeng Biotechnol 7:219 2564. Galoni´c DP, Barr EW, Walsh CT, Bollinger JM Jr, Krebs C (2007) Two Interconverting Fe(IV) intermediates in aliphatic chlorination by the halogenase CytC3. Nat Chem Biol 3:113 2565. Wong C, Fujimori DG, Walsh CT, Drennan CL (2009) Structural analysis of an open active site conformation of nonheme iron halogenase CytC3. J Am Chem Soc 131:4872 2566. Neumann CS, Walsh CT (2008) Biosynthesis of (–)-(1S,2R)-allocoronamic acyl thioester by an FeII -dependent halogenase and a cyclopropane-forming flavoprotein. J Am Chem Soc 130:14022 2567. Hillwig ML, Zhu Q, Ittiamornkul K, Liu X (2016) Discovery of a promiscuous non-heme iron halogenase in ambiguine alkaloid biogenesis: implication for an evolvable enzyme family for late-state halogenation of aliphatic carbons in small molecules. Angew Chem Int Ed 55:5780 2568. Mitchell AJ, Zhu Q, Maggiolo AO, Ananth NR, Hillwig ML, Liu X, Boal AK (2016) Structural basis for halogenation by iron- and 2-oxo-glutarate-dependent enzyme Wel05. Nat Chem Biol 12:636 2569. Hayashi T, Ligibel M, Sager E, Voss M, Hunziker J, Schroer K, Snajdrova R, Buller R (2019) Evolved aliphatic halogenases enable regiocomplementary C-H functionalization of a pharmaceutically relevant compound. Angew Chem Int Ed 58:18535 2570. Duewel S, Schmermund L, Faber T, Harms K, Srinivasan V, Meggers E, Hoebenreich S (2020) Directed evolution of an FeII -dependent halogenase for asymmetric C(sp3 )–H chlorination. ACS Catal 10:1272

532

G. W. Gribble

2571. Pratter SM, Ivkovic J, Birner-Gruenberger R, Breinbauer R, Zangger K, Straganz GD (2014) More than just a halogenase: modification of fatty acyl moieties by a trifunctional metal enzyme. ChemBioChem 15:567 2572. Eustáquio AS, Pojer F, Noel JP, Moore BS (2008) Discovery and characterization of a marine bacterial SAM-dependent chlorinase. Nat Chem Biol 4:69 2573. Xu F, Merkley A, Yu D, Zhan J (2016) Selective biochlorination of hydroxyquinolines by a flavin-dependent halogenase. Tetrahedron Lett 57:5262 2574. Menon BRK, Brandenburger E, Sharif HH, Klemstein U, Shepherd SA, Greaney MF, Micklefield J (2017) RadH: a versatile halogenase for integration into synthetic pathways. Angew Chem Int Ed 56:11841 2575. Ismail M, Frese M, Patschkowski T, Ortseifen V, Niehaus K, Sewald N (2019) Flavindependent halogenases from Xanthomonas campestris pv. campestris B100 prefer bromination over chlorination. Adv Synth Catal 361:2475 2576. Fisher BF, Snodgrass HM, Jones KA, Andorfer MC, Lewis JC (2019) Site-selective CH halogenation using flavin-dependent halogenases identified via family-wide activity profiling. ACS Cent Sci 5:1844 2577. Gkotsi DS, Ludewig H, Sharma SV, Connolly JA, Dhaliwal J, Wang Y, Unsworth WP, Taylor RJK, McLachlan MMW, Shanahan S, Naismith JH, Goss RJM (2019) A marine viral halogenase that iodinates diverse substrates. Nat Chem 11:1091 2578. Liu M, Ohashi M, Hung Y-S, Scherlach K, Watanabe K, Hertweck C, Tang Y (2021) AoiQ catalyzes germinal dichlorination of 1,3-diketone natural products. J Am Chem Soc 143:7267 2579. Mondal D, Fisher BF, Jiang Y, Lewis JC (2021) Flavin-dependent halogenases catalyze enantioselective olefin halocyclization. Nat Commun 12:3268 2580. Frese M, Sewald N (2015) Enzymatic halogenation of tryptophan on a gram scale. Angew Chem Int Ed 54:298 2581. Payne JT, Poor CB, Lewis JC (2015) Directed evolution of RebH for site-selective halogenation of large biologically active molecules. Angew Chem Int Ed 54:4226 2582. Bastviken D, Svensson T, Karlsson S, Sandén P, Oberg G (2009) Temperature sensitivity indicates that chlorination of organic matter in forest soil is primarily biotic. Environ Sci Technol 43:3569 2583. Ruecker A, Weigold P, Behrens S, Jochmann M, Laaks J, Kappler A (2014) Predominance of biotic over abiotic formation of halogenated hydrocarbons in hypersaline sediments in Western Australia. Environ Sci Technol 48:9170 2584. Ruecker A, Weigold P, Behrens S, Jochmann M, Barajas XLO, Kappler A (2015) Halogenated hydrocarbon formation in a moderately acidic salt lake in Western Australia—role of abiotic and biotic processes. Environ Chem 12:406 2585. Malle E, Buch T, Grone H-J (2003) Myeloperoxidase in kidney disease. Kidney Int 64:1956 2586. Klebanoff SJ (2005) Myeloperoxidase: friend and foe. J Leukocyte Biol 77:598 2587. Malle E, Marsche G, Arnhold J, Davies MJ (2006) Modification of low-density lipoprotein by myeloperoxidase-derived oxidants and reagent hypochlorous acid. Biochim Biophys Acta 1761:392 2588. Yap YW, Whiteman M, Cheung NS (2007) Chlorinative stress: an under appreciated mediator of neurodegeneration? Cell Signal 19:219 2589. Lau D, Baldus S (2006) Myeloperoxidase and its contributory role in inflammatory vascular disease. Pharmacol Ther 111:16 2590. Heinecke JW (2007) The role of myeloperoxidase in HDL oxidation and atherogenesis. Curr Atheroscler Rep 9:249 2591. Malle E, Furtmüller PG, Sattler W, Obinger C (2007) Myeloperoxidase: a target for new drug development? Brit J Pharmacol 152:838 2592. Pattison DI, Davies MJ (2006) Reactions of myeloperoxidase-derived oxidants with biological substrates: gaining chemical insight into human inflammatory diseases. Curr Med Chem 13:3271 2593. Nauseef WM (2007) How human neutrophils kill and degrade microbes: an integrated view. Immunol Rev 219:88

Naturally Occurring Organohalogen Compounds …

533

2594. Gugliucci A (2008) Hypochlorous acid is a potent inactivator of human plasminogen at concentrations secreted by activated granulocytes. Clin Chem Lab Med 46:1403 2595. Marsche G, Furtmüller PG, Obinger C, Sattler W, Malle E (2008) Hypochlorite-modified high-density lipoprotein acts as a sink for myeloperoxidase in vitro. Cardiovasc Res 79:187 2596. Rensen SS, Slaats Y, Nijhuis J, Jans A, Bieghs V, Driessen A, Malle E, Greve JW, Buurman WA (2009) Increased hepatic myeloperoxidase activity in obese subjects with nonalcoholic steatohepatitis. Am J Pathol 175:1473 2597. Nusshold C, Kollroser M, Köfeler H, Rechberger G, Reicher H, Üllen A, Bernhart E, Waltl S, Kratzer I, Hermetter A, Hackl H, Trajanoski Z, Hrzenjak A, Malle E, Sattler W (2010) Hypochlorite modification of sphingomyelin generates chlorinated lipid species that induce apoptosis and proteome alterations in dopaminergic PC12 neurons in vitro. Free Radical Biol Med 48:1588 2598. Snell JA, Jandova J, Wondrak GT (2022) Hypochlorous acid: from innate immune factor and environmental toxicant to chemopreventive agent targeting solar UV-induced skin cancer. Front Oncol 12:887220 2599. Frangie C, Daher J (2022) Role of myeloperoxidase in inflammation and atherosclerosis (review). Biomed Rep 16:53 2600. Marsche G, Stadler JT, Kargl J, Holzer M (2022) Understanding myeloperoxidase-induced damage to HDL structure and function in the vessel wall: implications for HDL-based therapies. Antioxidants 11:556 2601. Wang Y-C, Lu Y-B, Huang X-L, Lao Y-F, Zhang L, Yang J, Shi M, Ma H-L, Pan Y-W, Zhang Y-N (2022) Myeloperoxidase: a new target for the treatment of stroke? Neural Regen Res 17:1711 2602. Valadez-Cosmes P, Raftopoulou S, Mihalic ZN, Marsche G, Kargl J (2022) Myeloperoxidase: growing importance in cancer pathogenesis and potential drug target. Pharmacol Ther 236:108052 2603. Schöler HF, Keppler F (2003) Abiotic formation of organohalogens in the terrestrial environment. Chimia 57:33 2604. Huber SG, Kotte K, Schöler HF, Williams J (2009) Natural abiotic formation of trihalomethanes in soil: results from laboratory studies and field samples. Environ Sci Technol 43:4934 2605. Comba P, Kerscher M, Krause T, Schöler HF (2015) Iron-catalysed oxidation and halogenation of organic matter in nature. Environ Chem 12:381 2606. Poerschmann J, Trommler U, Górecki T, Kopinke F-D (2009) Formation of chlorinated biphenyls, diphenyl ethers and benzofurans as a result of Fenton-driven oxidation of 2chlorophenol. Chemosphere 75:772 2607. Gallard H, Allard S, Nicolau R, von Gunten U, Croué JP (2009) Formation of iodinated organic compounds by oxidation of iodide-containing waters with manganese dioxide. Environ Sci Technol 43:7003 2608. Calza P, Massolino C, Pelizzetti E, Minero C (2008) Solar driven production of toxic halogenated and nitroaromatic compounds in natural seawater. Sci Total Environ 398:196 2609. Vione D, Maurino V, Man SC, Khanra S, Arsene C, Olariu R-I, Minero C (2008) Formation of organobrominated compounds in the presence of bromide under simulated atmospheric aerosol conditions. Chemsuschem 1:197 2610. Lin K, Yan C, Gan J (2014) Production of hydroxylated polybrominated diphenyl ethers (OH-PBDEs) from bromophenols by manganese dioxide. Environ Sci Technol 48:263 2611. Lin K, Song L, Zhou S, Chen D, Gan J (2016) Formation of brominated phenolic contaminants from natural manganese oxides-catalyzed oxidation of phenol in the presence of Br– . Chemosphere 155:266 2612. Liu H, Pu Y, Qiu X, Li Z, Sun B, Zhu X, Liu K (2021) Humic acid extracts leading to the photochemical bromination of phenol in aqueous bromide solutions: influences of aromatic components, polarity and photochemical activity. Molecules 26:608 2613. Deng H, O’Hagan D (2008) The fluorinase, the chlorinase and the duf-62 enzymes. Curr Opin Chem Biol 12:582

534

G. W. Gribble

2614. O’Hagan D, Schmidberger JW (2010) Enzymes that catalyse SN 2 reaction mechanisms. Nat Prod Rep 27:900 2615. O’Hagan D, Deng H (2015) Enzymatic fluorination and biotechnological developments of the fluorinase. Chem Rev 115:634 2616. Carvalho MF, Oliveira RS (2017) Natural production of fluorinated compounds and biotechnological prospects of the fluorinase enzyme. Crit Rev Biotechnol 37:880 2617. Yeo WL, Chew X, Smith DJ, Chan KP, Sun H, Zhao H, Lim YH, Ang EL (2017) Probing the molecular determinants of fluorinase specificity. Chem Commun 53:2559 2618. Winkler M, Domarkas J, Schweiger LF, O’Hagan D (2008) Fluorinase-coupled base swaps: synthesis of [18 F]-5 -deoxy-5 -fluorouridines. Angew Chem Int Ed 47:10141 2619. Deng H, Ma L, Bandaranayaka N, Qin Z, Mann G, Kyeremeh K, Yu Y, Shepherd T, Naismith JH, O’Hagan D (2014) Identification of fluorinases from Streptomyces sp. MA37, Norcardia brasiliensis, and Actinoplanes sp. N902-109 by genome mining. ChemBioChem 15:364 2620. Bartholomé A, Janso JE, Reilly U, O’Hagan D (2017) Fluorometabolite biosynthesis: isotopically labeled glycerol incorporations into the antibiotic nucleocidin in Streptomyces calvus. Org Biomol Chem 15:61 2621. Sun H, Zhao H, Ang EL (2018) A coupled chlorinase–fluorinase system with a high efficiency of trans-halogenation and a shared substrate tolerance. Chem Commun 54:9458 2622. Walker MC, Chang MCY (2014) Natural and engineered biosynthesis of fluorinated natural products. Chem Soc Rev 43:6527 2623. Neumann CS, Fujimori DG, Walsh CT (2008) Halogenation strategies in natural product biosynthesis. Chem Biol 15:99 2624. Nett M, Ikeda H, Moore BS (2009) Genomic basis for natural product biosynthetic diversity in the actinomycetes. Nat Prod Rep 26:1362 2625. Ryan KS, Drennan CL (2009) Divergent pathways in the biosynthesis of bisindole natural products. Chem Biol 16:351 2626. Jones AC, Gu L, Sorrels CM, Sherman DH, Gerwick WH (2009) New tricks from ancient algae: natural products biosynthesis in marine cyanobacteria. Curr Opin Chem Biol 13:216 2627. Jones AC, Monroe EA, Eisman EB, Gerwick L, Sherman DH, Gerwick WH (2010) The unique mechanistic transformations involved in the biosynthesis of modular natural products from marine cyanobacteria. Nat Prod Rep 27:1048 2628. van Pée K-H (2012) Biosynthesis of halogenated alkaloids. The Alkaloids 71:167 2629. Alkhalaf LM, Ryan KS (2015) Biosynthetic manipulation of tryptophan in bacteria: pathways and mechanisms. Chem Biol 22:317 2630. Tang M-C, Zou Y, Watanabe K, Walsh CT, Tang Y (2017) Oxidative cyclization in natural product biosynthesis. Chem Rev 117:5226 2631. Kleigrewe K, Gerwick L, Sherman DH, Gerwick WH (2016) Unique marine derived cyanobacterial biosynthetic genes for chemical diversity. Nat Prod Rep 33:348 2632. Adak S, Moore BS (2021) Cryptic halogenation reactions in natural product biosynthesis. Nat Prod Rep 38:1760 2633. Schmidberger JW, James AB, Edwards R, Naismith JH, O’Hagan D (2010) Halomethane biosynthesis: structure of a SAM-dependent halide methyltransferase from Arabidopsis thaliana. Angew Chem Int Ed 49:3646 2634. Toda H, Itoh N (2011) Isolation and characterization of a gene encoding a S-adenosyll-methionine-dependent halide/thiol methyltransferase (HTMT) from the marine diatom Phaeodactylum tricornutum: biogenic mechanism of CH3 I emissions in oceans. Phytochemistry 72:337 2635. Okada M, Saito K, Wong CP, Li C, Wang D, Iijima M, Taura F, Kurosaki F, Awakawa T, Abe I (2017) Combinatorial biosynthesis of (+)-daurichromenic acid and its halogenated analogue. Org Lett 19:3183 2636. Zheng J, McKinnie SMK, El Gamal A, Feng W, Dong Y, Agarwal V, Fenical W, Kumar A, Cao Z, Moore BS, Pessah IN (2018) Organohalogens naturally biosynthesized in marine environments and produced as disinfection byproducts alter sarco/endoplasmic reticulum Ca2+ dynamics. Environ Sci Technol 52:5469

Naturally Occurring Organohalogen Compounds …

535

2637. Küpper FC, Carrano CJ (2019) Key aspects of the iodine metabolism in brown algae: a brief critical review. Metallomics 11:756 2638. Herget K, Frerichs H, Pfitzner F, Tahir MN, Tremel W (2018) Functional enzyme mimics for oxidative halogenation reactions that combat biofilm formation. Adv Mater 30:1707073 2639. Hudlicky T, Reed JW (2009) Applications of biotransformations and biocatalysis to complexity generation in organic synthesis. Chem Soc Rev 38:3117 2640. Hudlicky T, Reed JW (2009) Celebrating 20 years of SYNLETT —special account on the merits of biocatalysis and the impact of arene cis-dihydrodiols on enantioselective synthesis. Synlett:685 2641. Matveenko M, Willis AC, Banwell MG (2008) A chemoenzymatic synthesis of the antiinfluenza agent tamiflu. Tetrahedron Lett 49:7018 2642. Werner L, Machara A, Sullivan B, Carrera I, Moser M, Adams DR, Hudlicky T (2011) Several generations of chemoenzymatic synthesis of oseltamivir (tamiflu): evolution of strategy, quest for a process-quality synthesis, and evaluation of efficiency metrics. J Org Chem 76:10050 2643. Sullivan B, Hudlicky T (2008) Chemoenzymatic formal synthesis of (–)-balanol. Provision of optical data for an often-reported intermediate. Tetrahedron Lett 49:5211 2644. Gilmet J, Sullivan B, Hudlicky T (2009) Formal total synthesis of (–)- and (+)-balanol: two complementary enantiodivergent routes from vinyloxiranes and vinylaziridines. Tetrahedron 65:212 2645. Findlay AD, Banwell MG (2009) A chemoenzymatic total synthesis of (+)-amabiline. Org Lett 11:3160 2646. Jones MT, Schwartz BD, Willis AC, Banwell MG (2009) Rapid and enantioselective assembly of the lycorine framework using chemoenzymatic techniques. Org Lett 11:3506 2647. Pinkerton DM, Banwell MG, Willis AC (2009) Chemoenzymatic access to versatile epoxyquinol synthons. Org Lett 11:4290 2648. Labora M, Pandolfi EM, Schapiro V (2010) Efficient enantiodivergent total synthesis of (+) and (–)-bromoxone. Tetrahedron: Asymmetry 21:153 2649. Bellomo A, Bonilla JB, López-Prados J, Martín-Lomas M, Gonzalez D (2009) Chemoenzymatic synthesis of glycosyl-deoxyinositol derivatives. First example of a fagopyritol β-analogue containing an aminoinositol unit. Tetrahedron: Asymmetry 20:2061 2650. Bellomo A, Bertucci A, Stefani H, Vázquez A, Gonzalez D (2009) Novel deoxyselenylconduritols: chemoenzymatic synthesis and biological evaluation. Tetrahedron: Asymmetry 20:2673 2651. Banwell MG, Ma X, Karunaratne OP, Willis AC (2010) A first generation chemoenzymatic synthesis of (+)-galanthamine. Aust J Chem 63:1437 2652. Ramos JC, Bracco P, Mazzini M, Fernández JR, Gamenara D, Seoane GA (2010) Concise chemoenzymatic synthesis of methyl d-2,3-dideoxyriboside. Tetrahedron: Asymmetry 21:969 2653. Schwartz BD, Banwell MG, Cade IA (2011) A chemoenzymatic total synthesis of the amaryllidaceae alkaloid narseronine. Tetrahedron Lett 52:4526 2654. White LV, Schwartz BD, Banwell MG, Willis AC (2011) A chemoenzymatic total synthesis of (+)-clividine. J Org Chem 76:6250 2655. Carrilho RMB, Heguaburu V, Schapiro V, Pandolfi E, Kollár L, Pereira MM (2012) An efficient route for the synthesis of chiral conduritol-derivative carboxamides via palladiumcatalyzed aminocarbonylation of bromocyclohexenetetraols. Tetrahedron 68:6935 2656. Lan P, Banwell MG, Ward JS, Willis AC (2014) Chemoenzymatic total synthesis and reassignment of the absolute configuration of ribisin C. Org Lett 16:228 2657. Lan P, Banwell MG, Willis AC (2014) Chemoenzymatic total syntheses of ribisins A, B, and D, polyoxygenated benzofuran derivatives displaying NGF-potentiating properties. J Org Chem 79:2829 2658. Vshyvenko S, Reisenauer MR, Rogelj S, Hudlicky T (2014) Synthesis and biological evaluation of unnatural derivatives of narciclasine: 7-aza-nornarciclasine and its N-oxide. Bioorg Med Chem Lett 24:4236

536

G. W. Gribble

2659. White LV, Banwell MG (2016) Conversion of the enzymatically derived (1S,2S)-3bromocyclohexa-3,5-diene-1,2-diol into enantiomerically pure compounds embodying the pentacyclic framework of vindoline. J Org Chem 81:1617 2660. Yang S, Banwell MG, Willis AC, Ward JS (2015) A chemoenzymatic route to the (+)-form of the Amaryllidaceae alkaloid narseronine. Aust J Chem 68:241 2661. Boyd DR, Sharma ND, Acaru CA, Malone JF, O’Dowd CR, Allen CCR, Stevenson PJ (2010) Chemoenzymatic synthesis of carbasugars (+)-pericosines A-C from diverse aromatic cis-dihydrodiol precursors. Org Lett 12:2206 2662. White LV, Dietinger CE, Pinkerton DM, Willis AC, Banwell MG (2010) An enantioselective synthesis of the epoxyquinol (+)-isoepiepoformin. Eur J Org Chem, 4365 2663. Lan P, White LE, Taher ES, Guest PE, Banwell MG, Willis AC (2015) Chemoenzymatic synthesis of (+)-asperpentyn and the enantiomer of the structure assigned to aspergillusol A. J Nat Prod 78:1963 2664. Ma X, Banwell MG, Willis AC (2013) Chemoenzymatic total synthesis of the phytotoxic geranylcyclohexentriol (–)-phomentrioloxin. J Nat Prod 76:1514 2665. Sharma MK, Banwell MG, Willis AC, Rae AD (2012) Approaches to the neurotrophically active natural product 11-O-debenzoyltashironin: a chemoenzymatic total synthesis of the structurally related sesquiterpene khusiol. Chem Asian J 7:676 2666. Vo Y, Banwell MG, Willis AC (2014) Chemoenzymatic routes to polyoxygenated cyclooctenones related to the eastern hemisphere of the macrolactam tripartilactam. Chem Asian J 9:67 2667. White LV, Lan P, Schwartz BD, Willis AC, Banwell MG (2015) New, homochiral synthons obtained through simple manipulations of enzymatically derived 3-halo-cis-1,2dihydrocatechols. Aust J Chem 68:1467 2668. Schwartz BD, Jones MT, Banwell MG, Cade IA (2010) Synthesis of the enantiomer of the structure assigned to the natural product nobilisitine A. Org Lett 12:5210 2669. Ramos JC, Brovetto M, Seoane GA (2013) Chemoenzymatic synthesis of transtetrahydrofuran cores of annonaceous acetogenins from bromobenzene. Org Lett 15:1982 2670. Semak V, Metcalf TA, Endoma-Arias MAA, Mach P, Hudlicky T (2012) Toluene dioxygenase mediated oxidation of halogen-substituted benzoate esters. Org Biomol Chem 10:4407 2671. Griffen JA, Le Coz AM, Kociok-Köhn G, Ali Khan M, Stewart AJW, Lewis SE (2011) Expanding the chiral pool: oxidation of meta-bromobenzoic acid by R. eutrophus B9 allows access to new reaction manifolds. Org Biomol Chem 9:3920 2672. Boyd DR, Sharma ND, Malone JF, McIntyre PBA, Stevenson PJ, Allen CCR, Kwit M, Gawronski J (2012) Structure, stereochemistry and synthesis of enantiopure cyclohexenone cis-diol bacterial metabolites derived from phenols. Org Biomol Chem 10:6217 2673. Leisch H, Omori AT, Finn KJ, Gilmet J, Bissett T, Ilceski D, Hudlicky T (2009) Chemoenzymatic enantiodivergent total syntheses of (+)- and (–)-codeine. Tetrahedron 65:9862 2674. Duchek J, Piercy TG, Gilmet J, Hudlicky T (2011) Chemoenzymatic total synthesis of entneopinone and formal total synthesis of ent-codeinone from β-bromoethylbenzene. Can J Chem 89:709 2675. Boyd DR, Bell M, Dunne KS, Kelly B, Stevenson PJ, Malone JF, Allen CCR (2012) Chemoenzymatic synthesis of a mixed phosphine–phosphine oxide catalyst and its application to asymmetric allylation of aldehydes and hydrogenation of alkenes. Org Biomol Chem 10:1388 2676. Kurihara T (2011) A mechanistic analysis of enzymatic degradation of organohalogen compounds. Biosci Biotechnol Biochem 75:189 2677. Olaniran AO, Igbinosa EO (2011) Chlorophenols and other related derivatives of environmental concern: properties, distribution and microbial degradation processes. Chemosphere 83:1297 2678. Moreira IS, Amorim CL, Murphy CD, Castro PML (2018) Strategies for biodegradation of fluorinated compounds. In: Prasad R, Aranda E (eds) Approaches in bioremediation, chap 11. Springer Nature, Cham, Switzerland, p 239

Naturally Occurring Organohalogen Compounds …

537

2679. He H, Li Y, Shen R, Shim H, Zeng Y, Zhao S, Lu Q, Mai B, Wang S (2021) Environmental occurrence and remediation of emerging organohalides: a review. Environ Pollut 290:118060 2680. Jugder B-E, Ertan H, Bohl S, Lee M, Marquis CP, Manefield M (2016) Organohalide respiring bacteria and reductive dehalogenases: key tools in organohalide bioremediation. Front Microbiol 7:249 2681. Kunka A, Damborsky J, Prokop Z (2018) Haloalkane dehalogenases from marine organisms. Methods Enzymol 605:203 2682. Zakary S, Oyewusi HA, Huyop F (2021) Dehalogenases for pollutant degradation: a mini review. J Trop Life Sci 11:17 2683. Wackett LP (2022) Nothing lasts forever: understanding microbial biodegradation of polyfluorinated compounds and perfluorinated alkyl substanes. Microb Biotechnol 15:773 2684. Gelman F, Dybala-Defratyka A (2020) Bromine isotope effects: Predictions and measurements. Chemosphere 246:125746 2685. Sen S, Karn SK (2019) Cyanobacteria: the eco-friendly tool for the treatment of industrial wastewater. In: Bharagava RN (ed) Environmental contaminants: ecological implications and management, microorganisms for sustainability, chap 8. Springer Nature Singapore Pte Ltd., p 163 2686. Zinder SH (2016) The genus Dehalococcoides. In: Adrian L, Löffler FE (eds) Organohaliderespiring bacteria, chap 6. Springer, Berlin, Heidelberg, p 107 2687. Chen K, Huang L, Xu C, Liu X, He J, Zinder SH, Li S, Jiang J (2013) Molecular characterization of the enzymes involved in the degradation of a brominated aromatic herbicide. Mol Microbiol 89:1121 2688. Atashgahi S, Shetty SA, Smidt H, de Vos WM (2018) Flux, impact, and fate of halogenated xenobiotic compounds in the gut. Frontiers Physiol 9:888 2689. Maucourt B, Vuilleumier S, Bringel F (2020) Transcriptional regulation of organohalide pollutant utilisation in bacteria. FEMS Microbiol Rev 44:189 2690. Ichiyama S, Kurihara T, Kogure Y, Tsunasawa S, Kawasaki H, Esaki N (2004) Reactivity of asparagine residue at the active site of the D105N mutant of fluoroacetate dehalogenase from Moraxella sp. B. Biochim Biophys Acta 1698:27 2691. Osborne RL, Taylor LO, Han KP, Ely B, Dawson JH (2004) Amphitrite ornata dehaloperoxidase: enhanced activity for the catalytically active globin using MCPBA. Biochem Biophys Res Commun 324:1194 2692. Osborne RL, Coggins MK, Walla M, Dawson JH (2007) Horse heart myoglobin catalyzes the H2 O2 -dependent oxidative dehalogenation of chlorophenols to DNA-binding radicals and quinones. Biochemistry 46:9823 2693. Osborne RL, Coggins MK, Raner GM, Walla M, Dawson JH (2009) The mechanism of oxidative halophenol dehalogenation by Amphitrite ornata dehaloperoxidase is initiated by H2 O2 binding and involves two consecutive one-electron steps: role of ferryl intermediates. Biochemistry 48:4231 2694. Murphy CD (2007) Fluorophenol oxidation by a fungal chloroperoxidase. Biotechnol Lett 29:45 2695. Chen K, Mu Y, Jian S, Zang X, Chen Q, Jia W, Ke Z, Gao Y, Jiang J (2018) Comparative transcriptome analysis reveals the mechanism underlying 3,5-dibromo-4hydroxybenzoatae catabolism via a new oxidative decarboxylation pathway. Appl Environ Microbiol 84:e02467–e02517 2696. Louie TS, Pavlik EJ, Häggblom MM (2021) Genome analysis of Thauera chlorobenzoica strain 3CB-1, a halobenzoate-degrading bacterium isolated from aquatic sediment. Arch Microbiol 203:5095 2697. Solyanikova IP, Emelyanova EV, Shumkova ES, Travkin VM (2019) Pathways of 3chlorobenzoate degradation by Rhodococcus opacus strains 1CP and 6a. Microbiology 88:563 2698. Uhnáková B, Petˇríˇcková A, Biedermann D, Homolka L, Vejvoda V, Bednár P, Papoušková B, Šulc M, Martínková L (2009) Biodegradation of brominated aromatics by cultures and laccase of Trametes versicolor. Chemosphere 76:826

538

G. W. Gribble

2699. Golan R, Gelman F, Kuder T, Taylor AA, Ronen Z, Bernstein A (2019) Degradation of 4-bromophenol by Ochrobactrum sp. HI1 isolated from desert soil: pathway and isotope effects. Biodegradation 30:37 2700. Zhang Q, Liu Y, Lin Y, Kong W, Zhao X, Ruan T, Liu J, Schnoor JL, Jiang G (2019) Multiple metabolic pathways of 2,4,6-tribromophenol in rice plants. Environ Sci Technol 53:7473 2701. Nikolaivits E, Agrafiotis A, Termentzi A, Machera K, Le Goff G, Álvarez P, Chavanich S, Benayahu Y, Ouazzani J, Fokialakis N, Topakas E (2019) Unraveling the detoxification mechanism of 2,4-dichlorophenol by marine-derived mesophotic symbiotic fungi isolated from marine invertebrates. Mar Drugs 17:564 2702. Watson JA Jr, McTamney PM, Adler JM, Rokita SE (2008) Flavoprotein iodotyrosine deiodinase functions without cysteine residues. ChemBioChem 9:504 2703. Fortino M, Marino T, Russo N, Sicilia E (2015) Mechanism of thyroxine deiodination by naphthyl-based iodothyronine deiodinase mimics and the halogen bonding role: a DFT investigation. Chem Eur J 21:8554 2704. Lindqvist D, Gustafsson J (2021) Degradation of naturally produced hydroxylated polybrominated diphenyl ethers in Baltic Sea sediment via reductive debromination. Environ Sci Pollut Res 28:25878 2705. Lee LK, He J (2010) Reductive debromination of polybrominated diphenyl ethers by anaerobic bacteria from soils and sediments. Appl Environ Microbiol 76:794 2706. Zanaroli G, Negroni A, Häggblom MM, Fava F (2015) Microbial dehalogenation of organohalides in marine and estuarine environments. Curr Opin Biotechnol 33:287 2707. Nelson JL, Fung JM, Cadillo-Quiroz H, Cheng X, Zinder SH (2011) A role for Dehalobacter spp. in the reductive dehalogenation of dichlorobenzenes and monochlorobenzene. Environ Sci Technol 45:6806 2708. Nelson JL, Jiang J, Zinder SH (2014) Dehalogenation of chlorobenzenes, dichlorotoluenes, and tetrachloroethene by three Dehalobacter spp. Environ Sci Technol 48:3776 2709. Liang X, Devine CE, Nelson J, Lollar BS, Zinder S, Edwards EA (2013) Anaerobic conversion of chlorobenzene and benzene to CH4 and CO2 in bioaugmented microcosms. Environ Sci Technol 47:2378 2710. Zhang S, Wondrousch D, Cooper M, Zinder SH, Schüürmann G, Adrian L (2017) Anaerobic dehalogenation of chloroanilines by Dehalococcoides mccartyi strain CBDB1 and Dehalobacter strain 14DCB1 via different pathways as related to molecular electronic structure. Environ Sci Technol 51:3714 2711. Krzmarzick MJ, Miller HR, Yan T, Novak PJ (2014) Novel Firmicutes group implicated in the dechlorination of two chlorinated xanthones, analogues of natural organochlorines. Appl Environ Microbiol 80:1210 2712. Suzuki Y, Nakamura M, Otsuka Y, Suzuki N, Ohyama K, Kawakami T, Sato K, Kajita S, Hishiyama S, Fujii T, Takahashi A, Katayama Y (2011) Novel enzymatic activity of cell free extract from thermophilic Geobacillus sp. UZO 3 catalyzes reductive cleavage of diaryl ether bonds of 2,7-dichlorodibenzo-p-dioxin. Chemosphere 83:868 2713. Chen G, Murdoch RW, Mack EE, Seger ES, Löffler FE (2017) Complete genome sequence of Dehalobacterium formicoaceticum strain DMC, a strictly anaerobic dichloromethanedegrading bacterium. Genome Announc 5:e00897–e00917 2714. Kleindienst S, Higgins SA, Tsementzi D, Chen G, Konstantinidis KT, Mack EE, Löffler FE (2017) ‘Candidatus dichloromethanomonas elyunquensis’ gen. nov., sp. nov., a dichloromethane-degrading anaerobe of the Peptococcaceae family. Syst Appl Microbiol 40:150 2715. Chen G, Shouakar-Stash O, Phillips E, Justicia-Leon SD, Gilevska T, Lollar BS, Mack EE, Seger ES, Löffler FE (2018) Dual carbon–chlorine isotope analysis indicates distinct anaerobic dichloromethane degradation pathways in two members of Peptococcaceae. Environ Sci Technol 52:8607 2716. Kleindienst S, Chourey K, Chen G, Murdoch RW, Higgins SA, Iyer R, Campagna SR, Mach EE, Seger ES, Hettich RL, Löffler FE (2019) Proteogenomics reveals novel reductive dehalogenases and methyltransferases expressed during anaerobic dichloromethane metabolism. Appl Environ Microbiol 85:e02768–e2818

Naturally Occurring Organohalogen Compounds …

539

2717. Chen G, Fisch AR, Gibson CM, Mack EE, Seger ES, Campagna SR, Löffler FE (2020) Mineralization versus fermentation: evidence for two distinct anaerobic bacterial degradation pathways for dichloromethane. ISME J 14:959 2718. Skopelitou K, Georgakis N, Efrose R, Flemetakis E, Labrou NE (2013) Sol–gel immobilization of haloalkane dehalogenase from Bradyrhizobium japonicum from the remediation 1,2-dibromoethane. J Mol Catal B: Enzymatic 97:5 2719. Koudelakova T, Chovancova E, Brezovsky J, Monincova M, Fortova A, Jarkovsky J, Damborsky J (2011) Substrate specificity of haloalkane dehalogenases. Biochem J 435:345 2720. Hug LA, Maphosa F, Leys D, Löffler FE, Smidt H, Edwards EA, Adrian L (2013) Overview of organohalide-respiring bacteria and a proposal for a classification system for reductive dehalogenases. Phil Trans R Soc B 368:20120322 2721. Buryska T, Daniel L, Kunka A, Brezovsky J, Damborsky J, Prokop Z (2016) Discovery of novel haloalkane dehalogenase inhibitors. Appl Environ Microbiol 82:1958 2722. Kotik M, Vanacek P, Kunka A, Prokop Z, Damborsky J (2017) Metagenome-derived haloalkane dehalogenases with novel catalytic properties. Appl Microbiol Biotechnol 101:6385 2723. Novak HR, Sayer C, Isupov MN, Paszkiewicz K, Gotz D, Spragg AM, Littlechild JA (2013) Marine Rhodobacteraceae l-haloacid dehalogenase contains a novel His/Glu dyad that could activate the catalytic water. FEBS J 280:1664 2724. Zhang J, Xin Y, Cao X, Xue S, Zhang W (2014) Purification and characterization of 2haloacid dehalogenase from marine bacterium Paracoccus sp. DEH99, isolated from marine sponge Hymeniacidon perlevis. J Ocean Univ China 13:91 2725. Peng P, Zheng Y, Koehorst JJ, Schaap PJ, Stams AJM, Smidt H, Atashgahi S (2017) Concurrent haloalkanoate degradation and chlorate reduction by Pseudomonas chloritidismutans AW-1. Appl Environ Microbiol 83:e00325 2726. Grigorian E, Groisillier A, Thomas F, Leblanc C, Delage L (2021) Functional characterization of a l-2-haloacid dehalogenase from Zobellia galactanivorans DsijT suggests a role in haloacetic acid catabolism and a wide distribution in marine environments. Front Microbiol 12:725997 2727. Wahhab BHA, Samsulrizal NH, Edbeib MF, Wahab RA, Al-Nimer MSM, Hamid AAA, Oyewusi HA, Kaya Y, Notarte KIR, Shariff AHM, Huyop F (2021) Genomic analysis of a functional haloacid-degrading gene of Bacillus megaterium strain HBS1 isolated from Blue Lake (Mavi Gölü, Turkey). Ann Microbiol 71:12 2728. Akcay K, Kaya Y (2019) Isolation, characterization and molecular identification of a halotolerant Bacillus megaterium CTBmeg1 able to grow on halogenated compounds. Biotechnol Biotechnol Equip 33:945 2729. Chekan JR, Lee GY, El Gamal A, Purdy TN, Houk KN, Moore BS (2019) Bacterial tetrabromopyrrole debrominase shares a reductive dehalogenation strategy with human thyroid deiodinase. Biochemistry 58:5329 2730. Yaffee HS, Stargardter F (1963) Erythema multiforme from Tedania ignis. Report of a case and an experimental study of the mechanism of cutaneous irritation from the fire sponge. Arch Dermatol 87:601 2731. Thorpe E, Ford EJH (1968) Development of hepatic lesions in calves fed with ragwort (Senecio jacobea). J Comp Pathol 78:195 2732. Scheuer PJ (1982) Marine ecology—some chemical aspects. Naturwissenschaften 69:528 2733. König GM, Wright AD, Sticher O, Angerhofer CK, Pezzuto JM (1994) Biological activities of selected marine natural products. Planta Med 60:532 2734. Pedersén M, Collén J, Abrahamsson K, Ekdahl A (1996) Production of halocarbons from seaweeds: an oxidative stress reaction? Sci Mar 60:257 2735. Kubanek J, Jensen PR, Keifer PA, Sullards MC, Collins DO, Fenical W (2003) Seaweed resistance to microbial attack: a targeted chemical defense against marine fungi. Proc Natl Acad Sci USA 100:6916 2736. Paul NA, de Nys R, Steinberg PD (2006) Seaweed-herbivore interactions at a small scale: direct tests of feeding deterrence by filamentous algae. Mar Ecol Prog Ser 331:1

540

G. W. Gribble

2737. Paul NA, de Nys R, Steinberg PD (2006) Chemical defence against bacteria in the red alga Asparagopsis armata: linking structure with function. Mar Ecol Prog Ser 306:87 2738. Nylund GM, Cervin G, Persson F, Hermansson M, Steinberg PD, Pavia H (2008) Seaweed defence against bacteria: a poly-brominated 2-heptanone from the red alga Bonnemaisonia hamifera inhibits bacterial colonisation. Mar Ecol Prog Ser 369:39 2739. Svensson JR, Nylund GM, Cervin G, Toth GB, Pavia H (2013) Novel chemical weapon of an exotic macroalga inhibits recruitment of native competitors in the invaded range. J Ecol 101:140 2740. Salgado LT, Viana NB, Andrade LR, Leal RN, da Gama BAP, Attias M, Pereira RC, Filho GMA (2008) Intra-cellular storage, transport and exocytosis of halogenated compounds in marine red alga Laurencia obtusa. J Struct Biol 162:345 2741. Amsler CD, Iken K, McClintock JB, Baker BJ (2009) Defenses of polar macroalgae against herbivores and biofoulers. Bot Mar 52:535 2742. Paul C, Pohnert G (2011) Production and role of volatile halogenated compounds from marine algae. Nat Prod Rep 28:186 2743. Al-Adilah H, Feiters MC, Carpenter LJ, Kumari P, Carrano CJ, Al-Bader D, Küpper FC (2022) Halogens in seaweeds: biological and environmental significance. Phycology 2:132 2744. Vieira C, Thomas OP, Culioli G, Genta-Jouve G, Houlbreque F, Gaubert J, De Clerck O, Payri CE (2016) Allelopathic interactions between the brown algal genus Lobophora (Dictyotales, Phaeophyceae) and scleractinian corals. Sci Rep 6:18637 2745. Greff S, Aires T, Serrão EA, Engelen AH, Thomas OP, Pérez T (2017) The interaction between the proliferating macroalga Asparagopsis taxiformis and the coral Astroides calycularis induces changes in microbiome and metabolomic fingerprints. Sci Rep 7:42625 2746. Silva CO, Simões T, Félix R, Soares AMVM, Barata C, Novais SC, Lemos MFL (2021) Asparagopsis armata exudate cocktail: the quest for the mechanisms of toxic action of an invasive seaweed on marine invertebrates. Biology 10:223 2747. Putz A, König GM, Wägele H (2010) Defensive strategies of cladobranchia (Gastropoda, Opisthobranchia). Nat Prod Rep 27:1386 2748. Figuerola B, Núñez-Pons L, Moles J, Avila C (2013) Feeding repellence in Antarctic bryozoans. Naturwissenschaften 100:1069 2749. Ni N, Li M, Wang J, Wang B (2009) Inhibitors and antagonists of bacterial quorum sensing. Med Res Rev 29:65 2750. Dickschat JS (2010) Quorum sensing and bacterial biofilms. Nat Prod Rep 27:343 2751. Fletcher MH, Jennings MC, Wuest WM (2014) Draining the moat: disrupting bacterial biofilms with natural products. Tetrahedron 70:6373 2752. Wang K-L, Wu Z-H, Wang Y, Wang C-Y, Xu Y (2017) Mini-review: antifouling natural products from marine microorganisms and their synthetic analogs. Mar Drugs 15:266 2753. Chen L, Qian P-Y (2017) Review on molecular mechanisms of antifouling compounds: an update since 2012. Mar Drugs 15:264 2754. Stowe SD, Richards JJ, Tucker AT, Thompson R, Melander C, Cavanagh J (2011) Antibiofilm compounds derived from marine sponges. Mar Drugs 9:2010 2755. Al-Lihaibi SS, Abdel-Lateff A, Alarif WM, Nogata Y, Ayyad S-EN, Okino T (2015) Potent antifouling metabolites from Red Sea organisms. Asian J Chem 27:2252 2756. Messina CM, Renda G, Laudicella VA, Trepos R, Fauchon M, Hellio C, Santulli A (2019) From ecology to biotechnology, study of the defense strategies of algae and halophytes (from Trapani Saltworks, NW Sicily) with a focus on antioxidants and antimicrobial properties. Int J Mol Sci 20:881 2757. Lawson CA, Possell M, Seymour JR, Raina J-B, Suggett DJ (2019) Coral endosymbionts (Symbiodiniaceae) emit species-specific volatilomes that shift when exposed to thermal stress. Sci Rep 9:17395 2758. Amsler CD, McClintock JB, Baker BJ (2001) Secondary metabolites as mediators of trophic interactions among Antarctic marine organisms. Am Zool 41:17 2759. Birkedal H, Khan RK, Slack N, Broomell C, Lichtenegger HC, Zok F, Stucky GD, Waite JH (2006) Halogenated veneers: protein cross-linking and halogenation in the jaws of Nereis, a marine polychaete worm. ChemBioChem 7:1392

Naturally Occurring Organohalogen Compounds …

541

2760. Schofield RMS, Niedbala JC, Nesson MH, Tao Y, Shokes JE, Scott RA, Latimer MJ (2009) Br-rich tips of calcified crab claws are less hard but more fracture resistant: a comparison of mineralized and heavy-element biological materials. J Struct Biol 166:272 2761. Pizzi A, Sori L, Pigliacelli C, Gautieri A, Andolina C, Bergamaschi G, Gori A, Panine P, Grande AM, Linder MB, Bombelli FB, Soncini M, Metrangolo P (2022) Emergence of elastic properties in a minimalist resilin-derived heptapeptide upon bromination. Small, 2200807 2762. Venturi S (2011) Evolutionary significance of iodine. Curr Chem Biol 5:155 2763. de Jong E, Field JA, Spinnler H-E, Wijnberg JBPA, de Bont JAM (1994) Significant biogenesis of chlorinated aromatics by fungi in natural environments. Appl Environ Microbiol 60:264 2764. de Jong E, Cazemier AE, Field JA, de Bont JAM (1994) Physiological role of chlorinated aryl alcohols biosynthesized de novo by the white rot fungus Bjerkandera sp. strain BOS55. Appl Environ Microbiol 60:271 2765. Bengtson P, Bastviken D, de Boer W, Öberg G (2009) Possible role of reactive chlorine in microbial antagonism and organic matter chlorination in terrestrial environments. Environ Microbiol 11:1330 2766. Barnum TP, Coates JD (2022) The biogeochemical cycling of chlorine. Geobiology 20:634 2767. Spiteller P (2008) Chemical defence strategies of higher fungi. Chem Eur J 14:9100 2768. Henschler D (1994) Toxicity of chlorinated organic compounds: effects of the introduction of chlorine in organic molecules. Angew Chem Int Ed Engl 33:1920 2769. Gerwick WH, Roberts MA, Proteau PJ, Chen J-L (1994) Screening cultured marine microalgae for anticancer-type activity. J Appl Phycol 6:143 2770. Moussavou G, Kwak DH, Obiang-Obonou BW, Maranguy CAO, Dinzouna-Boutamba S-D, Lee DH, Pissibanganga OGM, Ko K, Seo JI, Choo YK (2014) Anticancer effects of different seaweeds on human colon and breast cancers. Mar Drugs 12:4898 2771. Mridha A, Paul S (2017) Algae as potential repository of anti cancerous natural compounds. Int J Phytomed 9:181 2772. Alves C, Silva J, Pinteus S, Gaspar H, Alpoim MC, Botana LM, Pedrosa R (2018) From marine origin to therapeutics: the antitumor potential of marine algae-derived compounds. Front Pharmacol 9:777 2773. Lefranc F, Koutsaviti A, Ioannou E, Kornienko A, Roussis V, Kiss R, Newman D (2019) Algae metabolites: from in vitro growth inhibitory effects to promising anticancer activity. Nat Prod Rep 36:810 2774. Olano C, Méndez C, Salas JA (2009) Antitumor compounds from marine actinomycetes. Mar Drugs 7:210 2775. Deshmukh SK, Prakash V, Ranjan N (2017) Marine fungi: a source of potential anticancer compounds. Front Microbiol 8:2536 2776. Schinke C, Martins T, Queiroz SCN, Melo IS, Reyes FGR (2018) Antibacterial compounds from marine bacteria, 2010–2015. J Nat Prod 80:1215 2777. van Geelen L, Meier D, Rehberg N, Kalscheuer R (2018) (Some) current concepts in antibacterial drug discovery. Appl Microbiol Biotechnol 102:2949 2778. Brown DG, Lister T, May-Dracka TL (2014) New natural products as new leads for antibacterial drug discovery. Bioorg Med Chem Lett 24:413 2779. El Sayed KA, Bartyzel P, Shen X, Perry TL, Zjawiony JK, Hamann MT (2000) Marine natural products as antituberculosis agents. Tetrahedron 56:949 2780. Hikmawan BD, Wahyuono S, Setyowati EP (2020) Marine sponge compounds with antiplasmodial properties: Focus on in vitro study against Plasmodium falciparum. J Appl Pharm Sci 10:142 2781. Moodie LWK, Sepˇci´c K, Turk T, Frangež R, Svenson J (2019) Natural cholinesterase inhibitors from marine organisms. Nat Prod Rep 36:1053 2782. Ezzat SM, El Bishbishy MH, Habtemariam S, Salehi B, Sharifi-Rad M, Martins N, SharifiRad J (2018) Looking at marine-derived bioactive molecules as upcoming anti-diabetic agents: a special emphasis on PTP1B inhibitors. Molecules 23:3334

542

G. W. Gribble

2783. Mateos R, Pérez-Correa JR, Domínguez H (2020) Bioactive properties of marine phenolics. Mar Drugs 18:501 2784. Kochanowska-Karamyan AJ, Hamann MT (2010) Marine indole alkaloids: potential new drug leads for the control of depression and anxiety. Chem Rev 110:4489 2785. Stonik VA, Fedorov SN (2014) Marine low molecular weight natural products as potential cancer preventive compounds. Mar Drugs 12:636 2786. Matulja D, Wittine K, Malatesti N, Laclef S, Turks M, Markovic MK, Ambroži´c G, Markovi´c D (2020) Marine natural products with high anticancer activities. Curr Med Chem 27:1243 2787. Mbaoji FN, Nweze JA, Yang L, Huang Y, Huang S, Onwuka AM, Peter IE, Mbaoji CC, Jiang M, Zhang Y, Pan L, Yang D (2021) Novel marine secondary metabolites worthy of development as anticancer agents: a review. Molecules 26:5769 2788. Jha RK, Xu Z (2004) Biomedical compounds from marine organisms. Mar Drugs 2:123 2789. Mayer AMS, Rodríguez AD, Taglialatela-Scafati O, Fusetani N (2013) Marine pharmacology in 2009–2011: marine compounds with antibacterial, antidiabetic, antifungal, antiinflammatory, antiprotozoal, antituberculosis, and antiviral activities; affecting the immune and nervous systems, and other miscellaneous mechanisms of action. Mar Drugs 11:2510 2790. Hu Y, Chen J, Hu G, Yu J, Zhu X, Lin Y, Chen S, Yuan J (2015) Statistical research on the bioactivity of new marine natural products discovered during the 28 years from 1985 to 2012. Mar Drugs 13:202 2791. Falkenberg M, Nakano E, Zambotti-Villela L, Zatelli GA, Philippus AC, Imamura KB, Velasquez AMA, Freitas RP, de Freitas TL, Colepicolo P, Graminha MAS (2019) Bioactive compounds against neglected diseases isolated from macroalgae: a review. J Appl Phycol 31:797 2792. Gál B, Bucher C, Burns NZ (2016) Chiral alkyl halides: underexplored motifs in medicine. Mar Drugs 14:206 2793. Martínez-Poveda B, Quesada AR, Medina MÁ (2017) Pleiotropic role of puupehenones in biomedical research. Mar Drugs 15:325 2794. Molinski TF, Dalisay DS, Lievens SL, Saludes JP (2009) Drug development from marine natural products. Nat Rev Drug Discov 8:69 2795. Villa FA, Gerwick L (2010) Marine natural product drug discovery: leads for treatment of inflammation, cancer, infections, and neurological disorders. Immunopharmacol Immunotoxicol 32:228 2796. Mayer AMS, Glaser KB, Cuevas C, Jacobs RS, Kem W, Little RD, McIntosh JM, Newman DJ, Potts BC, Shuster DE (2010) The odyssey of marine pharmaceuticals: a current pipeline perspective. Trends Pharmacol Sci 31:255 2797. Torres FAE, Passalacqua TG, Velásquez AMA, de Souza RA, Colepicolo P, Graminha MAS (2014) New drugs with antiprotozoal activity from marine algae: a review. Rev Bras Farmacogn 24:265 2798. Kobayashi J (2016) Search for new bioactive marine natural products and application to drug development. Chem Pharm Bull 64:1079 2799. Jiménez C (2018) Marine natural products in medicinal chemistry. ACS Med Chem Lett 9:959 2800. Radjasa OK, Vaske YM, Navarro G, Vervoort HC, Tenney K, Linington RG, Crews P (2011) Highlights of marine invertebrate-derived biosynthetic products: their biomedical potential and possible production by microbial associants. Bioorg Med Chem 19:6658 2801. Gochfeld DJ, El Sayed KA, Yousaf M, Hu JF, Bartyzel P, Dunbar DC, Wilkins SP, Zjawiony JK, Schinazi RF, Wirtz SS, Tharnish PM, Hamann MT (2003) Marine natural products as lead anti-HIV agents. Mini Rev Med Chem 3:401 2802. Laurent D, Pietra F (2006) Antiplasmodial marine natural products in the perspective of current chemotherapy and prevention of malaria. A review. Mar Biotechnol 8:433 2803. Liu X, Ashforth E, Ren B, Song F, Dai H, Liu M, Wang J, Xie Q, Zhang L (2010) Bioprospecting microbial natural product libraries from the marine environment for drug discovery. J Antibiot 63:415

Naturally Occurring Organohalogen Compounds …

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2804. Njoroge M, Njuguna NM, Mutai P, Ongarora DSB, Smith PW, Chibale K (2014) Recent approaches to chemical discovery and development against malaria and the neglected tropical diseases human African trypanosomiasis and schistosomiasis. Chem Rev 114:11138 2805. Burrows JN, Elliott RL, Kaneko T, Mowbray CE, Waterson D (2014) The role of modern drug discovery in the fight against neglected and tropical diseases. Med Chem Commun 5:688 2806. Sachs-Barrable K, Conway J, Gershkovich P, Ibrahim F, Wasan KM (2014) The use of the United States FDA programs as a strategy to advance the development of drug products for neglected tropical diseases. Drug Dev Ind Pharm 40:1429 2807. Genovese G, Tedone L, Hamann MT, Morabito M (2009) The Mediterranean red alga Asparagopsis: a source of compounds against Leishmania. Mar Drugs 7:361 2808. Gullo VP, McAlpine J, Lam KS, Baker D, Petersen F (2006) Drug discovery from natural products. J Ind Microbiol Biotechnol 33:523 2809. Fenical W, Jensen PR (2006) Developing a new resource for drug discovery: marine actinomycete bacteria. Nat Chem Biol 2:666 2810. Montaser R, Luesch H (2011) Marine natural products: a new wave of drugs? Future Med Chem 3:1475 2811. Atanasov AG, Zotchev SB, Dirsch VM, International Natural Product Sciences Taskforce, Supuran CT (2021) Natural products in drug discovery: advances and opportunities. Nat Rev Drug Dis 20:200 2812. Cheung PCW (2017) A historical review of the benefits and hypothetical risks of disinfecting drinking water by chlorination (updated and revised). J Environ Ecol 8:73 2813. Dennis C (2003) Close encounters of the jelly kind. Nature 426:12 2814. Roark EB, Guilderson TP, Dunbar RB, Ingram BL (2006) Radiocarbon-based ages and growth rates of Hawaiian deep-sea corals. Mar Ecol Prog Ser 327:1 2815. Houlbrèque F, McCulloch M, Roark B, Guilderson T, Meibom A, Kimball J, Mortimer G, Cuif J-P, Dunbar R (2010) Uranium-series dating and growth characteristics of the deep-sea scleractinian coral: Enallopsammia rostrata from the equatorial Pacific. Geochim Cosmochim Acta 74:2380 2816. Barley S (2009) Deep-sea denizens make their debut. NewScientist: 12, November 28 2817. Lutz RA, Falkowski PG (2012) A dive to challenger deep. Science 336:301 2818. Johnson TA, Morgan MVC, Aratow NA, Estee SA, Sashidhara KV, Loveridge ST, Segraves NL, Crews P (2010) Assessing pressurized liquid extraction for the high-throughput extraction of marine-sponge-derived natural products. J Nat Prod 73:359 2819. Esquenazi E, Daly M, Bahrainwala T, Gerwick WH, Dorrestein PC (2011) Ion mobility mass spectrometry enables the efficient detection and identification of halogenated natural products from cyanobacteria with minimal sample preparation. Bioorg Med Chem 19:6639 2820. Nyadong L, Hohenstein EG, Galhena A, Lane AL, Kubanek J, Sherrill CD, Fernández FM (2009) Reactive desorption electrospray ionization mass spectrometry (DESI-MS) of natural products of a marine alga. Anal Bioanal Chem 394:245 2821. Hauler C, Vetter W (2015) A non-targeted gas chromatography/electron capture negative ionization mass spectrometry selected ion monitoring screening method for polyhalogenated compounds in environmental samples. Rapid Commun Mass Spectrom 29:619 2822. Hoh E, Dodder NG, Lehotay SJ, Pangallo KC, Reddy CM, Maruya KA (2012) Nontargeted comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry method and software for inventorying persistent and bioaccumulative contaminants in marine environments. Environ Sci Technol 46:8001 2823. Shaul NJ, Dodder NG, Aluwihare LI, Mackintosh SA, Maruya KA, Chivers SJ, Danil K, Weller DW, Hoh E (2015) Nontargeted biomonitoring of halogenated organic compounds in two ecotypes of bottlenose dolphins (Tursiops truncatus) from the southern California bight. Environ Sci Technol 49:1328 2824. Dalisay DS, Molinski TF (2009) NMR quantitation of natural products at the nanomole scale. J Nat Prod 72:739

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2825. Andrews KG, Spivey AC (2013) Improving the accuracy of computed 13 C NMR shift predictions by specific environment error correction: fragment referencing. J Org Chem 78:11302 2826. Casella G, Bagno A, Komorovsky S, Repisky M, Saielli G (2015) Four-component relativistic DFT calculations of 13 C chemical shifts of halogenated natural substances. Chem Eur J 21:18834 2827. Wang X, Duggan BM, Molinski TF (2017) Ultra-high resolution band-selective HSQC for nanomole-scale identification of chlorine-substituted 13 C in natural products drug discovery. Magn Reson Chem 55:263 2828. Maier ME (2009) Structural revisions of natural products by total synthesis. Nat Prod Rep 26:1105 2829. Usami Y (2009) Recent synthetic studies leading to structural revisions of marine natural products. Mar Drugs 7:314 2830. Capon RJ (2020) Extracting value: mechanistic insights into the formation of natural product artifacts—case studies in marine natural products. Nat Prod Rep 37:55 2831. Aranami K, Rowland SJ, Readman JW (2006) Discriminating biogenic and anthropogenic chlorinated organic compounds using multi-isotope analyses of individual compounds. Radioactiv Environ 8:24 2832. Renpenning J, Horst A, Schmidt M, Gehre M (2018) Online isotope analysis of 37 Cl/35 Cl universally applied for semi-volatile organic compounds using GC-MC-ICPMS. J Anal At Spectrom 33:314 2833. Vetter W, Schurig V (1997) Enantioselective determination of chiral organochlorine compounds in biota by gas chromatography on modified cyclodextrins. J Chromatogr A 774:143 2834. Rosenfelder N, Ostrowicz P, Fu L, Gribble GW, Tittlemier SA, Frey W, Vetter W (2010) Enantioseparation and absolute configuration of the atropisomers of a naturally produced hexahalogenated 1,1 -dimethyl-2,2 -dipyrrole. J Chromatogr A 1217:2050 2835. Powell RG (2009) Plant seeds as sources of potential industrial chemicals, pharmaceuticals, and pest control agents. J Nat Prod 72:516 2836. Sanders L (2009) Venom hunters. Science News August 15:16 2837. Timms BV (2005) Salt lakes in Australia: present problems and prognosis for the future. Hydrobiologia 552:1 2838. Francezon N, Tremblay A, Mouget J-L, Pasetto P, Beaulieu L (2021) Algae as a source of natural flavors in innovative foods. J Agric Food Chem 69:11753 2839. Mouritsen OG, Dawczynski C, Duelund L, Jahreis G, Vetter W, Schröder M (2013) On the human consumption of the red seaweed dulse (Palmaria palmata (L.) Weber & Mohr). J Appl Phycol 25:1777 2840. Yamazaki H (2022) Exploration of marine natural resources in Indonesia and development of efficient strategies for the production of microbial halogenated metabolites. J Nat Med 76:1 2841. Williams GC (2011) The global diversity of sea pens (Cnidaria: Octocorallia: Pennatulacea). PLoS One 6:e22747 2842. McCauley E, Radjasa OK, Trianto A, Crews MS, Smith A, Smith GC, Zerebinski P, Sabdono A, Crews P (2018) The UNDIP-USCS campaign to culture chemically prolific gram-negative bacteria from Indonesian Jaspis sponges. Arkivoc iv:123 2843. Cembella AD, Ibarra DA, Diogene J, Dahl E (2005) Harmful algal blooms and their assessment in fjords and coastal embayments. Oceanography 18:158 2844. Smith JE, Kuwabara J, Flanagan K, duPlessis S, Coney J, Beets J, Takabayashi M, Barnes S, Turner J, Brown D, Griesemer BK, Stanton F (2008) An unusual cyanobacterial bloom in Hawai’i. Coral Reefs 27:851 2845. Steffen MM, Belisle BS, Watson SB, Boyer GL, Wilhelm SW (2014) Status, causes and controls of cyanobacterial blooms in Lake Erie. J Great Lakes Res 40:215 2846. Singh RK, Tiwari SP, Rai AK, Mohapatra TM (2011) Cyanobacteria: an emerging source for drug discovery. J Antibiot 64:401

Naturally Occurring Organohalogen Compounds …

545

2847. Kalaitzis JA, Lauro FM, Neilan BA (2009) Mining cyanobacterial genomes for genes encoding complex biosynthetic pathways. Nat Prod Rep 26:1447 2848. Raloff J (2005) Squirt alert. A tiny marine alien is emerging as a coastal Grinch. Science News 168:411 2849. Hoegh-Guldberg O, Mumby PJ, Hooten AJ, Steneck RS, Greenfield P, Gomez E, Harvell CD, Sale PF, Edwards AJ, Caldeira K, Knowlton N, Eakin CM, Iglesias-Prieto R, Muthiga N, Bradbury RH, Dubi A, Hatziolos ME (2007) Coral reefs under rapid climate change and ocean acidification. Science 318:1737 2850. Lejeusne C, Chevaldonné P, Pergent-Martini C, Boudouresque CF, Pérez T (2009) Climate change effects on a miniature ocean: the highly diverse, highly impacted Mediterranean Sea. Trends Ecol Evol 25:250 2851. Bidleman TF, Andersson A, Haglund P, Tysklind M (2020) Will climate change influence production and environmental pathways of halogenated natural products? Environ Sci Technol 54:6468 2852. Xu Z, Yang Z, Liu Y, Lu Y, Chen K, Zhu W (2014) Halogen bond: its role beyond drug–target binding affinity for drug discovery and development. J Chem Inf Model 54:69 2853. Lu Y, Shi T, Wang Y, Yang H, Yan X, Luo X, Jiang H, Zhu W (2009) Halogen bonding—a novel interaction for rational drug design? J Med Chem 52:2854 2854. Mendez L, Henriquez G, Sirimulla S, Narayan M (2017) Looking back, looking forward at halogen bonding in drug discovery. Molecules 22:1397 2855. Metrangolo P, Resnati G (2008) Halogen versus hydrogen. Science 321:918 2856. Bradley SA, Zhang J, Jensen MK (2020) Deploying microbial synthesis for halogenating and diversifying medicinal alkaloid scaffolds. Front Bioeng Biotechnol 8:594126 2857. de Oliveira BFR, Carr CM, Dobson ADW, Laport MS (2020) Harnessing the sponge micobiome for industrial biocatalysts. Appl Microbiol Biotechnol 104:8131 2858. Reverter M, Rohde S, Parchemin C, Tapissier-Bontemps N, Schupp PJ (2020) Metabolomics and marine biotechnology: coupling metabolite profiling and organism biology for the discovery of new compounds. Front Mar Sci 7:613471 2859. Yonekura-Sakakibara K, Saito K (2009) Functional genomics for plant natural product biosynthesis. Nat Prod Rep 26:1466 2860. Walsh CT, Fischbach MA (2010) Natural products version 2.0: connecting genes to molecules. J Am Chem Soc 132:2469 2861. Gerwick WH, Moore BS (2012) Lessons from the past and charting the future of marine natural products drug discovery and chemical biology. Chem Biol 19:85 2862. Pawlik JR (2011) The chemical ecology of sponges on Caribbean reefs: natural products shape natural systems. Bioscience 61:888 2863. Lachance H, Wetzel S, Kumar K, Waldmann H (2012) Charting, navigating, and populating natural product chemical space for drug discovery. J Med Chem 55:5989 2864. Leys D, Adrian L, Smidt H (2013) Organohalide respiration: microbes breathing chlorinated molecules. Phil Trans R Soc B 368:20120316 2865. Atashgahi S, Häggblom MM, Smidt H (2018) Organohalide respiration in pristine environments: implications for the natural halogen cycle. Environ Microbiol 20:938 2866. Liang Y, Lu Q, Liang Z, Liu X, Fang W, Liang D, Kuang J, Qiu R, He Z, Wang S (2021) Substrate-dependent competition and cooperation relationships between Geobacter and Dehalococcoides for their organohalide respiration. ISME Commun 1:23 2867. Zhang C, Atashgahi S, Bosma TNP, Peng P, Smidt H (2022) Organohalide respiration potential in marine sediments from Aarhus Bay. FEMS Microbiol Ecol 98:1 2868. Winterton N (1996) A role for methyl chloride in evolution? Mutat Res 372:147

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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.