Fortschritte der Chemie organischer Naturstoffe. Progress in the Chemistry of Organic Natural Products. Founded by L. Zechmeister

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4 Fortschritte der Chemie organischer Naturstoffe Progress in the Chemistry of Organic Natural Products Founded by L. Zechmeister Editors: A.D. Kinghorn, Columbus, OH H. Falk, Linz J. Kobayashi, Sapporo Honorary Editor: W. Herz, Tallahassee, FL Editorial Board: V.M. Dirsch, Vienna S. Gibbons, London N.H. Oberlies, Greensboro, NC Y. Ye, Shanghai

5 93 Fortschritte der Chemie organischer Naturstoffe Progress in the Chemistry of Organic Natural Products Authors: S.A. Begum, M. Sahai, and A.B. Ray E. Gössinger M. Luzhetska, J. Härle, and A. Bechthold SpringerWienNewYork

6 Prof. A. Douglas Kinghorn, College of Pharmacy, Ohio State University, Columbus, OH, USA em. Univ.-Prof. Dr. H. Falk, Institut für Organische Chemie, Johannes-Kepler-Universität, Linz, Austria Prof. Dr. J. Kobayashi, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying machines or similar means, and storage in data banks. # 2010 Springer-Verlag/Wien Printed in Germany SpringerWienNewYork is a part of Springer Science þ Business Media springer.at Product Liability: The publisher can give no guarantee for the information contained in this book. This also refers to that on drug dosage and application thereof. In each individual case the respective user must check the accuracy of the information given by consulting other pharmaceutical literature. The use of registered names, trademarks, 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. Library of Congress Catalog Card Number: Typesetting: SPI, Chennai Printed on acid-free and chlorine-free bleached paper SPIN: With 40 (partly coloured) Figures ISSN ISBN e-isbn DOI / SpringerWienNewYork

7 Contents List of Contributors... vii Non-conventional Lignans: Coumarinolignans, Flavonolignans, and Stilbenolignans... 1 Sajeli A. Begum, Mahendra Sahai, and Anil B. Ray 1. Introduction Coumarinolignans Occurrence of Coumarinolignans Classification of Coumarinolignans Structure Elucidation of Coumarinolignans Chemistry of Coumarinolignans Biological Activity of Coumarinolignans Biogenesis of Coumarinolignans Flavonolignans Occurrence of Flavonolignans Features of Flavonolignans and Their Classification Structure Elucidation of Flavonolignans Chemistry of Flavonolignans Biological Activity of Flavonolignans Biogenesis of Flavonolignans Stilbenolignans Occurrence and Features of Stilbenolignans Structure Elucidation and Synthesis of Stilbenolignans Biological Activity of Stilbenolignans Biogenesis of Stilbenolignans References Picrotoxanes Edda Gössinger 1. Introduction v

8 vi Contents 2. Tabular Overview of the Picrotoxanes Occurrence Systematic and Geographic Occurrence of Picrotoxane-Containing Plants Parasitic Plants Picrotoxanes Found in Animals and Animal Products The Riddle of the Scattered Taxonomic Occurrence of Picrotoxanes Isolation of Picrotoxanes Examples of Recent Isolation Procedures Structure Determination of Picrotoxanes Main Picrotoxanes of the Menispermaceae Main Picrotoxanes of the Coriariaceae Picrotoxanes Isolated from Toxic Honey Picrotoxanes of the Picrodendraceae Picrotoxanes from Dendrobium Species Total Syntheses of Picrotoxanes Overview Description of the Syntheses Biosynthesis of Picrotoxanes Investigations on the Biosynthesis of Dendrobines Investigations on the Biosynthesis of Sesquiterpene Picrotoxanes Physiological Activity of Picrotoxanes Toxicity Picrotoxanes as Therapeutics Picrotoxanes as Epileptogenic Compounds Picrotoxanes as Tools in Neurobiological Research Abbreviations References Combinatorial and Synthetic Biosynthesis in Actinomycetes Marta Luzhetska, Johannes Härle, and Andreas Bechthold 1. Introduction Combinatorial Biosynthesis and Synthetic Biosynthesis Achievements in Combinatorial Biosynthesis Challenges for Combinatorial Biosynthesis Synthetic Biosynthesis References Author Index Subject Index Listed in PubMed

9 Contributors Andreas Bechthold Institut für Pharmazeutische Wissenschaften, Lehrstuhl für Pharmazeutische Biologie und Biotechnologie der Albert-Ludwigs-Universität Freiburg, Stefan-Meier-Strasse 19, Freiburg, Germany Sajeli A. Begum Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi , India Edda Gössinger Institut für Organische Chemie der Universität Wien, Währinger Strasse 38, 1090 Vienna, Austria Johannes Härle Institut für Pharmazeutische Wissenschaften, Lehrstuhl für Pharmazeutische Biologie und Biotechnologie der Albert-Ludwigs-Universität Freiburg, Stefan-Meier-Strasse 19, Freiburg, Germany Marta Luzhetska Institut für Pharmazeutische Wissenschaften, Lehrstuhl für Pharmazeutische Biologie und Biotechnologie der Albert-Ludwigs-Universität Freiburg, Stefan-Meier-Strasse 19, Freiburg, Germany Anil B. Ray C-38 Ashokpuram, Dafi, Varanasi , India Mahendra Sahai Department of Medicinal Chemistry, IMS, Banaras Hindu University, Varanasi , India vii

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11 Born in 1978 in Cuddalore, India, Dr. (Mrs) Sajeli A. Begum studied for her M. Pharm. in Pharmaceutical Chemistry (2001) and performed a chemical investigation into the non-alkaloidal constituents of Solanaceous plants for her doctoral thesis. She received a Ph.D. in Medicinal Chemistry (2005) from Banaras Hindu University, Varanasi, India. She is a recipient of a Council of Scientific Industrial Research (CSIR) Senior Research Fellowship, India, for her Ph.D. project and a Deutscher Akademischer Austausch Dienst (DAAD) Fellowship (2004) to pursue part of her doctoral research at Eberhard Karls Universität, Tübingen, in the group of Dr. Roderich Suessmuth. Since 2005, she has been working as an assistant professor in the Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, and doing research on phytochemical constituents. Her prime research interests are centered on isolation, structure elucidation, chemical transformation, and pharmacological screening of bioactive natural products. In 2008, she visited the Indian Institute of Chemical Technology (IICT-CSIR), Hyderabad, India, through a INSA-Visiting Fellowship. ix

12 Dr. Mahendra Sahai received his Master s degree (Organic Chemistry) from the University of Gorakhpur in He joined the laboratory of Professor A.B. Ray in the Department of Medicinal Chemistry, IMS, Banaras Hindu University, Varanasi, India, for his Ph.D. work on the chemistry of withasteroids and other natural products. He obtained his Ph.D. in He continued his research work in the laboratory until 1981 as a Research Associate, at CSIR, New Delhi. He then joined the Weizmann Institute of Science, Israel, as a Postdoctoral Fellow of the Feinberg Graduate School and worked in the group of Professor Ehud Keinan for a period of three years in the area of organic synthesis until In 1984, Dr. Sahai joined the Department of Medicinal Chemistry of Banaras Hindu University as a lecturer and subsequently became professor in the year He is still working in the department in the same capacity. He was selected as Visiting Scientist at the TECHNION, Israel ( ), and worked there on organic synthesis. He received a Centenary Memorial Fellowship of The Tokyo Institute of Technology, Japan, in the year He has worked mainly on the chemistry of natural products and has a total of 82 publications in reputed refereed journals. x

13 After having received his Master s degree in Applied Chemistry (Pharmaceutical Chemistry) from Calcutta University in 1955, Anil B. Ray spent brief periods in the School of Tropical Medicine, Calcutta, as a Junior Research Fellow and in the Directorate of Health Services, Govt. of West Bengal, India, as an Inspector of Drugs. In 1961, he joined the laboratory of the late Professor (Mrs.) Asima Chatterjee, D.Sc., F.N.A, and worked on the isolation and structure elucidation of complex indole alkaloids for his doctoral thesis and received his Ph.D. in He then joined the Research group of the late Professor Jack L. Beal, of the College of Pharmacy, Ohio State University, Columbus, Ohio, U.S.A., and worked as a Research Associate for three years on the isolation, structure determination, and synthesis of bis-benzylisoquinoline alkaloids. He also worked on the structure determination of spermidine alkaloids and codonocarpines. After his return to India, he joined the Department of Medicinal Chemistry, Institute of Medical Sciences, Banaras Hindu University, in 1971 as a Reader and subsequently became Professor. He worked on the chemistry and biological activity of different groups of plant constituents and has a total of 147 publications including several review articles in standard refereed journals. He visited Japan and USSR under a bilateral exchange program with INSA. After superannuation, he worked as an Emeritus Scientist, CSIR, until the age of 65. xi

14 Edda Gössinger was born in Asparn/Zaya, Austria, in She completed her studies in chemistry at the University of Vienna with a Ph.D. thesis on the isolation and structure determination of natural products. She then went as a postdoctoral fellow to ETH/Zürich, where she assisted in the partial synthesis of a steroid alkaloid and later on was allowed to work on a total synthesis of her own design. With this synthesis, she moved to NIH in Bethesda, MD, where she continued to work on total syntheses of natural products. She concluded her stay in the United States by getting acquainted with high-pressure chemistry at the State University of New York at Stony Brook. Back in Austria, she joined the Institute of Organic Chemistry at the University of Vienna. There she received the venia legendi in 1982, which enabled her to lecture about planning of synthesis and diverse themes about natural products chemistry. Her research interests were mainly with the total synthesis of natural products with excursions into chemical methodology and mechanistic aspects. She has retired recently. xii

15 Marta Luzhetska was born in L viv, Ukraine, in She studied genetics and biotechnology at Ivan Franko National University, L viv, and in 2007 obtained her Ph.D. in the genetics of Streptomycetes at Polytechnic National University, L viv, under the supervision of Professor Novikov. During , she was a DAAD fellow of Professor Bechthold at the Albert-Ludwigs-Universität, Freiburg. In 2007, she started her work as a postdoctoral researcher in the laboratory of professor Bechthold. Her major interest is investigation of secondary metabolites biosynthetic pathways in Actinomycetes. xiii