BIOTECHNOLOGY JULIAN E. DAVIES, Editor Pasteur Institute Paris, France Editorial Board L. Bogorad Harvard University, Cambridge, USA J. Brenchley Pennsylvania State University, University Park, USA P. Broda University of Manchester Institute of Science and Tech- nology, Manchester, United Kingdom A.L. Demain Massachusetts Institute of Technology, Cambridge, USA D.E. Eveleigh Rutgers University, New Brunswick, USA D.H. Gelfand Cetus Corporation, Emeryville, California, USA D.A. Hopwood John Innes Institute, Norwich, United Kingdom S.-D. Kung University of Maryland, College Park, USA J.-F. Martin University of Leon, Leon, Spain C. Nash Schering-Plough Research Institute, Kenilworth, New Jersey, USA T. Noguchi Suntory, Ltd., Tokyo, Japan W. Reznikoff University of Wisconsin, Madison, USA R.L. Rodriguez University of California, Davis, USA A.H. Rose University of Bath, Bath, United Kingdom P. Valenzuela Chiron, Inc., Emeryville, California, USA D. Wang Massachusetts Institute of Technology, Cambridge, USA BIOTECHNOLOGY SERIES 1. R. Saliwanchik Legal Protection for Microbiological and Genetic Engineering Inventions 2. L. Vining (editor) Biochemistry and Genetic Regulation of Commercially Important Antibiotics 3. K. Herrmann and Amino Acids: Biosynthesis and Genetic R. Somerville Regulation (editors) 4. D. Wise (editor) Organic Chemicals from Biomass 5. A. Laskin (editor) Enzymes and Immobilized Cells in Biotechnology 6. A. Demain and Biology of Industrial Microorganisms N. Solomon (editors) 7. Z. Vanek and Overproduction of Microbial Metabolites: Z. Hostälek (editors) Strain Improvement and Process Control Strategies 8. W. Reznikoff Maximizing Gene Expression and L. Gold (editors) 9. W. Thilly (editor) Mammalian Cell Technology 10. R. Rodriguez Vectors: A Survey of Molecular Cloning and D. Denhardt Vectors and Their Uses (editors) 11. S.-D. Kung and Plant Biotechnology C. Arntzen (editors) 12. D. Wise (editor) Applied Biosensors 13. P. Barr, A. Brake, Yeast Genetic Engineering and P. Valenzuela (editors) iv Biotechnology Series 14. S. Narang (editor) Protein Engineering: Approaches to the Manipulation of Protein Folding 15. L. Ginzburg (editor) Assessing Ecological Risks of Biotechnology 16. N. First and Transgenic Animals F. Haseltine (editors) 17. C. Ho and Animal Cell Bioreactors D. Wang (editors) 18. I. Goldberg and Biology of Methylotrophs J.S. Rokem (editors) 19. J. Goldstein (editor) Biotechnology of Blood 20. R. Ellis (editor) Vaccines: New Approaches to Immunological Problems 21. D. Finkelstein and Biotechnology of Filamentous Fungi C. Ball (editors) 22. R. Doi and Biology of Bacilli: Applications to Industry M. McGloughlin (editors) 23. J. Bennett and Aspergillus: Biology and Industrial M. Klich (editors) Applications 24. J. Davies and Milestones in Biotechnology: Classic Papers on W. Reznikoff (editors) Genetic Engineering 25. D. Woods (editor) The Clostridia and Biotechnology 26. V. Gullo (editor) The Discovery of Natural Products with Therapeutic Potential The Discovery of Natural Products with Therapeutic Potential Edited by Vincent P. Gullo Schering-Plough Research Institute Kenilworth, New Jersey Butterworth-Heinemann Boston London Oxford Singapore Sydney Toronto Wellington Copyright © 1994 by Butterworth-Heinemann -6^ A member of the Reed Elsevier group All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publisher. Recognizing the importance of preserving what has been written, it is the policy of © Butterworth-Heinemann to have the books it publishes printed on acid-free paper, and we exert our best efforts to that end. Library of Congress Cataloging-in-Publication Data The Discovery of natural products with therapeutic potential / edited by Vincent P. Gullo. p. cm.—(Biotechnology series ; 26) Includes bibliographical references and index. ISBN 0-7506-9003-8 (acid-free paper) 1. Pharmacognosy. 2. Natural products—Therapeutic use. I. Gullo, Vincent Philip, 1950- . II. Series: Biotechnology series (Reading, Mass.) ; 26. RS160.D58 1994 615'.3—dc20 93-23111 CIP British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. Butterworth-Heinemann 80 Montvale Avenue Stoneham, MA 02180 10 9 8 7 6 5 4 3 21 Printed in the United States of America CONTRIBUTORS R. Albin Jill E. Hochlowski Antiviral Chemotherapy Bioactive Microbial Metabolites Schering-Plough Research Institute Project Kenilworth, New Jersey Pharmaceutical Products Discovery Research and Angela Belt Development The Biotic Network Abbott Laboratories Sonora, California Abbot Park, Illinois Anna M. Casazza Ann C. Horan Department of Experimental Microbial Products Schering-Plough Research Institute Therapeutics Kenilworth, New Jersey Bristol Myers Squibb Pharmaceutical Research Institute J.C. Hunter-Cevera Princeton, New Jersey The Biotic Network Sonora, California I.H. Chapela Preclinical Research Sunil Kadam Sandoz Pharmaceuticals Ltd. Anti-infective Research Division Basel, Switzerland Pharmaceutical Products Discovery Research and Beth J. DiDomenico Development Molecular Genetics/Chemotherapy Abbott Laboratories Schering-Plough Research Institute Abbott Park, Illinois Kenilworth, New Jersey A. Douglas Kinghorn M.M. Dreyfuss Program for Collaborative Preclinical Research Research in the Pharmaceutical Sandoz Pharmaceuticals Ltd. Sciences and Department of Basel, Switzerland Medicinal Chemistry and Pharmacognosy Akira Endo College of Pharmacy Department of Applied Biological University of Illinois at Chicago Science Chicago, Illinois Tokyo Noko University Tokyo,Japan Toru Kino Exploratory Research Otto D. Hensens Laboratories Merck Research Laboratories Fujisawa Pharmaceutical Co., Ltd. Rahway, New Jersey Tsukuba,Japan vii VÜi Contributors Donald R. Kirsch Oliver J. McConnell Agricultural Research Division Division of Biomedical Marine American Cyanamid Research Princeton, New Jersey Harbor Branch Oceanographic Institution Frank E. Koehn Fort Pierce, Florida Division of Biomedical Marine Research Harbor Branch Oceanographic Masakuni Okuhara Institution Exploratory Research Fort Pierce, Florida Laboratories Fujisawa Pharmaceutical Co., Ltd. Byron H. Long Tsukuba,Japan Department of Experimental Therapeutics Bristol Myers Squibb Pharmaceutical Research E. Rozhon Institute Antiviral Chemotherapy Princeton, New Jersey Schering-Plough Research Institute Kenilworth, New Jersey Ross E. Longley Division of Biomedical Marine Research J. Schwartz Harbor Branch Oceanographic Antiviral Chemotherapy and Institution Molecular Pharmacology Fort Pierce, Florida Schering-Plough Research Institute Kenilworth, New Jersey James B. McAlpine Bioactive Microbial Metabolites Project Pharmaceutical Products Kazuo Umezawa Discovery Research and Department of Applied Chemistry Development Faculty of Science and Technology Abbott Laboratories Keio University Abbott Park, Illinois Yokohama, Japan PREFACE Although effective drugs for many of the diseases that afflict humankind have been discovered, many health problems remain untreatable. These problems include various types of cancer; viral infections such as HIV; severe fungal infections, particularly in immunocompromised patients; cardiovascular dis- eases; and inflammatory and allergic disorders. Even when significant progress is made, as in the treatment of bacterial infections, resistant, highly pathogenic organisms can appear. However, as knowledge of various disease processes expand, new targets for intervention are discovered. Therefore, the search for novel therapeutic agents continues. From where are drugs derived? There are only two sources of drugs, natural products and synthetic chemicals. The trend in recent years has been to focus attention on rational drug design, highlighting the synthetic chemical approach. However, rational drug design has proven to be effective in refining structural leads that interact with a particular target, for example, an enzyme or receptor. The need still remains to uncover the initial structural lead that interacts with the therapeutic target. The myriad of structurally diverse com- pounds found in nature offers a unique source for drug discovery. It is in this scenario that natural products play an important role. xv xvi Preface The authors of each chapter are a diverse group of experts, who, together, present the knowledge base required to discover potential therapeutic agents from natural sources. The subject matter included in each chapter is intended to be useful for scientists currently working in this broad field, as well as to enlighten those interested in the current status and complexity of natural product research. The authors have highlighted successes, but, for the most part, they have concentrated on the strategies employed. I am deeply indebted to them for their efforts. The purpose of this book is to capture what we perceive as the rational process of natural product drug discovery. The book has been divided into three major sections that represent this process. Chapters 1-5 describe some of the diverse sources of natural products. Both terrestrial and marine en- vironments represent ecological niches where therapeutically active, complex molecules can be discovered. Chapters 6-12 describe how molecular biolog- ical and biochemical research have increased knowledge of biological systems and human disease. This knowledge has led to the design of targeted assays, amenable to high-volume screening. Chapters 13 and 14 describe the current methods that natural product chemists employ to isolate and identify com- pounds with biological activity from natural product extracts. Vincent P. Gullo CHAPTER 1 Aerobic Actinomycetes: A Continuing Source of Novel Natural Products Ann C. Horan A Natural Products Program begins at the source, whether it be extracts of plants and/or marine organisms or fermentation products of actinomycetes, fungi, and bacteria. All have yielded abundant diverse compounds, many with therapeutic utility. Ten of the top selling 30 branded prescription products for 1990 (Scripts Review Issue 1990, p. 21) were either natural products or their derivatives and accounted for U.S. $8.2 billion in sales. Methods for detecting biological activity with therapeutic potential have shifted from simple determinations of antibacterial and antifungal activity to assays using genetically engineered eukaryotic cells that can detect regulators of specific gene expression, inhibitors of signal transduction, small molecular weight agonists/antagonists of cytokines, and/or specific receptors and re- ceptor subtypes. The shift in emphasis away from antibacterials is reflected in the reported activities of novel secondary metabolites found in The Journal of Antibiotics. During the years from 1986 to 1991 (Table 1-1), the total number of novel compounds increased 20%; anti-infectives were reduced by 24%, and pharmacologically active compounds increased 87%. When new targets for drug intervention are defined and new assays developed to exploit 3
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