Discovery of Novel Natural Products with Therapeutic Potential

460 Pages·1994·7.44 MB·English

by  Vincent P. Gullo (Eds.)

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
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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
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Copyright © 1994 by Butterworth-Heinemann
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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.
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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