Human Medicinal Agents from Plants

358 Pages·1993·7.55 MB·English

by  A. Douglas Kinghorn and Manuel F. Balandrin (Eds.)

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In Human Medicinal Agents from Plants; Kinghorn, A., el al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
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In Human Medicinal Agents from Plants; Kinghorn, A., el al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
534
ACS SYMPOSIUM SERIES
Human Medicinal Agents
from Plants
A. Douglas Kinghorn,
EDITOR
01 University of Illinois at Chicago
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0 Manuel F. Balandrin,
3- EDITOR
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1 NPS Pharmaceuticals, Inc.
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9 Developed from a symposium sponsored
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at the 203rd National Meeting
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American Chemical Society, Washington, DC 1993
In Human Medicinal Agents from Plants; Kinghorn, A., el al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
Library of Congress Cataloging-in-Publication Data
Human medicinal agents from plants / [edited by] A. Douglas Kinghorn,
Manuel F. Balandrin.
p. cm—(ACS symposium series, ISSN 0097-6156; 534)
"Developed from a symposium sponsored by the Division of
Agricultural and Food Chemistry of the American Chemical Society at
the 203rd Meeting of the American Chemical Society, San Francisco,
California, April 5-10, 1992."
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0 Includes bibliographical references and index.
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34.f ISBN 0-8412-2705-5
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3- 1. Materia medica, Vegetable—Congresses. 2. Medicinal plants—
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9 Congresses. 3. Pharmacognosy—Congresses.
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10 Chemistry. IV. American Chemical Society. Meeting (203rd: 1992: San
0. Francisco, Calif.) V. Series.
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doi: RS164.H88 1993
3 | 615'.32—dc20 93-22180
9 CIP
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e: The paper used in this publication meets the minimum requirements of American National
at Standard for Information Sciences—Permanence of Paper for Printed Library Materials, ANSI
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PRINTED IN THE UNITED STATES OF AMERICA
In Human Medicinal Agents from Plants; Kinghorn, A., el al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
1993 Advisory Board
ACS Symposium Series
M. Joan Comstock, Series Editor
V. Dean Adams Bonnie Lawlor
University of Nevada— Institute for Scientific Information
Reno
Douglas R. Lloyd
Robert J. Alaimo The University of Texas at Austin
Procter & Gamble
Pharmaceuticals, Inc. Robert McGorrin
Kraft General Foods
1 Mark Arnold
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w University of Iowa Julius J. Menn
4.f Plant Sciences Institute,
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0 David Baker U.S. Department of Agriculture
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99 University of Tennessee
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k- Vincent Pecoraro
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21/ Arindam Bose University of Michigan
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1 Pfizer Central Research
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oi: 1 Marshall Phillips
d Robert F. Brady, Jr. Delmont Laboratories
93 | Naval Research Laboratory
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5, 1 George W. Roberts
y Margaret A. Cavanaugh North Carolina State University
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e: National Science Foundation
at A. Truman Schwartz
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n Dennis W. Hess Macalaster College
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ati Lehigh University
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bli John R. Shapley
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Hiroshi Ito University of Illinois
IBM Almaden Research Center at Urbana—Champaign
Madeleine M. Joullie L. Somasundaram
University of Pennsylvania DuPont
Gretchen S. Kohl Peter Willett
Dow-Corning Corporation University of Sheffield (England)
In Human Medicinal Agents from Plants; Kinghorn, A., el al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
Foreword
THE ACS SYMPOSIUM SERIES was first published in 1974 to
provide a mechanism for publishing symposia quickly in book
form. The purpose of this series is to publish comprehensive
books developed from symposia, which are usually "snapshots
in time" of the current research being done on a topic, plus
some review material on the topic. For this reason, it is neces
01 sary that the papers be published as quickly as possible.
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w Before a symposium-based book is put under contract, the
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3 proposed table of contents is reviewed for appropriateness to
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3- the topic and for comprehensiveness of the collection. Some
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19 papers are excluded at this point, and others are added to
bk- round out the scope of the volume. In addition, a draft of each
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2 paper is peer-reviewed prior to final acceptance or rejection.
0
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0. This anonymous review process is supervised by the organiz
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oi: ers) of the symposium, who become the editor(s) of the book.
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3 | The authors then revise their papers according to the recom
99 mendations of both the reviewers and the editors, prepare
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5, camera-ready copy, and submit the final papers to the editors,
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a who check that all necessary revisions have been made.
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e: As a rule, only original research papers and original re
Dat view papers are included in the volumes. Verbatim reproduc
on tions of previously published papers are not accepted.
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Series Editor
In Human Medicinal Agents from Plants; Kinghorn, A., el al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
Preface
NATURAL SUBSTANCES ONCE SERVED AS THE SOURCES of all drugs
and medicinal agents, and higher plants provided most of these therapeu
tic entities. The serious and systematic studty of the chemistry and biolog
ical properties of natural products, which commenced in earnest at the
start of the 19th century, has been a major factor in the development of
1 modern synthetic organic chemistry. As the many interesting biologically
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pr0 active compounds described in the various chapters of this book exem
4. plify, plants not only continue to retain their historical significance as
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0 important sources of new drugs but also are extremely useful as sources
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99 of "lead" compounds for structural modification and optimization that
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k- can also be employed as specific probes in biochemical studies. For all of
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1/ these reasons, biologically active constituents of plants have served as
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1 sources of inspiration for generations of medicinal and organic chemists.
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oi: 1 In the foreseeable future, plants will no doubt continue to provide
d humankind with valuable agents of potential use in the investigation,
93 | prevention, and treatment of diseases such as cancer, acquired immunode
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5, 1 ficiency syndrome (AIDS) and other viral infections, malaria, and schisto
y somiasis; disorders of the cardiovascular and central nervous systems; and
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e: many others.
at Powerful new chemical and biological technologies now permit recep
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n tor isolation and characterization so that drug design principles can be
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ati applied rapidly to "fast-track" natural product leads as never before. The
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formed with minimal delay by using a combination of sophisticated spec
troscopic and X-ray crystallographic techniques. High-throughput
automated bioassays are widely available, so that a detailed biological pro
file can be obtained easily on just a few milligrams of a natural product.
Thus, there is every indication that the direct utility and promise of plants
for the improvement of human health will continue well into the 21st
century.
The publication of this volume is timely because during the closing
stages of its preparation, the plant-derived drug taxol was accorded final
approval by the U.S. Food and Drug Administration (FDA) for the treat
ment of refractory ovarian cancer [Holden, C Science (Washington, D.C.)
1993, 259, 181]. Although semisynthetic natural products have recently
been approved, taxol is the first naturally occurring plant-derived drug
product to gain FDA approval in more than a quarter of a century. Taxol
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In Human Medicinal Agents from Plants; Kinghorn, A., el al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
has attracted widespread interest in the United States not only for its
therapeutic potential but also because of the need to preserve the native
stands of the Pacific yew, the plant of origin of taxol, and at the same
time ensure an adequate supply of the drug.
Several of the chapters in this book touch on the crucial natural-
product supply issue; information is also provided on a number of com
pounds that hold the potential for being the next approved plant-derived
drugs after taxol. Contributions to this book address each of the various
aspects involved in plant-derived drug discovery and development, includ
ing botany and taxonomy, phytochemistry, biological evaluation, and regu
lation. Attention is paid to the value of the tropical rain forests in afford
ing important biologically active compounds, as well as to the urgent need
to avoid further species extinction and consequent loss of biodiversity,
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0 which threaten our future ability to discover new drugs from these parts
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4. of the world. Current research endeavors in laboratories in academic,
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1/ the treatment of cancer, AIDS, malaria, and other diseases. Some recent
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1 initiatives of the U.S. government in supporting plant drug discovery are
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93 | also in countries in western Europe, and in Japan, India, and China.
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5, 1 The symposium on which this book is based was generously supported
y by the Division of Agricultural and Food Chemistry of the American
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Chemical Society and was cosponsored by the American Society of Phar
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at macognosy and the Society for Economic Botany. We are very grateful to
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bli Glaxo Group Research Ltd.; Murdock Healthcare, Inc.; NPS Pharmaceut
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P icals, Inc.; Phytopharm Ltd.; Schering-Plough Research Institute; Sha
man Pharmaceuticals, Inc.; and Wyeth-Ayerst Laboratories. We thank
the scientists who served as referees for the chapters in this book. Finally,
during the course of completing this volume, we were very saddened to
learn of the passing of one of the symposium participants and chapter
authors, Daniel L. Klayman.
A. DOUGLAS KINGHORN MANUEL F. BALANDRIN
Program for Collaborative Research NPS Pharmaceuticals, Inc.
in the Pharmaceutical Sciences University of Utah Research Park
College of Pharmacy Salt Lake City, UT 84108
University of Illinois at Chicago
Chicago, IL 60612
March 23, 1993
xii
In Human Medicinal Agents from Plants; Kinghorn, A., el al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
Chapter 1
Plant-Derived Natural Products
in Drug Discovery and Development
An Overview
Manuel F. Balandrin1, A. Douglas Kinghorn2, and Norman R. Farnsworth2
1NPS Pharmaceuticals, Inc., University of Utah Research Park, Salt
Lake City, UT 84108
2Program for Collaborative Research in the Pharmaceutical Sciences,
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00 College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612
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93- The natural world once served as the source of all medicinal
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k-1 agents, with higher plants constituting by far the principal
1/b sources of these. Today, higher plants continue to retain
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0. compounds useful directly as medicinal agents, as model
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3 | cations and optimization, as biochemical and/or pharmaco
99 logical probes, and as sources of inspiration for generations
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5, of synthetic organic medicinal chemists. Plant-derived
ay compounds which have recently undergone development
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e: include the anticancer agents, taxol and camptothecin, the
Dat Chinese antimalarial drug, artemisinin, and the East Indian
n Ayurvedic drug, forskolin. These and many other examples
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Higher plants have served humankind as sources of medicinal agents since
its earliest beginnings. In fact, natural products once served as the source of
all drugs. Today, natural products (and their derivatives and analogs) still
represent over 50% of all drugs in clinical use, with higher plant-derived
natural products representing ca. 25% of the total. On numerous occasions,
the folklore records of many different cultures have provided leads to plants
with useful medicinal properties (1-11). In the past two centuries, the
chemical investigation and purification of extracts of plants purported to have
medicinal properties, and those used as toxins and hunting poisons in their
native habitats, have yielded numerous purified compounds which have
0097-6156/93/0534-0002$06.00/0
© 1993 American Chemical Society
In Human Medicinal Agents from Plants; Kinghorn, A., el al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
1. BALANDRIN ET AL. Plant-Derived Natural Products in Drug Development 3
proven to be indispensable in the practice of modern medicine (3,9,12). For
example, the curare alkaloids were obtained from South American vines that
had long been used by natives to make arrow poisons, and African
Strophantus species and Calabar beans yielded medicinally useful cardiac
glycosides and physostigmine, respectively, which were originally used as
arrow and ordeal poisons in their native habitats. The East Indian
snakeroot, Rauvolfia serpentina (L.) Benth. ex Kurz, has been used for
centuries as a native East Indian medicinal plant, and its main active
principle, reserpine, is now used in western medicine as an antihypertensive
and tranquilizer. Similarly, other bioactive and poisonous plants with
extensive folklore histories have yielded the cardiac (Digitalis) glycosides,
AMetrahydrocannabinol, the opiates (codeine, morphine), the Cinchona
alkaloids (quinine, quinidine), the solanaceous tropane alkaloids (atropine,
Ahyoscyamine, scopolamine), pilocarpine, ephedrine, cocaine, theophylline,
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0 vincristine, vinblastine, taxol, and other well-known and useful drugs (3,9-
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3- The Role of Plant-Derived Natural Products in Modern Medicine
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bk- The commercial value of drug products still derived directly from higher
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2 plants is considerable and should not be underestimated. For example, in
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0.1 1980 American consumers paid about $8 billion for prescription drugs
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d drugs derived from higher plants represented a constant 25% of all new and
93 | refilled prescriptions dispensed from community pharmacies in the United
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5, 1 States (this does not take into account non-prescription drug products or
y drugs used exclusively in hospital settings). Plant-derived drugs thus
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ate: addition, worldwide markets in plant-derived drugs are difficult to estimate,
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n but undoubtedly amount to many additional billions of dollars (13-21).
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ati Some important plant-derived drugs and intermediates that are still obtained
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Pu I.

Plants continue to be important sources of new drugs, as evidenced
by the recent approvals in the United States of several new plant-derived
drugs, and semi-synthetic and synthetic drugs based on plant secondary
compounds. For example, taxol, an anticancer taxane diterpenoid derived
from the relatively scarce Pacific or western yew tree, Taxus brevifolia Nutt.,
has recently (December, 1992) been approved in the United States for the
treatment of refractory ovarian cancer (see chapter by Kingston, this
volume). Etoposide is a relatively new semisynthetic antineoplastic agent
based on podophyllotoxin, a constituent of the mayapple (also known as
American mandrake), Podophyllum peltatum L, which is useful in the
chemotherapeutic treatment of refractory testicular carcinomas, small cell
lung carcinomas, nonlymphocytic leukemias, and non-Hodgkin's
lymphomas (22-27). Atracurium besylate is a relatively new synthetic
In Human Medicinal Agents from Plants; Kinghorn, A., el al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1993.