Probing Bioactive Mechanisms

404 Pages·1989·7.68 MB·English

by  Philip S. Magee

413
ACS SYMPOSIUM SERIES
Probing Bioactive Mechanisms
Philip S. Magee, EDITOR
BIOSAR Research Project
Douglas R. Henry, EDITOR
Molecular Design Limited
John H. Block, EDITOR
Oregon State University
Developed from a symposium sponsored
by the Division of Agrochemicals
at the 196th National Meeting
of the American Chemical Society,
Los Angeles, California,
September 25-30, 1988
American Chemical Society, Washington, DC 1989
In Probing Bioactive Mechanisms; Magee, P., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
Library of Congress Cataloging-in-Publication Date
Probing bioactive mechanisms
Philip S. Magee, editor, Douglas R. Henry, editor,
John H. Block, editor
Developed from a symposium sponsored by the Division
of Agrochemicals at tne 196th National Meeting of the
American Chemical Society, Los Angeles, California,
September 25-30, 1988.
p. cm.—(ACS Symposiu
Bibliography: p.
Includes index.
ISBN 0-8412-1702-5
1. Structure—activity relationships (Biochemistry)—
Congresses. 2. Pharmacolocy—Methodology—Congresses.
3. Agricultural chemistry—Methodology—Congresses. 4.
Toxicology—Methodology—Congresses.
I. Magee, Philip, 1926- . II. Henry, Douglas R.
III. Block, John H. IV. American Chemical Society.
Division of Agrochemicals. V. American Chemical
Society. Meeting (196th: 1988: Los Angeles, Calif.)
VI. Series.
QP517.S85P76 1989
574.19'283—dc20 89-17998
CIP
Copyright © 1989
American Chemical Society
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PRINTED IN THE UNITED STATES OF AMERICA
In Probing Bioactive Mechanisms; Magee, P., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
ACS Symposium Series
M. Joan Comstock, Series Editor
1989 ACS Books Advisory Board
Paul S. Anderson Mary A. Kaiser
Merck Sharp & Dohme Research E. I. du Pont de Nemours and
Laboratories Company
Alexis T. Bell
Purdue University
University of California—Berkeley
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Harvey W. Blanch
Dow Chemical Company
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Alan Elzerman Exxon Chemical Company
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U.S. Naval Research Laboratory
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Lehigh University
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Conoco Inc.
Marye Anne Fox
The University of Texas—Austin Wendy A. Warr
Imperial Chemical Industries
G. Wayne Ivie
U.S. Department of Agriculture, Robert A. Weiss
Agricultural Research Service University of Connecticut
In Probing Bioactive Mechanisms; Magee, P., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
Foreword
The ACS SYMPOSIUM SERIES was founded in 1974 to provide a
medium for publishing symposia quickly in book form. The
format of the Series parallels that of the continuing ADVANCES
IN CHEMISTRY SERIES except that, in order to save time, the
papers are not typeset but are reproduced as they are submitted
by the authors in camera-ready form. Papers are reviewed under
the supervision of the Editors with the assistance of the Series
Advisory Board and
symposia; however, verbati reproductions o previously pub
lished papers are not accepted. Both reviews and reports of
research are acceptable, because symposia may embrace both
types of presentation.
In Probing Bioactive Mechanisms; Magee, P., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
Preface
SEVERAL YEARS AGO, ONE OF US (P.S.M.) participated in a 1984 ACS
Symposium Series book that described quantitative structure-activity
relationship (QSAR) research (Pesticide Synthesis Through Rational
Approaches, ACS Symposium Series 255, edited by Philip S. Magee,
Gustave K. Kohn, and Julius J. Menn). The prevalent theme at that time
was drug and pesticide design d book fell int thi category No
it is increasingly clear tha
hands of the best investigators are also addressing mechanisms in both
simple and complex biochemical systems. The classical approaches of
experimental kinetic, equilibrium, and isotopic studies still form the
basis of mechanistic proof that is acceptable to the scientific community.
However, the data developed in these and related studies can be
extended by statistical and modeling techniques to provide mechanistic
inferences beyond experimental results. Such inferences are probabilistic
in nature and do not enjoy the same standing as experimental proof.
What they do provide are clear working hypotheses that point the way to
new experimental designs. This book addresses the inferential approach
to extending mechanistic insight by developing relations from raw,
experimental data and molecular structure.
Among other changes in recent years is the lowering of conceptual
barriers among medicinal, agrochemical, and environmental problems.
These problems address analogous underlying mechanisms where cuticle
penetration, transport, active-site binding, and irreversible processes can
be described by a common model. Moreover, scientists in each area
employ related experimental methods and identical computer-assisted
methods for developing structure-activity relationship models. This
book reflects the merging of these apparently diverse fields under a
canopy of common mechanistic events.
The editors of this volume are typical of many in the QSAR field,
working alone, without immediately close colleagues. Each of us
practices and teaches within the general fields of modeling and statistical
QSAR. Though physically separated, we converse by letter, telephone,
and modem. We like to call ourselves Research Triangle-West.
ix
In Probing Bioactive Mechanisms; Magee, P., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
PHILP S. MAGEE
BIOSAR Research Project
Vallejo, CA 94591
and
School of Medicine
University of California
San Francisco, CA 94143
DOUGLAS R. HENRY
Molecular Design limited
2132 Farallon Drive
San Leandro, CA 94577
JOHN H. BLOCK
College of Pharmacy
Oregon State University
Corvallis, OR 97331-3507
June 29, 1989
X
In Probing Bioactive Mechanisms; Magee, P., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
Chapter 1
Progress in the Design of Bioactive Molecules
John H. Block
College of Pharmacy, Oregon State University, Corvallis, OR 97331-3507
The traditional search for drugs and agricultural chemicals has
been based on observing the use of plants by human
populations, dietary habits, general pharmacological screens,
and chance observations
active chemicals bega
products. These substances became the prototype molecules
from which modifications were made. Other drug discoveries
have been based on what could be called the shotgun approach
and chance favors the prepared mind. For the former, a
large number of compounds are synthesized or plant extracts
are isolated and then subjected either to general or specific
pharmacological screens. In today's economic and regulatory
climate, this latter approach is very expensive because there
are relatively few commercially successful products obtained
from the thousands of compounds tested. Increasingly, a
productive search for biologically active molecules requires a
fundamental understanding of the disease for which the drug
is targeted. Statistical techniques, conformational analysis, and
receptor characterization will provide valuable information for
the synthetic chemist to better tailor the molecular structure
required for desired activity.
Over the long history in the development of bioactive molecules, there have
been many approaches used. These range from rational, carefully thought
out hypotheses, to general and specific pharmacological screens used to
identify compounds with desired biological activity, to serendipity. Listed
below are different ways that commercially useful bioactive molecules have
been discovered. Because of the author's background, there will be more
examples from human medicine than from agrochemicals. At the same time,
the principles discussed for humans will apply generally to mammals
0097-6156/89/O413-OO02$O7.00/0
© 1989 American Chemical Society
In Probing Bioactive Mechanisms; Magee, P., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
1. BLOCK Progress in the Design of Bioactive Molecules 3
including commercial livestock. In the broad sense, the development of
chemicals used to maximize crop yields use the same approaches.
NATURAL PRODUCTS.
This has been and probably will remain one of the main means of
discovering biologically active molecules. It is realized that there is a
tremendous number of terrestrial plants that have never been screened and,
unfortunately, may never be.QJ There is concern that, with the loss of the
tropical rain forests, many plant species will become extinct before there is
a chance to evaluate their chemical constituents. On the other hand, the
examination of natural sources now includes marine species. The search for
active compounds from natural product will continu becaus
little is known about the
design potentially active molecules for these conditions. Some classic
examples of successful drugs and agrochemicals derived from plant extracts
and the results from attempts at chemically modifying their structures
include the following.
Cardiac glycosides: These are the drugs of choice in the treatment of
congestive heart failure. The synthetic medicinal chemist has not
produced a product superior to cardiac glycosides such as digoxin.
Atropine: This is a classic example of the prototype drug from which the
anticholinergic class of agents are derived. In contrast with digitalis,
a wide variety of anticholinergics, chemicals which block the
cholinergic receptors, which are superior to the parent alkaloid have
been made and continue to be introduced into medicine.
Cocaine: This drug, which has become such a pariah in our society, is the
prototype for the local anesthetics. It is one of the success stories as
evidenced by the wide variety of local anesthetics that have been
made free of any abuse potential. Indeed, the structure of procaine,
which is a simple benzoic acid ester, illustrates how the
pharmacophore moiety can be abstracted from a more complex
natural product.
Penicillins, cephalosporins, tetracyclines, actinomvdns: These are examples
of classes of antibiotics each from a microorganism producing
cytotoxic agents. The first three classes are selectively cytotoxic to
bacteria, and the fourth cytotoxic to mammalian cancer cells,
unfortunately with poor selective toxicity. The penicillins and
cephalosporins inhibit bacterial cell wall synthesis, and tetracyclines
selectively block protein synthesis at the bacterial ribosome. The
actinomycins intercalate in a relative nonselective manner the
In Probing Bioactive Mechanisms; Magee, P., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
4 PROBING BIOACIWE MECHANISMS
In Probing Bioactive Mechanisms; Magee, P., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1989.
1. BLOCK Progress in the Design of Bioactive Molecules 5
chromosomal DNA in both malignant and benign cells. They were
initially screened in the 1940's for their antibacterial activity and,
while active against bacteria, were found to be too toxic. Several
years later they were found to be successful against selected cancers.
While synthetic and semi-synthetic analogues of the antibiotics are
continually being synthesized, evaluated and marketed,
microorganisms are still being actively screened for new leads.
Pyrethrins: This family of insecticides from plants of the genus
Chrysanthemum were first used in the early 1800's and continue to
be widely used to the present, particularly in household insecticide
products because of their relatively low toxicity in humans. Classical
compounds like the pyrethrins illustrate one of the more frustrating
aspects in the desig
chemical class has y years
regarding their mechanism of action. Further, it is doubtful that
much basic research will be reported in the immediate future because
there is little economic incentive in the private sector, and the
government funding agencies likely will continue to award grants for
projects that investigate more novel chemistry.
Cyclosporin: The history of this drug, isolated from the fungus
Cylindrocarpon ludidium and Trichoderma potysporum, shows how
perseverance of an individual scientist, Dr. Jean-Francoise Borel
(Sandoz), has led to the marketing of a drug which has increased
significantly the prognosis of patients receiving organ transplants. In
1978, the one year survival rate for was only 66 percent for
transplanted hearts and 65 percent for transplanted kidneys. The
most recent figures show the one year survival rates now to be 80
percent for hearts and 91 percent for kidneys. (2) The search for
additional immunosuppressant drugs has led to a new natural
product, FK-506, isolated from Streptomyces tsukubaensis No.
9993.(2) It appears that both compounds, as structurally diverse as
they appear, possibly have the same mechanism of action. Using the
newer techniques of conformational analysis, it will be interesting to
determine if there is a common pharmacophore.
The list of commercial products from natural sources could fill
volumes. It must be emphasized that their discoveries range from systematic
searches, to tradition to chance favors the prepared mind. The latter is
reemphasized in the discovery of the alkaloids from the periwinkle plant
(vincristine and vinblastine) which were first screened for their
hypoglycemic activity based on reports of their use by local groups in
Madagascar. While the hypoglycemic response could not be confirmed
under controlled laboratory conditions, an immunosuppressive effect due to
In Probing Bioactive Mechanisms; Magee, P., et al.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1989.