Table Of ContentThis is Volume 36 of
ORGANIC CHEMISTRY
A series of monographs
Editors: ALFRED T. BLOMQUIST and HARRY H. WASSERMAN
A complete list of the books in this series appears at the end of the volume.
Prostaglandin
Research
EDITED BY
Pierre Crabbe
Laboratoire de Chimie Organique
Universito Scientifique et Modicale
CE.R.M.O.
Grenoble, France
ACADEMIC PRESS New York San Francisco London 1977
A Subsidiary of Harcourt Brace Jovanovich, Publishers
COPYRIGHT © 1977, BY ACADEMIC PRESS, INC.
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Library of Congress Cataloging in Publication Data
Main entry under title:
Prostaglandin research.
(Organic chemistry series)
Bibliography: p.
Includes index.
1. Prostaglandins. I. Crabbe', Pierre.
[DNLM: 1. Prostaglandins. 2. Research. QU90
P962]
QP801.P68P68 599'.0l'924 76-9153
ISBN 0-12-194660-6
PRINTED IN THE UNITED STATES OF AMERICA
To
Professor Carl Djerassi
and
Professor Guy Ourisson
List of Contributors
Numbers in parentheses indicate the pages on which the authors' contributions begin.
Pierre Crabbe (1, 121, 223, 315), Laboratoire de Chimie Organique, Universite
Scientifique et Medicale, C.E.R.M.O., Grenoble, France
Gustavo A. Garcia (121, 223), Facultad de Quimica, Universidad Nacional
Autonoma de Mexico, Mexico City, Mexico
Christopher Hensby (89), British Postgraduate Medical Federation, Institute of
Dermatology, St. Johns Hospital, London, England
Robert L Jones (65), Department of Pharmacology, University of Edinburgh,
Edinburgh, Scotland
Luis Angel Maldonado (121, 223), Facultad de Quimica, Universidad Nacional
Autonoma de Mexico, Mexico City, Mexico
Bengt Samuelsson (17), Department of Chemistry, Karolinska Institutet,
Stockholm, Sweden
Jacques L. Theodor (47), Laboratoire Arago, Universite de Paris, Banyuls-sur-
Mer, France
XI
Preface
/ want only to share what I have found, to show those horizons out ahead for
us all.
Richard Bach
in "Jonathan Livingston Seagull"
At each period of time in science you have to judge what are the relevant and
significant things to do.
Sir Derek Barton
The aim of this book is to present a general outline of the present status of
prostaglandin research, with particular emphasis on chemistry. It discusses some
aspects not thoroughly covered in other works. It tries to show how scientific
research can play a role in society in attempting to find drugs, with potential
application to therapy, the chief impetus for prostaglandin research.
Chapter 1 presents a general introduction on the origin and properties of
prostaglandins. Chapter 2 outlines the present stage of research in the area of
biosynthesis of natural entities, with emphasis on endoperoxides and
thromboxanes. Chapter 3 deals with a rich source of natural prostaglandins, the
gorgonian Plexaura homomalla. Chapter 4 discusses the pharmacology of
prostaglandins. Chapter 5 mentions the physical methods currently used in
prostaglandin research. Chapters 6 and 7 consider the chemistry of natural and
modified prostaglandins, respectively. Finally, an Appendix which includes a
table of physical properties of some natural prostaglandins concludes the
monograph.
The book is presented in such a way that not only experts in the field will
find it useful, but also scientists with a general interest in chemistry and biology.
They will discover that sometimes close relationships exist among organic
chemists, biologists, and pharmacologists working in this area. The book also
attempts to show that prostaglandin research is unusual in that it has promoted
both competitive and collaborative programs between academic institutions and
industrial laboratories at an international level, a need of our times.
xiii
xiv Preface
Another objective of this monograph is to illustrate the fertility of the
scientist's imagination. Indeed, this new field of research has stimulated
scientific creativity and has been a catalyst for original ideas. In contrast to
many other research areas, numerous reactions have been designed specifically
for the prostaglandin molecule as a consequence of the requirements of great
selectivity in poly functional and stereochemical situations. The chemistry of
prostaglandins also constitutes a wealth of invaluable information on general
principles and experimental conditions in organic synthesis. Significantly, there
is practically no newly discovered synthetic reaction that is not immediately
applied to a prostaglandin molecule, which thus constitutes a fertile field for
experimentation.
This book is especially addressed to graduate students who wish to familiarize
themselves with modern methodology used in biological and chemical research,
in general, and in organic synthesis, in particular. Research chemists will also
find this monograph useful as a reference source for mild alkylation with
organometallic reagents, epoxide formation and opening, preparation of alkynes,
alkenes, allenes, photochemical processes, regio- and stereoselective reductions,
oxidations, alkylations, etc. Finally, the book is especially addressed to literature
browsers who will not only find that this field constitues a prodigious technical
armamentarium, but will also encounter stimuli for pondering a multitude of
unsolved problems.
For about four million years Nature achieved the biosynthesis of
prostaglandins in man, but it was only in 1930 that their existence was
suspected. About thirty years elapsed between the recognition of the biological
activity of prostaglandins and the structure elucidation of two of them. The first
total synthesis was achieved less than ten years ago, and it is only recently that
prostaglandin analogues have been prepared and submitted to careful biological
screening. Although there are side effects associated with some natural and
modified entities, it would be premature perhaps to conclude that prostanoids
will not become useful drugs and will not find applications in therapy. To
mention only one example, research in the steroid field has shown that the
development of new analogues is time-consuming. It is hoped that the chemists
and biologists actively engaged in prostaglandin research will be able to demon-
strate that their effort has been useful to society.
One of the crucial stimuli for writing these chapters is that the prostaglandin
field constitutes a unique page in the history of science as so much has been
achieved in such a short period of time. We hope that the reader will find these
chapters both interesting and useful.
I am indebted to Professor D. A. van Dorp (Vlaardingen, Holland) for helpful
comments and for permitting reference to several unpublished manuscripts.
Thanks are due to Professor J. Fried (University of Chicago) and Professor G.
Stork (Columbia University) who also communicated information prior to
Preface XV
publication. I am most grateful to Dr. G. T. DeTitta (Medical Foundation of
Buffalo) for the X-ray diffraction spectra. I wish to express my gratitude to Dr.
E. Chambaz and Mr. P. Rolland (University of Grenoble) for stimulating
discussions on biological aspects, and, in particular, to Dr. Andrew Greene
(University of Grenoble) who read and made valuable comments on Chapters 6
and 7. I wish to thank my co-workers, Mrs. G. Gagnaire and Miss Ma.C. Meana,
for assembling many of the physical data on natural prostaglandins, and Mr. J.P.
Depres for the drawings in Chapters 6 and 7. Finally, it is with special pleasure,
that I express my gratitude to Professor H. H. Wasserman (Yale University) for
his kind proposal to include this book in the Organic Chemistry Series.
Pierre Crabbe
1
Introduction, Origin,
and Properties
Pierre Crabbe
I. History 1
II. Nomenclature, Structure, and Stereochemistry 2
III. Natural Occurrence 5
IV. Biological Properties. 6
References 13
I. HISTORY
The prostaglandins (PG) form a class of natural products with diverse and
potent biological activities. The natural PG are unsaturated hydroxylated fatty
acids, all derivatives of a parent compound called prostanoic acid (1). As yet,
their precise physiological role has not been clearly defined, but their potency
and activity in many apparently unrelated biological systems have awakened the
interest of scientists of various disciplines. Indeed, PG are associated with most
mammalian tissues and implicated in an ever-increasing number of physiological
systems [1].
From the historical point of view, in 1930 Kurzrok and Lieb showed that the
human semen could induce strong contractions or relaxations when applied to a
human uterus [2]. A few years later, von Euler and Goldblatt demonstrated
independently the presence of a vasodepressor agent and a stimulating factor of
muscles in human seminal plasma and sheep vesicular glands [3]. von Euler
indicated that the biological activity was due to a lipid soluble material with
acidic properties and called it "prostaglandin" [4].
About 30 years elapsed between the discovery of the biological activity of PG
and the structure elucidation of two of them. The reasons why this field
remained dormant for so long are multiple and in part are due to the technical
difficulties encountered earlier in the isolation of natural PG. In addition, the
dramatic development of antibiotics and hormone therapy made during the past
30 years somehow caused PG research to fall into oblivion. In 1957, Bergström
1
2 Pierre Crabbe*
and Sjövall isolated the crystalline PGEi (2) and PGF , (3) from sheep vesicular
lQ
seminal extracts [5]. A short time later, Bergström, Sjövall, and Samuelsson
were able to differentiate and then isolate 13 different substances. It was only
after this isolation and structure work when PG were shown to be biologically
active entities that the field came to life. Previously their biological properties
had been attributed to other known substances [6-9].
II. NOMENCLATURE, STRUCTURE, AND
STEREOCHEMISTRY
Natural occurring PG may be regarded as derivatives of prostanoic acid (1), an
organic acid with a substituted cyclopentane unit [10].
CO2H
1 Prostanoic acid
HO
,[CH]-C0H
26 2
HO
C02H COsH
HO OH HO OH
4 PGE? 5 PGF2rv
HO
COzH C02H
HO OH
7 PGF
Sft
Scheme 1
