Steroid Biochemistry and Pharmacology 0121346501, 9780121346508

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Steroid Biochemistry and Pharmacology

Steroid Biochemistry and Pharmacology M. H. BRIGGS Schering Chemicals Ltd. Burgess Hill, Sussex England

J. BROTHERTON Biochemistry Department University of Surrey Guildford, England

1970

ACADEMIC PRESS LONDON AND NEW YORK LIBRARY EAST TEXAS STATE UNIVERSITY COMMERCE, TEXAS 75428

ACADEMIC PRESS INC. (LONDON) LTD. Berkeley Square House Berkeley Square London W1X 6BA

U.S. Edition published by ACADEMIC PRESS INC. Ill Fifth Avenue, New York, New York 10003

Copyright © 1970 By ACADEMIC PRESS INC. (LONDON) LTD.

All Rights Reserved No part of this book may be reproduced in any form by photostat, microfilm, or any other means, without written permission from the publishers

SBN: 12-134650-1 Library of Congress Catalog Card Number: 75-109036

Printed in Great Britain by Spottiswoode, Ballantyne and Co. Ltd London and Colchester

PREFACE During 1968 and 1969 one of us (MHB) gave courses of lectures on steroid biochemistry at the Universities of Surrey and Sussex. It became clear that there existed no book on the subject that could be recommended to advanced students as providing an adequate introduction to the subject and, at the same time, providing background information and indications for further reading. The coverage of steroid biochemistry by general textbooks is too slight, and while advanced texts are available on steroid endocrinology, metabolism and pharma¬ cology, there is no book that surveys the whole field. We offer this book to fill the gap. It is aimed at graduates in biochemistry, medicine or pharmacology either taking post-graduate courses, or beginning research involving steroids. It is our experience that many students, especially of medicine or of biological sciences, approach the study of steroids with considerable trepidation. This appears to be due mainly to their difficulties in distinguishing one steroid structure from another. Yet surely it is this chemical similarity, associated with vastly different physiological effects, that is the fascination of steroid bio¬ chemistry? The difference between masculinity and femininity is only four H and one C atoms (testosterone and estradiol). Our first chapter consequently sets out the rules for the recognition and naming of steroids. We do not pretend that this is easy, but it is essential to master the various rules before proceeding. Throughout the book we have attempted not to present steroid biochemistry in isolation. Wherever possible we have dealt with the biological and physio¬ logical backgrounds to the metabolism and actions of particular steroids. As far more is known of steroid biochemistry in the human than for any other species, we have emphasized this in most chapters. We have consequently presented a good deal of material on human abnormalities involving steroids, and wherever relevant we have discussed steroid pharmaceuticals used in medicine. We have also briefly mentioned non-steroid pharmaceuticals that have profound effects on steroid biochemistry. We have included a chapter on plant steroids in which we have largely dealt with substances of medicinal interest. The final chapter deals briefly with the production of steroid pharmaceuticals on an industrial scale. V

PREFACE

VI

For the sake of ease of reading we have not included literature references in the text. A selected bibliography is, however, provided at the end of the book. While we have adopted our native English spelling throughout the book, we have bowed to the I.U.P.A.C. rule and used the spelling “estrogen” rather than “oestrogen". We have also used the term "progestogen” rather than "progestin” or "gestogen”. We would like to thank Miss Virginia C. Baines, B.Sc., for extensive proof reading.

May, 1970

MICHAEL H. BRIGGS JANET BROTHERTON

4

FOREWORD Steroids represent a class of chemical compounds to be found in the whole animal and plant kingdoms. For a very long time, their structure has fascinated chemists and stimulated them into continuous endeavours towards total syn¬ theses. The very reasons for this were the various biological activities found in this class of compounds which one has learned to augment or to differentiate by synthetic changes. The importance of sexual and adrenal cortex hormones, and the interest in them, is so great that one might incline to forget other non-steroidal hormones. The catch-word “the pill” needs no further explanation! The corticoids should not be overlooked in the series of available drugs. The cardio-active steroids still await an amelioration of their therapeutic index. The discovery of a steroidal insect hormone has led to an interesting speculation on mechanisms of hormonal action, thus reminding us of the present lack of knowledge in this field. On the other hand, the multiple and various metabolic pathways are much

better known

and understood. The extent to which

fundamental knowledge and practical applications may still be discovered in the steroidal area can scarcely be estimated. Inevitably, pharmacologists, endo¬ crinologists, physicians active in clinical chemistry, and biochemists sooner or later get into at least some contact with the steroids. This textbook should stimulate advanced students of science and medicine, or scientists without experience in this field, to become theoretically and practically interested in it; it gives a first, necessarily incomplete, but condensed survey and provides a key to the recent relevant literature and special review articles.

May, 1970

H. GIBIAN

Main Research Laboratories Schering A. G. Berlin

vii

CONTENTS Preface

...........

v

Foreword

...........

vii

Chapter 1 Nomenclature of the Steroids I. Definition

..........

II. Conformation and Configuration

......

2

........

7

.........

8

III. Parent Hydrocarbons IV. Substituents

1

V. The Side Chain

.

VI. Trivial Names

.

.

.

.

.

.

.

.14

.........

VII. Ring Contractions, Additions and Clevages • VIII. Some Other Prefixes

.

.

.

.17

........

IX. Reactivities of Ring Substituents

17

......

21 22

Chapter 2 Neuroendocrinology and Sites of Steroid Biosynthesis I. The Steroid Cycle II. Neuroendocrinology

.........

23

........

25

III. Sites of Steroid Biosynthesis and Metabolism

•

.

.

.35

Chapter 3 Pathways of Biosynthesis and Metabolism of Steroids I. Summary

.

.........

II. Biosynthesis of Cholesterol

.......

III. Degradation of Cholesterol to Corticoids, Androgens and Estrogens IV. Biosynthesis and Metabolism of Corticosteroids

.

V. Biosynthesis and Metabolism of the Androgens

•

VI. Biosynthesis and Metabolism of the Estrogens

1*

IX

52 52 59

.

.

.61

.

.

.70

....

75

CONTENTS

X

VII. Steroid Dehydrogenases and Hydroxylases ..... VIII. Conjugation

..........

'IX. Vitamin D

.

X. Bile Salts

.

.

.

.

.

.

.

.

75 80

.81

..........

83

Chapter 4 Target Organ Effects-A. Estrogens and Progestogens I. Introduction

..........

II. Effects of Estrogens III. Effects of Progesterone

86

........

88

........

89

IV. Cyclic Effects of Estrogens and Progesterone V. Estrogenic Potency: Biological Assay .

.

.

.

.

.91

.

.

.

.102

VI. Progestational Potency: Biological Assay.106 VII. Contraceptive Effects of Estrogens and Progestogens

.

.

.108

Chapter 5 Target Organ Effects— B. Androgens and Anabolics 1. Introduction ........ II. Growth Hormone ....... III. Androgens

.......

IV. Anabolics

........

V. Anti-androgens

.

121 122 122

.....

VI. Effects ot Steroids on Skin, Hair Follicles and Sebaceous Glands VII. Anti-spermatogenic Compounds ....

.

125

.

130

•

131

.

134

Chapter 6 Target Organ Effects-C. Corticoids I. Introduction

........

.

139

II. Mineralocorticoids .......

.

140

III. Glucocorticoids

.......

.

144

.....

.

147

......

.

168

IV. Anti-inflammatory Steroids V. Steroid Anaesthetics

Chapter 7 Effects of Non-Hormonal Steroids I. Cholesterol II. Bile Salts III. Vitamin D

........

.

171

........

.

183

......

.

188

CONTENTS

xi

Chapter 8 Clinical Aspects of the Pituitary-Adrenal Axis I. ACTH in Blood and Urine II. Urinary Corticosteroids III. Blood Corticosteroids

.......

192

........

193

........

197

IV. Corticosteroid Secretion Rates .......

201

.

203

' VI. Some Abnormalities

V. Clinical Tests for Adrenal-Pituitary-Hypothalamic Functions .

........

206

VII. Corticosteroid Therapy

.

.

.

VIII. Drugs Affecting Adrenal Steroidogenesis

.

.

.

.

.211

.

.

.

.

.214

Chapter 9 Clinical Aspects of the Pituitary-Gonad Axis I. Gonadotrophins II. Estrogens

•

.

.

.

.

.

.

III. Progestogens .

.

IV. The Menstrual Cycle

.219

.

.

.

.

.

.

.

224

.231

........

V. Endocrine Relations Between Mother, Foetus and Placenta VI. Androgens

.

..........

.

235

.

23u

..........

VII. Secretion Rates of Androgens and Estrogens VIII. Abnormalities of Gonadal and Pituitary Function IX. Sex Hormone Therapy

240

.... .

.

245 .

247

.......

262

Chapter 10 Plant Steroids I. C-28 and C-29 Sterols.265 II. C-30 Sterols.271 III. Cardenolides, Cardiac Glycosides

......

276

IV. Bufadienolides, Scilladienolides.......

285

V. Steroid Saponins, Spirostanols . VI. Steroid Antibiotics VII. Ecdysones

......

288

........

294

..........

295

VIII. Steroidal Alkaloids, Aza Steroids

......

296

Chapter 11 Industrial Production of the Steroids I. Introduction

•

.

.

.

.

.

.

.

.

.301

II. Isolation from Human Extracts .......

302

xii

CONTENTS

III. Synthesis of Progesterone from Plant Steroids IV. Synthesis from Bile Acids V. Synthesis from Sapogenins

....

.......

306

.......

309

VI. Microbiological Conversions used in Syntheses VII. Total Synthesis

.

303

.

315

........

317

VIII. Modifications of the Natural Steroids

.

.

.....

Bibliography ...........

322 328

Appendix I Index of Trivial and Systematic Names of Steroids

.

338

.......

350

Appendix II Some Recent Work I. Feedback of Gonadotrophins

II. Composition of Protein Hormones

.

.

.

.

.

.351

III. The Haynes and Berthet Hypothesis of the Mechanism of Action of ACTH.354 IV. Comparison of the Menstrual and Estrous Cycles .... 354 V. Steroid Muscle Relaxants

.......

356

VI. Protein Binding of Steroids

.......

357

VII. Biosynthesis of Triterpenes

.......

368

.

399

VIII. Nomenclature Bibliography .

Subject Index

.

.

.

.

.

.

.

...

.........

.

.

.

.

.

.

.

.

408

.411

1 NOMENCLATURE OF THE STEROIDS

I. Definition .......... 1 II. Conformation and Configuration ...... 2 III. Parent Hydrocarbons ........ 7 A. Saturated .......... 7 B. Unsaturated ......... 7 IV. Substituents .......... 8 A. Carboxylic Acids, their Esters and Lactones . . .10 B. Esters of Steroid Alcohols . . . . . . .12 C. Aldehydes, Ketones and Alcohols . . . . . .13 D. Amines . . . . . . . . . -13 E. Ethers . . . . . . . . . -13 F. Hydrocarbon and Halogen Additions . . . . .14 G. Additional Rings Within or On the Steroid Nucleus . . .14 V. The Side Chain . . . . . . . .14 VI. Trivial Names . . . . . . . . -17 VII. Ring Contractions, Additions and Cleavages . . . .17 VIII. Some Other Prefixes . . . . . . . -21 IX. Reactivities of Ring Substituents ...... 22

I. DEFINITION Steroids are a class of organic compounds biologically derived from six isopentenyl pyrophosphate units and containing the perhydrocyclopentanephenanthrene nucleus, i.e. three six-membered rings (A, B and C) and one five-membered ring (D). The carbon atoms are numbered as shown in Fig. 1.1 21

Fig. 1.1. Stigmastane showing the numbering of the carbon skeleton and of the rings.

I

2

STEROID BIOCHEMISTRY AND PHARMACOLOGY

for stigmastane (24-ethylcholestane), a fully saturated molecule with twentynine carbon atoms. If one or more of the side chain carbon atoms is absent, the numbering of the remainder is unaltered. Every ring junction may be either cis or trans, which gives six centres of asymmetry (C-5, 8, 9, 10, 13 and 14) and therefore sixty-four steroisomeric forms are theoretically possible. With the introduction of a side chain at C-17, a seventh asymmetric centre is produced with 128 theoretical isomers and so on.

II. CONFORMATION AND CONFIGURATION The six carbon atoms of the cyclohexane ring can exist in either the chair, boat, or twist conformation (Fig. 1.2). a

a

Twist

Half-chair for a mono-ene

Fig. 1.2. Conformations of cyclohexane. Conformation has been defined as denoting different possible spatial arrange¬ ments of the atoms in a single organic configuration. The chair form is less strained and therefore preferred. The two hydrogen atoms attached to each carbon atom then take up their positions either in the general plane of the ring, being called equatorial (e), or perpendicular to the plane of the ring, being called axial (a). By convention, the axial atoms are depicted with a solid line if they are projected above the plane of the ring (^-configuration) and with a dotted line if they are projected below the plane of the ring (a-configuration). When the configuration is not known, a wavy line is used with the prefix £ in the nomenclature. In the chair form each axial hydrogen atom is 2.5 A from the other two axial hydrogen atoms on the same side of the ring and non-bonded interactions between hydrogen atoms at C-l and C-2, C-l and C-3, and C-l and C-4 are least. A twist form may be regarded as an intermediate boat form which permits the relief of strong 1:4 interactions present in the complete boat form and is a likely form for some steroid ring systems.

1. NOMENCLATURE

3

In all naturally-occurring steroids, the junction between rings C and B is tram and they are both locked in the chair conformation. In the sterols and bile acids, the junction between rings C and D is also trans, but in the plant glycosides this

Fig. 1.3. 5a (Alio) series, rings A/B trans (from Shoppee, 1964).

Fig. 1.4. 5/3 (Normal) series, rings A/B cis (from Shoppee, 1964).

4

STEROID BIOCHEMISTRY AND PHARMACOLOGY

junction is cis. The junction between rings A and B can be either trans, giving the 5a or “alio” series of compounds, or cis, giving the 5/3 or “normal” series of compounds. Ring A is free to form either the chair or boat conformation but will form the chair under most circumstances. Most of the biologically-active steroids have a trans junction between rings A and B and belong to the 5a or “alio” series. This makes the 4-rings almost completely planar as shown in Fig. 1.3, which represents four different ways of showing the same molecule. Figure 1.3a shows a sideways view of the four rings without the hydrogen bonds, Fig. 1.3b shows the same view with the position of the hydrogen bonds, Fig. 1,3c shows a three-dimensional picture of the carbon skeleton, and Fig. 1.3d shows the conventional drawing of the basic structure. Note the heavy line at C-10 denoting a H-atom above the ring and the dotted line at C-5 denoting a H-atom below the ring, i.e. two trans H-atoms. The H-atoms at C-8 and C-9, C-13 and C-14 are also trans. Figure 1.4 shows the same four drawings for the normal series. Note the two heavy lines denoting cis H-atoms above the ring at C-5 and C-10.

Until

recently,

to distinguish between

methyl groups and H-atoms

projecting above and below the place of the ring, the hydrogen atoms have been written into the conventional drawing, i.e. Fig. 1.5a not Fig. 1.5b to represent Fig. 1.5c, but the latest IUPAC rules recommend Fig. 1.5b. It is also common to insert the configuration of the hydrogen atom at C-5, the configurations of the remainder being assumed. When configuration of the four rings is known, the position of the axial and equatorial bonds is as shown in Table 1.1. The

b. IUPAC, 1967

Fig. 1.5. Five ways of drawing 5ot-androstane.

1. NOMENCLATURE

5

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73

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