PHARMACOCHEMISTRY LIBRARY Editor: H. Timmerman

Volume 15

MEDICINAL CHEMISTRY OF STEROIDS

RJ.ZEELEN Floraliastraat 2, 5384 GPHeesch, The Netherlands

ELSEVIER — Amsterdam — Oxford — New York — Tokyo 1990 CONTENTS Chapter 1. The Steroids 1 Introduction 1 Configuration 2 The nomenclature of the steroids 3 Conformation 6 Polymorphism 11 References 13 Scientific names of the compounds mentioned 14 Chapter 2. Steroid-Protein Interactions 15 Introduction 15 The steroid receptor proteins 16 Steroid binding serum proteins 20 The binding of steroids to transforming enzymes 28 References 37 Scientific names of the compounds mentioned 41 Chapter 3. The Biosynthesis of the Sterols 43 Cholesterol and ergosterol 43 The cyclization of squalene 45 Removal of the 14a-methyl group 48 Reduction of the 14(15)-double bond 50 Removal of the methyl groups at C-4 . 51 Introduction of the 5(6)-double bond 51 Reduction of the 24(25)-double bond 52 The biosynthesis of ergosterol 52 Regulation of cholesterol biosynthesis 52 Oxygenated sterols as inhibitors of cholesterol synthesis 55 Inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A synthase . .55 Competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase 56 Inhibitors of squalene epoxidase 56 Inhibitors of 2,3-oxidosqualene cyclase 59 Inhibitors of cytochrome P-450DM 59 Inhibitors of A8(14)-sterolA14-reductase 61 Inhibitors of 4-methylsterol oxidase 62 Inhibitor of the sterol A -reductase 63 Inhibitor of the sterol A -reductase 63 Inhibitors of C-24 methylation 64 Vlll

Cholesterol derivatives as organ-imaging agents 65 References 66 Scientific names of the compounds mentioned 70 Chapter 4. The Cytochrome P-450 Isoenzymes 73 Nomenclature of the cytochromes P-450 73 Location of the cytochromes P-450 76 Structure of the cytochromes P-450 77 Mechanism of action of the cytochromes P-450 81 Cytochrome P-450SCC 83 Inhibitors of cytochrome P-450SCC 86 References 91 Scientific names of the compounds mentioned 94 Chapter 5. The Progestins 97 Progesterone 97 Biosynthesis 99 Metabolism 100 Structure and progestational activity 101 Therapeutic use of the progestins 109 Contraception 109 Inhibitors of ovarian progesterone synthesis Ill Progesterone antagonists 113 References 116 Scientific names of the compounds mentioned 121 Chapter 6. Central Nervous System Activity of Progesterone Metabolites 123 Structure and anaesthetic activity 124 Modulation of the GABA system 124 References 126 Scientific names of the compounds mentioned 127 Chapter 7. The Mineralocorticoids 129 Aldosterone 129 Biosynthesis of aldosterone 133 Structure and mineralocorticoid activity 134 Therapeutic use of the mineralocorticoids 136 Aldosterone antagonists 136 Inhibitors of aldosterone synthesis 139 References 139 Scientific names of the compounds mentioned 141 IX

Chapter 8. The Glucocorticoids 143 Hydrocortisone 143 Biosynthesis 144 Metabolism 145 Structure and glucocorticoid activity 148 Therapeutic use of the glucocorticoids 162 Glucocorticoid antagonists 164 Inhibitors of hydrocortisone synthesis 167 References 168 Scientific names of the compounds mentioned 172 Chapter 9. TheAndrogens 177 Testosterone and stanolone 177 Biosynthesis 178 Metabolism 180 Structure and biological activity 181 Therapeutic use of the androgens 182 Anti-androgens 185 Inhibitors of testosterone synthesis 187 Inhibitors of steroid 5cc-reduetase 188 References 191 Scientific names of the compounds mentioned 194 Chapter 10. The Steroid Odorants 197 References 199 Scientific names of the compounds mentioned 199 Chapter 11. The Estrogens 201 Estradiol and estrone 201 Biosynthesis 203 Metabolism 204 Estriol 206 Anti-estrogens 208 Structure and estrogenic activity 210 Prodrugs for the estrogens 212 Estrogens in therapy 215 Inhibitors of estrogen sulfotransferase 217 Aromatase inhibitors 218 References 226 Scientific names of the compounds mentioned 232 Chapter 12. Steroids and Cancer 235 Hormonal steroids 235 Alkylating steroids 235 Plant steroids with anticancer activity 237 Inhibitors of cholesterol synthesis 237 The withanolides . . 238 References 240 Scientific names of the compounds mentioned 241 Chapter 13. The Bile Acids 243 Introduction 243 Biosynthesis 244 Therapeutic use 244 Pharmaceutical use of the bile salts 247 References 248 Scientific names of the compounds mentioned 249 Chapter 14. Vitamin D 251 Calcitriol 251 The biosynthesis of calcitriol 252 Use of "vitamin D" and related steroids 253 Metabolism 255 Structure and biological activity 257 Psoriasis 259 Inhibitors of calcitriol biosynthesis 260 References 261 Scientific names of the compounds mentioned 263 Chapter 15. Biological Activities of Sterols 265 Cholesterol synthesis in insects 265 Insect-inhibiting and insect-deterring sterols 267 The ecdysteroids 269 Sex hormones of the water-mould Achlya ambisexualis 274 Ovulatory-active steroids from crops of Job's Tears 275 The Brassino-steroids 275 References 278 Scientific names of the compounds mentioned 280 Chapter 16. Steroid Antibiotics 283 References 285 Scientific names of the compounds mentioned 285 Chapter 17. The Cardiotonic Steroids 287 Digitalis glycosides 287 The squill glycosides 290 The strophanthus glycosides 290 Mechanism of action 291 Structure and cardiotonic activity 292 Therapeutic use of the cardiotonic steroids 296 References 297 Scientific names of the compounds mentioned 298 Chapter 18. Synthetic Steroids with Pharmacological Activities . . 301 Introduction 301 Steroids for treatment of head and spinal-cord injuries 303 Steroids with anti-arrhythmic activity 304 Steroids with neuromuscular blocking activity 306 References 310 Scientific names of the compounds mentioned 312 Chapter 19. Steroid Synthesis 315 Introduction 315 Total syntheses of cortisone and hydrocortisone 316 Partial syntheses of cortisone 323 Microbiological llcc-hydroxylation 327 Synthesis of halopredone acetate 330 Testosterone from diosgenin 330 Canrenone and spironolactone 332 Synthesis of the 19-norsteroids 334 Total Synthesis of 19-norsteroids 336 Microbiological degradation of sterols 337 Synthesis of corticosteroids from 9a-hydroxyandrost-4-ene-3,20-dione 338 Synthesis of norethisterone 341 Synthesis of vitamin D 342 References 347 Scientific names of the major compounds 349 Subject Index 351