PCOL 826B 2022 Medicinal Chemistry of Steroids Introduction Lecture 1 PDF

Medicinal Chemistry of Steroids Introduction lecture 1 PCOL 826B [pages 1386- 1433 in Foye’s MedChem] [email protected] 1 Next 4 Lectures: - General introduction to steroid medicinal chemistry - Medicinal chemistry of estrogens progestins androgens adrenocorticoids Today’s Learning Object...

Medicinal Chemistry of Steroids Introduction lecture 1 PCOL 826B [pages 1386- 1433 in Foye’s MedChem] [email protected] 1 Next 4 Lectures: - General introduction to steroid medicinal chemistry - Medicinal chemistry of estrogens progestins androgens adrenocorticoids Today’s Learning Objectives: - steroid hormone structure and nomenclature - steroid stereochemistry - endogenous estrogens General Rule: Don’t panic. Information will be presented in a repetitive, redundant manner. 2 Steroid-based medications lecture 1: steroid intro + estrogens lecture 2: estrogens and progestins / oral contraceptives lecture 3: androgens / anabolics lecture 4: adrenocorticoids 3 Drugs targeting the estrogen receptor 4 oral contraception breast cancer chemoprevention and chemotherapy infertility hormone replacement therapy [HRT] osteoporosis Steroid Drugs: From Endogenous Ligand to Pharmaceutical Agent Optimization through Medicinal Chemistry hydrocortisone [cortisol] - potency - specificity - dissociated ligands 17b-estradiol 17a-ethinylestradiol - toxicity - duration of action - oral bioavailability - etc. 5 Exam question OH H 1 2 H H H O 5 3 4 Five chemical compounds that target the estrogen receptor are shown above. Identify the three synthetic agents: A. 1, 2, 3 B. 2, 3, 4 C. 3, 4, 5 D. 1, 2 ,4 E. 1, 4, 5 6 Cyclopentanoperhydrophenanthrene: parent compound of steroids phenanthrene 18 19 cholesterol sex steroids: androgens estrogens progestins corticosteroids glucocorticoids mineralocorticoids bile acids vitamin D precursors non-mammalian natural products cardenolides (plants) ergosterol (fungi) androstane Numbering of the fundamental saturated tetracyclic hydrocarbon skeleton: ring A > B > C > D > C-18 > C-19 > side chain 7 Steroid Stereochemistry: From Cyclohexane to Decaline cyclohexane 8 cholestane Decaline Stereochemisty: Configurational isomers cis decalin (bicyclo[4.4.0]decane) trans H H A B H A cis-configuration B trans-configuration H 9 Configurational Isomers of Steroids CH3 CH3 H CH3 R H H H H H H cis-trans-cis 10 R H H cis-trans-trans CH3 H H H H H trans-trans-trans CH3 CH3 CH3 R H CH 3 A C R D B tetracyclic system > three ring fusions > 23 (=8) isomers Cholic acid, a cis-trans-trans isomer CH3 CH3 H R H H H H cis-trans-trans cholic acid, a principal bile salt 11 Epimeric testosterone metabolites: Androsterone and its 5b-epimer etiocholanolone 5β-epimer flat trans-trans-trans curved androsterone, a weak androgen First isolated in 1931 (Johann Butenandt) from 17,000 litres of male urine, from which 50 milligrams of crystalline androsterone were obtained by distillation. cis-trans-trans etiocholanolone, inactive metabolite in urine, no androgenic activity, Two major metabolites of testosterone : - androsterone (5α-androstan-3α-ol-17-one), a neurosteroid that acts as a positive allosteric modulator of GABA A receptors, - and its 5β-epimer etiocholanolone (5β-androstan-3α-ol-17-one) (may be reduced in epilepsy). 12 testosterone Digitoxin: Cardiac (steroid) glycoside cis trans cis The cardenolides have an unsaturated butyrolactone ring substituent in position X ? Rings A/B and C/D are cis fused while rings B/C are trans fused. 13 Exam question Batrachotoxin (shown above) is a potent cardiotoxic and neurotoxic natural product found in the poison dart frog. Identify the incorrect statement: A. This agent contains a steroid ring system. B. This agent is an alkaloid. C. Rings A and B are trans-fused. D. This agent contains a pyrrole-ring substructure. E. This steroid molecule contains an unsaturated bond between carbons 7 and 8 [D 7,8]. 14 Exam question Rocuronium is a neuromuscular blocking agent that contains a rigid amino-steroid scaffold. Identify the specific connectivity between rings A&B, B&C, and C&D: A. cis-cis-cis. B. cis-cis-trans. C. cis-cis-trans. D. trans-cis-cis. E. trans-trans-trans. 15 5a and 5b-Cholestane 16 17a- and 17b-estradiol OH OH H H H H HO H H HO 17a-estradiol 17a-ethinylestradiol 17b-estradiol The basic steroid structure is a plane with a bottom (a) surface and a top (b) surface. Substituents oriented towards the bottom surface obtain the prefix ‘a‘ and substituents oriented towards the top surface obtain the prefix ‘b ‘. a-Substituents are drawn with cross-hatched bonds, bold bonds are used for b-substituents. 17 Aromatase: Which reaction does it catalyze ? Aromatase, is an enzyme that catalyzes a key step in estrogen biosynthesis. Aromatase is a member of the cytochrome P450 monooxygenase superfamily. During steroidogenesis, aromatase is responsible for the aromatization of androgens into estrogens. Aromatase is a drug target: Aromatase inhibitors are cancer therapeutics that suppress estrogen biosynthesis, thereby depriving estrogen-dependent breast cancer cells of this hormone. 18 More nomenclature… cholest-5-en-3a-ol, a D5-steroid 4-pregnene-3,20-dione 11β,17α,21-Trihydroxypregn-4-ene-3,20-dione 17b-hydroxyandrost-4-en-3-one 3b-hydroxyandrost-5-en-17-one estra-1,3,5-triene-3,17b-diol 19 Exam question The systematic name of the synthetic glucocorticoid dexamethasone (shown above) is: A. 10-fluoro-11β,17,21-trihydroxy-16a methylpregna-1,4-diene-3,20-dione. B. 10-chloro-11β,17,21-trihydroxy-16a methylpregna-1,4-diene-3,20-dione. C. 9-fluoro-11a,17,21-trihydroxy-16a methylpregna-1,4-diene-3,20-dione. D. 9-fluoro-11β,17,21-trihydroxy-16a methylpregna-1,4-diene-3,20-dione. E. 9-fluoro-11β,17,21-trihydroxy-16a methylpregna-1,4-diene-3-one. 20 exam question 1 3 2 4 5 Which of the steroid hormones displayed above is ‘estradiol’ ? A. B. C. D. E. 1 2 3 4 5 21 Drugs targeting the estrogen receptor 22 oral contraception breast cancer chemoprevention and chemotherapy infertility hormone replacement therapy [HRT] osteoporosis Drugs targeting the Estrogen Receptor SERM [selective ER modulators] ER agonists OH natural synthetic H H H HO OH O H HO H H O3S O O H ER antagonists H O3S O 23 Estrogen Receptor alpha: an estrogen-activated transcription factor dimerized ERa DNA binding domains [DBD] with DNA: gray spheres are Zn atoms contained in DNA binding Zn fingers. 24 dimerized ERa ligandbinding domains [LBD]