title: Synthesis and in vitro activity of some epimeric 20 alpha-hydroxy, 20-oxime and aziridine pregnene derivatives as inhibitors of human 17 alpha-hydroxylase/C17,20-lyase and 5 alpha-reductase.
abstract: Some epimeric 20-hydroxy, 20-oxime, 16 alpha, 17 alpha-, 17,20- and 20,21-aziridine derivatives of progesterone were synthesized and evaluated as inhibitors of human 17 alpha-hydroxylase/C17,20-lyase (P450(17) alpha) and 5 alpha-reductase (5 alpha-R). The reduction of 16-dehydropregenolone acetate (3a) was reinvestigated. NaBH4 in the presence of CeCl3 gave better stereo-selectivity for 20 beta-ol [20 alpha/20 beta-OH (4 alpha/4 beta) = 1/2.7] than LTBAH or the Meerwein-Pondroff method reported; reduction with Zn in HOAc formed exclusively 20 alpha-ol (4 alpha b). The 20 alpha- and 20 beta-hydroxy-4,16-pregnadien-3-one (9 alpha) and (9 beta) were synthesized from the alcohols 4 alpha b and 4 beta b. Several 20-oxime pregnadienes and 16 alpha, 17 alpha-, 17,20- and 20,21-aziridinyl-5-pregnene derivatives were also synthesized. LiAlH4 reduction of the 16-en-20-oxime (12b) yielded 20 (R)-(13a) and 20(S)-17 alpha,20-aziridine (13b) and 20(R)-17 beta,20-aziridine (14a). Several compounds inhibited the human P450(17) alpha with greater potency than ketoconzole. The 5 alpha-R enzyme assay showed that while (9 alpha) did not have any activity, (9 beta) and (3b) were potent 5 alpha-reductase (IC50 = 21 and 31 nM) inhibitors with activities similar to finasteride. The 20-oximes (17a) and (17b) were potent dual inhibitors for both 5 alpha-R (IC50 = 63 and 115 nM, compared to 33 nM for finasteride) and P450(17) alpha (IC50 = 43 and 25 nM, compared to 78 nM for ketoconazole).
authors.affiliation: Department of Pharmacology & Experimental Therapeutics, School of Medicine, University of Maryland, Baltimore 21201, USA.
authors.forename: Y Z
authors.initials: YZ
authors.lastname: Ling
authors.forename: J S
authors.initials: JS
authors.lastname: Li
authors.forename: K
authors.initials: K
authors.lastname: Kato
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: G T
authors.initials: GT
authors.lastname: Klus
authors.forename: K
authors.initials: K
authors.lastname: Marat
authors.forename: I P
authors.initials: IP
authors.lastname: Nnane
authors.forename: A M
authors.initials: AM
authors.lastname: Brodie
mesh_terms: D058891:5-alpha Reductase Inhibitors; D000728:Androgens / Q000378:metabolism; D000818:Animals; D001388:Aziridines / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007097:Imines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D010091:Oximes / Q000138:chemical synthesis* / Q000494:pharmacology*; D011245:Pregnadienes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011283:Pregnenes / Q000737:chemistry* / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C116515:20-hydroximino-4,16-pregnadien-3-one; C116514:4,16-pregnadiene-3,20-dione-20-oxime acetate; D058891:5-alpha Reductase Inhibitors; D000728:Androgens; D001388:Aziridines; D004791:Enzyme Inhibitors; D007097:Imines; D010091:Oximes; D011245:Pregnadienes; D011283:Pregnenes; C033132:aziridine; D013254:Steroid 17-alpha-Hydroxylase; D007654:Ketoconazole