title: Synthesis and biochemical studies of 16- or 19-substituted androst-4-enes as aromatase inhibitors.
abstract: Androst-4-en-17-one derivatives [19-acetoxide 4, 16-bromides 14 and 15, 19,19-difluoride 18, and (19R,S)-19-acetylenic alcohol 25] and androst-4-en-17 beta-ol derivatives 3, 5, 10, 12, and 19 were synthesized and tested for their ability to inhibit aromatase in human placental microsomes. All the 17-oxo steroids, except compound 25 and 17,19-diol 3 of this series, were effective competitive inhibitors with apparent Ki's ranging from 170 to 455 nM. 19,19-Difluoro steroid 18 and 19-acetylenic alcohol 25, a weak competitive inhibitor (Ki = 7.75 microM), caused a time-dependent, pseudo-first-order inactivation of aromatase activity with kinact's of 0.0213 and 0.1053 min-1 for compounds 18 and 25, respectively. NADPH and oxygen were required for the time-dependent inactivation, and the substrate, androst-4-ene-3,17-dione, prevented it, but a nucleophile, L-cysteine, did not in each case. The results strongly suggest that aromatase would attack the 19-carbon of steroids 18 and 25.
authors.affiliation: Tohoku College of Pharmacy, Sendai, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Numazawa
authors.forename: A
authors.initials: A
authors.lastname: Mutsumi
authors.forename: K
authors.initials: K
authors.lastname: Hoshi
authors.forename: M
authors.initials: M
authors.lastname: Oshibe
authors.forename: E
authors.initials: E
authors.lastname: Ishikawa
authors.forename: H
authors.initials: H
authors.lastname: Kigawa
mesh_terms: D000736:Androstenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000737:Androstenols / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors; D001665:Binding Sites; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D009249:NADP / Q000494:pharmacology; D010100:Oxygen / Q000494:pharmacology; D010920:Placenta / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D000736:Androstenes; D000737:Androstenols; D047072:Aromatase Inhibitors; C070478:19,19-difluoroandrost-4-en-17-one; C070479:19-ethynyl-19-hydroxyandrost-4-en-17-one; D009249:NADP; D001141:Aromatase; D010100:Oxygen