title: Synthesis and evaluation of bromoacetoxy 4-androsten-3-ones as active site-directed inhibitors of human placental aromatase.
abstract: 2 alpha-Bromoacetoxy (II), 6-bromoacetoxy (VII and X), and 19-bromoacetoxy (XII) derivatives of androstenedione and 17 beta-bromoacetoxy compounds (III, IV, XIII-XVI) were synthesized as potential affinity-labeling reagents for aromatase. 6 alpha-Bromoacetoxy derivative VII was the most potent inhibitor of human placental microsomal aromatase activity among this series. Its inhibitory activity was higher than that of the parent 6 alpha-hydroxy compound V, although other bromoacetates showed weaker inhibition of aromatase than the corresponding alcohols. The bromoacetates (except the 6 beta-bromoacetate X) inhibited aromatase activity in a time-dependent manner in the absence of NADPH, and the enzyme inactivation was blocked by the addition of androstenedione to the incubates. Kinetic analysis of the time- and concentration-dependent inhibition by the 6 beta-bromo-17 beta-bromoacetoxy compound XV gave an apparent Ki of 25 microM and kinact of 0.027 min-1.
authors.affiliation: Tohoku College of Pharmacy, Sendai, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Numazawa
authors.forename: M
authors.initials: M
authors.lastname: Tsuji
authors.forename: Y
authors.initials: Y
authors.lastname: Osawa
mesh_terms: D000736:Androstenes / Q000138:chemical synthesis* / Q000494:pharmacology; D047072:Aromatase Inhibitors; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D006801:Humans; D007700:Kinetics; D008861:Microsomes / Q000201:enzymology*; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy; D013237:Stereoisomerism
chemical_list: D000736:Androstenes; D047072:Aromatase Inhibitors