title: Synthesis and biochemical properties of 6-bromoandrostenedione derivatives with a 2,2-dimethyl or 2-methyl group as aromatase inhibitors.
abstract: To gain insight into the mechanism for irreversible inactivation of aromatase by 6beta-bromoandrostenedione (1), one of the earliest discovered suicide substrates, in relation to the catalytic function of the enzyme, the 2,2-dimethyl derivative of compound 1, steroid 4, and its 6alpha-isomer 5, as well as 2-methyl-1,4-diene steroid 8 and its 6alpha-bromide 10, were synthesized. All of the steroids inhibited aromatase activity in human placental microsomes with apparent K(i)'s ranging between 10 and 81 nM. The 2,2-dimethyl-6beta- and 6alpha-bromo steroids 4 and 5 were extremely powerful inhibitors (K(i): 14 and 10 nM, respectively), but these two did not cause a time-dependent inactivation of aromatase in the presence of NADPH; in contrast, the 2-methyl-1,4-diene steroids 8 and 10 caused time-dependent inactivation with apparent k(inact) of 0.035 and 0.071 min(-1), respectively, in a suicide manner. These results indicate that the 2,2-dimethyl function of the 6beta-bromide 4 would prevent the inactivation of aromatase caused by inhibitor 1 in a suicide manner, probably through steric activity, whereas the 2-methyl group of steroid 8 did not significantly affect the suicidal inactivation by the parent 1,4-diene steroid, a typical suicide substrate.
authors.affiliation: Tohoku Pharmaceutical University, Sendai, Japan. numazawa@tohoku-pharm.ac.jp
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Numazawa
authors.forename: Wakako
authors.initials: W
authors.lastname: Handa
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000735:Androstenedione / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010920:Placenta / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D047072:Aromatase Inhibitors; C025177:6-bromoandrostenedione; D000735:Androstenedione