Biochemical studies of estr-4-ene-3,6,17-trione and 5 alpha-androstan-17-ones with or without a carbonyl function at C-3 and/or C-6 as aromatase inhibitors.
19-Nor (2) and 5 alpha-reduced (3) derivatives of androst-4-ene-3,6,17-trione (1) as well as 5 alpha-androstan-17-ones 4-6 were tested for their abilities to inhibit aromatase in human placental microsomes. All the steroids except 5 alpha-6-one 4 were fair to good competitive inhibitors of the enzyme, with apparent Ki's ranging from 50 to 820 nM in which 5 alpha-3-one 5 was the most potent among them. The inhibitory activities of the 19-nor and 5 alpha-reduced derivatives (2 and 3) were less potent than that of the parent compound 1. Inhibitor 2 caused a time-dependent, pseudo-first-order inactivation of aromatase activity with a rate constant for inactivation of 0.148 min-1 in the presence of NADPH in air. The substrate androstenedione prevented the inactivation and L-cysteine did not protect aromatase from the inactivation.
Numazawa
M
M
Tohoku College of Pharmacy, Sendai, Japan.
Mutsumi
A
A
Tachibana
M
M
Nagaoka
M
M
D000731:Androstanes / Q000138:chemical synthesis* / Q000494:pharmacology; D047072:Aromatase Inhibitors; D004963:Estrenes / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D009249:NADP / Q000378:metabolism; D010920:Placenta / Q000187:drug effects / Q000201:enzymology; D011247:Pregnancy
D000731:Androstanes; D047072:Aromatase Inhibitors; D004963:Estrenes; D009249:NADP