A time-dependent inactivation of aromatase by 19-substituted androst-4-ene-3,6,17-triones.
Diastereomeric (19S)- and (19R)-19-ethynyl-19-acetoxy derivatives of androst-4-ene-3,6,17-trione (AT) (9 and 10) and 19,19-difluoro AT (12) were synthesized. The 19,19-difluoro compound (12) was an effective competitive inhibitor of human placental aromatase with an inhibition constant (ki) of 1.8 microM but the acetylenic 9 and 10 were poor inhibitors of the enzyme with k(is) of 75 and 67 microM, respectively. Inhibitor 12 caused a time-dependent, biphasic loss of aromatase activity in the presence of reduced nicotinamide-adenine-dinucleotide phosphate (NADPH) in air, whereas the other two caused a time-dependent, pseudo-first-order inactivation of the activity with rate constants for inactivation of 0.250, 0.077, and 0.065 min-1 for steroids 12, 9, and 10. NADPH was required for the time-dependent inactivation, and the substrate androst-4-ene-3,17-dione prevented it. L-Cysteine did not protect aromatase from the inactivation.
Numazawa
M
M
Tohoku College of Pharmacy, Sendai, Japan.
Mutsumi
A
A
Asano
N
N
Ito
Y
Y
D000736:Androstenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D047072:Aromatase Inhibitors; D001667:Binding, Competitive; D005260:Female; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008861:Microsomes / Q000201:enzymology; D009249:NADP / Q000494:pharmacology; D010920:Placenta / Q000201:enzymology / Q000648:ultrastructure; D013237:Stereoisomerism
D000736:Androstenes; D047072:Aromatase Inhibitors; C079541:19-ethynyl-19-acetoxyandrost-4-ene-3,6,17-trione; C079542:19,19-difluoroandrost-4-ene-3,6,17-trione; D009249:NADP