Competitive inhibition and suicide inactivation of human placental aromatase by androst-4-ene-3,6-dione derivatives and 3 alpha-methoxyandrost-4-ene-6,17-dione.
Androst-4-ene-3,6-dione derivatives 2-4 and 3 alpha-methoxy-4-en-6-one steroid 7 were prepared and tested for their ability to inhibit aromatase in human placental microsomes. The 16 alpha-bromide 2, the 16 alpha-alcohol 3, and the 3 alpha-methoxide 7 of this series were effective competitive inhibitors of aromatase with apparent Ki's of 150 nM, 1.18 microM, and 700 nM. Compound 2 caused a time-dependent, biphasic loss of aromatase activity in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) while compound 7 caused a time-dependent, pseudo-first order inactivation of the activity, with kinact's of 0.417 and 0.036 min-1 for compounds 2 and 7. NADPH and oxygen were required for the time-dependent inactivation and the substrate, androst-4-ene-3,17-dione, prevented it in each case.
Numazawa
M
M
Tohoku College of Pharmacy, Sendai, Japan.
Mutsumi
A
A
Kigawa
H
H
D000735:Androstenedione / Q000031:analogs & derivatives* / Q000494:pharmacology; D047072:Aromatase Inhibitors; D001665:Binding Sites / Q000187:drug effects; D005260:Female; D006801:Humans; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy; D013329:Structure-Activity Relationship
D047072:Aromatase Inhibitors; D000735:Androstenedione