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

• Published in: Chemical & pharmaceutical bulletin Vol. 38; no. 11; p. 3076
• Main Authors: NUMAZAWA, Mitsuteru, MUTSUMI, Ayako, KIGAWA, Hiroki
• Format: Journal Article
• Language: English
• Published: Tokyo Japan Science and Technology Agency 01.11.1990
• ISSN: 0009-2363; 1347-5223

Androst-4-ene-3, 6-dione derivatives 2-4 and 3α-methoxy-4-en-6-one steroid 7 were prepared and tested for their ability to inhibit aromatase in human placental microsomes. The 16α-bromide 2, the 16α-alcohol 3, and the 3α-methoxide 7 of this series were effective competitive inhibitors of aromatase with apparent Ki's of 150nM, 1.18 μM, and 70 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' 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.