SYNTHESIS AND EVALUATION OF BROMOACETOXY 4-ANDROSTEN-3-ONES AS ACTIVE SITE-DIRECTED INHIBITORS OF HUMAN PLACENTAL AROMATASE

Article abstract of DOI:10.1016/0039-128X(86)90021-8

2α-Bromoacetoxy (II), 6-bromoacetoxy (VII and X), and 19-bromoacetoxy (XII) derivatives of androstenedione and 17β-bromoacetoxy compounds (III, IV, XIII-XVI) were synthesized as potential affinity-labeling reagents for aromatase. 6α-Bromoacetoxy derivative VII was the most potent inhibitor of human placental microsomal aromatase activity among this series.Its inhibitory activity was higher than that of the parent 6α-hydroxy compound V, although other bromoacetates showed weaker inhibition of aromatase than the corresponding alcohols.The bromoacetates (except the 6β-bromoacetate X) inhibited aromatase activity in a time-dependent manner in the absence of NADPH, and the enzyme inactivation was blocked by the addition of androstenedione to the incubates.Kinetic analysis of the time- and concentration-dependent inhibition by the 6β-bromo-17β-bromoacetoxy compound XV gave an apparent Ki of 25 μM and K_inact of 0.027 min^-1.