Synthesis and biochemical studies of 7-substituted 4,6-androstadiene-3,17-diones as aromatase inhibitors

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Abstract
Inhibitors of aromatase, the cytochrome P-450 enzyme complex responsible for the biosynthesis of estrogens, may be useful as therapeutic agents for the treatment of estrogen-dependent disease states such as breast and endometrial cancer. Several 7.alpha.-thio-substituted androstenediones have proven to be potent inhibitors of aromatase in vitro and in vivo. Recent research efforts have focused on designing aromatase inhibitors with both substitution at C-7 and extended linear conjugation in rings A and B of the steroid nucleus. The targeted compounds, 7-substituted 4,6-androstadiene-3,17-diones 4-10, were prepared by the addition of either Grignard or lithium reagents to 3,3:17,17-bis(ethylenedioxy)-5-androsten-7-one (3). Inhibitory activities of the compounds were evaluated in vitro by enzyme kinetic studies employing the microsomal fraction isolated from human term placenta. 7-Benzyl- and 7-phenethyl-4,6-androstadiene-3,17-dione analogues are effective inhibitors with apparent Ki''s of 60.9-174 nM, while the 7-phenyl analogue exhibited an apparent Ki of 1.424 .mu.M. Thus, several 7-substituted 4,6-androstadiene-3,17-diones were prepared and exhibited good competitive inhibition of aromatase in vitro in human placental microsomes.