A-ring bridged steroids as potent inhibitors of aromatase

The design and syntheses of androstenedione derivatives with bridges spanning the 2,19-, 3,19-, 4,19- and 6, 19-positions are described. 2,19-Bridged compounds bearing hydroxyl groups on the two-carbon bridge (3a and 3b) were designed as stable carbon analogs of potential lactol intermediates in the enzymatic conversion of androgens to estrogens. Compounds 3a and 3b are competitive inhibitors of aromatase. Pyran 25 is a potent, time-dependent inhibitor of aromatase with partial NADPH dependence. These data suggest a mechanism of inhibition for 25 which involves both tight-binding competitive and mechanism-based components, with the former predominating. The sulfur, amino, and all carbon analogs of pyran 25 were prepared. Thiopyran 36, piperidine 42 and the all-carbon analog 47 are also time-dependent inhibitors of aromatase. Compound 47 is the most potent inhibitor and its time-dependent inhibition is not NADPH dependent. The kinetics of piperidine 42 suggest uncompetitive inhibition.