Design and action of steroidal aromatase inhibitors

The biosynthesis of estrogens involves three sequential hydroxylations, progressing from cholesterol, that are mediated by an enzyme complex referred to as aromatase. The last steps in this sequence involve aromatization of the A ring of the steroid nucleus. Compounds that inhibit aromatase have potential applications in the treatment of advanced estrogen-dependent mammary carcinoma and prostatic hyperplasia. The enzyme aromatase is currently a priority target for the development of active-site directed inhibitors. A number of steroid inhibitors may inactivate aromatase by diverse interactions with the enzyme and include competitive inhibitors, affinity labelling agents, and mechanism-based inhibitors (“suicide substrates”). By designing steroidal analogs with substituents at various positions on the steroid nucleus, information has been obtained on the structural requirements needed for favorable interactions with the enzymatic sites.