Design and synthesis of new steroidal inhibitors of estrogen synthase (aromatase)

Abstract

The estrogen synthase (aromatase) enzyme system is responsible for the biosynthesis of estrogen hormones in human females. Estrogens are vital for normal growth and development, but will promote the growth of certain breast cancers. Approximately 30-50% of breast cancers are considered to be hormone-dependent. Consequently regulation of estrogen biosynthesis has advanced as a potential therapeutic strategy. This has led to the development of active-site inhibitors, which may have potential for the control of breast cancer. We have recently prepared a number of new steroidal inhibitors that have been evaluated as aromatase inhibitors. These include steroidal A/B-ring isoxazoles and a series of A/B-ring pyrazoles with alkyl- and aryl-substituted nitrogen. In addition, we have developed new chemical procedures for the synthesis of 6beta-hydroxy steroids, which could be key intermediates in the preparation of C-19 inhibitors of aromatase activity.

Metabolic conversion as a pre‐receptor control mechanism for lipophilic hormones

“…A similar role has been suggested for 17β‐HSD4 in colonic cancer, where malignant biopsy material displayed an altered activity of this isozyme [64]. Local estrogen formation can also be reduced by blocking the CYP19 (cytochrome P450 aromatase) mediated production of estrone from androstenedione [65]. Importantly, estradiol can be inactivated in a tissue‐specific manner by sulfonation via estrogen sulfotransferase catalyzed transfer of a sulfonate radical to the 3‐hydroxy group.…”

Steroids: reactions and partial synthesis

“…The synthesis of modified androstanes as inhibitors of aromatase 55 and as mechanistic probes for the oxidative sequence of ring A has continued to attract attention. These compounds have included various 19-oxygenated derivatives of 4β,5βepoxy-, e.g.…”