Synthesis of 16-(bromoalkyl)-estradiols having inhibitory effect on human placental estradiol 17β-hydroxysteroid dehydrogenase (17-β-HSD type 1)

The activity of 17β-HSD type 1, the enzyme that converts estrone into its more potent metabolite estradiol, has been demonstrated in all classical steroidogenic tissues and almost all peripheral tissues from both rat and human. Since 17β-HSD is one of the most important enzymes involved in active steroid hormone formation, its inactivation could be a clinical approach to the treatment of hormono-dependent diseases like breast cancer. Herein we report the synthesis of 16-(bromoalkyl)-estradiols and their potency to inhibit the human placenta cytosolic estradiol 17β-HSD (type 1). Synthetic analogues possess various side chain lengths and orientation (α or β) at position 16 of the steroidal D ring. The most potent inhibitory effect was observed when the length of the side chain was 3 or 4 carbons. However, the 16β-(bromopropyl)-estradiol easily undergoes cyclization and its effect on 17β-HSD is lost. Consequently, 16α-(bromopropyl)-E 2, 16α-(bromobutyl)-E 2, and 16β-(bromobutyl)-E 2 were the best inhibitors discussed in this paper. Graphic