Structure-activity relationships of estrogens: Effects of esterification of the 11β-hydroxyl group

Abstract

Fourteen esters (formate, acetate, propionate, butyrate, hexanoate, heptanoate, and benzoate) located at C-11 of 11β-hydroxyestrone and 11β-hydroxyestradiol-17β were synthesized and evaluated for uterotropic and gonadotropin release inhibition in rats, as well as their ability to displace ( 3H) estradiol-17β from the rat uterine cytosolic estrogen receptor. The most potent uterotropic agent was 11β-formoxyesterone which was 1,625 or 2,500 times as active as 11β-hydroxyestrone in the uterotropic or gonadotropin release inhibition assay, respectively. 11β-Formoxyesterone was 7.5 times as uterotropic as estradiol-17β and equal to estradiol-17β in inhibiting gonadotropin release. However, the most potent inhibitor of gonadotropin release was 11β-acetoxy-estradiol-17β which had 133% of the activity of estradiol-17β, although it had only 38% of the activity of estradiol-17β in the uterotropic assay. Esters larger than the acetoxy group showed sharply decreased activities in either assay. Despite the high estrogenic potency of the 11-formates or 11-acetates, they were rather weak (6% to 35% as active as estradiol-17β) in displacing ( 3H) estradiol-17β from the rat uterine cytosolic estrogen receptor.