N-butyl, N-methyl, 11-[3′,17′ β-(dihydroxy)-1′,3′,5′(10′)- estratrien-16′ α-yl]-9(R/S)-bromo undecanamide: synthesis and 17β-HSD inhibiting, estrogenic and antiestrogenic activities

Abstract

The synthesis of a 16α-(bromoalkylamide) derivative of estradiol (N-butyl, N-methyl, 11-[3′,17′ β-(dihydroxy)-1′,3′,5′ (10′)-estratrien-16′ α-yl]-9 (R/S)-bromo undecanamide) was performed by two different approaches starting from estrone. Each approach has the same key intermediate, containing an aldehyde group, but differs by the bromination step and the timing of formation of the amide group. This compound was found to cause, at 100 μM, a complete inhibition of 17β-hydroxysteroid dehydrogenase (17β-HSD) responsible for the interconversion of estrone and estradiol. The corresponding IC 50 value was 10.6 μM. In the estrogen-sensitive ZR-75-1 human breast cancer cell line, this estradiol derivative has no estrogenic activity at 30 nM and only a minimal estrogenic activity (10% above the basal level) at 1 μM. At this latter concentration, this compound causes a 28% inhibition of 0.1 nM E 2-induced cell proliferation (antiestrogenic activity). Thus, the introduction of a side-chain with a secondary bromide and a butyl methyl amide group at the 16α-position of estradiol has two interesting effects; namely an inhibition of cytosolic 17β-HSD and a blockade of the estrogenic effect of estradiol. (Steroids 59:536–547, 1994)