Synthesis of 11β-ether-17α-ethinyl-3,17β-estradiols with strong ER antagonist activities

We have previously found that several families of nonpolar short chain 11β-ethers and esters of estradiol are selective estrogen receptor modulators (SERMs). Surprisingly, the transformation from potent estrogen to anti-estrogen occurs when the 11β-side chain is increased slightly in length from four to five non-hydrogen atoms. To generate strong antagonists for preclinical development, we have synthesized other similar ER ligands with 11β-ethers and with an additional ethinyl group at the 17α-position in order to slow metabolism of the steroidal moiety. Here we report the synthesis and biological activity of two such compounds (11β-i-PrO-propyl and 11β-t-BuO-propyl ethers) with extremely strong antagonist activities.

Graphical abstractWe report here the synthesis of 17α-ethinyl-E11-3,t-Buether and 17α-ethinyl-E11-3,i-Prether estradiols, and their extremely strong antagonist activities.Figure optionsDownload full-size imageDownload as PowerPoint slide