Discovery of a non-estrogenic irreversible inhibitor of 17ß-hydroxysteroid dehydrogenase type 1 from 3-substituted-16ß-(m-carbamoylbenzyl)-estradiol derivatives.

17ß-Hydroxysteroid dehydrogenase type 1 (17ß-HSD1) is thought to play a pivotal role in the progression of estrogen-sensitive breast cancer by transforming estrone (E1) into estradiol (E2). We designed three successive series of E2-derivatives at position C3 of the potent inhibitor 16ß-(m-carbamoylbenzyl)-E2 to remove its unwanted estrogenic activity. We report the chemical synthesis and characterization of 20 new E2-derivatives, their evaluation as 17ß-HSD1 inhibitors, and their proliferative (estrogenic) activity on estrogen-sensitive cells. The structure-activity relationship study provided a new potent and steroidal nonestrogenic inhibitor of 17ß-HSD1 named 3-{[(16ß,17ß)-3-(2-bromoethyl)-17-hydroxyestra-1(10),2,4-trien-16-yl]methyl}benzamide (23b). In fact, this compound inhibited the transformation of E1 into E2 by 17ß-HSD1 in T-47D cells (IC50 = 83 nM), did not inhibit 17ß-HSD2, 17ß-HSD7, 17ß-HSD12, and CYP3A4, and did not stimulate the proliferation of estrogen-sensitive MCF-7 cells. We also discussed the results of kinetic and molecular modeling (docking) experiments, suggesting that compound 23b is a competitive and irreversible inhibitor of 17ß-HSD1.

Diastereoselective Mukaiyama aldol reaction of 2-(trimethylsilyloxy)furan catalyzed by bismuth triflate.

We have developed an efficient vinylogous Mukaiyama aldol reaction of 2-(trimethylsilyloxy)furan with various aromatic aldehydes mediated by bismuth triflate in low catalyst loading (1 mol %). The reaction proceeds rapidly and affords the corresponding 5-(hydroxy(aryl)methyl)furan-2(5H)-ones in high yields with good to very good diastereoselectivities (dr up to >98:2). Such selectivities, albeit previously reported with other Lewis acids, could this time be achieved with a much lower catalyst loading. 5-(Hydroxy(alkyl)methyl)furan-2(5H)-ones derived from ketones could also be obtained with good diastereoselectivities.