Affiliation: Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center (CHUL, T4-42), 2705 Laurier Boulevard, Québec (Québec) G1V 4G2, Canada.
Various derivatives of a modified estradiol core bearing a fused γ-lactone were designed as non-estrogenic inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). The compounds were synthesized, characterized and tested for their ability to inhibit enzyme activity (transformation of estrone into estradiol). The proliferative (estrogenic) activity of the compounds was also investigated on estrogen-sensitive breast cancer T-47D cells. Interestingly, one of the estradiol derivatives (compound 24) showed a dual action by inhibiting 17β-HSD1 (IC50 = 1.0 µM) and by producing an antiestrogenic effect on T-47D cells.