Synthesis and Biological Evaluation of Estradiol-Core Derivatives Bearing a Fused γ-Lactone as Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1
Etienne Ouellet, Diana Ayan and Donald Poirier
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.
Keywords: Chemical synthesis, enzyme inhibitor, estrogen, lactone, steroid, 17β-hydroxysteroid dehydrogenase.
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 17γ-HSD1 (IC50 = 1.0 µM) and by producing an
antiestrogenic effect on T-47D cells.
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