Abstract
A new family of cyclic carbamate-estradiol derivatives has been designed to remove the intrinsic estrogenic activity of a parent acyclic compound reported as a potent inhibitor of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). The synthesis of two series of fused 16β,17β-oxazinone-estradiol derivatives, saturated compounds 7a-d and unsaturated compounds 10a-d, led to the identification of 10b, a 17β-HSD1 inhibitor (IC50 = 1.4 μM) without estrogenic activity in estrogen-sensitive T-47D cells. Interestingly, this compound was found selective over 17β-HSD2 and 17β-HSD12. A computational analysis of inhibitors into 17β-HSD1 by molecular docking also revealed interesting structure-activity relationships that could be helpful in the design of new generation of 16β,17β-oxazinone-estradiol analogs.
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Citations
Oct 26, 2016·Bioorganic & Medicinal Chemistry Letters·Donald PoirierRaphaël Dutour
Apr 6, 2018·Journal of Enzyme Inhibition and Medicinal Chemistry·Sanna NiinivehmasOlli T Pentikäinen
Feb 21, 2021·The Journal of Steroid Biochemistry and Molecular Biology·Francisco Cortés-BenítezDonald Poirier
Nov 21, 2017·ACS Medicinal Chemistry Letters·Raphaël DutourDonald Poirier