Identification of fused 16β,17β-oxazinone-estradiol derivatives as a new family of non-estrogenic 17β-hydroxysteroid dehydrogenase type 1 inhibitors

• Two series of fused 16β,17β-oxazinone-estradiol derivatives have been synthesized.
• The best compound of the two series (10b) inhibits 17β-HSD1 with IC50 values of 1.4 μM.
• The new inhibitor 10b is non estrogenic and selective toward other 17β-HSDs.

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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