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

Eur J Med Chem. 2015 Mar 26:93:470-80. doi: 10.1016/j.ejmech.2015.01.059. Epub 2015 Feb 11.

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.

Keywords: 17beta-hydroxysteroid dehydrogenase; Chemical synthesis; Enzyme inhibitor; Molecular modeling; Oxazinone; Steroid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 17-Hydroxysteroid Dehydrogenases / antagonists & inhibitors*
  • 17-Hydroxysteroid Dehydrogenases / chemistry
  • 17-Hydroxysteroid Dehydrogenases / metabolism
  • Cell Line, Tumor
  • Drug Design*
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Estradiol / chemical synthesis
  • Estradiol / chemistry*
  • Estradiol / metabolism
  • Estradiol / pharmacology*
  • Humans
  • Molecular Docking Simulation
  • Protein Conformation
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Estradiol
  • 17-Hydroxysteroid Dehydrogenases
  • 3 (or 17)-beta-hydroxysteroid dehydrogenase