Synthesis of substituted 15β-alkoxy estrone derivatives and their cofactor-dependent inhibitory effect on 17β-HSD1

J Enzyme Inhib Med Chem. 2019 Dec;34(1):1271-1286. doi: 10.1080/14756366.2019.1634064.

Abstract

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a key enzyme in the biosynthesis of 17β-estradiol. Novel estrone-based compounds bearing various 15β-oxa-linked substituents and hydroxy, methoxy, benzyloxy, and sulfamate groups in position C3 as potential 17β-HSD1 inhibitors have been synthesized. In addition, in vitro inhibitory potentials measured in the presence of excess amount of NADPH or NADH were investigated. We observed substantial inhibitory potentials for several derivatives (IC50 < 1 µM) and increased binding affinities compared to unsubstituted core molecules. Binding and inhibition were found to be cofactor-dependent for some of the compounds and we propose structural explanations for this phenomenon. Our results may contribute to the development of new 17β-HSD1 inhibitors, potential drug candidates for antiestrogen therapy of hormone-dependent gynecological cancers.

Keywords: 17β-HSD1; Michael addition; NADPH and NADH; estrogen biosynthesis; substituted 15β-alkoxy-estrone derivatives.

MeSH terms

  • 17-Hydroxysteroid Dehydrogenases / antagonists & inhibitors*
  • 17-Hydroxysteroid Dehydrogenases / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Estrone / chemical synthesis
  • Estrone / chemistry
  • Estrone / pharmacology*
  • Humans
  • Molecular Conformation
  • Structure-Activity Relationship

Substances

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

Grants and funding

The work of Anita Kiss was supported by a Ph.D. Fellowship of the Talentum Fund of Richter Gedeon Plc. Financial support by the National Research, Development and Innovation Office-NKFIH through Project [GINOP-2.3.2–15-2016–00038] is gratefully acknowledged. This research was supported by the Hungarian Scientific Research Fund [OTKA K113150, OTKA SNN 124329].