Synthesis and structure-activity relationships of 2- and/or 4-halogenated 13β- and 13α-estrone derivatives as enzyme inhibitors of estrogen biosynthesis

J Enzyme Inhib Med Chem. 2018 Dec;33(1):1271-1282. doi: 10.1080/14756366.2018.1490731.

Abstract

Ring A halogenated 13α-, 13β-, and 17-deoxy-13α-estrone derivatives were synthesised with N-halosuccinimides as electrophile triggers. Substitutions occurred at positions C-2 and/or C-4. The potential inhibitory action of the halogenated estrones on human aromatase, steroid sulfatase, or 17β-hydroxysteroid dehydrogenase 1 activity was investigated via in vitro radiosubstrate incubation. Potent submicromolar or low micromolar inhibitors were identified with occasional dual or multiple inhibitory properties. Valuable structure-activity relationships were established from the comparison of the inhibitory data obtained. Kinetic experiments performed with selected compounds revealed competitive reversible inhibition mechanisms against 17β-hydroxysteroid dehydrogenase 1 and competitive irreversible manner in the inhibition of the steroid sulfatase enzyme.

Keywords: 17β-HSD1; Estrone; STS; aromatase; halogenations.

MeSH terms

  • Aromatase / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Estradiol Dehydrogenases / antagonists & inhibitors*
  • Estradiol Dehydrogenases / metabolism
  • Estrogens / biosynthesis*
  • Estrone / chemical synthesis
  • Estrone / chemistry
  • Estrone / pharmacology*
  • Halogenation
  • Humans
  • Molecular Conformation
  • Steryl-Sulfatase / antagonists & inhibitors*
  • Steryl-Sulfatase / metabolism
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Estrogens
  • Estrone
  • Estradiol Dehydrogenases
  • HSD17B1 protein, human
  • Aromatase
  • Steryl-Sulfatase

Grants and funding

The work of Erzsébet Mernyák in this project was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences and by the ÚNKP-17–4 “New National Excellence Program Of The Ministry Of Human Capacities”. This work was supported by National Research, Development and Innovation Office-NKFIH through project Országos Tudományos Kutatási Alapprogramok (OTKA) SNN 124329.