Synthesis and evaluation of 4-cycloheptylphenols as selective Estrogen receptor-β agonists (SERBAs)

Eur J Med Chem. 2018 Sep 5:157:791-804. doi: 10.1016/j.ejmech.2018.08.006. Epub 2018 Aug 11.

Abstract

A short and efficient route to 4-(4-hydroxyphenyl)cycloheptanemethanol was developed, which resulted in the preparation of a mixture of 4 stereoisomers. The stereoisomers were separated by preparative HPLC, and two of the stereoisomers identified by X-ray crystallography. The stereoisomers, as well as a small family of 4-cycloheptylphenol derivatives, were evaluated as estrogen receptor-beta agonists. The lead compound, 4-(4-hydroxyphenyl)cycloheptanemethanol was selective for activating ER relative to seven other nuclear hormone receptors, with 300-fold selectivity for the β over α isoform and with EC50 of 30-50 nM in cell-based and direct binding assays.

Keywords: Cancer; Drug development; Estrogen receptor agonist; SERBA.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Cycloheptanes / chemical synthesis
  • Cycloheptanes / chemistry
  • Cycloheptanes / pharmacokinetics
  • Cycloheptanes / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Estrogen Receptor beta / agonists*
  • Estrogens / chemical synthesis
  • Estrogens / chemistry
  • Estrogens / pharmacology*
  • Humans
  • MCF-7 Cells
  • Methanol / chemical synthesis
  • Methanol / chemistry
  • Methanol / pharmacokinetics*
  • Models, Molecular
  • Molecular Structure
  • Phenols / chemical synthesis
  • Phenols / chemistry
  • Phenols / pharmacology*
  • Structure-Activity Relationship

Substances

  • 4-(4-hydroxyphenyl)cycloheptanemethanol
  • 4-cycloheptylphenol
  • Antineoplastic Agents
  • Cycloheptanes
  • Estrogen Receptor beta
  • Estrogens
  • Phenols
  • Methanol