Structure-activity relationships of bisphenol a analogs at estrogen receptors (ERs): Discovery of an ERα-selective antagonist

Keisuke Maruyama, Masaharu Nakamura, Shusuke Tomoshige, Kazuyuki Sugita, Makoto Makishima, Yuichi Hashimoto, Minoru Ishikawa

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)

Abstract

Our multi-template approach for drug discovery, focusing on protein targets with similar fold structures, has yielded lead compounds for various targets. We have also shown that a diphenylmethane skeleton can serve as a surrogate for a steroid skeleton. Here, on the basis of those ideas, we hypothesized that the diphenylmethane derivative bisphenol A (BPA) would bind to the ligand-binding domain of estrogen receptors (ERs) in a similar manner to estradiol and act as a steroid surrogate. To test this idea, we synthesized a series of BPA analogs and evaluated their structure-activity relationships, focusing on agonistic/antagonistic activities at ERs and ERα/ERβ subtype selectivity. Among the compounds examined, 18 was found to be a potent ERα-antagonist with high selectivity over ERβ and androgen receptor under our assay conditions. A computational docking study suggested that 18 would bind to the antagonistic conformation of ERα. ERα-selective antagonists, such as 18, are candidate agents for treatment of breast cancer.

Original languageEnglish
Pages (from-to)4031-4036
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number14
DOIs
Publication statusPublished - 2013 Jul 15
Externally publishedYes

Keywords

  • Antagonist
  • Estrogen receptor
  • Nuclear receptor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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