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

研究成果: Article査読

40 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)4031-4036
ページ数6
ジャーナルBioorganic and Medicinal Chemistry Letters
23
14
DOI
出版ステータスPublished - 2013 7 15
外部発表はい

ASJC Scopus subject areas

  • 生化学
  • 分子医療
  • 分子生物学
  • 薬科学
  • 創薬
  • 臨床生化学
  • 有機化学

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