Benzothiophene selective estrogen receptor modulators with modulated oxidative activity and receptor affinity

Zhihui Qin, Irida Kastrati, R. Esala P. Chandrasena, Hong Liu, Ping Yao, Pavel A. Petukhov, Judy L. Bolton, Gregory R.J. Thatcher

Research output: Contribution to journalArticlepeer-review

115 Scopus citations

Abstract

The regulation of estrogenic and antiestrogenic effects of selective estrogen receptor modulators (SERMs) is thought to underlie their clinical use. Most SERMs are polyaromatic phenols susceptible to oxidative metabolism to quinoids, which are proposed to be genotoxic. Conversely, the redox reactivity of SERMs may contribute to antioxidant and chemopreventive mechanisms, providing a new approach to improve the therapeutic properties of SERMs. An improved synthetic strategy was developed to generate a family of benzothiophene SERMs. Using computational modeling methods and measurements of antioxidant activity and estrogen receptor (ER) ligand binding, this SERM family was shown to provide both a range of ERα/ ERβ selectivity from 1.2- to 67-fold and a range of redox activity. Antioxidant activity was successfully modulated by varying a substituent remote from the OH group; the source of the antioxidant capacity. An efficient synthetic procedure is reported yielding benzothiophene SERMs wherein redox activity and ER affinity are modulated.

Original languageEnglish (US)
Pages (from-to)2682-2692
Number of pages11
JournalJournal of Medicinal Chemistry
Volume50
Issue number11
DOIs
StatePublished - May 31 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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