Screening and characterization of estrogenic activity from a hydroxystilbene library

Renee Williard, Vasu Jammalamadaka, David Zava, Cristopher C. Benz, C. Anthony Hunt, Peter J. Kushner, Thomas S. Scanlan

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Background: Compounds that either inhibit or induce an estrogen response in vivo are important as potential drugs and biochemical tools. Non-steroidal stilbene analogs such as tamoxifen are known to function as both estrogen agonists and antagonists depending upon the analog structure. This family of compounds is amenable to parallel-manifold synthesis because stilbene analogs are easily synthesized using a single-step olefination reaction. Results: We have prepared a small 23-component hydroxystilbene library using a solid phase synthesis approach. The library was screened for estrogenic and antiestrogenic activity using a cell-based bioassay that measures estrogen receptor-mediated transcription of a reporter gene. Three of the analogs proved to have dose-dependent estrogenic activity with EC50 values between 5 μM and 15 μM. Further characterization of the hydroxystilbene-mediated estrogenic activity suggests that the agonist activity results from direct binding to the steroid site on the estrogen receptor with IC50 values of 1-10 μM. Conclusions: The results of this study show that classic olefination chemistry can be adapted to a solid-phase format for parallel synthesis of analog libraries. Although yields varied for the individual analogs, sufficient quantity of pure material was obtained directly from the resin for structural characterization and biological evaluation. This study further validates solid-phase organic synthesis as a useful approach for rapid parallel-manifold library synthesis to augment both lead compound discovery and optinuzation.

Original languageEnglish (US)
Pages (from-to)45-51
Number of pages7
JournalChemistry and Biology
Volume2
Issue number1
DOIs
StatePublished - Jan 1995

Keywords

  • combinatorial organic synthesis
  • estrogen
  • estrogen receptor
  • solid-phase synthesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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