Synthesis and evaluation of estrogen receptor ligands with bridged oxabicyclic cores containing a diarylethylene motif: Estrogen antagonists of unusual structure

Hai Bing Zhou, John S. Comninos, Fabio Stossi, Benita S. Katzenellenbogen, John A. Katzenellenbogen

Research output: Contribution to journalArticle


A new series of ligands for the estrogen receptor (ER) based on a three-dimensional structural motif consisting of a bridged oxabicyclic core (7-oxabicyclo[2.2.1]heptene or heptadiene) were synthesized and examined for their receptor binding activity and as regulators of transcription through the two ER subtypes, ERα and ERβ. The prototypical ligands also contain a 1,2-diarylethylene motif, common to many nonsteroidal estrogens, as an embellishment on the oxabicyclic core. Thus, these ligands bear peripheral groups typically found in ER ligands, built here upon an overall three-dimensional core topology that is unusual for these targets. Most of these compounds were conveniently synthesized by a Diels-Alder reaction of various 3,4-diarylfurans with a variety of dienophiles, neat and under mild conditions in the absence of catalysts. Some of the synthesized compounds display good binding affinity for the ER, and in transcription assays, the highest affinity compounds are antagonists on both ERs. Molecular modeling studies suggest a structural basis for the antagonist activity of these compounds. These compounds, based on the bicyclo[2.2.1]core system, expand the structural diversity of ligands that can be antagonists for the estrogen receptors.

Original languageEnglish (US)
Pages (from-to)7261-7274
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number23
StatePublished - Nov 17 2005


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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