Differential Response of Estrogen Receptor Subtypes to 1,3-diarylindene and 2,3-diarylindene Ligands

J Med Chem. 2005 Sep 22;48(19):5989-6003. doi: 10.1021/jm050226i.

Abstract

Estrogen receptors (ERs) control transcription of genes important for normal human development and reproduction. The signaling networks are complex, and there is a need for a molecular level understanding of the roles of receptor subtypes ERalpha and ERbeta in normal physiology and as therapeutic targets. We synthesized two series of ER ligands, based on a common indene scaffold, in an attempt to develop compounds that can selectively modulate ER-mediated transcription. The 3-ethyl-1,2-diarylindenes, utilizing an amide linker for the 1-aryl extension, bind weakly to the ERs. The 2,3-diarylindenes bind with high affinity to the ER subtypes and demonstrate a range of different biological activities, both in transcriptional reporter gene assays and inhibition of estradiol-stimulated proliferation of MCF-7 cells. Several ligands differentiate between ERalpha and ERbeta subtypes at an estrogen response element (ERE), displaying various levels of partial to full agonist activity at ERalpha, while antagonizing estradiol action at ERbeta.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Binding, Competitive
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Estradiol / pharmacology
  • Estrogen Antagonists / chemical synthesis
  • Estrogen Antagonists / chemistry
  • Estrogen Antagonists / pharmacology
  • Estrogen Receptor alpha / agonists*
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor beta / antagonists & inhibitors*
  • Estrogen Receptor beta / genetics
  • Fluorescence Polarization
  • Fluorescent Dyes
  • Genes, Reporter
  • Humans
  • Indenes / chemical synthesis*
  • Indenes / chemistry
  • Indenes / pharmacology
  • Ligands
  • Response Elements
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Estrogen Antagonists
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Fluorescent Dyes
  • Indenes
  • Ligands
  • Estradiol