Synthesis and functional analysis of novel bivalent estrogens

Alison E. Wendlandt, Sharon M. Yelton, Dingyuan Lou, David S. Watt, Daniel J. Noonan

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

The steroid hormone estrogen plays a critical role in female development and homeostasis. Estrogen mediates its effects through binding and activation of specific estrogen receptors alpha (ERα) and beta (ERβ), members of the steroid/nuclear receptor family of ligand-induced transcription factors. Due to their intimate roles in genomic and nongenomic signaling pathways, these hormones and their receptors have been also implicated in the pathologies of a variety of cancers and metabolic disorders, and have been the target of large therapeutic development efforts. The binding of estrogen to its respective receptors initiates a cascade of events that include receptor dimerization, nuclear localization, DNA binding and recruitment of co-regulatory protein complexes. In this manuscript, we investigate the potential for manipulating steroid receptor gene expression activity through the development of bivalent steroid hormones that are predicted to facilitate hormone receptor dimerization events. Data are presented for the development and testing of novel estrogen dimers, linked through their C-17 moiety, that can activate estrogen receptor alpha (ERα)-mediated transcription events with efficacy and potency equal to or greater than that of ERα's cognate ligand, 17β-estradiol. These bivalent estrogen structures open the door to the development of a variety of steroid therapeutics that could dramatically impact future drug development in this area.

Original languageEnglish
Pages (from-to)825-833
Number of pages9
JournalSteroids
Volume75
Issue number12
DOIs
StatePublished - Dec 2010

Bibliographical note

Funding Information:
One of us (DSW) thanks the Vice President for Research for research funding. We also thank the University of Kentucky, Center for Structural Biology, Organic Chemistry Core Facility supported in part by funds from NIH National Center for Research Resources (NCRR) grant P20 RR020171. Mass spectra were acquired at the University of Kentucky Mass Spectrometry Facility.

Keywords

  • Dimerization
  • ERα
  • Girard reagent
  • Nuclear hormone

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology
  • Pharmacology
  • Clinical Biochemistry
  • Organic Chemistry

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