title: Synthesis and functional analysis of novel bivalent estrogens.
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 (ERalpha) and beta (ERbeta), 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 (ERalpha)-mediated transcription events with efficacy and potency equal to or greater than that of ERalpha's cognate ligand, 17beta-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.
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, 741 South Limestone Street, Lexington, KY 40536-0509, USA.
authors.forename: Alison E
authors.initials: AE
authors.lastname: Wendlandt
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Yelton
authors.forename: Dingyuan
authors.initials: D
authors.lastname: Lou
authors.forename: David S
authors.initials: DS
authors.lastname: Watt
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Noonan
mesh_terms: D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D010091:Oximes / Q000737:chemistry; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D013256:Steroids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013379:Substrate Specificity; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D010091:Oximes; D013256:Steroids