Steroidal bivalent ligands for the estrogen receptor: Design, synthesis, characterization and binding affinities

• Published in: Bioorganic & medicinal chemistry Vol. 17; no. 10; pp. 3528 - 3535
• Main Authors: LaFrate, Andrew L., Carlson, Kathryn E., Katzenellenbogen, John A.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-05-2009; Elsevier
• Subjects: Biological and medical sciences; Bivalent ligand; Dimer; Dimerization; Drug Design; Estrogen receptor; Estrogen Receptor alpha - chemistry; Estrogen Receptor alpha - metabolism; Estrogen Receptor beta - chemistry; Estrogen Receptor beta - metabolism; Ethinyl Estradiol - analogs & derivatives; Ethinyl Estradiol - chemical synthesis; Ethinyl Estradiol - pharmacology; Hormones. Endocrine system; Ligands; Medical sciences; Multivalent ligand; Pharmacology. Drug treatments; Estrogen receptor; Bivalent ligand; Dimer; Multivalent ligand; Steroid; Spacer arm; Acetylenic compound; Ligand; Oligomer; In vitro; Biological activity; Estrane derivatives; Ethylene oxide polymer; Biological fixation; Propylene oxide polymer; Chemical synthesis; Butene oxide polymer; Hormonal receptor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.04.016

Steroidal bivalent ligands for the estrogen receptor (ER) were designed using crystal structures of ERα dimers as a template. The syntheses of several 17α-ethynylestradiol-based bivalent ligands with varying linker compositions and lengths are described. The binding affinities of these bivalent ligands for ERα and ERβ were determined. In the two series of bivalent ligands that we synthesized, there is a clear correlation between linker length and binding affinity, both of which reach a maximum at the same tether length. Further studies are underway to explore aspects of bivalent ligand and control compound binding to the ERs and their effects on ER dimer formation; these results will be reported in a subsequent publication.