Synthesis of a spin-labeled anti-estrogen as a dynamic motion probe for the estrogen receptor ligand binding domain

• Published in: Bioorganic & medicinal chemistry letters 2012-02, Vol.22 (4), p.1743-1746
• Main Authors: Adam Hendricks, J., Gullà, Stefano V., Budil, David E., Hanson, Robert N.
• Format: Article
• Language: English
• Subjects: Anti-estrogen; binding capacity; Biological and medical sciences; chemistry; Dynamic motion probe; Electron Spin Resonance Spectroscopy; Estrogen Antagonists - chemical synthesis; Estrogen Antagonists - chemistry; Estrogen Antagonists - pharmacology; Estrogen Receptor alpha - drug effects; Estrogen Receptor alpha - metabolism; Estrogen receptor-ligand binding domain; estrogen receptors; Ligands; Medical sciences; Models, Molecular; Molecular Structure; Nitrogen Oxides - chemistry; Nitroxide spin label; Pharmacology. Drug treatments; Protein Binding - drug effects; Protein Isoforms - metabolism; Protein Structure, Tertiary; Receptors, Estrogen - drug effects; Receptors, Estrogen - metabolism; Selective estrogen receptor modulator
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.12.091

The preparation and characterization of a novel nitroxide spin probe based on a steroidal anti-estrogen is described. The probe 5 demonstrated very high binding affinity for both the alpha and beta isoforms of the estrogen receptor–ligand binding domain. EPR spectrometric studies demonstrate conformational constraints for the ligand, consistent with the nitroxyl moiety occupying a position just beyond the receptor-solvent interface.