Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 55, Issue 5, Pages 2324-2341Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm201556r
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Funding
- NSFC [20872116, 20972121, 91017005]
- Program for New Century Excellent Talents in University [NCET-10-0625]
- National Mega Project on Major Drug Development [2009ZX09301-014-1]
- Research Fund for the Doctoral Program of Higher Education of China [20100141110021]
- National Institutes of Health [PHS R37 DK015556, R01 DK077085]
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To develop estrogen receptor (ER) ligands having novel structures and activities, we have explored compounds in which the central hydrophobic core has a more three-dimensional topology than typically found in estrogen ligands and thus exploits the unfilled space in the ligand-binding pocket. Here, we build upon our previous investigations of 7-oxabicyclo[2.2.1]heptene core ligands, by replacing the oxygen bridge with a sulfoxide. These new 7-thiabicyclo[2.2.1]hept-2-ene-7-oxides were conveniently prepared by a Diels-Alder reaction of 3,4-diarylthiophenes with dienophiles in the presence of an oxidant and give cycloadducts with endo stereochemistry. Several new compounds demonstrated high binding affinities with excellent ER alpha selectivity, but unlike oxabicyclic compounds, which are transcriptional antagonists, most thiabicyclic compounds are potent, ER alpha-selective agonists. Modeling suggests that the gain in activity of the thiabicydic compounds arises from their endo stereochemistry that stabilizes an active ER conformation. Further, the disposition of methyl substituents in the phenyl groups attached to the bicyclic core unit contributes to their binding affinity and subtype selectivity.
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