Abstract
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 ERα selectivity, but unlike oxabicyclic compounds, which are transcriptional antagonists, most thiabicyclic compounds are potent, ERα-selective agonists. Modeling suggests that the gain in activity of the thiabicyclic 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
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Bridged Bicyclo Compounds, Heterocyclic / chemistry
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Cycloheptanes / chemical synthesis*
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Cycloheptanes / chemistry
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Cycloheptanes / pharmacology
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Drug Partial Agonism
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Estradiol / pharmacology
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Estrogen Receptor alpha / agonists
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Estrogen Receptor alpha / antagonists & inhibitors
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Estrogen Receptor alpha / metabolism
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Estrogen Receptor beta / agonists
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Estrogen Receptor beta / antagonists & inhibitors
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Estrogen Receptor beta / metabolism
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Estrogens / pharmacology
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Hep G2 Cells
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Humans
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Ligands
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Luciferases / genetics
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Luciferases / metabolism
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Models, Molecular
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Protein Conformation
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Radioligand Assay
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Receptors, Estrogen / agonists
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Receptors, Estrogen / antagonists & inhibitors
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Receptors, Estrogen / metabolism*
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Response Elements
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Stereoisomerism
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Structure-Activity Relationship
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Thiophenes / chemical synthesis
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Thiophenes / chemistry
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Thiophenes / pharmacology
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Transcription, Genetic / drug effects
Substances
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Bridged Bicyclo Compounds, Heterocyclic
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Cycloheptanes
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Estrogen Receptor alpha
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Estrogen Receptor beta
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Estrogens
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Ligands
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Receptors, Estrogen
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Thiophenes
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Estradiol
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Luciferases