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Hydroxylated 2,3-diarylindenes: synthesis, estrogen receptor binding affinity, and binding orientation considerations
G M Anstead1, C S Peterson, J A Katzenellenbogen
1Department of Chemistry, University of Illinois, Urbana 61801.
Journal of Steroid Biochemistry
|November 1, 1989
Summary
Hydroxyl groups on 2-arylindene ligands significantly impact estrogen receptor binding affinity. Para-hydroxylation on the 2-phenyl ring enhances binding, suggesting a new hydrogen bonding site.
Area of Science:
- Medicinal Chemistry
- Molecular Pharmacology
- Endocrinology
Background:
- Understanding non-steroidal estrogen ligand orientation in the estrogen receptor (ER) binding site is crucial for developing high-affinity fluorescent probes.
- Hydroxyl substituents on ligands can modulate binding affinity and provide insights into receptor-ligand interactions.
Purpose of the Study:
- To investigate the effect of hydroxyl substituents on the binding affinity of 2-arylindene ligands for the estrogen receptor.
- To elucidate the binding orientation of 2,3-diphenylindene derivatives within the estrogen receptor binding site.
Main Methods:
- Synthesis of a series of dihydroxyl-substituted 2,3-diphenylindenes via cyclization of alpha-benzyldesoxybenzoins.
- Measurement of ligand binding affinities for the estrogen receptor using a competitive radiometric binding assay.
Main Results:
- Para-hydroxylation on the 2-phenyl ring of 2,3-diphenyl-6-hydroxyindene systems increased binding affinity threefold.
- Para-hydroxylation on the 3-phenyl ring resulted in a twofold decrease in binding affinity.
- Consistent changes in binding affinity suggest a specific, conserved orientation of 2,3-diarylindene systems in the ER binding site.
Conclusions:
- The binding orientation of 2,3-diarylindene ligands aligns with estradiol's A/B-ring system, with potential for a novel hydrogen bonding site.
- Meta-hydroxylation on the 3-phenyl ring minimally affects binding affinity, offering a strategy to reduce non-specific binding in fluorescent ligand design.
- Para-hydroxylation on the 2-phenyl ring, while increasing affinity, may not be ideal for electron-accepting fluorophore requirements in fluorescent ligand development.