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Benz[a]anthracene diols: predicted carcinogenicity and structure-estrogen receptor binding affinity relationships
1Department of Internal Medicine, Albert B. Chandler Medical Center, University of Kentucky, Lexington 40536, USA.
Steroids
|May 1, 1995
Summary
Benz[a]anthracene diols, environmental carcinogens, exhibit varying estrogen receptor binding affinities. The 7-methyl derivative shows enhanced affinity due to structural and charge similarities with estradiol.
Area of Science:
- Environmental Science
- Toxicology
- Molecular Biology
Background:
- Benz[a]anthracenes are environmental carcinogens with known estrogenic and antiestrogenic activities.
- Their hydroxylated metabolites can interact with the estrogen receptor (ER).
Purpose of the Study:
- To investigate the structure-estrogen receptor binding relationships of four 3,9-benz[a]anthracene diols.
- To understand how structural modifications affect ER binding affinity.
Main Methods:
- Synthesis and characterization of four benz[a]anthracene diols (unsubstituted, 7-methyl, 12-methyl, 7,12-dimethyl).
- Estrogen receptor binding assays.
- Molecular graphics and molecular orbital (AM1) calculations.
Main Results:
- Binding affinities varied, ranging from 0.43% to 26% of estradiol.
- 7-Methyl substitution enhanced ER binding affinity, while 12-methyl substitution decreased it.
- Molecular modeling suggested binding modes mimicking steroid structures, with the anthracene fragment acting as a steroid AB-ring mimic.
Conclusions:
- Structural features, particularly methyl substitution at the 7-position, significantly influence benz[a]anthracene diol binding to the estrogen receptor.
- The 7-methyl compound's high affinity is attributed to charge similarity with estradiol and favorable hydrophobic/dispersive interactions.
- Some benz[a]anthracene derivatives may act as carcinogens via radical cation mechanisms.
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