Benz[a]anthracene diols: Predicted carcinogenicity and structure-estrogen receptor binding affinity relationships

Gregory M. Anstead, Philip R. Kym

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Benz[a]anthracenes are ubiquitous environmental carcinogens that exert estrogenic and antiestrogenic effects directly or via hydroxylated metabolities. In this paper, the structure-estrogen receptor binding relationships of four, 3,9-benz[a]anthracene diols are described: unsubstituted, 7-methyl, 12-methyl, and 7,12-dimethyl. Compounds unsubstituted at the 12-position have flat molecular topology, whereas methyl subsitution at the 12-position in the bay region induces twisting of the molecular framework. The oxygen-oxygen distances (11.94-11.98 Å) are similar to diethylstilbestrol (12.1 Å). The binding affinities range from 0.43% to 26% that of estradiol. Methyl substitution at the 7-position enhances affinity; 12-methyl substitution decreases it. These results are contrary to many estrogen receptor (ER) ligand systems, in which the compounds with the flatter molecular geometries typically have lower binding affinity. Molecular graphics were used to analyzed the fit of the four compounds with a receptor excluded volume model for the ER. These studies suggest that these compounds bind to the ER in a manner in which the anthracene fragment acts as the steroid AB-ring mimic (i.e, the benz[a]anthracene 9-position corresponds to the estradiol 3-position). Molecular orbital (AM1) calculations were used to calculate the charges of selected atoms. The 7-methyl compound was found to have greater charge similarity to estradiol than the other three compounds. The high affinity of the 7-methyl compound is ascribed to its charge similarity to estradiol, hydrophobic interactions in the receptor region that would accommodate a substituent in the planar 6-position of a Δ6,7-steroid, and favorable dispersive interactions with the receptor secondary to its extended planar system. Molecular orbital calculations also suggest that some of the benz[a]anthracene monophenols and diphenols have sufficiently low ionization potentials to act as carcinogens by a radical cation process.

Original languageEnglish (US)
Pages (from-to)383-394
Number of pages12
JournalSteroids
Volume60
Issue number5
DOIs
StatePublished - May 1995
Externally publishedYes

Keywords

  • antiestrogen
  • carcinogenesis
  • environment
  • ionization potential
  • orientation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology
  • Pharmacology
  • Clinical Biochemistry
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Benz[a]anthracene diols: Predicted carcinogenicity and structure-estrogen receptor binding affinity relationships'. Together they form a unique fingerprint.

Cite this