TY - JOUR
T1 - Benz[a]anthracene diols
T2 - Predicted carcinogenicity and structure-estrogen receptor binding affinity relationships
AU - Anstead, Gregory M.
AU - Kym, Philip R.
N1 - Funding Information:
We thank Charles Morreal of Roswell Park Memorial Institute for supplying us with samples of the benz\[a\]anthracenes that stimulated our interest in these compounds, and John Katzenellenbogen of the University of Illinois for the use of the SYBYL system. This study was funded by the National Institutes of Health (PHS RO1 DK15556). We thank Vickie Watson and Krista Gallagher for preparation of the manuscript.
PY - 1995/5
Y1 - 1995/5
N2 - 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.
AB - 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.
KW - antiestrogen
KW - carcinogenesis
KW - environment
KW - ionization potential
KW - orientation
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U2 - 10.1016/0039-128X(94)00070-S
DO - 10.1016/0039-128X(94)00070-S
M3 - Article
C2 - 7570711
AN - SCOPUS:0029032012
SN - 0039-128X
VL - 60
SP - 383
EP - 394
JO - Steroids
JF - Steroids
IS - 5
ER -