Reactions of stereoisomeric non-bay-region benz[a]anthracene diol epoxides with DNA and conformations of non-covalent complexes and covalent adducts

The reactions of the non-bay-region diol epoxides racemic trans-8,9-dihydroxy-anti-10,11-epoxy-8,9,10,11-tetrahydro-benz[a]anthracene (anti-BA-10,11-DE) and racemic trans-8,9-dihydroxy-syn-10,11-epoxy-8,9,10,11-tetrahydrobenz[a]-anthracene (syn-BA-10,11-DE) with native double-stranded DNA in aqueous solutions (5 mM sodium cacodylate buffer, pH 7.0, 23°C) was investigated utilizing various spectroscopic techniques. The results of linear dichroism experiments suggest that both diastereomers form non-covalent, intercalative complexes with DNA prior to undergoing chemical reactions; the association constant for the anti stereoisomers is about twice as large (850 ± 100 M^-1) as that for the syn-diastereomers, thus qualitatively paralleling the behavior established previously for the bay-region diol epoxides of benzo[a]pyrene and benz[a]anthracene. The reaction rates of both anti- and syn-BA-10,11-DE are significantly accelerated in the presence of DNA, and the fraction of diol epoxide molecules which bind covalently to DNA is 13 ± 2% and 3 ± 1% respectively; these levels of covalent binding are lower by factors of about two respectively, than in the case of the bay-region diol epoxides of benz The phenanthrenyl residues in the covalent anti-BA-10,11-DE-DNA adducts are tilted with their long axes closer to the average orientations of the normals to the DNA bases; in contrast, the adducts derived from the binding of the syn diastereomers, appear to be characterized by intercalative-type conformations; however, the overall degrees of orientations are weak in the cases of these non-bay-region diol epoxide-DNA adducts. Nevertheless, these adduct conformations resemble those derived from the highly tumorigenic anti and the less active syn diastereomers of benzo[a] and benz[a]anthracene, thus providing one additional example to the previously observed correlations between adduct structure and biological activity.