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

Abstract

The reactions of the non-bay-region diol epoxides racemic trans-8,9-dihydroxy-anti-10,11-epoxy-8,9,10,11-tetrahydrobenz[a]an thracene (anti-BA-10,11-DE) and racemic trans-8,9-dihydroxy-syn-10,11-epoxy-8,9,10,11-tetrahydrobenz[a]ant hracene (syn-BA-10,11-DE) with native double-stranded DNA in aqueous solutions (5 mM sodium cacodylate buffer, pH 7.0, 23 degrees 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[a]anthracene. 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 diasteromers of benzo[a]pyrene and benz[a]anthracene, thus providing one additional example to the previously observed correlations between adduct structure and biological activity.