Stereoselective covalent binding of anti-benzo(A)pyrene diol epoxide to dna conformation of enantiomer adducts

The conformation of adducts derived from the reactions and covalent binding of the (+) and (-) enantiomers of 7/3, 8a-dihydroxy-9a, 10a-epoxy-7, 8,9, 10-tetrahydrobenzo(a)pyrene (anti- BaPDE) with double-stranded calf thymus DNA in vitro were investigated utilizing the electric linear dichroism technique. The linear dichroism and absorption spectra of the covalent DNA complexes are interpreted in terms of a superposition of two types of binding sites. One of these conformations (site I) is a complex in which the plane of the pyrene residue is close to parallel (within 30°) to the planes of the DNA bases (quasi-intercalation), while the other (site II) is an external binding site; this latter type of adduct is attributed to the covalent binding of an/j-BaPDE to the exocyclic amino group of deoxyguanine (N2-dG), while site I adducts are attributed to the 06-deoxyguanine and N6-deoxyadenine adducts identified in the product analysis of P. Brookes and M.R. Osborne (Carcinogenesis (1982) 3, 1223-1226). Site II adducts are dominant (~90% in the covalent complexes derived from the (+) enantiomer), but account for only 50±5% of the adducts in the case of the (-)-enantiomer. The orientation of site II complexes is different by 20±10° in the adducts derived from the binding of the (+) and the (-) enantiomers to DNA, the long axis of the pyrene chromo- phore being oriented more parallel to the axis of the DNA helix in the case of the (+) enantiomer. These findings support the proposals by Brookes and Osborne that the difference in spatial orientation of the N2-dG adducts of (-)-an<(-BaPDE together with their lower abundance may account for the lower biological activity of the (-) enantiomer. The external site II adducts, rather than site I adducts, appear to be correlated with the biological activity of these compounds.