Carcinogenicity of benzo[a]pyrene diol epoxide stereoisomers: A linear free energy relationship study

In this work, we use linear free energy relationships as a comparative tool to study chemical reactivity of the four stereoisomers of the ultimate carcinogen benzo[a]pyrene 7,8-diol-9,10-epoxide at N-cyclic or N-exocyclic positions of guanine and adenine. Calculations were performed with PM3 semiempirical method and by applying density functional theory at B3LYP/6-31G* level of theory. Reaction free energies were obtained with water environment modeled by either the dielectric continuum method of Tomasi and co-workers, or the discrete Langevin dipoles model of Florián and Warshel. Except for reactions occurring at N2 site of guanine, good correlations with literature data were found, highlighting in particular the (+)-7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene molecule often reported as being the most tumorigenic of the four isomers. The possibility of an anchimeric assistance mechanism for this specific stereomer is discussed. Finally, an interesting relationship between hydration free energies and the total dipole moment of the adducts was evidenced, suggesting a possible solvent effect to play a particularly important role in the reactivity of these polyaromatic hydrocarbons toward N7 position of adenine.