Chemical reactivity as a tool to study carcinogenicity: reaction between chloroethylene oxide and guanine.

Chloroethylene oxide, an ultimate carcinogen of vinyl chloride, reacts with DNA giving rise to 7-(2-oxyethyl)guanine adduct in a nearly quantitative yield. This reaction represents an initial step of carcinogenesis associated with vinyl chloride. From experimental data for this reaction we calculated the second-order rate constant of 0.049 s(-1) M(-1), which corresponds to the activation free energy of 19.5 kcal/mol. We also performed a series of medium high ab initio and density functional theory simulations. Effects of hydration were considered in the framework of the Langevine dipoles solvation model and the solvent reaction field method of Tomasi and co-workers. In silico calculated activation free energies are in a good agreement with the experimental value. This fact presents strong evidence in favor of the validity of the proposed reaction mechanism and points to the applicability of quantum-chemical methods to studies of other reactions associated with carcinogenesis. Insignificant stereoselectivity of the studied reaction was also predicted.