Quantum chemical metabolism‐based simulation of carcinogenic potency of benzene derivatives

Using an oxenoid model, we investigated dependences of carcinogenic potency of the benzenes C₆H₅‐X on a nature of substituents X. According to the model, a P450 enzyme breaks a dioxygen molecule and generates the oxens, which readily react with substrates. We suggest that a stability of the intermediate OC₆H₆‐X with tetrahedrally coordinated C atom relative to the molecule C₆H₅‐X determines a rate of substrate biotransformation. Using MO LCAO MNDO approach, we calculated the total energies of molecules C₆H₆‐X and arene oxides OC₆H₆‐X. A difference ΔE_min of these values determines activation energy of oxidation reaction. The compounds with the low ΔE_min values are noncarcinogenic. Benzene derivatives with high ΔE_min values belong to carcinogenic compounds series. The carcinogenicity of amino‐ and nitro‐substituted benzenes is also determined by N‐oxidation of amino and reduction of the nitro group. As the phenylhydroxylamines XC₆H₄NHOH and nitrenium ions XC₆OH₄NH⁺ are the common metabolites of the nitro‐ and amino‐substituted benzenes and nitrenium ions XC₆H₄NH⁺ are the ultimate carcinogens, we use the differences ΔE_N = E(XC₆H₄NH⁺) ? E(XC₆H₄NHOH) as the second parameter characterizing the carcinogenic activity of amino‐ and nitro‐substituted benzenes. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010