Molecular orbital studies of the hydrolysis reactions of benzo[a]pyrene diol epoxides

Abstract

Kinetic studies of the hydrolysis of benzo[a]pyrene diol epoxides have shown that hydrolysis proceeds through an acid-catalyzed SN1 mechanism and that the rate-determining step is the formation of a benzylic carbocation. The formation of this carbocation indicates that the diol epoxide can react with nucleophilic sites on DNA as an alkylating agent. Previous work has indicated that the kinetic data could be accurately fit to kobsd = kH [H+] + k0, in which kH [H+] is the pseudo first-order rate constant for acid-catalyzed hydrolysis and k0 is the rate constant for spontaneous hydrolysis. The observation made in several laboratories, that DNA catalyzes the hydrolysis of carcinogenic diol epoxides, is of direct interest in light of our recent calculation indicating that the local environment of DNA has a high concentration of hydrogen ions. The significance of acidic domains around nucleic acids is primarily in the ability of the protons to catalyze reactions. We have hypothesized that the high concentration of hydrogen ions at the DNA surface is responsible for the catalysis and that the generation of benzylic carbocations at the DNA surface can result in either nontoxic tetraols or in mutagenic nucleotide adducts, depending on the nucleophile with which the carbocation reacts. The calculations presented here are concerned with qualitatively understanding the rate constants in terms of the mechanisms of the acid-catalyzed and the spontaneous (H2O-catalyzed) hydrolyses. © 1992 John Wiley & Sons, Inc.