Reaction of the tamoxifen cation and the bis-(4-methoxyphenyl)methyl cation in aqueous solutions containing 2'-deoxyguanosine

Abstract

The competition between 2'-deoxyguanosine (dG) and water has been quantitatively evaluated for the allylic carbocation derived from tamoxifen and for the stabilized diarylmethyl cation (bis-(4-methoxyphenyl)methyl). Both systems were examined by the competition kinetics method, in which the products were quantitatively analyzed after the SN1 solvolysis of the corresponding acetate esters in aqueous solutions containing the nucleoside. The principal product of the reaction of both cations with dG is the adduct at the NH2 group, a characteristic of delocalized carbocations. The tamoxifen cation was also examined by laser flash photolysis, with absolute rate constants for the reaction with dG and water being obtained and converted into rate constant ratios. The principal result of this study is that there is a three orders of magnitude difference in the reactivity of these cations towards the neutral form of dG and its conjugate base. Under acidic conditions where the reaction occurs with neutral dG, the guanine–water selectivity is low. Even at relatively high concentrations of dG, the majority of the product is alcohol derived from the water reaction. At pH 10 to 11, in contrast, dG is present as the anion and this is highly competitive. Yields of adduct as high as 90% can be attained. A consequence of the large difference in reactivities is that at neutral pH the majority of the reaction of the cation with dG is actually occurring via the small amount of conjugate base present. A further feature of the results is that the NH2 adduct is the predominant stable product from the anion. To explain the high rate constant for the reaction forming this product, a mechanism is proposed whereby one of the protons of the NH2 group is transferred to N1 as the N2-cation bond is forming.Key words: guanine, DNA adduct, carbocation, tamoxifen.