Nitrosoureas (NUs) are potent carcinogens, which spontaneously decompose to electrophilic alkylating agents under physical conditions and cause DNA damage. As shown in , NUs undergo decomposition to yield isocyanate and diazonium hydroxides (DH), the latter further degrading to diazonium cations (DC) and carbocations (CC). In this study, three pathways indicated in the figure were explored using DFT method. The N7 atom in guanine was selected as the model of DNA nucleophilic site. Four alkylnitrosoureas, including methyl-, ethyl-, isopropyl- and benzyl-nitrosourea, which exhibit significantly different carcinogenicity in animal experiments, were employed as the NU models. The results are summarized as follows. First, all the energy barriers for the alkylation of guanine by the four DHs are higher than those for the corresponding O-N� bond cleavage reactions, which suggests that DC should be a necessary intermediate in the DNA alkylation by NUs. Second, the energy barriers for the alkylation of guanine by DCs decrease with the increase of the steric hindrance of the alkyl groups. The energy barriers for the alkylation by methyl-, ethyl-, and isopropyl DCs are lower than those for the corresponding Na-C bond cleavage reactions, whereas similar for benzyl-DC. Therefore, it was postulated that DCs were the ultimate alkylating agents for the NUs having small alkylating groups on the Na atom; whereas the nitrogen-separated ion pair should exist in the alkylation of NUs having large alkylating groups.

Mechanism for the formation of guanine adducts induced by alkylnitrosoureas: A theoretical investigation

248th National Meeting (2014)

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