Insight into the molecular initiating event of mutagenic N-nitrosamines: a computational study on DNA alkylation by their diazonium ions.

N-Nitrosamines are a class of compounds that includes the potent mutagenicity and carcinogenicity of many of its members and is distributed widely throughout the human environment. DNA alkylation by their diazonium ions formed metabolically acts as a molecular initiating event (MIE) that links molecular chemistry to mutagenicity. However, the regiochemistry for diazonium ions reacting with DNA bases is still under debate. Hence, density functional theory calculations involving SN2 alkylation of guanine (Gua) by 14 diverse diazonium ions are presented, the results of which showed the mutagenicity-related shift from GuaN7- to GuaO6-alkylation proceeds by increasing complexity of the alkylating agents, along with a greater proportion of SN1 characteristic in SN2 transition states. Hence, "high oxyphilic" and "low oxyphilic" alkylating agents may instead be "SN1" and "SN2" species, respectively. As the degree of MIE selectivity for hard-hard interactions can be quantified by hard and soft acids and bases theory, quantitative relationships were modeled between the nucleophilic index (ω-) and hydrophobicity (log P) of diazonium ions and their carcinogenic potency. Therefore, the mechanistic link from MIE to target toxicity can be bridged by computational chemistry.