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

This article focuses on the mechanistic investigation of DNA alkylation by diazonium ions derived from N-nitrosamines, a class of environmental carcinogens, using density functional theory (DFT) calculations. It demonstrates that the shift in alkylation from the N7 to the O6 site of guanine (Gua) correlates with increasing structural complexity and "oxyphilicity" of the alkylating agents, reflecting a continuum between SN2 and SN1 reaction characteristics. The study further establishes quantitative relationships between the nucleophilic index (ω⁻) and hydrophobicity (log P) of diazonium ions and their carcinogenic potency, supporting the use of hard and soft acids and bases (HSAB) theory to model molecular initiating events (MIEs) relevant to mutagenicity. These findings provide a computational framework for predicting the carcinogenic risk of N-nitrosamines and contribute to the development of mechanistically transparent quantitative structure–activity relationship (QSAR) models for toxicological assessment.