Computational chemical toxicology: Deamination in gas-phase, solution, and anisotropic environments

Nitric oxide (NO) and nitrous acid (HNO2) comprise an important class of DNA damaging agents. Chronic inflammation is associated with increased endogeneous NO production and its direct relationship to different types of human cancers have been suggested. A complete understanding of the deamination chemistry caused by these nitrosating reagents is important because of the considerable dietary and environmental exposure of humans to nitrogen oxides.;The products of nitrosative nucleobase deamination are considered to result from DNA base diazonium ions by nucleophilic dediazoniation while keeping the pyrimidine rings intact. However, the previous theoretical studies in our group have revealed that in the absence of cytosine unimolecular dediazoniation of guaninediazonium ion is accompanied by pyrimidine ring-opening. This dissertation focuses on the study of effects of the anisotropic DNA environment on nitrosative guanosine deamination. While guaninediazonium ion can be a highly reactive intermediate in reactions of the 'free nucleobase' (or its nucleoside or nucleotide), the pyrimidine ring-opening intermediate, 5-cyanoimino-4-oxomethylene-4,5-dihydroimidazole, emerges as the key intermediate in nitrosative guanine deamination in ds-DNA and ds-oligonucleotides. In essence, the complementary nucleobase cytosine provides base-catalysis and switches the sequence of deprotonation and dediazoniation. It is argued that this environment-induced switch causes entirely different reaction paths to products as compared to the respective 'free nucleobase' chemistry and the complete consistency is demonstrated of this mechanistic model with all known experimental results. 5-cyanoimino-4-oxomethylene-4,5-dihydroimidazole and/or its hydrolysis products can account for the formations of xanthosine, the pH-dependency and the environment-dependency of oxanosine formation, the formation of the classical cross-link dG(N2)-to-dG(C2) , including the known sequence specificity of its formation, and for the formation of the structure-isomeric cross-link dG(N1)-to-dG(C2) . Our previous 18O-labeling experiments of nitrosative guanosine deamination observe the two isotopomers of oxanosine,6-( 18O)-dO and [7-18O]-dO, formed in a unity, however we proposes that in ds-DNA and ds-oligonucleotides only [7-18O]-dO would be observed due to high rotational barrier of C-OOOH.