Many alkylating agents covalently bind to nucleophilic positions in cellular DNA, causing DNA damage. This has been directly linked to mutagenic and carcinogenic activity. Methane diazonium ions, which are the reactive intermediates formed from several potent carcinogenic methylating agents including methyl nitrosourea, can simultaneously react with different DNA sites. Ab initio quantum mechanical SCF and density functional methods have been employed to examine diazonium ion-DNA base transition states and diazonium ion-oligonucleotide model transition states in the gas phase and in an aqueous environment. This characterization of transition states was used to provide descriptions of site and sequence specific reaction patterns of methane diazonium ions at different DNA bases and at different guanine sites in sequences containing multiply stacked guanines. This work provides a computational methodology that, in principle, can describe the DNA reaction specificity of a large number of mutagens and carcinogens.

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