A theoretical study of the mechanism of the alkylation of guanine by N-nitroso compounds
N-nitroso compounds are potent, organ-specific carcinogens which effect chemical mutations via alkylation of the DNA base guanine. The resulting G:C [yields] A:T transition is believed to be due to anomalous base pairing of O[sup 6]-alkylguanine with thymine during replication. The ultimate metabolite involved in the alkylation reaction has generally been thought to be an alkyldiazonium ion or its decomposition product, a carbocation. In this study, semiempirical (MOPAC) analysis of the enthalpy changes associated with the alkylation on guanine of the O[sup 6] oxygen, the purported promutagenic site, and the N[sup 7] nitrogen by alkyldiazonium ions and by carbocations indicate that the alkyldiazonium ion is the more likely ultimate mutagen. However, the deprotonation of the N[sup 1] nitrogen, as observed in x-ray studies of O[sup 6]-methylguanine, was not apparent in these semiempirical calculations. Subsequent calculations on the possible involvement of water in the loss of the N[sup 1] hydrogen were performed using both semiempirical and density-functional (DGauss) techniques. The density-functional calculations proved comparable to high-level traditional ab inito calculations on model reactions and allowed such rigor to be reasonably applied to a guanine-sized system. A two-step mechanism is proposed in which an intact alkydiazonium ion attacks the O[sup 6] position and, then, deprotonation at N[sup 1] occurs with water acting as a proton acceptor.
- Research Organization:
- North Carolina Univ., Chapel Hill, NC (United States)
- OSTI ID:
- 7308869
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
550400 -- Genetics
560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ALKYLATION
AMINES
AMMONIUM COMPOUNDS
AROMATICS
AZAARENES
AZO COMPOUNDS
CHEMICAL REACTION KINETICS
CHEMICAL REACTIONS
DNA
GUANINE
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
KINETICS
MUTAGENESIS
NITROSO COMPOUNDS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PURINES
QUATERNARY COMPOUNDS
REACTION KINETICS