A Theoretical Study of the Mechanism of the Alkylation of Guanine by N- Nitroso Compounds.
AIR FORCE INST OF TECH WRIGHT-PATTERSON AFB OH
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N-nitroso compounds are potent, organ-specific carcinogens which effect chemical mutations via alkylation of the DNA base guanine. The resulting GC - AT transition is believed to be due to anomalous base pairing of 06- 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-06 oxygen, the purported promutagenic site, and the N7 nitrogen by alkyldiazonium ions and by carbocations indicate that the alkyldiazonium ion is the more likely ultimate mutagen. However, the deprotonation of the N1 nitrogen, as observed in x-ray studies of 06-methylguanine, was not apparent in these semiempirical calculations. Subsequent calculations on the possible involvement of water in the loss of the N1 hydrogen were performed using both semiempirical and density-functional DGauss techniques. The density-functional calculations proved comparable to high-level traditional ab initio 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 06 position and, then, deprotonation at N1 occurs with water acting as a proton acceptor.
- Genetic Engineering and Molecular Biology
- Organic Chemistry