Article

Tautomerism of 1-Methyl Derivatives of Uracil, Thymine, and 5-Bromouracil. Is Tautomerism the Basis for the Mutagenicity of 5-Bromouridine?

06/1998; DOI:10.1021/jp981005+

ABSTRACT The tautomerism of the N-1-methylated derivatives of uracil, thymine, and 5-bromouracil has been studied in order to analyze its implications in the mutagenicity of 5-bromouridine. The tautomeric preference in the gas phase was determined by means of state-of-the-art ab initio quantum mechanical calculations. The influence of solvation in water on the tautomerism was examined by using ab initio self-consistent reaction field and Monte Carlo free energy perturbation techniques. Finally, the effect of the DNA environment on the relative stability between tautomers was estimated from Poisson−Boltzmann calculations. The theoretical results indicate that there are no relevant differences in the intrinsic tautomeric preference of the three pyrimidine bases. The canonical oxo form is the main, if not the exclusive, form in the gas phase. Indeed, neither solvation in water nor solvation in the duplex DNA changes sensibly the relative stability between tautomers. Therefore, our results provide a basis for ruling out the involvement of noncanonical enol tautomers as the origin of the mutagenic properties of 5-bromouridine.

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Modesto Orozco