DNA-damaging disinfection byproducts: alkylation mechanism of mutagenic mucohalic acids |
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Authors: | Gómez-Bombarelli Rafael González-Pérez Marina Arenas-Valgañón Jorge Céspedes-Camacho Isaac Fabián Calle Emilio Casado Julio |
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Affiliation: | Departamento de Química física, Facultad de Ciencias Químicas Universidad de Salamanca, Plaza de los Caídos, 1-5 E-37008 Salamanca, Spain. |
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Abstract: | Hydroxyhalofuranones form a group of genotoxic disinfection byproduct (DBP) of increasing interest. Among them, mucohalic acids (3,4-dihalo-5-hydroxyfuran-2(5H)-one, MXA) are known mutagens that react with nucleotides, affording etheno, oxaloetheno, and halopropenal derivatives. Mucohalic acids have also found use in organic synthesis due to their high functionalization. In this work, the alkylation kinetics of mucochloric and mucobromic acids with model nucleophiles aniline and NBP has been studied experimentally. Also, the alkylation mechanism of nucleosides by MXA has been studied in silico. The results described allow us to reach the following conclusions: (i) based on the kinetic and computational evidence obtained, a reaction mechanism was proposed, in which MXA react directly with amino groups in nucleotides, preferentially attacking the exocyclic amino groups over the endocyclic aromatic nitrogen atoms; (ii) the suggested mechanism is in agreement with both the product distribution observed experimentally and the mutational pattern of MXA; (iii) the limiting step in the alkylation reaction is addition to the carbonyl group, subsequent steps occurring rapidly; and (iv) mucoxyhalic acids, the hydrolysis products of MXA, play no role in the alkylation reaction by MXA. |
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