Reactivity of the Mutagen 1,4-Dinitro-2-methylpyrrole as an Alkylating Agent

The formation of chemical species with DNA-damaging and mutagenic activity for bacterial test systems was detected in sorbic acid-nitrite mixtures. 1,4-Dinitro-2-methylpyrrole (NMP), one the main products resulting from the reaction between sorbic acid and nitrite, has mutagenic properties, and here its alkylating capacity was investigated. The conclusions drawn are as follows: (i) In aqueous medium, after the addition of a hydroxide ion and the subsequent loss of nitrite, NMP affords 5-methyl-3-nitro-1<i>H</i>-pyrrol-2-ol. This species is in equilibrium with 5-methyl-3-nitro-1<i>H</i>-pyrrol-2(5<i>H</i>)-one, the effective alkylating agent responsible for the genotoxic capacity of NMP; (ii) 5-methyl-3-nitro-1<i>H</i>-pyrrol-2(5<i>H</i>)-one alkylates 4-(<i>p</i>-nitrobenzyl)pyridine (NBP), a molecule with nucleophilic characteristics similar to those of DNA bases, forming an adduct (AD; ε = 1.14 × 10<sup>4</sup> M<sup>−1</sup> cm<sup>−1</sup>); (iii) The calculated energy barrier for the alkylation of NBP for NMP and the value of the fraction of alkylating agent forming the adduct are consistent with the observed mutagenicity of NMP; (iv) The reactivity of NMP can be explained in terms of the instability of the <i>N</i>-NO<sub>2</sub> bond as well as the effect of this group on aromaticity.