Computational study related to the mutagenic activity of heterocyclic aromatic amines

BOROSKY, GABRIELA L.

Santiago de Compostela

Congreso; World Congress of World Association of Theoretical and Computational Chemists, WATOC 2011; 2011

Heteroaromatic amines found in well-done or over cooked meats and protein rich foods have been determined to be mutagenic and carcinogenic.1 They are metabolically converted into aryl N-hydroxylamines, which are further activated to their sulfuric or acetic acid esters.2 The esters undergo N-O bond cleavage to yield highly reactive arylnitrenium ions. These nitrenium ions are the ultimate electrophilic metabolites that covalently bind and alter DNA, causing their mutagenic and carcinogenic potential.2 Nitrenium ion stability has been pointed out to be important in determining the activity of aromatic and heteroaromatic amines.             In the present work, computational calculations were performed in order to study several 2-amino-trimethylimidazopyridine isomers, which only differ in the position of the methyl substituents. Consequently, the nitrenium ions derived from these compounds present very similar relative stabilities. For these molecules, the influence of the structure on the bioactivity was analyzed, and correlations were sought between calculated properties and mutagenic potencies reported in the literature. The effect of molecular structure on the amine-DNA intercalation step, which is prior to covalent adduct formation, was evaluated. For this aim, quantum-mechanical calculations (ONIOM (DFT:PM3MM)), and molecular docking techniques were applied. In this way, the influence of noncovalent interactions, which determine the affinity of the carcinogenic amines with DNA, was examined. The solvation effect was evaluated by means of the PCM method.           REFERENCES   1- Schut, H.A.J., Snyderwine, E.G., Clayson, D.B., Carcinogenesis 1999, 20, 353-368. 2-Beland, F.A., Kadlubar, F.F., in Handbook of Experimental Pharmacology, Cooper, C.S., Grover, P.L. (Eds.), Springer-Verlag, Heidelberg, 1990, Vol. 94, Part 1, pp. 267-325.