Mutagenic heteroaromatic amines: modelling the interactions with DNA.

BOROSKY, GABRIELA L.

Santiago

Congreso; 10th Congress of the World Association of Theoretical and Computational Chemists, WATOC 2014; 2014

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, and further activated to 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 this work, computational calculations were performed in order to study isomeric heteroaromatic amines which only differ in the position of methyl substituents. Consequently, the nitrenium ions derived from these compounds present very similar relative stabilities. The influence of the structure on the bioactivity of these molecules was analyzed in the search for correlations between computed properties and the 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 with a two-layer QM/QM-ONIOM system using Density Functional Theory (DFT) and a semiempirical method were carried out at the ωB97X-D/6-31G*:PM6 level. Molecular docking techniques were also 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 considered by means of the IEFPCM method. Acknowledgments: G. L. Borosky acknowledges CONICET and Secyt-UNC for financial support. References: [1] H. A. J. Schut, E. G. Snyderwine, D. B. Clayson, Carcinogenesis 20 (1999) 353. [2] F. A. Beland, F. F. Kadlubar, in Handbook of Experimental Pharmacology, C. S. Cooper, P. L. Grover (Eds.), Springer-Verlag, Heidelberg, 94 (1990) 267.