The role of DNA sequence and structure of the electrophile on the mutagenicity of nitroarenes and arylamine derivatives

Abstract

The mutagenicities of a series of nitroarenes and related electrophilic metabolites of aromatic amines were studied in Salmonella typhimurium strains TA98 and TA97, which have, respectively, (GCGC/CGCG)₂ and (CCC/GGG)₂ as their mutational sites. For electrophiles, primarily bicyclic species, that form adducts with nucleophilic sites other than the C8 of guanine (G), the ratios of activities in the two strains is near unity. On the other hand, for electrophiles consisting of cyclic structures with more than two rings and that are reported to react solely with the C8 of G, the ratio of activities (TA98/TA97) is in excess of 1.6. Quantum mechanical calculations indicate that (1) in the plane of G, the N7. N3, and 06 of G are more likely nucleophilic targets than C8 and (2) adduct formation at the C8 of G requires electrophilic attack from above or below the plane of G. It is hypothesized that because of steric hindrances, nitroarenes and derivatives containing in excess of two rings cannot react with the preferred nucleophilic sites and, therefore, form adducts with the more accessible C8. However, such an out‐of‐the‐plane attack is influenced by the nature of the nearest neighbor, as evidenced by the difference in mutagenic responses of TA98 and TA97, alternating GCs being preferred over other combinations. Further quantum mechanical calculations indicate that the nature of the nearest neighbor does indeed affect the nucleophilicity of the C8 of G but that the expression of this effect is apparently masked by the overriding steric effects.