Structural features of nitroaromatics that determine mutagenic activity in Salmonella typhimurium.
Seventeen structurally homologous nitroaromatics were tested for direct-acting mutagenic potency in nine strains of Salmonella typhimurium. The following four structural features were determined to have a strong influence on mutagenic activity: physical dimensions of the aromatic rings, isomeric position of the nitro group, conformation of the nitro group with respect to the plane of the aromatic rings, and ability to resonance-stabilize the ultimate electrophile. Progressive addition of five- and six-membered rings to a nitrobenzene nucleus demonstrated that mutagenic activity was a direct function of size. Fluoranthene was of optimal size (four rings) for mutagenicity; an additional benzene ring, giving benzo[k]fluoranthene, reduced mutagenic activity. Nitroaromatics with a nitro group oriented along the long axis of symmetry of the molecule were more potent mutagens than those with the nitro group oriented along the short axis. These results are discussed in light of the insertion-denaturation model for intercalation of certain DNA adducts. Nitroaromatics with nitro groups sterically forced out of the plane of the aromatic rings were weakly mutagenic or nonmutagenic. Nitro groups located between two peri hydrogens or in a bay-region are examples of this conformation. Finally, structural features that contribute to resonance stabilization of the reactive nitrenium ion enhance mutagenic potency. Thus, 6-nitroindene was at least tenfold more mutagenic than 5-nitroindene. These positional isomers are structurally identical with the exception of the position of an olefinic bond in the adjacent five-membered ring which can contribute to resonance stabilization of a carbonium ion formed after bioactivation of 6-nitroindene but not of 5-nitroindene. The predictive value of these structure-activity relationships should permit a first approximation in the assessment of mutagenic potency of nitroaromatics.
D008968:Molecular Conformation; D009152:Mutagenicity Tests; D009154:Mutation / Q000187:drug effects*; D009574:Nitro Compounds / Q000633:toxicity; D011083:Polycyclic Compounds / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship
D009574:Nitro Compounds; D011083:Polycyclic Compounds