A Novel Pathway to the Ultimate Mutagens of Aromatic Amino and Nitro Compounds

Abstract

A Novel Pathway to the Ultimate Mutagens of Aromatic Amino and Nitro Compounds by Dieter Wild* Photolysis of arylazides in aqueous media was recently found to generate presumed nitrenium ions, species which are generally considered as the ultimate mutagens/carcinogens derived from arylamines and nitroarenes. The primary photolysis products of arylazides, the arylnitrenes, can possibly react as electrophiles themselves, or they can be protonated and thus form the electrophilic nitrenium ions. Numerous arylazides and aryldiazides can be photoactivated to short-lived mutagens detectable in Salmonella typhimurium TA98. Structure-activity comparisons between arylazides and the matching arylamines and nitroarenes show correlations; e.g., phenyl azide and methyl-substituted phenyl azides are not mutagenic or only weakly mutagenic like aniline, nitrobenzene, and their methyl homologues, whereas 4-azidodiphenyl, 2-azidofluorene, 1-azidopyrene, azido-IQ, and azido-isoIQ are increasingly mutagenic in that order, like the matching amino and nitro compounds. It is hypothesized on the basis of these data that the nitrene/nitrenium ion is the reactive intermediate common to the three mutagenic pathways and that the reaction of the nitrene/nitrenium ion with DNA is rate limiting for the overall mutagenic process in Salmonella. The photochemical generation from arylazides of the reactive species, the nitrene/nitrenium ions, opens new perspectives for the understanding of the genotoxic activity of arylamines and nitroarenes in general and, specifically, of the food mutagens/carcinogens of the IQ type.

An in Silico Method for Predicting Ames Activities of Primary Aromatic Amines by Calculating the Stabilities of Nitrenium Ions

“…According to this mechanism the stability of the nitrenium ion is fundamental in determining the extent of that mutagenic effect. We note that, in addition to aromatic amines Wild and co-workers have used evidence from photolysis experiments to suggest that the genotoxicity observed for arylazides and nitroaryl compounds is also the result of the stability of the common nitrenium intermediate formed by these compounds . In addition to DNA adduct formation intercalation into the DNA without the formation of a covalent bond is another mechanism known to lead to genotoxicity.…”

Rationally Designing Safer Anilines: The Challenging Case of 4-Aminobiphenyls

“…Many compounds, including most aromatic amines, are not inherently mutagenic, but metabolism generates species that are inherently mutagenic. This is achieved in the Ames test by incorporating S9 fraction from the livers of rats in which metabolic activity has been induced; in this study, this employed Aroclor 1254. , Aromatic amines are generally thought to yield mutagens after N-hydroxylation often with subsequent O-conjugation to create an electrophilic species (such as an ester, sulfate, or phosphate) that is able to react with DNA (Scheme ). − …”

Quantum chemical simulation of cytochrome P450 catalyzed aromatic oxidation: Metabolism, toxicity, and biodegradation of benzene derivatives

“…Many chemical compounds require a bioactivation to exert the toxic effects and initiate the tumors 1–10. Particularly, a concept of enzymatic activation of the procarcinogens to the proximate and ultimate carcinogens has been approved by the in vitro and in vivo studies, as well as by structure‐carcinogenic activity relationships obtained using quantum chemical parameters in the series of polycyclic aromatic compounds and their derivatives 11–26, haloidalkanes and haloidalkenes 27–32. The oxidation catalyzed by a microsomal P450 monooxygenase system is a common mechanism of the xenobiotics activation.…”