A novel pathway to the ultimate mutagens of aromatic amino and nitro compounds

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.