Mutagenic nitrenes/nitrenium ions from azido-imidazoarenes and their structure-activity relationships.
New heterocyclic arylazides (azido-imidazoarenes) structurally related to the food mutagen/carcinogen 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ) have been prepared. Their photolysis yields nitrenes and/or nitrenium ions which induce mutations in Salmonella typhimurium. The relationships between the chemical structure and mutagenic activity of these species are the same as those found in our previous studies of the amino- and nitro-imidazoarenes. Therefore the efficiency of the reaction with DNA of the ultimate metabolite, the nitrene/nitrenium ion, is the critical step governing the mutagenic potency of the amino- and nitro-imidazoarenes. The efficiency of DNA-binding depends on the delocalization of the positive charge of the nitrenium ion or of the electron deficiency of the nitrene. It is typical of the N-1-substituted and N-3-substituted arenimidazolyl-nitrenium ions that they can form another nitrenium resonance structure very similar to the parent nitrenium ion structure. We suggest that this property of the nitrene/nitrenium ion, in combination with its aromatic structure facilitating carbonium ion resonance structures, is the basic reason for the extremely potent mutagenic activity of IQ and related food mutagens/carcinogens.
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Institute of Pharmacology and Toxicology, University of Würzburg, FRG.
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D000588:Amines / Q000633:toxicity*; D001386:Azides / Q000633:toxicity*; D004269:DNA, Bacterial / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000633:toxicity*; D007093:Imidazoles / Q000633:toxicity*; D009152:Mutagenicity Tests; D009153:Mutagens; D010782:Photolysis; D000644:Quaternary Ammonium Compounds / Q000633:toxicity*; D011804:Quinolines / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship; D014466:Ultraviolet Rays
D000588:Amines; D001386:Azides; D004269:DNA, Bacterial; D006571:Heterocyclic Compounds; D007093:Imidazoles; D009153:Mutagens; D000644:Quaternary Ammonium Compounds; D011804:Quinolines