Synthesis of 2-azido-3-methylimidazo[4,5-f]quinoline and photolytic generation of a highly reactive and mutagenic IQ derivative

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Abstract
Azido-IQ (2-azido-3-methylimidazo[4,5-fquinoline), a novel analog of the food mutagen and carcinogen IQ (2-amino-3-methylimidazo[4,5-f]quinoline) was synthesized and characterized. Both thermolysis and photolysis of this azide yield a short-lived nitrene which can react as an electrophile either directly or via protonation to a nitrenium ion. Reaction of the nitrene/nitrenium ion with water produces N-hydroxy-IQ; reactions with nucleotides and with DNA (in vitro and in cells) produce adducts efficiently. Correspondingly, high frequencies of mutations are induced in Salmonella typhimurium by photolyzed azido-IQ. Comparative mutation assays with the S.typhimurium strains TA98 and the hydroxyl-amine-resistant TA98/1,8-DNP6 provide evidence for a novel mechanism of mutation, direct reaction of the nitrene or nitrene-derived nitrenium ion with DNA without involvement of the hydroxylamine. The photolysis of arylazides promises to be a very convenient and generally applicable non-enzymatic procedure for the cell-free or intracellular generation of short-lived and highly reactive electrophilic species which are assumed to be identical with the metabolically formed ultimate mutagens/carcinogens of arylamines and nitroarenes.