Synthesis and mutagenic activity of nitro-imidazoarenes. A study on the mechanism of the genotoxicity of heterocyclic arylamines and nitroarenes

Abstract

A series of nitro-imidazoarenes (nitro-IAs) were synthesized from the corresponding amino-imidazoarenes (amino-IAs). These two classes of compounds are structurally related to the potent food mutagen and carcinogen, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). The mutagenic activities of the nitro-IAs were assayed in the Salmonella typhimurium frameshift tester strains TA98, TA98/1,8-DNP6 and TA98NR without use of extracellular metabolization. Nitro-IQ, the nitro counterpart of IQ, was two times more mutagenic than IQ. In general, the mutagenic activities of the nitro-IAs varied over 50,000-fold. The relationships between the chemical structures and mutagenic activities are identical with those previously reported for the corresponding amino-IAs: the methyl group on the imidazole ring and the quinoline-nitrogen were found to be required for potent mutagenic activity. The reductive activation of the nitro-IAs is not carried out primarily by the 'classical' nitroreductase of Salmonella which is defective in TA98NR. The O-acetyltransferase defective in TA98/1,8-DNP6 is required for the efficient production of the ultimate mutagens of the nitro-IAs. The interchangeability of the structure-activity relationships of the nitro-IAs and amino-IAs reflects a basic similarity of the mechanisms of the mutagenicity of the two classes of compounds. It is likely that N-hydroxy compounds are proximate metabolites common to the nitro-IAs and amino-IAs; they are further activated by an acetyl-CoA-dependent O-acetyltransferase of Salmonella. It is very likely a property of the ultimate mutagen, possibly a nitrenium ion, which governs the mutagenic potency of the different nitro- and amino-IAs and thus determines the structure-activity relationships.