Mechanism of genotoxic quinoline derivatives : the Enamine Epoxide Theory

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Our proposed "Enamine-Epoxide" theory on the metabolic activation of genotoxic quinoline derivatives comprises the idea that genotoxic quinolines are metabolized to the enamine epoxide structure via 1,4-hydration followed by enamine epoxidation. We confirmed this theory by the following experimental evidences. Thus, halogen-substitution (either fluorine, chlorine, or bromine) at the alpha or beta position of the ring nitrogen deprived quinoline derivatives completely of mutagenicity. On the other hand, halogen-substitutions on the benzene moiety of quinoline nucleus enhanced the mutagenicity, suggesting that oxidations of the benzene moiety, that are regarded as detoxication processes in this series of compounds, are suppressed by the halogen-substitution. All the data obtained in this research confirmed our proposed theory.In addition, this theory was applied to the structure-mutagenicity relationship among benzene-fused quinoline derivatives, i.e., benzo[f]quionolines and benzo[h]quinolines, and evidenced to be rational for their metabolic activation leading to genotoxicity. This was supported by the findings that halogen-substitution at the alpha or beta position of the ring nitrogen deprived them of mutagenicity, whereas those on benzene moiety enhanced the mutagenic capacity of the halogeno derivatives concerned.