Mechanism of genotoxic quinoline derivatives : the Enamine Epoxide Theory

我们提出的关于遗传毒性喹啉衍生物代谢激活的“烯胺-环氧化物”理论包括遗传毒性喹啉通过1,4水化和烯胺环氧化代谢成环氧胺结构。我们用下面的实验证据证实了这个理论。因此，在环氮的α或β位置上的卤素取代（氟、氯或溴）完全剥夺了喹啉衍生物的诱变性。另一方面，喹啉核苯基上的卤素取代增强了致突变性，这表明在该系列化合物中被视为解毒过程的苯基的氧化被卤素取代抑制。本研究获得的所有数据都证实了我们提出的理论。此外，将这一理论应用于苯融合喹啉衍生物（即苯并[f]喹啉和苯并[h]喹啉）之间的结构-致突变性关系，并证明了其代谢激活导致遗传毒性的合理性。在环氮的α或β位置上的卤素取代使它们失去了诱变能力，而在苯部分上的卤素取代则增强了相关卤素衍生物的诱变能力。

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.