Mechanism of genotoxic quinoline derivatives : the Enamine Epoxide Theory

喹啉衍生物的遗传毒性机制：烯胺环氧化物理论

• 批准号: 03671060
• 负责人: KAWAZOE Yutaka
• 金额: $ 1.34万
• 依托单位: Nagoya City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1991
• 资助国家: 日本
• 起止时间: 1991 至 1992
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-03671060/
• 关键词: quinoline; enamine epoxide; metabolic activation; detoxication; liver microsomal enzymes; エナミンエポキシド仮説; 発がん性; エナミンエポキシド説; ベイ領域エポキシド; 変異原性

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.

我们提出的关于遗传毒性喹啉衍生物代谢活化的“烯胺-环氧化物”理论包括遗传毒性喹啉通过1，4-水合然后烯胺环氧化代谢为烯胺环氧化物结构的想法。我们通过以下实验证据证实了这一理论。因此，在环氮的α或β位的卤素取代（氟、氯或溴）完全剥夺了喹啉衍生物的致突变性。另一方面，喹啉核的苯部分上的卤素取代增强了致突变性，这表明在这一系列化合物中被认为是解毒过程的苯部分的氧化被卤素取代抑制。本研究所获得的数据证实了我们提出的理论，并将该理论应用于苯稠合喹啉衍生物的结构-致突变性关系，即，苯并[f]喹啉类和苯并[h]喹啉类，并证明其代谢活化导致遗传毒性是合理的。这是支持的研究结果，卤素取代的α或β位的环氮剥夺了他们的致突变性，而那些在苯部分增强的致突变能力的卤代衍生物有关。

项目成果

Ken-ichi Saeki: "Spin-spin coupling between fluorine and aromatic protons of 3-fluoroquinoline:dependence of the electronic structure of the ring nitrogen" Heterocyles. 33. 35-38 (1992)

Ken-ichi Saeki：“3-氟喹啉的氟和芳香质子之间的自旋-自旋耦合：环氮电子结构的依赖性”杂环。

Ken-ichi Saeki: "Spin-spin coupling between fluorine and aromatic protons of 3-fluoroquinoline:dependence of the electronic structure of the ring nitrogen" Heterocycles. 33. 35-38 (1992)

Ken-ichi Saeki：“3-氟喹啉的氟和芳香质子之间的自旋-自旋耦合：环氮电子结构的依赖性”杂环。

Kenーichi Saeki: "Spinーspin coupling between fluorine and aromatic protons of 3ーfluroquinoline:Dependence on the electronic structure of the ring nitrogen" Hetercycles. 33. 35-38 (1992)

Kenichi Saeki：“氟和 3-氟喹啉芳香质子之间的自旋耦合：对环氮电子结构的依赖性”Hetercycles 33. 35-38 (1992)。