Deprivation of Genotoxicity of N-Containing Heteroaromatics: Effect of Fluorine Substitution

基于芳环上的卤素原子阻止多环芳烃中卤素取代位的氧化代谢的概念，在分子中的假定位置引入卤素原子将剥夺分子的任何遗传毒性性质。在卤素中，F原子有时在与包括酶在内的生物分子的相互作用中被忽略。因此，F-取代可能在不影响亲本分子其他生物学活性的情况下剥夺分子的遗传毒性。对喹啉类化合物的结构-致突变关系的研究表明，3-氟喹啉类化合物的致突变性较差，而在4-、5-、6-或8-位带有卤素的所有衍生物都具有致突变性。值得注意的是，在3位引入氟剥夺了具有遗传毒性的喹啉分子的诱变性，并可能具有致癌性。本研究还揭示了遗传毒性喹啉的代谢活化是通过吡啶部分的微体氧化进行的，而不是通过苯部分进行的。最终结构被认为是1，4-水合喹啉的2，3-环氧化物。本研究结果表明，在苯并喹啉等多种杂芳烃中，通过在可能发生遗传毒性环氧化反应的位置进行氟取代，可以消除含氮杂环芳烃的遗传毒性。

Based on the concept that a halogen atom substituted on the aromatic ring blocks the oxidative metabolism at the site of the halogen-substitution in polycyclic aromatic hydrocarbons, it is expected that introducing a halogen atom at a putative site in the molecule would deprive the molecule of any genotoxic properties. Among halogens, F atom is sometimes ignored in the interactions with biomolecules, including enzymes. Therefore, F-substitution might possibly deprive the molecules of genotoxicity without affecting other biologcial activities of the parent molecules. The present study on the structure-mutagenicity relationship among quinoline derivatives revealed that 3-fluoro derivative of genotoxic quinoline was deficient in mutagenicity, whereas all the derivatives carrying a halogen at the 4-, 5-, 6-, or 8-position were mutagenic. It is noteworthy that the introduction of a fluorine on the position-3 deprived genotoxic quinoline molecule of its mutagenic, and probably carcinogenic, property. The present study also revealed that the metabolic activation of genotoxic quinoline proceeded through a microsomal oxidation of the pyridine moiety but not the benzene moiety. The ultimate structure is proposed to be the 2,3-epoxide of 1, 4-hydrated quinoline. The present result suggests that deprivation of genotoxic property of N-containing heteroaromatics might be accomplished in a wide variety of heteroaromatics such benzoquinolines by a fluorine substitution at the putative site for genotoxic epoxidation.