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

基于芳环上取代的卤素原子阻断多环芳烃中卤素取代位点处的氧化代谢的概念，预期在分子中的推定位点处引入卤素原子将使分子丧失任何遗传毒性特性。在卤素中，F原子在与生物分子（包括酶）的相互作用中有时被忽略。因此，F-取代可能使分子丧失遗传毒性，而不影响母体分子的其他生物活性。对喹啉衍生物结构与致突变性关系的研究表明，具有遗传毒性的喹啉3-氟衍生物缺乏致突变性，而在4-、5-、6-和8-位上带有卤素的喹啉衍生物均具有致突变性。值得注意的是，在3位引入氟使喹啉分子失去了其致突变性和可能致癌性。本研究还表明，遗传毒性喹啉的代谢活化通过吡啶部分而非苯部分的微粒体氧化进行。最终的结构被认为是1，4-水合喹啉的2，3-环氧化物。目前的结果表明，剥夺的含氮杂环化合物的遗传毒性性能可能会在各种各样的杂环化合物，如苯并喹啉通过氟取代在推定的遗传毒性环氧化位点完成。

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.