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

基于在多环芳烃中，在芳香环上取代卤素原子会阻碍卤素取代位点的氧化代谢的概念，预计在分子中假定的位点上引入卤素原子将剥夺分子的任何遗传毒性。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取代可能在不影响亲本分子其他生物活性的情况下剥夺分子的遗传毒性。目前对喹啉衍生物的结构-致突变性关系的研究表明，基因毒性喹啉的3-氟衍生物缺乏致突变性，而在4-、5-、6-或8位上携带卤素的衍生物均具有致突变性。值得注意的是，在位置3上引入氟剥夺了基因毒性喹啉分子的致突变性和可能的致癌性。本研究还表明，遗传毒性喹啉的代谢激活是通过微粒体氧化吡啶部分而不是苯部分进行的。最终结构为1,4水合喹啉的2,3-环氧化物。目前的结果表明，通过在假定的基因毒性环氧化位点上进行氟取代，可以剥夺含n杂芳烃的遗传毒性，例如苯并喹啉。

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.