醛肟类神经性毒剂防治药物的新型解毒分子作用机制  

A new detoxification mechanism for aldoxime therapeutic antidotes for chemical warfare nerve-agents

作　　者：任福荣 肖璇 谢琳娜 徐丹 邵杰 黄春华[1,2] 朱本占 Fu-Rong Ren;Xuan Xiao;Lin-Na Xie;Dan Xu;Jie Shao;Chun-Hua Huang;Ben-Zhan Zhu(State Key Laboratory of Environmental Chemistry and Ecotoxicology,Research Center for Eco-Environmental Sciences,Chinese Academy of Sciences,Beijing 100085,China;University of Chinese Academy of Sciences,Beijing 100049,China)

机构地区：[1]中国科学院生态环境研究中心环境化学与生态毒理学国家重点实验室,北京100085 [2]中国科学院大学,北京100049

出　　处：《中国科学：化学》2018年第10期1247-1259,共13页SCIENTIA SINICA Chimica

基　　金：中国科学院战略性先导科技专项(B类)(编号:XDB01020300);国家自然科学基金(编号:21577149;21477139;21621064;21777180)资助项目

摘　　要：吡啶盐醛肟类药物是一类常见的有机磷类神经性毒剂和农药的解毒剂.卤代苯醌是一类致癌性的活性中间体,最近在饮用水消毒副产物中也被检出.我们发现, 2-吡啶盐醛肟类代表性药物如解磷定可快速促进四氯-1,4-苯醌通过连续两步的脱氯水解反应转化为2,5-二氯-3,6-二羟基-1,4-苯醌,比其自然水解的速率提高了18万倍.然而,当解磷定中的氮羟基被掩蔽后则不能促进四氯-1,4-苯醌水解.通过联合运用多种分离和分析鉴定方法发现,解磷定最终转化为其相应的腈类化合物.采用^(18)O-H_2O标记等实验,最终确定2-吡啶盐醛肟类药物对四卤苯醌类致癌物的解毒机理是通过亲核取代同时伴随两次Beckmann裂解反应.本文介绍了这类可在正常生理条件下发生的连续两步Beckmann裂解反应,以期对将来研究这两类具有重要生物学和环境学意义的醛肟类药物及多卤代醌类环境致癌物具有指导作用.Pyridinium aldoximes are best-known as therapeutic antidotes for organophosphorus chemical warfare nerve-agents and pesticides. Polyhalogenated quinones are a class of carcinogenic intermediates and newly identified chlorination disinfection byproducts in drinking water. However, it is not clear what is the exact chemical mechanism underlying such detoxication. Here we showed that pralidoxime, one of the representatives ofpyridinium aldoximes, can markedly enhance the dechlorination and hydroxylation of the highly reactive and toxic tetrachloro-1,4-benzoquinone （also called chloranil） in two-consecutive steps to produce the much less toxic 2,5-dichloro-3,6-dihydroxy-1,4- benzoquonine （chloranilic acid）, with rate acceleration of up to 180000-times. In contrast, no enhancing effect was observed when the hydroxylamine group was blocked via methylation to form O-methylated pralidoxime. The major reaction product from pralidoxime was characterized as its corresponding nitrile （2-cyano-l-methylpyridinium chloride）. Along with oxygen-18 isotope-labeling studies, we proposed that nucleophilic substitution coupled with an unprecedented double Beckmann fragmentation reaction was responsible for this dramatic enhancement of the detoxification reaction. This paper reviewed the unprecedented double Beckmann fragmentation reaction. Our findings may have broad biological and environmental implications for future research on the aldoxime therapeutic agents and carcinogenic polyhalogenated quinones, which are two important classes of compounds of major biomedical and environmental interest.

关 键 词：Beckmann裂解反应 吡啶盐醛肟 神经性毒剂防治药物 四氯-1 4-苯醌 解毒机理 

分 类 号：R96[医药卫生—药理学]