硝基还原酶催化硝基咪唑还原机理的密度泛函理论研究  

Reduction Mechanism of Nitroimidazole Catalyzed by Nitroreductase:A DFT Investigation

作　　者：王圣博 王娇娇 任婷[1] 孙国辉[1] 张娜[1] 赵丽娇[1] 钟儒刚[1] WANG Sheng-bo;WANG Jiao-jiao;REN Ting;SUN Guo-hui;ZHANG Na;ZHAO Li-jiao;ZHONG Ru-gang(Beijing Key Laboratory of Environmental&Viral Oncology,Faculty of Environment&Life,Beijing University of Technology,Beijing 100124,China)

机构地区：[1]北京工业大学、环境与生命学部、环境与病毒肿瘤学北京市重点实验室,北京100124

出　　处：《化学试剂》2023年第9期29-37,共9页Chemical Reagents

基　　金：北京市百千万人才工程培养项目(2019A16);北京市教委重点实验室项目(PXM2015-014204-500175);国家自然科学基金资助项目(82003599)。

摘　　要：低氧是实体肿瘤的重要特征之一,靶向肿瘤低氧的抗肿瘤药物在临床上有广泛的应用。硝基咪唑具有低氧选择特性,在常氧环境下可稳定存在但在低氧环境下可经还原酶代谢发生还原反应,因而一些将硝基咪唑作为低氧响应基团的靶向性抗肿瘤前药近年来被研发并投入临床研究。采用密度泛函理论(Density functional theory,DFT)对硝基还原酶中辅酶还原性黄素单核苷酸(Reduced flavin mononucleotide,FMNH)介导的硝基咪唑还原机理进行了研究。结果表明,还原反应的优势途径为硝基咪唑首先经过第一次1e^(-)/1H^(+)转移,再通过1分子H 2O作为质子转移通道接受来自FMNH的1e^(-)/1H^(+)生成亚硝基咪唑,后续再发生连续的4步1e^(-)/1H^(+)转移,最终生成氨基咪唑。上述结果为新型抗肿瘤低氧激活前药的研发提供了理论参考。Hypoxia is one of the significant characteristics of solid tumors,and related antitumor drugs targeting tumor hypoxia have been widely applied in clinic treatment of cancer.Nitroimidazole possesses hypoxia-selective properties and exists stably under normoxia but undergoes reductive reactions via reductase metabolism under hypoxia environment.Therefore,in recent years,some antitumor prodrugs with nitroimidazole as a hypoxic response group have been developed and put in clinical researches.In this study,density functional theory(DFT)was employed to investigate the reduction mechanism of nitroimidazole mediated by the coenzyme reduced flavin mononucleotide(FMNH)within nitroreductase.The results indicated that the dominant reaction pathway was that nitroimidazole underwent a first 1e^(-)/1H^(+)transfer and then accepted 1e^(-)/1H^(+)from FMNH through H 2O as a proton transfer channel to generate nitrosoimidazole,followed by successive four steps of 1e^(-)/1H^(+)transfer to yield aminoimidazole.The results provide a theoretical reference in the development of novel hypoxia-activated antitumor prodrugs.

关 键 词：硝基咪唑 密度泛函理论 低氧激活前药 还原机制 肿瘤低氧 硝基还原酶 

分 类 号：O641[理学—物理化学]