FMNH介导偶氮苯还原机理的密度泛函理论研究  

Reduction Mechanism of Azobenzene Mediated by FMNH:A DFT Investigation

作　　者：宋佳宸 郑大威[1] 王圣博 王娇娇 孙国辉[1] 张娜[1] 赵丽娇[1] 钟儒刚[1] SONG Jia-chen;ZHENG Da-wei;WANG Sheng-bo;WANG Jiao-jiao;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》2022年第11期1598-1604,共7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);北京市教委科技计划一般项目(KM202110005005);国家自然科学基金资助项目(82003599)。

摘　　要：实体瘤的低氧微环境是恶性肿瘤的重要特征之一,针对肿瘤低氧的靶向化疗药物为癌症治疗带来了新策略。偶氮苯中的偶氮基团具有低氧激活的特异性,能够在常氧条件下稳定存在而在低氧条件下发生还原裂解,因此一些偶氮苯衍生物前药也因其具有肿瘤低氧靶向潜力,近年来被开发并应用于临床研究。使用密度泛函理论(DFT)对在辅酶还原型黄素单核苷酸(FMNH)作用下的偶氮苯还原机理进行了研究。结果表明,优势反应路径为偶氮苯首先经过连续的两步1e^(-)/1H^(+)转移形成1,2-二苯肼,然后依次再发生第3次1e^(-)/1H^(+)转移、氮氮裂解和第4次1e^(-)/1H^(+)转移后最终形成两分子苯胺。其中,前两步1e^(-)/1H^(+)转移需要克服最高能垒,为反应的控速步骤。这些结果为设计开发新型的肿瘤靶向性低氧激活前药提供了重要理论依据。The hypoxic microenvironment of solid tumor is a significant feature of malignant tumor, so that the hypoxia-targeted chemotherapies have becomed a new strategy for the treatment of cancer.The azo groups in azobenzene have the specificity of hypoxia activation, which can be stable under normoxic condition while be activated under hypoxic condition.Therefore, some azobenzene derivative prodrugs have been developed and applied to clinical research in recent years because of their tumor-hypoxia targeting potential.In this study, the reduction mechanism of azobenzene mediated by the coenzyme reduced flavin mononucleotide(FMNH) was studied by density functional theory(DFT).The results indicated that the dominant pathway of the reduction was that azobenzene underwent successive two steps of 1 e^(-)/1 H^(+) transfer to yield 1,2-diphenylhydrazine, followed by the formation of two aniline molecules via the third 1 e^(-)/1 H^(+) transfer, cleavage of azo groups and then the forth 1 e^(-)/1 H^(+) transfer.The rate-determining step was the first two steps of 1 e^(-)/1 H^(+) transfer, which needed to overcome the highest energy barriers.This study provided an important theoretical basis for the design and development of novel hypoxia-activated prodrugs with tumor targeting.

关 键 词：偶氮苯 低氧激活前药 还原机理 密度泛函理论 肿瘤低氧 

分 类 号：O641[理学—物理化学]