碳自由基参与的基于嘌呤C-H键官能化构建烷基/芳基嘌呤核苷（酸）的研究

The modified purine nucleosides display significant antitumor and antiviral activities. There are nearly 30 modified purine nucleosides were developed as antitumor and antiviral drugs. The introduction of alkyl or aryl groups to purine cycles could improve their metabolic stability and lipotropy, thus improve their biological activities significantly. It shows important research significance for the synthesis of purine nucleosides with different alkyl or aryl groups and testing of their antiviral activities. However, the reported synthetic processes have some faults: (1) using of toxic transition-metals, organic solvents and metal regents, leading high cost and environmental pollution, (2) needing prefunctionalization, poor substrate tolerance and low product diversity. The C-H bond functionalization with carbon radicals has emerged as a promising approach towards heterocycles with high atom economy from non-prefunctionalized materials under mild conditions. The synthesis of alkyl- or aryl-substituted purine nucleosides (nucleotides) via C-H bond functionalization with carbon radicals has never been reported up to now. In this project, the introduction of alkyl or aryl groups into purine nucleosides (nucleotides) will be accomplished through decarboxylation in water, C-B bond transformation in water and visible light photoredox radical reactions. Subsequently, we will build the compound library of alkyl- or aryl-substituted purine nucleosides (nucleotides). By screening their biological activities, we will summarize their structure-activity relationship, and screen out the drug candidate with better biological activities.

嘌呤修饰核苷具有显著的抗肿瘤和抗病毒活性，世界上有近30种嘌呤修饰核苷被开发为药物。其中，烷基/芳基的引入可以增加其代谢稳定性和亲脂性，显著改善其生理活性，因此合成含有多样性烷基/芳基取代基的烷基/芳基嘌呤核苷（酸），并研究其生理活性具有重要的意义。但是，现有的合成方法存在以下缺点：（1）用到重金属催化剂、有机溶剂和金属试剂，成本高，污染大；（2）底物需预官能化，普适性差，多样性不足。碳自由基参与的C-H键官能化具有原子经济性好、不需预官能化及条件温和的优点，其用于合成烷基/芳基嘌呤核苷（酸），至今尚未见报道。本项目拟通过水体系中的脱羧反应、脱硼反应及光催化自由基反应，产生烷基和芳基等碳自由基，然后和嘌呤C-H键反应，在嘌呤环上引入烷基/芳基，建立烷基/芳基嘌呤核苷（酸）的合成方法。然后，建立烷基/芳基嘌呤核苷（酸）类化合物库，进行药物活性筛选，研究构效关系，以发现具有更好活性的候选药物。

烷基/芳基引入嘌呤核苷可以增加其代谢稳定性和亲脂性，显著改善其生理活性。本项目围绕6位是氢原子的嘌呤（核苷）类化合物通过C-H键的官能化反应这一研究主线，使6位是氢原子的嘌呤（核苷）类化合物和烷基/芳基自由基前体反应，开展相关研究工作，合成了一系列6-烷基/芳基嘌呤（核苷）类化合物，发展了6-烷基/芳基嘌呤（核苷）类化合物的合成方法学。其中，在蓝光催化下芳基重氮盐分解为芳基自由基，和6位是氢原子的嘌呤（核苷）类化合物发生芳基化反应，合成了6-芳基嘌呤（核苷）类化合物；以6位是氢原子的嘌呤（核苷）类化合物、烯烃和三氟代甲烷亚磺酸钠为原料，在蓝光催化下发生烷基化反应，合成了含三氟甲基的6-烷基嘌呤（核苷）类化合物；以6位是氢原子的嘌呤（核苷）类化合物和碘代烷烃为原料，在蓝光催化下发生烷基化反应，合成6-烷基嘌呤（核苷）类化合物；以6位是氯/碘原子的嘌呤（核苷）类化合物和Hantzsch Ester为原料，在蓝光催化下发生脱卤素反应，合成6位是氢原子的嘌呤（核苷）类化合物；以6位是氢原子的嘌呤（核苷）类化合物和芳香醛为原料，在硝酸银催化下发生酰基化反应，合成6-芳基酰基嘌呤（核苷）类化合物。本研究为嘌呤核苷的结构修饰提供了参考依据。.本项目共发表标注本项目编号（21602189）的论文5篇，其中SCI源期刊论文2篇；授权国家发明专利4项；作为第四完成人获得首届河南省专利奖一等奖1项；出版学术著作1部。