ZL006衍生物的设计、合成及神经保护活性研究

Design,synthesis and biological evaluation of ZL006Derivatives as neuroprotective agents

目的:探究突触后密度蛋白95(PSD95)-神经元型一氧化氮合酶(neuronal nitric oxide synthase,nNOS)解耦联剂ZL006(1)的构效关系,探明其解偶联机制。方法:以前期研究发现的PSD95-nNOS解耦联剂ZL006(1)为先导化合物,通过对其亲脂端、连接臂和水杨酸结构3部分进行修饰,设计合成了4个系列共21个ZL006衍生物,其结构均经^(1)H NMR、^(13)C NMR和ESI-MS确认。采用LDH实验测试目标化合物对谷氨酸诱导损伤的人神经母细胞瘤细胞(SH-SY5Y)的保护作用,以CCK-8染色法测试了目标化合物的细胞毒性。结果:大部分化合物对细胞具有保护活性,其中化合物5e和27a与阳性对照化合物ZL006的神经保护活性相当(10μmol/L时51.24%、48.42%),化合物23表现出优于ZL006的细胞保护活性(10μmol/L时54.34%,1μmol/L时29.58%),并表现出较低的细胞毒性(25μmol/L时2.85%)。结论:研究丰富了PSD95-nNOS解耦联剂的结构类型,并对其应用于神经保护提供了借鉴。

Objective:The aimofthestudywasto explore the structure⁃activity relationship of PSD95⁃nNOS decoupling agent ZL006(1),and the mechanism of decoupling.Methods:Basedon the PSD95⁃nNOS protein⁃protein interaction inhibitor ZL006 reported by our group,four series of 21 novel ZL006 derivatives were designed andsynthesized by modifying its lipophilic part,linker and Salicylic acid structure.All the structures were confirmed by ^(1)H NMR,^(13)C NMR and ESI⁃MS.The protective effect of the target compounds on glutamate⁃induced damage of human neuroblastoma cells(SH⁃SY5Y)was tested by LDH experiment,and the cytotoxicity of the target compounds was tested by CCK⁃8 staining.Results:Most of the compounds had protective activity against cells,among which compounds 5e and 27a were comparable to the neuroprotective activity of the positive control compound ZL006(51.24%,48.42%at 10μmol/L),and compound 23 showed better cytoprotective activity than ZL006(54.34%at 10μmol/L,29.58%at 1μmol/L)and showed lower cytotoxicity(2.85%at 25μmol/L).Conclusion:This study not only enriches the diversity of chemical structures suitable for PSD95⁃nNOS protein⁃protein interaction but also provides a useful tool to further explore the neuroprotection therapeutic potential.