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目的设计并合成凋亡抑制蛋白(IAPs)小分子抑制剂。方法基于对Smac和Caspase-9分别与XIAP-BIR3结合位点的分析,辅以分子对接实验,设计并合成两类结构的化合物;采用荧光极化各向异性(FPA)竞争试验法测定合成的目标化合物对XIAP和cIAP1的抑制活性。结果合成两类结构共16个新类肽化合物,其结构经MS和1H-NMR谱确证;荧光极化各向异性(FPA)竞争试验结果显示,噻唑烷环衍生物Ⅱ对XIAP-BIR3和cIAP1-BIR3具有显著的抑制活性,其中,化合物Ⅱf抑制XIAP-BIR3和cIAP-BIR3的IC50值分别为0.29、0.055μmo.lL-1。结论发现了新的IAPs抑制剂,并得出初步构效关系,为进一步的结构优化奠定了基础。
Objective To design and synthesize small molecule inhibitor of apoptosis inhibitory protein (IAPs). Methods Based on the analysis of the binding sites of Smac and Caspase-9 to XIAP-BIR3 and the molecular docking experiments, two structures of compounds were designed and synthesized. The fluorescence intensity-anisotropic (FPA) Inhibitory activity of the target compounds on XIAP and cIAP1. Results A total of 16 new classes of peptide compounds were synthesized and their structures were confirmed by MS and 1H-NMR spectra. Fluorescence polarization anisotropy (FPA) competition test results showed that the thiazolidine ring derivativesⅡhave the effects on XIAP-BIR3 and cIAP1 - BIR3 had significant inhibitory activity. Among them, the IC50 values of compound Ⅱf for inhibiting XIAP-BIR3 and cIAP-BIR3 were 0.29,0.055μmo.lL-1, respectively. Conclusion The new inhibitors of IAPs were found and the preliminary structure-activity relationship was obtained, which laid the foundation for further structural optimization.