凋亡抑制蛋白抑制剂的设计、合成及体外活性初步评价  

Design,synthesis and preliminary activity evaluation in vitro of IAPs inhibitors

作　　者：顾为[1] 谭祖磊[1] 李斐[1] 汤立合[1] 陶林[1] 苏瑞斌[1] 聂爱华[1] 

机构地区：[1]军事医学科学院毒物药物研究所,北京100850

出　　处：《中国药物化学杂志》2010年第1期1-10,共10页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(30873136)

摘　　要：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。Aim To find small molecule inhibitors of inhibitor apoptosis proteins （LAPs）. Methods Combining with Dock method and basing on the structure of active site of XIAP-BIR3 binding to Smac and Caspase-9, two series target compounds were designed and synthesized. Fluorescence polarization anisotropy （FPA） competitive test were used to evaluate the inhibitory activity of these target compounds against XIAP-BIR3 and cIAP1-BIR3. Results Sixteen peptidomimeptics were synthesized and their structures were identified by MS and ^1H-NMR. Binding assay（FPA） showed that the thiazolidine derivatives Ⅱ had obvious inhibitory activity against XIAP and cIAP1. Especially, the IC50 values of compound Ⅱ f against XIAP-BIR3 and cIAP1-BIR3 were 0. 29 and 0. 055 μmol· L^-1 respectively. Conclusion New LAPs inhibitors were discovered. The preliminary structure-activity relationship concluding from this research will give a foundation for the further structural optimization of these IAPs inhibitors.

关 键 词：凋亡抑制蛋白 抑制剂 荧光极化各向异性(FPA)竞争试验法 设计 合成 

分 类 号：R914[医药卫生—药物化学]