凋亡抑制蛋白抑制剂的设计、合成及体外活性初步评价

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个新肽类化合物，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、0.055 μmol·L^-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。

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

Aim To find small molecule inhibitors of inhibitor apoptosis proteins(IAPs).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 ...