凋亡抑制蛋白抑制剂的设计合成与抗肿瘤活性评价

目的设计并合成具有抗肿瘤活性的小分子凋亡抑制蛋白广泛性抑制剂。方法运用基于靶点结构的药物设计策略改造前期得到的苗头化合物，设计合成新结构化合物，并进行多靶点的凋亡抑制蛋白家族（IAPs）结合实验和多个细胞系的肿瘤细胞增殖抑制活性评价。结果合成了25个新结构化合物，部分表现出较强的IAPs抑制活性和多种肿瘤细胞增殖抑制能力（微摩尔级别），Ⅱc系列化合物显示出较强的ciAP1选择性（〉1000）。结论五元杂环烷当中的4s-甲基是化合物对两类IAPs产生选择性差异的结构基础。

Design, synthesis and evaluation of biological activity of IAPs inhibitors for the treatment of cancer

Inhibitor apoptosis proteins （IAPs） exert a range of biological activities that promote cancer cell survival and proliferation. To find small-molecule antagonist of IAPs for the treatment of cancer, a series of LAPs antagonists based on thiazohdine and oxazolidine were designed and synthesized. 25 Target compounds were synthesized and identified by MS and 1H-NMR. These compounds were tested for binding to the XIAP/cIAP1-BIR3 using a fluorescence polarization assay（FPA） and cell growth inhibition with 3 cell lines using MTT/WST-8/ELISA assay. Compounds lib showed potent activity against SK-OV-3 and Hela cell lines. Compounds lie showed high affinities（Ki 〈3 nmol.L-1 ） and selectivity（ 〉 1000） for cIAP1. Preliminary structure-activity relationship was concluded from this research. The 4 （S）-Me is important for ciAP1- selectivity, and the affinities for XlAP-BIR3 is crucial for the cell growth inhibition.