芳香环并咪唑环类凋亡抑制蛋白抑制剂的设计、合成与抗肿瘤活性评价

目的设计并合成新的小分子凋亡抑制蛋白抑制剂。方法运用计算机辅助药物设计模拟靶蛋白与目标分子的结合作用,设计并合成新结构的化合物,以紫杉醇作为阳性对照,进行与多个凋亡抑制蛋白的结合实验和多个细胞系的抗肿瘤细胞增殖抑制活性评价,并比较目标物对癌细胞的抑制率。结果合成两个系列共21个目标化合物,部分化合物表现出对多个凋亡抑制蛋白有强烈的抑制活性(纳摩尔级)和对多种肿瘤细胞的抑制能力,其中,ⅡA-1活性最为突出,对XIAP L-BIR2-BIR3抑制作用的IC50值为77.2 nmol·L-1;对乳腺癌细胞系MDA-MB-231的抑制率为70.9%,相同条件下紫杉醇的抑制率仅为38.5%。结论合成的部分化合物有较好的活性,将为今后此类凋亡抑制蛋白抑制剂的研究奠定基础。

Design, synthesis and antitumor activity evaluation of IAPs inhibitors characterized by aromatic benzimidazole

Two series （ Ⅰ / Ⅱ ） of IAPs inhibitors characterized by aromatic benzimidazole were designed based on CADD to imitate the link between target protein and target molecule. Twenty-one compounds were designed and synthesized. These compounds were tested for XIAP-BIR3/XIAP-BIR2-BIR3/cIAP1-BIR3 using a fluorescence polarization assay（FPA） and cell growth inhibition of SK-OV-3 and MDA-MB-231. Some of these compounds bind to XIAP and cIAP1 with low nanomolar affinities and show strong inhibition to cancer cell to contrast with paclitaxel. Compound IIA-1 shows high affinity to XIAP-BIR2-BIR3 with IC50 values of 77.2 nmol.L-1 and inhibits cancer cell（ MDA-MB-231 ） growth with rate 70. 9% at 1 p, mol.L-I while paclitaxel is 38.5% under the same conditions. The SAR laid the foundation for bivalent inhibitor were concluded.