新型微管稳定剂吲哚美辛衍生物的合成与抗肿瘤活性研究

目的设计合成一系列吲哚美辛衍生物并测定其体外抗肿瘤和微管蛋白抑制活性。方法以5-甲氧基-2-甲基-3-吲哚乙酸为起始原料经两步酰化反应合成12个化合物,MTT法检测目标化合物对HT29、A549、Hep-2、MCF-7肿瘤细胞的抑制活性,同时采用浊度法评价其体外微管蛋白的抑制作用。结果 12种目标化合物均呈现了优于吲哚美辛的体外抗肿瘤作用和微管蛋白抑制活性,其中3位羧基侧链苯乙基取代的化合物12作用于人结肠癌细胞HT29的IC_(50)(2.2μmol)为吲哚美辛的400倍,并且可以干扰微管聚合,其作用于微管蛋白的IC_(50)为5.6μmol。结论改变吲哚美辛1位酰胺和3位羧酸侧链所得的系列衍生物是一类新型的以微管为靶点的抗肿瘤候选药物。

Synthesis and anticancer activity of indomethacin analogues targeting tubulin

Objective To design and synthesize a series of indomethacin derivatives,and to evaluate the activity of antitumor and tubulin interfering.Methods The target compounds were synthesized through two acylation using 5-methoxy-2-methyl-3-indoleacetic acid as starting material.The antitumor activities against HT29,A549,Hep-2 and MCF-7 were assayed by MTT.The turbidity method was used to evaluate the anti-tubulin activity.Results Inhibitory effects of most compounds on tumor cells and tubulin were higher than the positive control indomethacin.Moreover,the compound 12 was generated from substituted products with phenethyl at the 3rd position of the carboxyl,and showed the lowest IC50 value of 2.2 μmol (400 times of indomethacin) against HT29 and 5.6 μmol against tubulin.Conclusion The indomethacin derivatives replaced by much flexible groups or polar groups at the position of amide and carboxyl chain are a novel and potential antitumor drug targeted on tubulin.