新型3,5-二取代1H-吲哚衍生物的合成及抗肿瘤活性研究

Syntheses and Anticancer Evaluations of Novel 3,5-disubstituted-1H-indole Derivatives

新型抗肿瘤药物研究是全球药物开发的重点任务之一。鉴于前期我们发现3,5-二取代1H-吲哚衍生物具有明显抗胰腺癌活性,本文通过维尔斯迈尔-哈克反应、仲胺的叔丁氧羰基(Boc)保护、醛还原、羧酸与胺的缩合等反应获得了一条高效简洁的3-取代硫甲基-5-酰氨基吲哚衍生物合成路线,并合成了8个新化合物11a^11h。经细胞活性测试发现,它们对胰腺癌细胞株BxPC-3均有较好抑制活性,其中11e活性最高,IC_(50)为2.28μmol/L。对多种肿瘤细胞及人正常肝细胞HL-7702的抑制活性测试表明,11e为特异性BxPC-3抑制剂而非细胞毒化合物。鉴于此,11e可能是一个较好的抗胰腺癌苗头化合物,值得进一步深入研究。

Study on new anticancer drugs is one of the key tasks of global drug development. We previously found that 3,5-disubstituted-1H-indole derivatives have apparent inhibitory activity against pancreatic cancer cells.Here we reported a new simple and efficient route for the synthesis of 3-（（substituted-thio） methyl）-5-acylamino-1 Hindole derivatives,which involves Vilsmeier-Haack reaction,Boc protection of secondary amine,aldehyde reduction,carboxylic acid and amine condensation reaction,and eight new target compounds（11 a - 11 h） were synthesized.The cell-based assays revealed that 11 a - 11 h have good inhibitory activity against pancreatic cancer cell line BxPC-3,and 11 e is the most potent compound with an IC50 value of 2. 28μmol/L. 11 e was observed to have no/low activity to other tested cancer cell lines and human normal liver cell line HL-7702,indicating that it is not a cytotoxic compound. Overall,11 e may be a good hit compound for further efforts to develop new inhibitors against pancreatic cancer.