胡椒碱-双环酰胺衍生物的设计、合成及抗宫颈癌活性

Design,Synthesis and Anti-cervical Cancer Activity of Piperine-bicycloamide Derivatives

以胡椒碱为母核进行结构改造,合成了一系列胡椒碱-双环酰胺衍生物;并用核磁共振氢谱(1H NMR),核磁共振碳谱(^(13)C NMR)和高分辨质谱(HRMS)进行了结构确证.噻唑蓝(MTT)比色法测试结果表明,目标化合物对肾细胞(293T)、宫颈癌(HeLa)和乳腺癌(MDA-MB-321)细胞有良好的抑制活性,大多数衍生物对HeLa细胞的抑制活性优于阳性对照药5-氟尿嘧啶(5-FU)和胡椒碱.化合物6b对HeLa细胞的抗增殖活性最高,半数抑制浓度(IC_(50))为3.49μmol/L,对MDA-MB-321细胞的IC50值为20.89μmol/L.机理研究发现,化合物6b不仅可有效抑制HeLa细胞的迁移、侵袭、黏附和克隆能力,而且对HeLa细胞肿瘤异种移植物的生长表现出强烈的抑制作用.因此,化合物6b有可能成为肿瘤治疗中潜在的先导化合物.

In this paper,a series of piperine-dicycloamide derivatives was synthesized using piperine as parent nucleus,and their structures were confirmed by means of nuclear magnetic resonance hydrogen spectroscopy(1H NMR),nuclear magnetic resonance carbon spectroscopy(^(13)C NMR)and high-resolution mass spectrometry(HRMS).Methyl thiazolyl tetrazolium(MTT)assay showed that these compounds had good inhibitory effects on kidney cells(293T),cervical cancer(HeLa)and breast cancer(MD-MB-321).Most derivatives had better inhibitory activity on HeLa cells than positive controls fluorouracil(5-FU)and piperine,and compound 6b had the highest anti-proliferative activity on HeLa cells.The half maximal inhibitory concentration(IC50)of MDA-MB-321 cells was 3.49μmol/L,and the IC_(50) of MDA-MB-321 cells was 20.89μmol/L.The mechanism study showed that compound 6b not only effectively inhibited the migration,invasion,adhesion and cloning ability of HeLa cells,but also showed a strong inhibitory effect on the growth of xenografts of HeLa cells.Therefore,compound 6b has the potential to be a lead compound in tumor therapy.