吲哚-3-甲酰胺类化合物的合成及抗肿瘤活性研究

Design,synthesis and biological activities of 1H-indole-3- carboxamide derivatives as the antitumor agents

目的初步探讨吲哚-3-甲酰胺类化合物的合成及其抗肿瘤活性。方法根据已报道的吲哚类化合物的构效关系数据,以具有抗肿瘤细胞增殖活性的N-(3-溴苯基)-6-甲氧基-9H-嘧啶并[4,5-b]吲哚-4-胺作为先导化合物,利用分子对接技术设计了一系列吲哚-3-甲酰胺类化合物,再经数步化学反应合成得到了目标化合物,并采用MTT法测试了目标化合物的抗肿瘤细胞增殖活性。结果以乙酰乙酸乙酯作为起始原料,经亲核取代反应、Nenitzescu吲哚合成法、水解反应、缩合反应、Williamson醚合成法得到目标化合物,所有目标化合物结构均经质谱、红外光谱和核磁共振氢谱确证。其抗肿瘤活性筛选结果表明,部分化合物对EGFR阳性表达的人肺癌细胞株A549、人宫颈癌细胞株HeLa和人结肠癌细胞株SW480具有显著的抑制作用,对EGFR阴性表达人肝癌细胞株HepG2抑制效果不佳,同时大部分目标化合物对人正常肝脏细胞株HL7702没有抑制作用。结论吲哚-3-甲酰胺类化合物具有显著的抗肿瘤细胞增殖活性,且对正常细胞具有较低毒性,有望成为具有全新结构的新型EGFR抑制剂。

Malignant tumor is a major disease that affects human health.As known,EGFR signaling pathways are closely related to various physiological activities of tumor cells.Because tumor cells are susceptible to mutations to develop resistance,discovering novel EGFR inhibitors remains the focus of antitumor drug development.Taking N-(3-bromophenyl)-6-methoxy-9H-pyrimido[4,5-b]indole-4-amine with antitumor cell proliferation activity as a lead compound,a new series of indole-3-carboxamide compounds were designed by using docking methods.Using ethyl acetoacetate as a starting material,the target compounds were yielded by nucleophilic substitution reaction,Nenitzescu indole synthesis,hydrolysis reaction,condensation reaction,and Williamson ether synthesis.The structures of all target compounds were confirmed by MS,IR and^1H-NMR.The antitumor activity screening results showed that some compounds had potent inhibition on human lung cancer cell line A549,human cervical cancer cell line HeLa and human colon cancer cell line SW480,but had little inhibition on human liver cancer cell line HepG2.At the same time,most target compounds had no inhibitory effect on human normal liver cell line HL7702.In conclusion,the indole-3-carboxamide compounds have significant antitumor proliferative activity,and have low toxicity to normal cells,which are expected to become a new type of EGFR inhibitors ■.