摘要/Abstract

作为开发新型有效抗癌药物的进一步工作, 采用分子杂交策略和路易斯酸催化偶联反应设计合成了一系列新型喹啉-吲哚类化合物. 使用噻唑蓝(MTT)法评估了所合成的化合物对人胃癌细胞(MGC-803)、人食管癌细胞(Kyse450)和人结肠癌细胞(HCT-116)的体外抑制活性. 其中, 2-氯-4-(5-甲氧基-1H-吲哚-3-基)喹啉(9b)展示较好的体外抗肿瘤活性, 对MGC-803、Kyse450和HCT-116三种人源癌细胞IC₅₀值分别为0.58, 0.60和0.68 µmol•L^–1, 优于阳性对照药5-氟尿嘧啶(5-Fu)对这三种肿瘤细胞的抑制活性. 进一步机制研究表明, 化合物9b能够剂量依赖地抑制人胃癌细胞MGC-803和HGC-27的增殖和克隆形成. 化合物9b能够诱导人胃癌细胞MGC-803和HGC-27内源性凋亡和下调相关凋亡蛋白的表达, 并使细胞周期阻滞在G2/M期. 以上结果表明, 化合物9b可以作为先导化合物, 用于进一步研究开发新型高效抗肿瘤药物.
关键词: 喹啉, 吲哚, 抗肿瘤活性, 增值, 凋亡, 细胞周期阻滞
As the continuation of our studies on novel and effective anti-cancer agents, a series of novel quinoline-indole derivatives were firstly designed and synthesized by molecular hybridization strategy and Lewis acid‐catalyzed coupling reactions. Their antiproliferative potency on gastric cancer cell line MGC-803, colon cancer cell line HCT-116, and esophageal cancer cell line Kyse450 of all the targeted compounds was explored using methyl thiazolyl tetrazolium (MTT) assay. 2-Chloro-4-(5-methoxy-1H-indol-3-yl)quinoline (9b) exhibited potently inhibitory activity against MGC-803, HCT-116, and Kyse450 cells with IC₅₀ values of 0.58, 0.68 and 0.59 µmol•L^–1. Further mechanism studies suggested that compound 9b inhibited the cell colony formation of MGC-803 and HGC-27 cells. Compound 9b induced an intrinsic apoptosis and down- regulated the levels of apoptosis related proteins in MGC-803 and HGC-27 cells. Meanwhile, compound 9b arrested MGC-803 and HGC-27 cells at the G2/M phase. Taken together, these results indicated that compound 9b might be a valuable lead compound for anticancer agents.
Key words: quinoline, indole, anticancer activity, proliferation, apoptosis, cell cycle arrest


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