Design, synthesis and pharmacological evaluation of new 3-(1Hbenzimidazol-2-yl)quinolin-2(1H)-one derivatives as potential antitumor agents
Design, synthesis and pharmacological evaluation of new 3-(1Hbenzimidazol-2-yl)quinolin-2(1H)-one derivatives as potential antitumor agents
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新型3-(1H-苯并咪唑-2-基)喹啉-2(1H)-酮衍生物作为潜在抗肿瘤药物的设计、合成和药理学评价
DOI：
10.1016/j.ejmech.2018.07.066
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发表时间：
2018-09-05
影响因子：
6.7
通讯作者：
Zhang, Ye
中科院分区：
文献类型：
--
作者：
Kuang, Wen-Bin;Huang, Ri-Zhen;Zhang, Ye
设计并合成了一系列新的3-（1H-苯并咪唑-2-基）喹啉-2（1H）-酮衍生物（5a（1）-5d（6））。体外抗肿瘤活性实验结果表明，部分化合物对HepG 2、SK-OV-3、NCI-H460和BEL-7404肿瘤细胞具有中到高度的抑制活性，而大部分化合物对HL-7702正常细胞的细胞毒性远低于5-FU和顺铂。体内抗肿瘤测定结果表明，5a（3）在NCI-H460异种移植小鼠模型中显示出对肿瘤生长的有效抑制，并且5d（3）在BEL-7402异种移植模型中显示出优异的抗增殖活性。这些结果表明，5a（3）和5d（3）都可以作为抗癌药物的候选者。机制研究表明，化合物5a（3）和5d（3）通过上调Bax、胞内Ca 2+释放、ROS产生、下调Bcl-2、激活caspase-9和caspase-3并随后裂解PARP、抑制CDK活性和激活p53蛋白来发挥其抗肿瘤活性。(C)2018 Elsevier Masson SAS。All rights reserved.
A series of new 3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one derivatives (5a(1)-5d(6)) were designed and synthesized as antitumor agents. In vitro antitumor assay results showed that some compounds exhibited moderate to high inhibitory activity against HepG2, SK-OV-3, NCI-H460 and BEL-7404 tumor cell lines, and most compounds exhibited much lower cytotoxicity against the HL-7702 normal cell line compared to 5-FU and cisplatin. In vivo antitumor assay results demonstrated that 5a(3) exhibited effective inhibition on tumor growth in the NCI-H460 xenograft mouse model and that 5d(3) displayed excellent antiproliferative activity in the BEL-7402 xenograft model. These results suggested that both 5a(3) and 5d(3) could be used as anticancer drug candidates. Mechanistic studies suggested that compounds 5a(3) and 5d(3) exerted their antitumor activity by up-regulation of Bax, intracellular Ca2+ release, ROS generation, downregulation of Bcl-2, activation of caspase-9 and caspase-3 and subsequent cleavage of PARP, inhibition of CDK activity and activation of the p53 protein. (C) 2018 Elsevier Masson SAS. All rights reserved.