Discovery of 4-((4-(4-(3-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)ureido)-2-fluorophenoxy)-6-methoxyquinolin-7-yl)oxy)-N, N-diethylpiperidine-1-carboxamide as kinase inhibitor for the treatment of colorectal cancer
Discovery of 4-((4-(4-(3-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)ureido)-2-fluorophenoxy)-6-methoxyquinolin-7-yl)oxy)-N, N-diethylpiperidine-1-carboxamide as kinase inhibitor for the treatment of colorectal cancer
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DOI：
10.1016/j.bioorg.2020.104511
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发表时间：
2021-01-01
影响因子：
5.1
通讯作者：
Qi, Baohui
中科院分区：
文献类型：
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作者：
Zhou, Yuting;Xu, Xingwei;Qi, Baohui
本研究在前期工作的基础上，设计并合成了一系列新型的含噻唑烷酮的4，6，7-三取代喹啉类似物。其中，最有效的化合物15I，4-((4-(4-(3-(2-(2，6-difluorophenyl)-4-oxothiazolidin-3-yeureido)-2-fluorophenoxy)-6-methoxyquinolin-7-yl)oxy)-N，N-二乙基哌啶-1-甲酰胺被鉴定为一种多激酶抑制剂。体外抑瘤实验结果表明，化合物15I对HT-29细胞具有较强的抗肿瘤活性，其IC50值为0.19 mU/M，是雷戈拉非尼的14.5倍。在细胞方面，IncuCyte活细胞成像分析证实，对HT-29细胞具有显著的抗增殖、细胞毒性和诱导凋亡作用，并呈剂量和时间依赖关系。此外，化合物15I通过阻止细胞周期进入G2/M期而强烈诱导细胞凋亡。在10.0微克/毫升或更低的浓度下，化合物15I对人正常大肠黏膜上皮细胞FHC无抗增殖和细胞毒性作用，表明化合物15I对正常细胞的毒性远低于瑞可非尼。基于上述发现，将进行进一步的结构改造，以开发更有效的激酶抑制剂作为抗癌剂。
In this study, a novel series of 4,6,7-trisubstituted quinoline analogues bearing thiazolidinones were designed and synthesized based on our previous study. Among them, the most potent compound 15i, 4-((4-(4-(3-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yeureido)-2-fluorophenoxy)-6-methoxyquinolin-7-yl)oxy)-N,N-diethylpiperidine-1-carboxamide was identified as a multi-kinase inhibitor. The results of MTT assay revealed in vitro antitumor activities against HT-29 cells of compound 15i with an IC50 value of 0.19 mu M which was 14.5-fold more potent than that of Regorafenib. In the cellular context, significant antiproliferation, cytotoxicity and induction of apoptosis on HT-29 cells in a dose- and time-dependent manner were confirmed by IncuCyte live-cell imaging assays. Moreover, compound 15i strongly induced apoptosis by arresting cell cycle into the G2/M phase. No antiproliferation and cytotoxicity against human normal colorectal mucosa epithelial cell FHC was observed at 10.0 mu g/mL or lower concentrations which indicated that the toxicity to normal cells of compound 15i was much lower than that of Regorafenib. Based on the above findings, further structural modification will be conducted for the development of more potent kinase inhibitors as anticancer agents.