Discovery of 3-(((9H-purin-6-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one derivatives as novel tubulin polymerization inhibitors for treatment of cancer

被引：11
|
作者：
Zhang, Qiangsheng [1 ,2 ,3 ]
Hu, Xi [1 ,2 ,3 ]
Wan, Guoquan [1 ,2 ,3 ]
Wang, Jia [1 ,2 ,3 ]
Li, Lu [1 ,2 ,3 ]
Wu, Xiuli [1 ,2 ,3 ]
Liu, Zhihao [1 ,2 ,3 ]
Yu, Luoting [1 ,2 ,3 ]
机构：
[1] Sichuan Univ, West China Med Sch, West China Hosp, State Key Lab Biotherapy, 17 3rd Sect,Ren Min South Rd, Chengdu 610041, Sichuan, Peoples R China
[2] Sichuan Univ, West China Med Sch, West China Hosp, Canc Ctr, 17 3rd Sect,Ren Min South Rd, Chengdu 610041, Sichuan, Peoples R China
[3] Collaborat Innovat Ctr Biotherapy, 17 3rd Sect,Ren Min South Rd, Chengdu 610041, Sichuan, Peoples R China
来源：
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 184卷
关键词：
Microtubule; Tubulin polymerization inhibitors; Anti-cancer agents; Colorectal carcinoma; BIOLOGICAL EVALUATION; CELL-GROWTH; POTENT; DESIGN; ANALOGS; TARGET; IDENTIFICATION; MICROTUBULES; RESISTANCE; PURINES;
D O I：
10.1016/j.ejmech.2019.111728
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
A new series of 3-(((9H-purin-6-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one derivatives were designed, synthesized and demonstrated to act as tubulin polymerization inhibitors. These new derivatives showed significant antitumor activities, among which SKLB0533 demonstrated to be the most potent compound, with IC50 values ranging from 44.5 to 135.5 nM against seven colorectal carcinoma (CRC) cell lines. Remarkably, SKLB0533 exhibited no activity against other potential targets, such as 420 kinases and EZH2. Besides, SKLB0533 inhibited tubulin polymerization, arrested the cell cycle at the G2/M phase and induced apoptosis in CRC cells. Furthermore, SKLB0533 suppressed tumour growth in the HCT116 xenograft model without inducing notable major organ-related toxicity, suggesting that SKLB0533 could be used as a promising lead compound for the development of new antitumor agents. (C) 2019 Elsevier Masson SAS. All rights reserved.
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页数：16
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