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.
引用
收藏
页数：16
相关论文
共 50 条
  • [31] 3-Hydroxy-1-[(morpholin-4-yl)methyl]pyridazin-6(1H)-one
    Santhi, P. R.
    Selvanathan, G.
    Poongothai, G.
    Srinivasan, T.
    Velmurugan, D.
    ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, 2013, 69 : O778 - +
  • [32] Discovery of 1,6-Naphthyridin-2(1H)-one Derivatives as Novel, Potent, and Selective FGFR4 Inhibitors for the Treatment of Hepatocellular Carcinoma
    Zhang, Xiaomeng
    Wang, Yazhou
    Ji, Jianfeng
    Si, Dongjuan
    Bao, Xueting
    Yu, Zhuangzhuang
    Zhu, Yueyue
    Zhao, Liwen
    Li, Wei
    Liu, Jian
    JOURNAL OF MEDICINAL CHEMISTRY, 2022, 65 (11) : 7595 - 7618
  • [33] Investigations on crystal structure of a novel 3-((4,6-dimethylpyrimidin-2-yl)amino)isobenzofuran-1(3H)-one, and related theoretical studies
    Yilmaz, Zeynep Tanrikulu
    Odabasoglu, H. Yasin
    Senel, Pelin
    Adimcilar, Veselina
    Erdogan, Taner
    Ozdemir, Ayse Daut
    Golcu, Aysegul
    Odabasoglu, Mustafa
    Buyukgungor, Orhan
    ARABIAN JOURNAL OF CHEMISTRY, 2020, 13 (06) : 5564 - 5580
  • [34] Synthesis of N-substituted derivatives of 2-(4-amino-2-methyl-1H-indol-3-yl)- and 2-(6-amino-2-methyl-1H-indol-3-yl)acetic acids
    Maklakov S.A.
    Smushkevich Yu.I.
    Magedov I.V.
    Chemistry of Heterocyclic Compounds, 2002, 38 (08) : 904 - 907
  • [35] Discovery of novel 3-(1H-pyrazol-4-yl)-1H-indazole derivatives as potent type II TRK inhibitors against acquired resistance
    Qin, Qiaohua
    Guo, Zhiqiang
    Lu, Shuyu
    Wang, Xin
    Fu, Qinglin
    Wu, Tianxiao
    Sun, Yixiang
    Liu, Nian
    Zhang, Haoyu
    Zhao, Dongmei
    Cheng, Maosheng
    EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2024, 264
  • [36] Discovery, Optimization, and Evaluation of Novel Pyridin-2(1H)-one Analogues as Potent TRK Inhibitors for Cancer Treatment
    Xu, Zichao
    Peng, Xia
    Zhang, Renjie
    Ji, Yinchun
    You, Mengke
    Wang, Danyi
    Shen, Yanyan
    Zheng, Mingyue
    Li, Chunpu
    Ai, Jing
    Liu, Hong
    JOURNAL OF MEDICINAL CHEMISTRY, 2024, 67 (02) : 1168 - 1183
  • [37] Design and Synthesis of Novel 1-((1-Phenyl-1H-1,2,3-triazol-4-yl)methyl)pyridin-2(1H)-one Derivatives
    Keskin, Selbi
    CHEMISTRYSELECT, 2023, 8 (32):
  • [38] Bis[(2,2-dimethylpropanoyloxy)methyl] {[2-(6-amino-9H-purin-9-yl)ethoxy]-methyl}phosphonate-succinic acid (2/1)
    Jung, Sungyup
    Ha, Jeong-Myeong
    Kim, Il Won
    ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, 2012, 68 : O809 - U2754
  • [39] New (3-(1H-benzo[d]imidazol-2-yl))/(3-(3H-imidazo[4,5-b]pyridin-2-yl))-(1H-indol-5-yl)(3,4,5-trimethoxyphenyl)methanone conjugates as tubulin polymerization inhibitors
    Mullagiri, Kishore
    Nayak, V. Lakshma
    Sunkari, Satish
    Mani, Geeta Sai
    Guggilapu, Sravanthi Devi
    Nagaraju, Burri
    Alarifi, Abdullah
    Kamal, Ahmed
    MEDCHEMCOMM, 2018, 9 (02) : 275 - 281
  • [40] Discovery of novel quinazoline-2,4(1H,3H)-dione derivatives as potent PARP-2 selective inhibitors
    Zhao, Hailong
    Ji, Ming
    Cui, Guonan
    Zhou, Jie
    Lai, Fangfang
    Chen, Xiaoguang
    Xu, Bailing
    BIOORGANIC & MEDICINAL CHEMISTRY, 2017, 25 (15) : 4045 - 4054
12345