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
  • [1] Crystal structures of the synthetic intermediate 3-[(6-chloro-7H-purin-7-yl)methyl]cyclobutan-1-one, and of two oxetanocin derivatives: 3-[(6-chloro-8,9-dihydro-7H-purin-7-yl)methyl]-cyclobutan-1-ol and 3-[(6-chloro-9H-purin-9-yl)methyl]cyclobutan-1-ol
    Yaseen, Ayat
    Hassan, Muhammad Murtaza
    Lee-Ruff, Edward
    Audette, Gerald F.
    ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, 2019, 75 : 732 - +
  • [2] Design, synthesis and biological evaluation of novel dihydroquinolin-4 (1H)-one derivatives as novel tubulin polymerization inhibitors
    Tan, Yuchen
    Hu, Han
    Zhu, Wenjian
    Wang, Tao
    Gao, Tian
    Wang, Hongqi
    Chen, Jian
    Xu, Jinyi
    Xu, Shengtao
    Zhu, Huajian
    EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2023, 262
  • [3] Synthesis of 3-amino-6-methyl-4-phenylpyridin-2(1H)-one and its derivatives
    Anton L. Shatsauskas
    Anton A. Abramov
    Elina R. Saibulina
    Irina V. Palamarchuk
    Ivan V. Kulakov
    Alexander S. Fisyuk
    Chemistry of Heterocyclic Compounds, 2017, 53 : 186 - 191
  • [4] Synthesis of 3-amino-6-methyl-4-phenylpyridin-2(1H)-one and its derivatives
    Shatsauskas, Anton L.
    Abramov, Anton A.
    Saibulina, Elina R.
    Palamarchuk, Irina V.
    Kulakov, Ivan V.
    Fisyuk, Alexander S.
    CHEMISTRY OF HETEROCYCLIC COMPOUNDS, 2017, 53 (02) : 186 - 191
  • [5] Discovery of novel 2-substituted 2, 3-dihydroquinazolin-4(1H)-one derivatives as tubulin polymerization inhibitors for anticancer therapy: The in vitro and in vivo biological evaluation
    Shi, Cai
    Yang, Boning
    He, Zhaolong
    Yang, Jingxiang
    Li, Ling
    Song, Jian
    Xu, Shiqiang
    Song, Wei
    Yang, Jian
    EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2024, 277
  • [6] Fluorinated derivatives of 2-phenyl-3-hydroxy-4(1H)-quinolinone as tubulin polymerization inhibitors
    Rehulka, Jiri
    Vychodilova, Kristyna
    Krejci, Petr
    Gurska, Sona
    Hradil, Pavel
    Hajduch, Marian
    Dzubak, Petr
    Hlavac, Jan
    EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2020, 192
  • [7] Discovery of Novel 3,4-Dihydro-2(1H)-Quinolinone Sulfonamide Derivatives as New Tubulin Polymerization Inhibitors with Anti-Cancer Activity
    Ma, Juan
    Gong, Guo-Hua
    MOLECULES, 2022, 27 (05):
  • [8] SAR of a series of 1H-and 3H-imidazo[4,5]pyridin-2-yl-pyridin-2(1H)-one and 9H-purin-8-yl-pyridin-2(1H)-one inhibitors of IGF-1R Kinase
    Ouellet, Carl
    Beaulieu, Francis
    Wittman, Mark D.
    Zimmermann, Kurt
    Carboni, Joan
    Lee, Francis Y.
    Balimane, Praveen
    Discenza, Lorell
    Greer, Ann
    Li, Aixin
    Yang, Zheng
    Banville, Jacques
    Martel, Alain
    Attar, Ricardo
    Gottartis, Marco
    Vyas, Dolatrai M.
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2007, 233 : 759 - 759
  • [9] Discovery of 3-(1-Amino-2-phenoxyethylidene)-6-methyl-2H-pyran-2,4(3H)-dione Derivatives as Novel Herbicidal Leads
    Wang, Chao-Chao
    Chen, Ke
    Li, Na
    Wang, Xue-Kun
    Wang, Shi-Ben
    Li, Pan
    Hua, Xue-Wen
    Lei, Kang
    Ji, Lu-Sha
    AGRONOMY-BASEL, 2023, 13 (01):
  • [10] Discovery of N-(3-((7H-purin-6-yl)thio)-4-hydroxynaphthalen-1-yl)-sulfonamide derivatives as novel protein kinase and angiogenesis inhibitors for the treatment of cancer: Synthesis and biological evaluation. Part III
    Xu, Fuming
    Xu, Hao
    Wang, Xuejian
    Zhang, Lei
    Wen, Qingli
    Zhang, Yingjie
    Xu, Wenfang
    BIOORGANIC & MEDICINAL CHEMISTRY, 2014, 22 (04) : 1487 - 1495
12345