2. Academic Validation
  3. Synthesis and biological evaluation of aurora kinases inhibitors based on N-trisubstituted pyrimidine scaffold

Synthesis and biological evaluation of aurora kinases inhibitors based on N-trisubstituted pyrimidine scaffold

  • Eur J Med Chem. 2018 Feb 10:145:805-812. doi: 10.1016/j.ejmech.2017.12.082.
Liang Long 1,  Yu Luo 1,  Zhi-Jie Hou 2,  Hua-Juan Ma 1,  Zi-Jie Long 3,  Zheng-Chao Tu 4,  Lin-Jie Huang 1,  Quentin Liu 5,  Gui Lu 6
Affiliations

Affiliations

  • 1 Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
  • 2 Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, PR China.
  • 3 Department of Hematology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, PR China.
  • 4 Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, PR China.
  • 5 State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou 510060, PR China; Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, PR China. Electronic address: liuq9@mail.sysu.edu.cn.
  • 6 Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China. Electronic address: lugui@mail.sysu.edu.cn.
PMID: 29358147 DOI: 10.1016/j.ejmech.2017.12.082
Abstract

The inhibition of the members of Aurora Kinase family using ATP-competitive small molecules is an effective method for Anticancer therapeutics. Based on our previous work, we synthesized 12 new N-trisubstituted pyrimidine derivatives and evaluated their biological activities and stabilities. Among them, compound 11j showed the best inhibition against Aurora A kinase (IC50 = 7.1 nM), human leukemia cell line U937 (IC50 = 12.2 nM) and the growth of U937 xenograft tumors in vivo. By the flow cytometry and immunofluorescence analysis of U937, we found that compound 11j can induced polyploidy formation including (4N, 8N and 16N) and induce defects in both chromosome alignment and spindle formation. Furthermore, compound 11j exhibited good chemical, physical, and thermal stabilities. All these results suggested that 11j is a promising lead compound for further development of Anticancer drugs.

Keywords

Anticancer drug; Aurora kinase inhibitor; Leukemia; N-trisubstituted pyrimidines; Synthesis.

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