2. Academic Validation
  3. Design, synthesis and SAR of novel 7-azaindole derivatives as potential Erk5 kinase inhibitor with anticancer activity

Design, synthesis and SAR of novel 7-azaindole derivatives as potential Erk5 kinase inhibitor with anticancer activity

  • Bioorg Med Chem. 2023 Oct 14:95:117503. doi: 10.1016/j.bmc.2023.117503.
Qin Zhang 1,  Xintao Gao 1,  Xiyu Duan 1,  Han Liang 1,  Mingyuan Gao 1,  Dianquan Dong 1,  Chuanlong Guo 2,  Longjiang Huang 3
Affiliations

Affiliations

  • 1 State Key Laboratory Base for Eco-Chemical Engineering, College of Chemical Engineering, Qingdao University of Science and Technology, 266042 Qingdao, Shandong, China.
  • 2 State Key Laboratory Base for Eco-Chemical Engineering, College of Chemical Engineering, Qingdao University of Science and Technology, 266042 Qingdao, Shandong, China. Electronic address: gcl_cpu@126.com.
  • 3 State Key Laboratory Base for Eco-Chemical Engineering, College of Chemical Engineering, Qingdao University of Science and Technology, 266042 Qingdao, Shandong, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College, 100050 Beijing, China. Electronic address: huanglj@qust.edu.cn.
PMID: 37862935 DOI: 10.1016/j.bmc.2023.117503
Abstract

The extracellular signal-regulated kinase 5 (ERK5) signaling plays a crucial role in Cancer, and regulating its activity may have potential in Cancer chemotherapy. In this study, a series of novel 7-azaindole derivatives (4a-5o) were designed and synthesized. Their antitumor activities on human lung Cancer A549 cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 4',6-diamidino-2-phenylindole (DAPI) staining and colony formation assay. Among them, compounds 4a, 4 h, 5d and 5j exhibited good anti-proliferative activity with the IC50 values of 6.23 µg/mL, 8.52 µg/mL, 7.33 µg/mL and 4.56 µg/mL, respectively, equivalent to ERK5 positive control XMD8-92 (IC50 = 5.36 µg/mL). The results of structure-activity relationships (SAR) showed that double bond on the piperidine ring and N atoms at the N7 position of 7-azaindole was essential for their antiproliferative activity. Furthermore, compounds 4a and 5j exhibited good inhibition on ERK5 kinase through Western blot analysis and possible action site of compounds with ERK5 kinase was elucidated by molecular docking.

Keywords

7-Azaindole; A549 cells; Anti-proliferative activity; Erk5; Molecular docking; SAR.

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