2. Academic Validation
  3. Quinoxalinone (Part II). Discovery of (Z)-3-(2-(pyridin-4-yl)vinyl)quinoxalinone derivates as potent VEGFR-2 kinase inhibitors

Quinoxalinone (Part II). Discovery of (Z)-3-(2-(pyridin-4-yl)vinyl)quinoxalinone derivates as potent VEGFR-2 kinase inhibitors

  • Bioorg Med Chem. 2016 Apr 15;24(8):1840-52. doi: 10.1016/j.bmc.2016.03.008.
Leilei Shi 1,  Jianfeng Zhou 2,  Jifeng Wu 3,  Junya Cao 4,  Yuemao Shen 1,  Hua Zhou 5,  Xun Li 6
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Key Laboratory of Chemistry and Chemical Biology (Ministry of Education), Shandong University, Ji'nan, Shandong 250012, PR China.
  • 2 School of Medicine and Pharmacy, Ocean University of China, Qingdao 266100, PR China.
  • 3 Institute of Criminal Science and Technology, Ji'nan Public Security Bureau, Ji'nan 250100, PR China.
  • 4 School of Medicine, Shandong University, Ji'nan 250012, PR China.
  • 5 Department of Chemistry, Texas A & M University, College Station, TX 77842, USA.
  • 6 School of Pharmaceutical Sciences, Key Laboratory of Chemistry and Chemical Biology (Ministry of Education), Shandong University, Ji'nan, Shandong 250012, PR China. Electronic address: tjulx2004@sdu.edu.cn.
PMID: 26968648 DOI: 10.1016/j.bmc.2016.03.008
Abstract

Inhibition of VEGFR-2 kinase has been highlighted as one of the well-defined strategies to suppress tumor growth via blockade of angiogenesis. Guided by the principles of bioisosteric replacement and pharmacophoric fragment migration, a series of novel quinoxalinone derivates were designed, synthesized and evaluated for their VEGFR-2 inhibitory potencies. Among them, compounds 7c, 8b, 8c, 8e and 10b displayed antiangiogenic abilities via the in vitro tube formation assay (cellular level) and ex vivo rat aortic ring assay (tissue level) at a low concentration (0.1 μM). By means of in vivo zebrafish embryo model, two (Z)-3-(2-(pyridin-4-yl)vinyl)quinoxalinone derivates 8c and 8e showed significant antiangiogenesis effects, suggesting they have potentials to be developed into antiangiogenesis agents via further structural optimization. Moreover, these two compounds also demonstrated potent inhibition toward VEGFR-2 and B-raf kinases in a low concentration (1 μM). A possible interpretation of our evaluation result has been presented by a molecular docking study by docking representative compound 8c with VEGFR-2.

Keywords

Activity evaluation; Antiangiogenesis; Pyridyl motif; Quinoxalinone derivates; VEGFR-2 inhibitor.

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