Quinoxalinone (Part II). Discovery of (Z)-3-(2-(pyridin-4-yl)vinyl)quinoxalinone derivates as potent VEGFR-2 kinase inhibitors |
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| Institution: | 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;1. Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran;2. Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China;1. College of Life Science and Bioengineering & Beijing Key Laboratory of Environmental and Oncology, Beijing University of Technology, Beijing 100124, China;2. Beijing Scitech-MQ Pharmaceuticals Limited, Beijing 101320, China;3. Guangxi Key Laboratory Cultivation Base for Polysaccharide Materials and Modifications, School of Marine Science and Biotechnology, Guangxi University for Nationalities, Nanning 530008, China;1. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt;2. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt;1. Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China;2. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China;3. Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA;4. Beijing Institute of Radiation Medicine, Beijing 100850, China;5. Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan |
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| 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. |
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| Keywords: | VEGFR-2 inhibitor Quinoxalinone derivates Antiangiogenesis Pyridyl motif Activity evaluation |
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