Discovery of arylamide-5-anilinoquinazoline-8-nitro derivatives as VEGFR-2 kinase inhibitors: Synthesis, in vitro biological evaluation and molecular docking
- Bioorg Med Chem Lett. 2019 Dec 1;29(23):126711. doi: 10.1016/j.bmcl.2019.126711.
- 1. Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China.
- 2. Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, PR China.
- 3. Biomedical Department, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, PR China. Electronic address: [email protected].
- 4. Institute of Drug Research and Development, Kunming Pharmaceutical Corporation, Kunming 650100, PR China.
- 5. Pharmaceutical Department, Kunming General Hospital of Chengdu Military Command, Kunming 650118, PR China.
- 6. Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China. Electronic address: [email protected].
- 7. Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, PR China. Electronic address: [email protected].
- 8. Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China. Electronic address: [email protected].
Herein, we embarked on a structural optimization campaign aiming at the discovery of novel Anticancer agents with our previously reported XL-6f as a lead compound. A library of 23 compounds has been synthesized based on the highly conserved active site of VEGFR-2. Several title compounds exhibited selective inhibitory activities against VEGFR-2, which also displayed selective anti-proliferation potency against HepG2 cell. All synthesized compounds were evaluated for anti-angiogenesis capability. Compound 7o showed the most potent anti-angiogenesis ability, the efficient cytotoxic activities (in vitro against HUVEC and HepG2 cell lines with IC50 values of 0.58 and 0.23 µM, respectively). The molecular docking analysis revealed 7o is a Type-II inhibitor of VEGFR-2 kinase. In general, these results indicated these arylamide-5-anilinoquinazoline-8-nitro derivatives are promising inhibitors of VEGFR-2 for the potential treatment of anti-angiogenesis.