Discovery of arylamide-5-anilinoquinazoline-8-nitro derivatives as VEGFR-2 kinase inhibitors: synthesis, in vitro biological evaluation and molecular docking
By: Yongqiang Zhao, Feifei Liu, Guojing He, Ke Li, Changcheng Zhu, Wei Yu, Conghai Zhang, Mingjin Xie, Jun Lin, Jihong Zhang, Yi Jin
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, P. R. China
Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming, 650500, P. R. China
Biomedical Department, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Kunming, 650118, P. R. China
Institute of Drug Research and Development, Kunming Pharmaceutical Corporation, Kunming, 650100, P. R. China
Pharmaceutical Department, Kunming General Hospital of Chengdu Military Command, Kunming, 650118, P. R. ChinaBioorganic & Medicinal Chemistry Letters, Available Online
Bioorganic & Medicinal Chemistry Letters, Available Online
doi.org/10.1016/j.bmcl.2019.126711
Publication Date (Web): October 19, 2019
Document Type: Article
Abstract
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.
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https://www.sciencedirect.com/science/article/pii/S0960894X19306699
