title: Synthesis and biological evaluation of novel oxazolo[5,4-d]pyrimidines as potent VEGFR-2 inhibitors.
abstract: Tumor angiogenesis is mediated by vascular endothelial growth factor receptor (VEGFR) and other protein kinases. Inhibition of these kinases presents an attractive approach for developing anticancer therapeutics. In this work, a series of 2,5,7-trisubstituted oxazolo[5,4-d]pyrimidines were synthesized, and their inhibitory activities were investigated against VEGFR-2 and human umbilical vein endothelial cells (HUVEC) in vitro. Compound 9n exhibited the most potent inhibitory activity with IC50 values of 0.33 and 0.29 μM for VEGFR-2 kinase and HUVEC, respectively. A further kinase selectivity assay revealed that these compounds exhibit good VEGFR and moderate EGFR inhibitory activities. Docking analysis suggested a common mode of interaction at the ATP-binding site of VEGFR-2.
authors: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, P. R. China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, P. R. China (phone: +86-25-83271445; fax: +86-25-83271351).
authors: Ya-Hui
authors: YH
authors: Deng
authors: Dan
authors: D
authors: Xu
authors: Ye-Xiang
authors: YX
authors: Su
authors: Yi-Juan
authors: YJ
authors: Cheng
authors: Yan-Li
authors: YL
authors: Yang
authors: Xiu-Yun
authors: XY
authors: Wang
authors: Juan
authors: J
authors: Zhang
authors: Qi-Dong
authors: QD
authors: You
authors: Li-Ping
authors: LP
authors: Sun
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical / Q000379:methods; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000255:Adenosine Triphosphate; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Antiproliferative activity; Antitumor activity; Oxazolo[5,4-d]pyrimidines; VEGFR-2 Inhibitor