Synthesis and Biological Evaluation of Novel Oxazolo[5,4-d]pyrimidines as Potent VEGFR-2 Inhibitors

• Published in: Chemistry & biodiversity 2015-04, Vol.12 (4), p.528-537
• Main Authors: Deng, Ya-Hui, Xu, Dan, Su, Ye-Xiang, Cheng, Yi-Juan, Yang, Yan-Li, Wang, Xiu-Yun, Zhang, Juan, You, Qi-Dong, Sun, Li-Ping
• Format: Article
• Language: English
• Subjects: 4-d]pyrimidines; Adenosine Triphosphate - metabolism; Antiproliferative activity; Antitumor activity; Binding Sites; Cell Proliferation - drug effects; Chemistry Techniques, Synthetic; Drug Evaluation, Preclinical - methods; Human Umbilical Vein Endothelial Cells - drug effects; Humans; Inhibitory Concentration 50; Molecular Docking Simulation; Oxazolo; Oxazolo[5,4‐d]pyrimidines; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyrimidines - chemistry; Structure-Activity Relationship; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - metabolism; VEGFR-2 Inhibitor
• ISSN: 1612-1872; 1612-1880
• DOI: 10.1002/cbdv.201400270

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.