Synthesis and biological evaluation of novel oxazolo[5,4-d]pyrimidines as potent VEGFR-2 inhibitors. 2015

Ya-Hui Deng, and Dan Xu, and Ye-Xiang Su, and Yi-Juan Cheng, and Yan-Li Yang, and Xiu-Yun Wang, and Juan Zhang, and Qi-Dong You, and Li-Ping Sun
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).

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.

UI MeSH Term Description Entries
D011743 Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
D004353 Drug Evaluation, Preclinical Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications. Drug Screening,Evaluation Studies, Drug, Pre-Clinical,Drug Evaluation Studies, Preclinical,Drug Evaluations, Preclinical,Evaluation Studies, Drug, Preclinical,Evaluation, Preclinical Drug,Evaluations, Preclinical Drug,Medicinal Plants Testing, Preclinical,Preclinical Drug Evaluation,Preclinical Drug Evaluations,Drug Screenings,Screening, Drug,Screenings, Drug
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000255 Adenosine Triphosphate An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. ATP,Adenosine Triphosphate, Calcium Salt,Adenosine Triphosphate, Chromium Salt,Adenosine Triphosphate, Magnesium Salt,Adenosine Triphosphate, Manganese Salt,Adenylpyrophosphate,CaATP,CrATP,Manganese Adenosine Triphosphate,MgATP,MnATP,ATP-MgCl2,Adenosine Triphosphate, Chromium Ammonium Salt,Adenosine Triphosphate, Magnesium Chloride,Atriphos,Chromium Adenosine Triphosphate,Cr(H2O)4 ATP,Magnesium Adenosine Triphosphate,Striadyne,ATP MgCl2
D001665 Binding Sites The parts of a macromolecule that directly participate in its specific combination with another molecule. Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D047428 Protein Kinase Inhibitors Agents that inhibit PROTEIN KINASES. Protein Kinase Inhibitor,Inhibitor, Protein Kinase,Inhibitors, Protein Kinase,Kinase Inhibitor, Protein,Kinase Inhibitors, Protein
D049109 Cell Proliferation All of the processes involved in increasing CELL NUMBER including CELL DIVISION. Cell Growth in Number,Cellular Proliferation,Cell Multiplication,Cell Number Growth,Growth, Cell Number,Multiplication, Cell,Number Growth, Cell,Proliferation, Cell,Proliferation, Cellular
D060326 Chemistry Techniques, Synthetic Methods used for the chemical synthesis of compounds. Included under this heading are laboratory methods used to synthesize a variety of chemicals and drugs. Inorganic Synthesis,Inorganic Synthesis Methods,Inorganic Synthesis Techniques,Methods of Inorganic Synthesis,Methods of Organic Synthesis,Methods of Peptide Synthesis,Organic Synthesis,Organic Synthesis Methods,Organic Synthesis Techniques,Peptide Synthesis Methods,Peptide Synthesis Techniques,Peptide Synthesis, Synthetic,Synthetic Chemistry Techniques,Synthetic Peptide Synthesis,Chemistry Technique, Synthetic,Inorganic Syntheses,Inorganic Synthesis Method,Inorganic Synthesis Technique,Method, Inorganic Synthesis,Method, Organic Synthesis,Method, Peptide Synthesis,Methods, Inorganic Synthesis,Methods, Organic Synthesis,Methods, Peptide Synthesis,Organic Syntheses,Organic Synthesis Technique,Peptide Syntheses, Synthetic,Peptide Synthesis Method,Peptide Synthesis Technique,Syntheses, Inorganic,Syntheses, Organic,Syntheses, Synthetic Peptide,Synthesis Method, Inorganic,Synthesis Method, Peptide,Synthesis Methods, Inorganic,Synthesis Methods, Peptide,Synthesis Technique, Inorganic,Synthesis Technique, Organic,Synthesis Technique, Peptide,Synthesis Techniques, Inorganic,Synthesis Techniques, Organic,Synthesis Techniques, Peptide,Synthesis, Inorganic,Synthesis, Organic,Synthesis, Synthetic Peptide,Synthetic Chemistry Technique,Synthetic Peptide Syntheses,Technique, Inorganic Synthesis,Technique, Organic Synthesis,Technique, Peptide Synthesis,Technique, Synthetic Chemistry,Techniques, Inorganic Synthesis,Techniques, Organic Synthesis,Techniques, Peptide Synthesis,Techniques, Synthetic Chemistry
D061307 Human Umbilical Vein Endothelial Cells Endothelial cells that line venous vessels of the UMBILICAL CORD. Human Umbilical Vein Endothelial Cell,Endothelial Cells, Human Umbilical Vein,HUVEC Cells,Cell, HUVEC,Cells, HUVEC,HUVEC Cell

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