title: CPU-12, a novel synthesized oxazolo[5,4-d]pyrimidine derivative, showed superior anti-angiogenic activity.
abstract: Angiogenesis is a crucial requirement for malignant tumor growth, progression and metastasis. Tumor-derived factors stimulate formation of new blood vessels which actively support tumor growth and spread. Various of drugs have been applied to inhibit tumor angiogenesis. CPU-12, 4-chloro-N-(4-((2-(4-methoxyphenyl)-5-methyloxazolo[5,4-d] pyrimidin-7-yl)amino)phenyl)benzamide, is a novel oxazolo[5,4-d]pyrimidine derivative that showed potent activity in inhibiting VEGF-induced angiogenesis in vitro and ex-vivo. In cell toxicity experiments, CPU-12 significantly inhibited the human umbilical vein endothelial cell (HUVEC) proliferation in a dose-dependent manner with a low IC50 value at 9.30 ± 1.24 μM. In vitro, CPU-12 remarkably inhibited HUVEC's migration, chemotactic invasion and capillary-like tube formation in a dose-dependent manner. In ex-vivo, CPU-12 effectively inhibited new microvessels sprouting from the rat aortic ring. In addition, the downstream signalings of vascular endothelial growth factor receptor-2 (VEGFR-2), including the phosphorylation of PI3K, ERK1/2 and p38 MAPK, were effectively down-regulated by CPU-12. These evidences suggested that angiogenic response via the induction of VEGFR through distinct signal transduction pathways regulating proliferation, migration and tube formation of endothelial cells was significantly inhibited by the novel small molecule compound CPU-12 in vitro and ex-vivo. In conclusion, CPU-12 showed superior anti-angiogenic activity in vitro.
authors.affiliation: Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Jiping
authors.initials: J
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Drug Design & Optimization, and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Deng
authors.affiliation: Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Drug Design & Optimization, and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yijuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Manzo
authors.initials: M
authors.lastname: Lawali
authors.affiliation: Jiangsu Key Laboratory of Drug Design & Optimization, and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: chslp@cpu.edu.cn.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Sun
authors.affiliation: Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: liuyuyaoda@163.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
mesh_terms: D020533:Angiogenesis Inhibitors; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D010080:Oxazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; C000608203:CPU-12; D010080:Oxazoles; D011743:Pyrimidines; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Angiogenesis; Oxazolo[5,4-d]pyrimidine derivatives; Receptor tyrosine kinase (RTK) inhibitor; The rat aortic ring assay; Vascular endothelial growth factor receptor (VEGFR)