RESUMO
Vascular endothelial growth factor receptor-2 (VEGFR-2) plays an important role in both vasculogenesis and angiogenesis. Inhibition of VEGFR-2 has been demonstrated as a key method against tumor-associated angiogenesis. Thiazolopyrimidine is an important analog of the purine ring, and we choose the thiazolopyrimidine scaffold as the mother nucleus. Two series of thiazolo[5,4-d]pyrimidine derivatives were synthesized and evaluated for their antiproliferative activity. In HUVEC inhibition assay, compounds 3l (=1-(5-{[2-(4-chlorophenyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]amino}pyridin-2-yl)-3-(3,4-dimethylphenyl)urea) and 3m (=1-(5-{[2-(4-chlorophenyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]amino}pyridin-2-yl)-3-(4-methoxyphenyl)urea) exhibited the most potent inhibitory effect (IC50 =1.65 and 3.52â µm, respectively). Compound 3l also showed the best potency against VEGFR-2 at 50â µm (98.5 %). These results suggest that further investigation of compound 3l might provide potential angiogenesis inhibitors.
Assuntos
Inibidores da Angiogênese/síntese química , Desenho de Fármacos , Pirimidinas/química , Tiazóis/química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Neovascularização Fisiológica/efeitos dos fármacos , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Angiogenesis is crucial for tumor growth and inhibition of angiogenesis has been regarded as a promising approach for cancer therapy. Vascular endothelial growth factor receptor-2 (VEGFR-2) is an important factor in angiogenesis. In this work, a novel series of thiazolo[5,4-d]pyrimidine derivatives inhibiting angiogenesis were rationally designed and synthesized. Their inhibitory activities against human umbilical vein endothelial cells (HUVEC) were investigated inâ vitro. 1-(4-Fluorophenyl)-3-{4-[(5-methyl-2-phenyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl)amino]phenyl}urea (19b) and 1-(3-Fluorophenyl)-3-{4-[(5-methyl-2-phenyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl)amino]phenyl}urea (19g) exhibited the most potent inhibitory effect on HUVEC proliferation (IC50 =12.8 and 5.3â µm, respectively). Compound 19g could inhibit the migration of human umbilical vein endothelial cells. These results support the further investigation of these compounds as potent anticancer agents.
Assuntos
Inibidores da Angiogênese/farmacologia , Desenho de Fármacos , Neovascularização Patológica/tratamento farmacológico , Tiazóis/farmacologia , Ureia/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Ureia/análogos & derivados , Ureia/química , Cicatrização/efeitos dos fármacosRESUMO
BACKGROUND: VEGFR-2 inhibitors have been widely used in the treatment of cancer. In our continued efforts to search for potent and novel VEGFR-2 inhibitors as antitumor agents, we have identified a series of ureas and amides bearing a oxazolopyrimidine scaffold. AIM OF THE STUDY: To discover more potent VEGFR-2 inhibitors with stronger binding affinity and better physical and chemical properties. METHODS: 23 pyrimidinylacetamide-based ureas were designed and synthesized. Replacement of oxazolopyrimidine with a pyrimidinylacetamide generated a series of novel VEGFR-2 inhibitors. RESULTS AND CONCLUSIONS: In HUVEC inhibition assay, the most potent compound (compound 16) possessed an IC50 value of 0.43 µM. Compound 16 also inhibited the migration and capillary like tube formation of HUVECs with inhibition rate at 22% (1 µM) and 17.5% (0.8 µM) respectively. These results support the further investigation of compound 16 as a potential anti-cancer agent.