Design and Synthesis of Novel Thiazolo[5,4-d]pyrimidine Derivatives as Potential Angiogenesis Inhibitors.

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 3.52 µm, respectively). Compound 3l also showed the best potency against VEGFR-2 at 50 µm (98.5 %). These results suggest that further investigation of compound 3l might provide potential angiogenesis inhibitors.

Chronic olanzapine administration causes metabolic syndrome through inflammatory cytokines in rodent models of insulin resistance.

Olanzapine is a second-generation anti-psychotic drug used to prevent neuroinflammation in patients with schizophrenia. However, the long-term administration of olanzapine leads to insulin resistance (IR); the mechanisms of this effect remains poorly understood. Using cellular and rodent models of IR induced by olanzapine, we found that chronic olanzapine treatment induces differential inflammatory cytokine reactions in peripheral adipose and the central nervous system. Long-term treatment of olanzapine caused metabolic symptoms, including IR, by markedly elevating the plasma levels of pro-inflammatory cytokines, including IL-1ß, IL-6, IL-8 and TNFα; these findings are consistent with observations from schizophrenia patients chronically treated with olanzapine. Our observations of differential inflammatory cytokine responses in white adipose tissues from the prefrontal cortex in the brain indicated cell type-specific effects of the drug. These cytokines induced IR by activating NF-kB through the suppression of IkBα. Functional blockade of the components p50/p65 of NF-kB rescued olanzapine-induced IR in NIH-3T3 L1-derived adipocytes. Our findings demonstrate that olanzapine induces inflammatory cytokine reactions in peripheral tissues without adversely affecting the central nervous system and suggest that chronic olanzapine treatment of schizophrenia patients may cause inflammation-mediated IR with minimal or no adverse effects in the brain.

Phenyl and Diaryl Ureas with Thiazolo[5,4-d]pyrimidine Scaffold as Angiogenesis Inhibitors: Design, Synthesis and Biological Evaluation.

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 in 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 5.3 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.

Pyrimidinylacetamide-based 2-pyridylureas as Angiogenesis Inhibitors: Design, Synthesis and Biological Evaluation.

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.

Diarylureas and Diarylamides with Oxazolo[5,4-d]pyrimidine Scaffold as Angiogenesis Inhibitors.

A series of oxazolopyrimidine-based ureas and amides were designed, synthesized, and biologically evaluated for their antiproliferative and antiangiogenic activities. These compounds were identified to exhibit inhibitory activities against human umbilical vein endothelial cells (HUVEC) in vitro. Among these compounds, compound 22 effectively inhibited the migration and capillary-like tube formation of human umbilical vein endothelial cells. It also exhibited a concentration-dependent inhibition on capillary sprouting from the rat aorta rings. Preliminary mechanistic studies revealed that compound 22 suppressed protein kinases activation, by decreasing PI3K and ERK 1/2 phosphorylation. These results support the further investigation of this class of compounds as potential anticancer agents.

CPU-12, a novel synthesized oxazolo[5,4-d]pyrimidine derivative, showed superior anti-angiogenic activity.

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.

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

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.