Design, Synthesis And Biological Activity Evaluation Of PI3K, VEGFR-2 Inhibitors

A kinase can transfer phosphate group from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. It is crucial in cell growth and proliferation. On the base of substrates type, kinases contain lipid kinase, protein kinase and so on. Over-expression of kinase is always been found in tumors. The field of kinase inhibitor dicovery has advanced dramatically since the launches of the first kinase inhibitor, imatinib. Here we choose PI3K and VEGFR-2 as target to do some research.This dissertation mainly consists of two parts:1) Design, synthesis and biological activity evaluation of acetohydrazone and 4-morpholinopyrimidine analogues as P13K inhibitors; 2) Design, synthesis and biological activity evaluation of pyrimidine analogues as VEGFR-2 inhibitors.1) Design, synthesis and biological activity evaluation of acetohydrazone and 4-morpholinopyrimidine analogues as PI3K inhibitors.The phosphoinositide 3-kinases (PI3K.s) are a family contains three distinct classes of lipid kinases, playing key roles in cell growth and metabolism. By catalyzing the phosphorylation of the 3’-hydroxyl group of phosphatidylinositols to form phosphatidylinositol 3,4,5-triphosphate (PIP3), which regulates cell growth, survival and proliferation. PI3K is a promising theraputic target since the deregulation of this signaling pathway was found in a wide variety of human cancers.Firstly, using Astellas Pharma’s PIK-75, a potent PI3K inhibitor, as lead compound, we designed and synthesized 48 acetohydrazone analogues by employing bioisoster replacement. Biological study, such as inhibition on DNA-PK, isoform selectivity and time/quantity-dependent relationship on Rh30/U87MG, showed that some analogues are superior to PIK-75.Secondly, we designed and synthesized fourteen 4-morpholinopyrimidine analogues, seeking for PI3K inhibitors with novel scaffold. Cytotoxicity activity of these analogues against Rh30 was evaluated. Most of the new compounds exhibited good activity. The most potent compound,3-8, had an IC50 of 0.8 μM. This indicates that 4-morpholinopyrimidine is a novel scaffold for PI3K inhibitor and deserves further structure modification.2) Design, synthesis and biological activity evaluation of pyrimidine analogues as VEGFR-2 inhibitors.Angiogenis, the formation of new blood vessels from pre-existing vessels, is a normal and vital process in cell growth and development, as well as in woud healing and female reproductive cycling. Tumor angiogenesis is a prerequisite for tumor growth as it is a fundmental step in the growth and transfer of tumor. This makes angiogenis inhibition a promising therapeutic strategy against cancer. Vascular endothelial growth factor-2 (VEGFR-2) is very important in the direct regulation of angiogenis, mitiogenic signaling, and permeability-enhacing effects. It is expressed at high level in many kinds of cancers. ATP-competitive VEGFR-2 inhibitors have been approved by FDA, such as Sunitinib, Sorafenib, Vandetanib, Pazopanib and Axitinib.Using GSK’s Pazopanib as lead compound, we designed and synthesized two series of pyrimidine analogues by employing hybrid design strategy. Twenty nine 2,4-substitued diaryl urea analogues and eighteen 4,6-substitued indole analogues are obtained as new scaffolds. Some of analogues show potent inhibitory activity.4-39 and 4-61 have an IC50 of 0.3 nM and 3.8 nM, respectively.In addition, we designed and synthesized 3 series of twenty derived NCTD, an analogue of our traditional Chinese medicine cantharidin, and screened their cytotoxic activities against HL60 and A549 cancer cell lines in vitr0.5-14 was obtained with HL60 cell line inhibitory activity.