Preparation Of Pyrazole [3,4-b] Pyridine Derivative XY-4 Cationic Liposomes And Study On It's Antitumor Activity In Combination With SiRNA

With the rapid development of molecular biology,genomics and proteomics,it has been found that many of the abnormal overexpression of the kinase can directly lead to the instability of the chromosome,which causes miss of a variety of anti-cancer factors and the the regulation of cancer protein and lead to the occurrence of cancer,so the cancer-related kinase as a therapeutic target designed synthesis of kinase inhibitors widespread concern.Aurora kinase is a class of important serine / threonine kinases responsible for regulating cell mitosis,and among them,Aurora-A is the most important and most important subtype of Aurora kinase.It is involved in the regulation of apoptosis and mitosis.The dysfunction of its function directly leads to the instability of chromosome,and the occurrence of cancer is related to this instability.In the early stage,Aurora-A kinase was used as a potential target for anticancer therapy,and a series of Aurora-A kinase inhibitor pyrazole [3,4-b] pyridine compounds were designed and synthesized by computer-assisted.The compound XY-4 was found to have the effect of inhibiting the proliferation of tumor cells in a variety of tissues,especially the IC50 of mouse melanoma cell B16 is 5.5?M,but its poor water solubility limited it's further research and development.Compared with the direct use of chemical therapy,liposomes as a carrier of transmission of chemotherapy drugs and diagnostic materials,can increase the solubility of drugs,reduce system toxicity and increase the drug cycle time.In particular,some functional liposomes such as pH-sensitive liposomes,temperature-sensitive liposomes,liposomes linked to transmembrane peptides,cationic liposomes,etc.,are targeted and precisely treated effect.Gene delivery is a method of introducing exogenous small interfering RNA(siRNA)into cancer cells to silence its anti-apoptotic gene expression and thereby promote tumor cell apoptosis to achieve the purpose of treating cancer.Based on the above research background,in order to improve the water solubility of XY-4,this subject has been prepared XY-4 as a water-soluble cationic liposome.The average particle size of the cationic liposomes was 91.31 nm and was monodispersed in water(polydispersity index = 0.183).In order to achieve better therapeutic effect,we then interacted with B16 cells with XY-4 cationic liposomes and Bcl-xl small interfering RNA(siRNA)to form liposome-gene complexes.The results showed that the complexes in vitro has a synergistic effect.Then,we further studied the anti-tumor mechanism of XY-4 cationic liposome combined with Bcl-xl siRNA.According to the results of Western-blotting,the mechanism may be related to the mechanism of mitochondrial apoptosis.