Design, Synthesis And Screening Of Protein Tyrosine Kinase Inhibitors

Protein tyrosine kinases (PTKs) are a class of proteins which catalyze a varietyof substrate phosphorylation of tyrosine residues in the enzyme, which can catalyzethe transfer of γ-phosphate of ATP to the tyrosine residues of many important the baseand to the residue phosphorylated, thereby causing the growth of tumor cells. PTKs insignal transduction within cells play a very large role in the path, a series of cells fromgrowing in vivo physiological process by which regulate death, which is alsoassociated with tumor cell proliferation, differentiation, migration and apoptosis isimportant Contact. Because it is important to contact the tumor, we aim to achieveanti-tumor, it can block the tyrosine kinases signal transduction method to destroytumor cells, leading to apoptosis of tumor cells.Traditional chemotherapies for tumor selectivity is not strong and side effect isobvious in clinical, so with the gradually clarification of tumor pathogenesis,moreattentions are paid on the research of the new anticancer drugs which act on specificmolecular targets, especially the studies of small molecule inhibitors which regardprotein tyrosine kinases as target spots have become the hot points of the research oninternational anti-tumor drugs, having broad prospects. Many protein tyrosine kinasesand cancer are closely related, the clinical studies have shown that over-expression ordecreased expression of important target protein tyrosine kinases may have theevaluation of prognostic value on the people who suffer from cancer. Targeted drugsthat treat protein tyrosine kinases as targets and that may aim at specific targets arenot only good for cancer treatment, but their side effects for normal cells are muchsmaller than traditional chemotherapy drugs.In this paper, we adopted protein tyrosine kinases as targets to design andsynthesize small molecule inhibitors of them. Dasatinib is selected as a referen-ces to transform its structure design a series of Abl、Src dual receptor tyrosinekinase inhibitors, in order to find the best drugs on treating chronic myelocytic leukemia activity, more selective, more broad-spectrum drugs with better anti-tumor effects.This paper also selected Dasatinib which is a kind of inhibitor of the Abl,Src dual inhibition to skeleton transition, in order to avoid patent protection，the paper replaced Dasatinib’s sulfur with selenium according to isostere princi-ple, thus determine the2-methyl-5-carbonyl-1,3-selenazoles as the nucleus stru-cture.Through the review of the literature and studying some dasatinib’s syntheticroutes as a reference, we design and improved synthetic route of target compounds.Eventually, I designed30target compounds in this paper and got20target compoundsthrough nine-step reaction, these structures were all confirmed by ESI-MS and1H-NMR.Target compounds were also screened in the Abl, Src kinases. The result showthat, in10μM concentrations, most of the Abl kinase and Src kinases were inhibited,wherein the compound of Abl, Src kinase inhibitory rate of greater than70%.Afterrescreening these12compounds we found that among the six compounds amongthem are similar with positive control drug activity, in which the active compound ismore competitive than the positive drug. This article provided the basis not only forthe discovery of highly active Abl, Src tyrosine kinase inhibitor targeting double, butalso for the further study of protein tyrosine kinase inhibitors...