2-Aminoxazole And 2-Aminothiazole Dasatinib Derivatives As Potent Inhibitors Of Chronic Myeloid Leukemia K562 Cells

Chronic myeloid leukemia is the first malignant tumor which was found in fixed cytogenetic abnormalities.Its main cause is due to a reciprocal translocation between chromosomes 9 and 22,oncogene Abl transferred to long arm breaking point form Bcr-Abl fusion gene,whose product is an abnormal protein tyrosine kinase receptor P210.This protein is not required in conjunction with the corresponding ligand to autophosphorylation,and also cause a lot of important substrate protein phosphorylation,thereby activating multiple signal transduction pathway and leading to the excessive cell proliferation,abnormal differentiation and blocked apoptosis.Present study suggests that,Bcr-Abl protein abnormally high levels of tyrosine kinase activity is the main cause of occurrence of CML.Dasatinib,A double-effect inhibitor for Scr and Abl kinase,was used in the treatment of CML patients with imatinib-resistant or intolerant to imatinib.Be different from Imatinib which can only act on the non-activated state of the ATP binding site,dasatinib in combination with an activated or non-activated state of the ATP active area.Unfortunately,dasatinib was resistant to T315I mutant and had many side effects,such as fever,pleural effusion,febrile neutropenia,gastrointestinal bleeding,pneumonia,thrombocytopenia,dyspnea,anemia,diarrhea,and heart failure.This study is intended to base on the ATP binding site of dasatinib and Abl protein and the structure-activity relationships of 2-amino thiazoles.According to the principle of "Me-too" drugs smallest modification,we synthesized a series of compounds by modifying the thiazole ring to the isosteres oxazole ring and retaining the basic skeleton of the lead compound.Then we screened efficient and low toxicity analogs of dasatinib.In the first chapter,we introduced the research progress of anticancer drugs,chronic myeloid leukemia,clinical research progress of dasatinib and the research aim and significance of this experiment.In the second chapter,we reviews the synthetic route of dasatinib and experimental course which was adopted in this experiment,and experimental mechanism and experimental results were discussed step by step.The third chapter is the synthetic experimental section.The synthetic route was mentioned in the previous.With ethyl vinyl ether and oxalyl chloride as a starting material,we get the(E)-3-ethoxyacryloyl chloride by removing HCl and high temperature decarburization,and then we get the(E)-3-ethoxy-N-aryl-propenamide by slowly putting(E)-3-ethoxyacryloyl chloride to aromatic amine,then cyclized with thiourea(or urea)to give the 2-Amino-N-aryl-thiazole(oxazole)-5-carboxamide,and then combined with the pyrimidine to give 6a-e,7a-e,and finally combined with piperazine to give 8a-e,9a-e.The fourth chapter is the active part.We do anti-K562 activity test of new compounds,with dasatinib and imatinib as positive control.Among others,8a,8b and 9a,9b had better activity,oxazole compound 9b(IC50 = 3.8 nM)was proved to be the highest activity compound against K562 cells,it can be used as a lead compound in future research.