2氨基噁唑和2氨基噻唑类达沙替尼类似物的合成及抗慢性白血病活性研究药学专业论文.docxVIP

AbstractABSTRACT Abstract ABSTRACT 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 arnl breaking point form Bcr—Abl fusion gene，whose product is an abnormal protein tyrosine kinase receptor P2 1 0．This protein is not required in conjunction、析t11 the corresponding ligand to autophosphorylation，and also cause a lot of important substrate protein phosphorylation，thereby activating multiple signal transducfion 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 T3 1 5I 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 ingoduced the research progress of anticancer drugs， chronic myeloid leukemia，clinical research progress of dasatinib and the research aim and significance of t