Study On Synthesis And Anti-CML Activity Of 2-Aminoxazole And 2-Aminothiazole Dasatinib Derivatives

CML is a multifunctional hematopoietic stem cell malignant hyperplasia of the disease,which main feature is the abnormal protein Bcr-Abl kinase activity increased.Studies have shown that the mechanism by which Src family kinases may progress in the progression of chronic myeloid leukemia may be through induction of cytokines and apoptosis.Dasatinib(BMS-354825)is a potent Bcr-Abl kinase inhibitor.We use molecular docking and other computer drug design methods and bio-electronic isometric principle Me-too drug design method,using 2-aminothiazole instead of dasatinib’s aromatic amine structure,to transformate dasatinib.Until now we have synthesized splicing structure of 2-aminothiazole and 2-aminothiazole.We also attempted to modify the basic efficacy structure of dasatinib by designing a series of novel compounds that replace the thiazole nucleus and contain structural groups of pyrimidine and hydroxyethylpiperazine.Up to now we have synthesized four intermediates and three final products.The first chapter of this article briefly describes the chronic myeloid leukemia and its treatment,tyrosine kinase inhibitors and their advances in research,Dacitinib and research progress of its Synthetic Route.The second chapter is the experimental design part,introduces the basis of the subject,design ideas,research content and innovation.The third chapter is the synthesis experiment part,Synthesis of ethyl2-aminothiazole-5-carboxylate or ethyl 2-aminooxazole-5-carboxylate with ethyl acetoacetate and thiourea(or urea)as starting materials;3-ethoxyacryloyl chloride was obtained by removing the acid and taking off the carbon with cheap vinyl ether and oxalyl chloride as starting materials;and then the two substances react to get(E)-N-3-ethoxyacrylamide-4-methylthiazole-5-carboxylic acid ethyl ester;and synthesis the product 10 a with thiourea.Or ethyl 2-aminothiazole-5-carboxylate(or ethyl2-aminooxazole-5-carboxylate)is bound to pyrimidine to give 10b-e,And then combined with piperazine to get 10f-h.The fourth chapter is the active part,with dasatinib and imatinib as apositivecontrol,the new compounds are tested their anti-K562 activity,wherein the activity of 10(a,b,c,f)is better,and thiazole-based analogs 10 a,10b have been shown to be the most potent compounds compared to K562 cell lines,which are eight times more effective than imatinib.This may be a potent lead alternative to the current treatment of dasatinib or imatinib-resistant patients.