Molecular Design And Modification Of Dasatinib Derivatives As Anti-leukemia Drug

Chronic myeloid leukemia(CML)was a great threat to human health.As a dual kinase inhibitor,Dasatinib can inhibit tyrosine kinase activity and cell proliferation(except for T315I)directly,which qualifies it as an commonly drug for CML.Therefore,discovery of novel kinase inhibitors with good efficacy is signifiant.Molecular docking,as a widely used computer-aided molecular design method,plays an important role in the drug design.We used the concept of computer-aided drug design and Click reaction to design and synthesize a novel series of dasatinib derivatives for the treatment of leukemia.In theory,the dasatinib derivatives show potential biological activity against CML,Which was explored by use molecular docking and compared with dasatinib.Then N-arylpropargylamides were synthesized by using propiolic acid and 14 kinds of arylamines as raw materials and the reaction conditions were optimized.Finally,8 kinds of N-arylpropargylamides were synthesized by using 8 kinds of arylamines and propiolic acid respectively.On the other hand,3 kinds of 4-azido-2-methyl-6-(4-alkylpiperazin-1-yl)-pyrimidines were synthesized by using 4,6-dichloro-2-methylpyrimidine and piperazine derivatives as raw material.The copper catalyzed "Click reaction" was used in the process of modules N-arylpropiolamides and 4-azido-2-methyl-6-(4-alkylpiperazin-1-yl)pyrimidines combined,which provided about 24 dasatinib derivatives.The final compounds were characterized with ’H NMR、13C NMR、IR and HRMS,and provided in experimental section.We will complete the activity test and comparison.These compounds can be used as lead compounds for the further development of novel inhibitors which can overcome resistance to imatinib.