Design,Synthesis And Antitumor Activity Evaluation Of Imatinib Derivatives

Chronic Myelogenous Leukemia（CML）is the result of mutations in pluripotent stem cells.The incidence ranks third in leukemia.The cause of the disease is the mutated Philadelphia（Ph）chromosome,on which the c-ABL gene of chromosome 9 interacts with the BCR gene of chromosome 22 to form a new Bcr-Abl fusion gene.Imatinib can effectively and selectively inhibit Bcr-Abl kinase by competitively binding with adenosine triphosphate kinase（ATP）or the substrates,so it has a significant effect on the treatment of CML.Most of the confirmed patients have a long-lasting response to imatinib.However,the frequent relapses and the gradual development of resistance in the patients have led researchers to develop much more effective Bcr-Abl kinase inhibitors.Indibulin can destroy the stability of tumor cells and microtubules in cell-free systems by selectively preventing cell cycle progression in G2/M phase.Compared with taxane and vinblastine,Indibulin has no neurotoxicity at therapeutic doses and is also effective for multidrug-resistant tumor cells.Indibulin has great potential in the treatment of various malignant tumors.Therefore,this thesis applied the hybridization strategy of dominant fragments,designed three series of imatinib derivatives,splicing the structure of6-methyl-N-[4-（pyridin-3-yl）pyrimidin-2-yl]benzene-1,3-diamine of Imatinib with the structure of 3-（2-amino-2-oxoacetyl）-1H-indole of Indibulin together,and explored the effect of this structural modification on the anti-tumor activity of the compounds.In this thesis,21 new compounds were synthesized by chemical methods,and their structures were confirmed by ¹H NMR,¹³C NMR,and HR-MS.The in vitro anti-tumor activity of these compounds was detected by MTT method,and molecular docking software was used to evaluate the derivatives with better activity.The experimental results show that the derivatives of A series all have certain inhibitory activity on Bcr-Abl,among which the compound 16b had the best activity,with IC₅₀value was 2.49μM for K562cells.The derivatives of the B series had more alkyl substituents at the 1-position of the indole ring than the A series,and the overall activity was slightly worse than that of the A series.It was likely that the substituent increased the steric hindrance and prevented the compound from binding to the target protein pocket.Compared with the corresponding compounds of the A series,two compounds of the C series,16t and 16u,lack a carbonyl group on the 3-position side chain of the indole,and their activity was slightly worse than that of the A series.This suggested that the double carbonyl group was beneficial to increase the activity of the compound.