Synthesis And Antitumor Activity Evaluation Of Imatinib Derivatives

Cancer has become the leading cause of death worldwide,and is the major threat to human health.Currently,antitumor drugs have made significant progress in the field of treatment,the design and synthesis of anti-cancer drugs with high efficiency,low toxicity and high selectivity is particularly important in the field of drug research and development.Imatinib,a small-molecule tyrosine kinase inhibitor,mainly targets three tyrosine kinase receptors including Bcr-Ab1,c-Kit and PDGFR receptors,and is also widely used in the treatment of other receptor-related tumor diseases.At present,imatinib has achieved remarkable curative effect in the treatment of CML,but with its wide application in clinical,the problems of drug resistance,adverse reaction and off-target effect caused by imatinib have also attracted people’s attention.To solve the above-mentioned problems,but the synthesis of novel tyrosine kinase inhibitors is still a hot research topic in the field of antitumor drugs.Therefore,in order to obtain potential drug candidates for clinical therapy,a series of imatinib derivatives were designed,synthesized and evaluated their biological activity.Based on the structure-activity relationship of imatinib in this study,A series compounds were obtained by replacing the hydrophobic group N-methylpiperazine structure with a novel small molecule amine through the principle of bioisosteric;keeping the key intermediate of imatinib,imaacid,then using the principle of drug splicing method,B series compounds were designed and synthesized by splicing the dominant fragments into the structure of imaacid.A total of 20 target compounds of the two series A and B compounds were confirmed by ¹H NMR,¹³C NMR and HR-MS spectra,and the antitumor activities of these target compounds were preliminarily evaluated by MTT assay in vitro.Among them,compound A-02,A-04,A-05,A-06,A-07,A-08,A-09,A-10,B-05,B-07 and B-09 showed good inhibitory activities,especially compound A-08 exhibited antiproliferative activities against MDA-MB-231,MCF-7,He La and A498 cell lines with IC₅₀values of 21.45μmol·L^-1,33.57μmol·L^-1,45.18μmol·L^-1,and 31.00μmol·L^-1,respectively.Besides,the results of cell scratch,cell adhesion,cell invasion and cell apoptosis assay showed that A-08 inhibited the proliferation of cancer cells in a dose-dependent manner,and all showed good inhibitory effect and it is worth further study.The thesis has 27 figures,11 tables and 98 references.