Design, Synthesis And Antitumor Activity Study Of Imatinib And Its Derivatives

Tumor continues to exist and endanger human health, and becomes the first major threat to human life. In recent years, selective inhibition of protein kinases is an important therapeutic approach for the treatment of human cancers. As the first successful targeted drug to cure cancer, imatinib opened the era of molecular targeting therapy and established a model for the development of future drug.As a part of our research program, we have directed our efforts towards developing a practical and novel strategy to synthesize imatinib with simple starting materials and reactions. By our efforts, an efficient procedure for the synthesis of imatinib was developed by using two pivotal intermediates:the amine, which could be obtained with5practical steps in57%overall yield, and4-((4-methylpiperazin-1-yl)methyl)benzoicacid dihydrochloride, which was prepared from commercial available4-(chloromethyl)benzonitrile via substitution and hydrolysis reactions in89%overall yield. This route, avoiding the use of cyanamide and having good yield, is suitable for large scale preparation.Pyrimidines are recongnized as one of the major classes of selective tyrosine kinase inhibitors, recently, efforts exerted on potent analogs of imatinib have been the focus of many studies, such as Nilotinib, INNO-406, Dastinib, AEE788, et al. In addition, some investigations have comfirmed that substituted thiazole moieties exhibit antitumor activities. To obtain more potent antitumor agents, a series of thiazolyl moiety containing pyrimidine compounds based on imatinib were designed and prepared. All compounds were evaluated in vitro their antitumor activities in two cell lines, namely chronic myelogenous leukemia cell line K562and human breast cancer cell line MCF-7. Furthermore, some structure-activity relationships have also been established. Most compounds showed good antitumor activities, and the synthetic route is simple. The results lay foundation for further research of these kinds of compounds.