Design,Synthesis And Bioactivity Research Of Small-molecule Targetd Tyrosine Kinase Inhibitor

Cancer is one of the world's most terrible diseases. In spite of great progress of basic science and clinical field, cancer is still the second leading cause of death in developing countries and developed countries.The article contains two parts. First part is the design, synthesis and biological activity research of Imatinib derivatives.The target of Imatinib is BCR-ABL. With the increase of Imatinib's clinical application,it's drug resistance gradually appears. It is extremely urgent to design and synthesis a series of novel, efficient and targeting imatinib derivatives.Thirteen imatinib derivatives were synthesized from 3-acetylpyridine and 2-acetylfuran after substitution, cyclization, reduction and acylation. PTK-1, PTK-2, PTK-3 and PTK-9 significantly inhibited the proliferation of K562 cells in MTT assay. In particular, PTK-9 showed good activity with the value of IC50(0.52 ?M) lower than the value of Imatinib (IC50?0.48 ?M), which provided a direction for the design and synthesis of Imatinib derivatives.The second part is the design, synthesis and bioactivity study of Ibrutinib derivatives.Ibrutinib is the first generation of small molecule BTK inhibitor. There is broad development and application prospect in the treatment of chronic lymphocytic leukemia with it's high activity and resistance.Eight Ibrutinib derivatives were prepared from 3- (4- Phenoxyphenyl)- 1H-pyrazolo[ 3,4- d] pyrimidin- 4- amine after Mitsunobu reaction. The bioactivity of the eight compounds was studied by MTT. BTK-6 and BTK-8 had a significant inhibitory effect on MCF-7. BTK-6 showed better activity than other compounds in K562. The data of compounds in MOLT-4 showed most of these compounds had no effect on human acute lymphoblastic leukemia.