Design,Synthesis And Biological Activity Of BRD4 And Small-molecule Targeted Tyrosine Kinase Inhibitor

Cancer has always been a difficult disease that has plagued the medical profession.Although the rapid development of medical science has led to an increase in the number of anti-tumor drugs,ideal anti-tumor drugs are relatively scarce.With the continuous in-depth study of anti-tumor drugs,targeted anti-cancer drugs have emerged,making cancer treatment has been a good improvement.The first part of this paper is the design,synthesis and biological activity of BRD4 small molecule inhibitors.BRD4 inhibitors are an unknown class of protein inhibitors that recognize lysine acetylate specificity.Due to the important post-translational modification in gene expression,BRD4 small molecule inhibitors have gradually become a research hotspot in recent years.In this paper,22 BRD4 small-molecule compounds were synthesized using3,4,5-trimethoxybenzoic acid.The characterization and biological activity tests showed that compound 3g significantly inhibited the proliferation of HCT116,MCF-7,K562 and KMS-1cells with IC₅₀ values of 1.22?M,0.59?M,6.8?M and 3.9?M,respectively,indicating that the anti-proliferative activity of the compound is better for these types of cells,providing new ideas for the further design and synthesis of novel BRD4 small molecule inhibitors in the future.The second part is the design,synthesis and biological activity of small-molecule targeted tyrosine kinase inhibitor.Dasatinib is a highly effective small molecule multi-targeted second-generation tyrosine kinase inhibitor directed against BCR-ABL.It has significant activity and resistance to chronic myelogenous leukemia and has a high research value.In this paper,2-aminothiazole-4-carboxylic acid and 4,6-dichloro-2-methylpyrimidine were used to synthesize a series of dasatinib and its derivatives through acylation and substitution reactions.The MTT assay was used to test the biological activity of the new compounds.It was found that some compounds have potential anti-proliferative activity on the tested cells,providing a new theoretical basis for the subsequent design and synthesis of some dasatinib derivatives.