Design, Synthesis And Anti-tumor Biological Activity Of Triazine FAK Inhibitors Containing Thiophene Fragment

FAK is a type of cytoplasmic non receptor protein tyrosine kinases.And it plays a central role in cell signal transduction and mediate multiple signal pathways.Researches have shown that FAK is an important target for the treatment of glioma,and many small molecule targeted drugs are currently in the clinical phase I/II research phase.Based on the classic FAK inhibitor TAE-226,this thesis analyzed its crystal structure,and adopted structure-based drug design method to develop a new triazine FAK inhibitor containing thiophene fragments.In the first part,twenty-two triazine compounds containing 3-aminothiophene fragments were designed and synthesized.Single crystals of compound A7b were successfully cultured and calculated using density functional theory at the B3LYP/6-311+G（d,p）level with Gauss 09 software.The results showed that compound A7b had a stable crystal structure.Subsequently,we evaluated the inhibition of A series compounds on human glioma cells U87-MG overexpressed with FAK under the MTT method.However,the activity of these compounds against U87-MG cells was not well,and did not agree with the design requirements to need further optimizations.In the second part,twenty-nine triazine compounds containing 2-aminothiophene fragments were designed and synthesized.The activity of these compounds against U87-MG tumor cells was evaluated with MTT method.The results showed that the inhibition of these compounds was generally better than A series.Especially,the inhibitory activity of compound B₁6q was significantly superior to the positive control TAE-226,with the IC₅₀ value of 1.791μM.Finally,the synthetic process of compound B₁6q with the best activity was developed.After five steps of reaction,the target compound was prepared in a total yield of 38.3%,and the post treatment of each step of reaction only required extraction or beating,without column chromatography separation and purification.