Design And Synthesis Of Anti-tumor Protein Tyrosine Kinase Inhibitor

Protein tyrosine kinases are responsible for the phosphorylation of tyrosine residues in proteins, which play important roles in cell growth, proliferation, differentiation and apoptosis. Over expression or activation of tyrosine kinase receptor will lead to cell mediated disorder, abnormal activation of intra-cellular signaling, cell transformation, constantly proliferation, resistance to apoptosis, and even tumors. Moreover, it is closely related to tumor invasion and metastasis, tumor angiogenesis, tumor resistance to chemotherapy. Human cancer can be treated through effectively inhibiting the activity of protein tyrosine kinase. Therefore, the development of protein tyrosine kinase inhibitors as anticancer drugs has been a hot research field.Based on the QSAR studies of a series of tyrosine kinase inhibitors and the bonding modes of the inhibitor-enzyme in literatures, a series of 6-(substituted-aminobenzoyl)-2-indolione derivatives and 4-substituted indirubin derivatives have been designed and synthesized applying computer-aided design methods, as the candidate compounds of anti-tumor activity screening. In this paper, the synthesis method of 6-(substituted-aminobenzoyl)-2-indolione derivatives has also been discussed. In the synthesis of indole rings, Sn and hydrochloric acid should not be used in one-pot method, because of multi-products and product seriously losses, the method of cyclization after decarboxylation will yield less by-products, and more feasible.In this thesis, nineteen target compounds had been synthesized, including sixteen indolione and three indirubin compounds. They all had been confirmed by H-NMR (600MHz) and MS (ESI). The main intermediate products had also been identificated by 13C-NMR (600MHz).