Design,Synthesis And Biological Evaluation Of Novel 3-substituted Indolin-2-one Derivatives

Cancer is a malignant threat to physical conditions determined by the incongruous expression of oncogenes and tumor suppressor genes in the body.It is essential to state that aberrant proliferation and the capability to invade or distract to other parts of the body is a hallmark characteristic of tumor cells.Moreover,the development of cancer is a cumulative and qualitative process involving a large number of potential genetic causes,which starts with mutations in the initial driver genes that lead to tumorigenesis and eventually results in metastasis.The signal transduction cascades involved in the sustained activation of protein kinases and the general limitation of apoptosis during these transitions are key factors in maintaining the survival,development,proliferation,deterioration and deregulation of tumor cells.Therefore,the development of effective protein kinase inhibitors or apoptosis inducers is of great significance for the discovery of specific and selective molecular targeted anti-tumor drugs.Indolin-2-one is a biheterocyclic molecule,and some substituted indolin-2-one derivatives with chemically modified molecular structure exhibit significant activity of kinase inhibitory or apoptotic inducing.Semaxanib(SU5416)is an effective VEGFR inhibitor,designed and found based on the molecular framework of indolin-2-one.Accordingly,compound AA-2 is a small molecule caspase-3 direct agonist,designed and discovered based on the theory that small molecule apoptosis inducer can directly activate some basic or specific apoptotic mechanisms to play an antitumor role.Moreover,it has a considerable killing effect on cancer cell lines derived by leukemia.Additionally,bioactive indolin-2-one derivatives K7 and K20 showed low micromolar growth inhibitory activity against various lymphoma cell lines and strongly induced tumor cell apoptosis.Hence,we designed and synthesised SA,SN and SO series compounds through the combination of typical drug groups and the related chemical structure modification to find novel structural compounds with well anticancer advantages.Accordingly,the structures of the 42 series compounds were confirmed by 1H spectra,13C spectra and high resolution mass spectrometry.Vitro enzymatic activity and cell activity of target compounds were evaluated.The results of enzyme activity assay showed that the target compounds had poor inhibitory activity against VEGFR-2 kinase or was basically inactivated.Furthermore,we screened 42 target compounds against Jurkat cells,and determined IC50 of preferred compounds against Jurkat,A549 and HCT116 cells.Overall,SN series of compounds exhibited better growth inhibition activity than SA and SO series against Jurkat cells and most of the compounds showed superior growth inhibition activity than the controlled compound SU5416.It should be noted that SN3,SN5,SN10,SN11 and SO11 exhibited low micromolar activity against Jurkat,A549 or HCT116 cells.Moreover,the growth inhibition activity of SN5 against Jurkat and A549 cells was better than AA-2 and ibrutinib,while the growth inhibitory activity of SN1l against Jurkat,A549 and HCT116 cell lines was both superior that AA-2 and ibrutinib.The structure-activity relationship between SA,SN and SO series compounds was analyzed and discussed by explaining the growth inhibitory activity of cells and the enzyme activity results.Hereafter,we will further evaluate the biological activities and study the mechanisms of action of the novel 3-substituted indolin-2-one derivatives with better activities.