Design,Synthesis And Biological Evaluation Of Novel Urea-Based 2,3-Dione Indole Derivatives

Cancer is the leading cause of death in the global population,and despite significant advances in cancer research,there is still a need to identify new target molecules and develop new therapeutic technologies.The family of protein kinases with more than 500 members represents the primary therapeutic target for drug development.To date,more than 150 protein kinases have been shown to be involved in the development of human diseases,particularly cardiovascular disease,immunodeficiency,rheumatoid arthritis,endocrine disorders,neurodegenerative diseases and cancer.So it is very important to develop potent kinase inhibitors.So far,most of the studies are small molecule inhibitors.Isatin is an important natural small molecule compound widely distributed in humans,animals and plants.It is an endogenous compound with various biological activities such as anti-cancer,anti-bacterial,anti-viral,anti-malarial,anti-inflammatory,anti-convulsive and anti-tuberculosis,and its derivatives also have various biological activities after chemical modification.When the apoptosis activator 2（AA-2）which has been reported can strongly induce the activation of caspase-3,PARP（poly（ADPribose）polymerase）and fragmentation of DNA,was tested on a panel of normal and tumor cell lines,the compound showed strong selectivity for cancer cells with little or no activity on normal cells.Many AA-2 derivatives were also obtained in the preliminary work of our laboratory,and the compound K20 showed good growth inhibitory activity against both mantle cell lymphoma cells.It exhibited significant apoptosis-inducing effects on Rec1 and Z138 cells at low micromolar concentrations.In the design of the target compound,we first changed the amide structure of the compound K20 to the urea structure,and attached different substituents on the benzene ring to compare the effect of different substituents on the activity of the compound;on this basis,we replaced the 3,4-dichlorobenzyl group at the N1 atom with methyl group and 4-fluorobenzyl group,and its anti-proliferative activity and apoptosis-inducing activity were investigated.The structure of target compounds was confirmed by 1H-NMR,13C-NMR and MS.The antiproliferative activity of the compounds against LNCaP and PC-3 cells was determined by MTT assay.Some compounds showed good growth inhibitory activity against LNCaP cells.Compounds U4,U6 and U16 had better growth inhibitory activity against LNCaP cells than the positive control AA-2（GI50 value of 1.05 μM）with GI50 values of 0.23,0.51 and 0.69 μM,respectively.From the results of the growth inhibitory activity assay against PC-3 cells,we found that most compounds had good growth inhibitory activity against PC-3 cells.The GI50 value of the compounds U1,U9,U10,Ull and U15 for PC-3 cells were 0.36,0.32,0.52,0₈6 and 0.81 pM,respectively,and was better than the positive control AA-2（GI50 value of 1.21 μM）.Compound U17 had a GI50 value of 1.30 μM,which was equivalent to the AA-2.At the beginning of the design,it is hoped that the series of compounds can exert the apoptosis-inducing activity through the apoptotic mechanism,and will be confirmed by specific experiments in later studies.