Design,Synthesis And Antitumor Activity Evaluation Of Novel Thiosemicarbazone-indole Derivatives

Malignant tumors seriously endanger human health,and the development of highly effective,low-toxic,and highly selective anti-tumor drugs are the most basic methods of tumor treatments.As a unique pharmacophore,thiosemicarbazone and its derivatives are widely used by chemists and biologists due to its potential diverse biological functions:anti-tuberculosis,anti-viral,anti-fungal,anti-malaria and anti-tumor activities.The research group reported earlier that a class of thiosemicarbazone derivatives represented by 5n（TS-1）can effectively inhibit the invasion and metastasis of human gastric cancer cells MGC-803.On this basis,this study will have the potential to inhibit tumor cells Two series of derivatives were designed and synthesized by introducing the indole structural unit of migration effect,and their anti-tumor activities were evaluated and representative compounds were selected for preliminary study of the mechanism of action.The research work of this paper mainly includes the following aspects:First,we designed and synthesized a series of compounds by using thiosemicarbazone as the backbone and introducing indole structural units at the end of thiourea,and used human prostate cancer cell PC-3,human gastric cancer cell MGC-803,and human esophageal cancer cell EC-109 and human normal prostate cells WPMY-1 were tested cells,and their proliferation inhibitory activity was evaluated.The evaluation results found that most of the compounds exhibited excellent antiproliferative activity against PC-3,MGC-803 and EC-109 at low micromolar levels（0.14-12μM）;among them,the representative compound 5j was selectively inhibited PC-3(IC₅₀=0.14μM),and showed no significant toxicity to normal cells WPMY-1（SI=70.4）,which was significantly better than the clinical positive control compound 3-AP and Dp C.The structure-activity relationship analysis found that the introduction of indole structural units can effectively enhance the activity of the parent thiosemicarbazone derivatives,especially for the prostate cancer cells.On the basis of series one,in order to further explores the influence of the"Linker"connected with thiosemicarbazone on the anti-proliferative activity of the compound,we introduced the amide structural unit into the design and synthesized a series of two compounds.The evaluation results of the proliferation inhibitory activity showed that most of the compounds showed good anti-proliferative activity against EC-109,MGC-803,human breast cancer cells MCF-7,and human prostate cancer cells（PC-3,DU-145）;especially It means that compound 16f can selectively inhibited PC-3(IC₅₀=0.054μM),and has no obvious toxicity to the normal cells WPMY-1（SI=360.6）.Structure-activity relationship analysis found that the introduction of benzamide fragments at the ends of indole and thiosemicarbazide can significantly enhance the proliferation inhibitory activity and selectivity of the compound.Cell-level mechanism studies have found that 16f was effectively inhibited the colony formation of PC-3 and DU-145,induce cell apoptosis and block the cell cycle in the G1/S phase.In addition,16f also significantly inhibited the growth of PC-3 xenograft tumors,and has no obvious toxicity in vivo or in vitro.In summary,based on the preliminary work of the research group and literature research,we designed and synthesized two series of 52 compounds with thiosemicarbazone as the backbone and introduced indole structural units at the end of thiourea,and evaluated their proliferation inhibitory activity.And carried out preliminary mechanism research.The structure-activity relationship study found that the change of the"Linker"between the indole and thiosemicarbazone structural units has a significant effect on the proliferation inhibitory activity,especially the introduction of benzamide,which can effectively enhance the compound’s proliferation inhibitory activity on prostate cancer cells.In vivo and in vitro experiments showed that the representative compound 16f effectively inhibited the growth of prostate cancer cells represented by PC-3,which provides a molecular basis and data support for the discovery of anti-prostate cancer drugs.