| Acanthopanax senticosus and acanthopanax sessiliflorus are shrubs belonging to the genus Acanthopanax in the family Acanthopanax.They are widely distributed in the northeast forest region of China,as well as the Korean Peninsula,Siberia of Russia and northern Japan.They are important medicinal and edible plant resources.The main chemical components in the leaves of Acanthopanax senticosus and acanthopanax sessiliflorus are flavonoids,triterpenoids,phenylpropanoids,organic acids,volatile oils and a few trace elements.Modern pharmacological research shows that the leaves of Acanthopanax senticosus mainly have sedative and hypnotic,anti obesity,anti-tumor,immune regulation,anti-inflammatory and other pharmacological activities.The leaves of Acanthopanax sessiliflorus have pharmacological activities such as sedation and hypnosis,inhibition of obesity,anti-tumor,immune and anti-inflammatory,and protective effects on myocardium and liver.Chiisanoside is a 3,4-split ring lupane type triterpenoid saponin,which has a wide range of pharmacological activities,including anti-tumor,sedative hypnosis,obesity inhibition,immune anti-inflammatory and protective effects on the myocardium and liver,etc.,of which the anti-tumor activity is significant,and it is expected to develop into a leading compound of anti-tumor drugs.It is of great theoretical and practical significance to modify the structure of chiisanoside to enhance its antitumor activity,and then find the lead compound as a candidate antitumor drug.In this study,the potential quality markers of Acanthopanax senticosus leaves and sessile Acanthopanax senticosus leaves were predicted based on the "five principles of quality markers".Secondly,the components with anti-tumor activity in Acanthopanax senticosus leaves and sessile Acanthopanax senticosus leaves were analyzed by network pharmacology.It was found that the active component chisanoside in both of them may have good anti-tumor activity and be related to iron death.In addition,our research group found that chiisanoside has a good effect of inhibiting the proliferation of tumor cells in the previous research work.Therefore,the compound chiisanoside was finally selected for structural derivatization,and the antitumor activity of chiisanoside derivatives in vitro was evaluated.The binding energy and binding sites of the dominant compounds with iron death related proteins were analyzed by molecular docking technology,hoping to provide new ideas for the design of anti-tumor active derivatives and new directions for the development of tumor therapeutic drugs.The main research results are as follows:1.Analysis and prediction of quality markers of Acanthopanax senticosus leaves and sessile Acanthopanax senticosus leaves and Research on the anti-tumor mechanism of network pharmacologyBased on the concept of "quality markers",relying on the "five principles of quality markers",the quality markers of Acanthopanax senticosus leaves were comprehensively analyzed and predicted from the aspects of chemical composition and component transmission,plant phylogeny,chemical component effectiveness,and chemical component measurability,and the contents of chiisanoside,chiisanogenin,Hyperoside,quercitrin,quercetin,Eleutheroside E,chlorogenic acid Caffeic acid can be used as a candidate quality marker of Acanthopanax senticosus leaves;The quality markers of the leaves of Acanthopanax sessiliflorus were predicted from three aspects:the measurability of chemical components,plant phylogeny and traditional medicinal properties.The terpenoids,saponins and phenylpropanoids in the leaves of Acanthopanax sessiliflorus were presumed to be the reference of the quality markers of the leaves of Acanthopanax sessiliflorus,and the active components chisanoside and chisanogenin were used as the potential quality markers of the leaves of Acanthopanax sessiliflorus,in order to provide some theoretical support for subsequent experiments.Using the method of network pharmacology,the active ingredients were obtained through literature collection and herb database and analysis platform(herb),the potential targets of active ingredients were obtained from Swiss targetprediction database,the anti-tumor related targets were obtained from genecards and OMIM databases,and the intersection targets of Acanthopanax senticosus and acanthopanax sessiliflorus leaves and tumors were screened.The data were imported into Cytoscape software to build the "active ingredient disease intersection target network map",and the key target proteins were obtained through string database analysis.The go entries and KEGG pathways were obtained through enrichment analysis and screening in metascape database.It was found that chiisanoside,a common component of Acanthopanax senticosus leaves and sessile Acanthopanax senticosus leaves,may inhibit the growth of tumor cells through the iron death pathway,providing a reference for subsequent experimental research.2.Preparation of chiisanoside derivativesChiisanoside was isolated from the leaves of Acanthopanax senticosus and acanthopanax sessiliflorus,and the aglycone product(GC)and acid alcohol product(SC)were obtained by acid hydrolysis and alkali hydrolysis.GC and SC were heated and refluxed with 1,3-dibromopropane,1,4-dibromobutane,1,5-dibromopentane,1,6-dibromohexane,1,10-dibromodecane in acetone,respectively,Ten intermediates gc1～gc5 and sc1～sc5 were synthesized and esterified and substituted.Seventeen derivatives were finally designed and synthesized,and their structures were characterized by spectroscopic technology.3.In vitro antitumor activity evaluation and molecular docking validation of chiisanoside derivativesThe cytotoxicity of compounds 2a～2e,3a～3d,4a～4e,5a～5c on human prostate cancer cells(PC-3M),human lung cancer cells(A549),human breast cancer cells(MCF-7),human liver cancer cells(Hep G2),human pancreatic cancer cells(PANC-1)was evaluated.The results showed that the derivatives with lower IC50 values were 5B and 5A in PC-3M cells;In A549 cells,the derivative with lower IC50 value was 5B;In MCF-7 cells,derivatives with lower IC50 values were 5A and;In Hep G2 cells,the derivatives with lower IC50 values were 4B and 4a;In PANC-1 cells,the derivatives with lower IC50 values were 5B and 5A.Derivatives 5B and 5C,which can inhibit the proliferation of a variety of tumor cells,were used as ligands for molecular docking with the iron death related protein TFRC(PDB id: 2nsu).It is generally believed that the binding energy of ligand receptor docking is less than 0,which means that ligand and receptor can spontaneously bind.The lower the binding energy,the greater the possibility of binding.The results showed that both 5B and 5C formed three hydrogen bonds with amino acid residues asp360 and thr359,with binding energies of-10.613 kj/mol and-10.368 kj/mol,respectively. |
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