Design, Synthesis And Antitumor Activity Of B-glycoside Derivatives Of Tetrandrine And Fangchinoline

Chemotherapy for cancer began in the 1940s.As of today,the FDA has approved about 200 drugs for the treatment of different types of cancer,either alone or in combination.Among the approved anticancer drugs,more than 75%of the drugs come from natural sources?eg,paclitaxel,doxorubicin,vincristine,etc.?and are used in their actual form or as simple structural modifications to their backbone.However,most chemotherapeutic drugs inhibit cancer cell proliferation through DNA damage,inhibit DNA replication,DNA/DNA replication,and the deregulation of the enzyme/protein mechanism of cell division,as well as by inducing apoptosis,but the drug action is non-specific and acts on normal It is difficult for cells to avoid side effects/toxicity by using this method to treat cancer.Therefore,there is a great demand for new anticancer agents.Targeted therapy is a treatment specific to cancer,a protein,or a tissue environment that contributes to the growth and survival of cancer.The main purpose of targeted therapies is to fight cancer cells with more precision and fewer side effects.Many targeted therapies are being used to treat cancer,and some are being tested in clinical trials.Tetrandrine?Tet?and Fangchinoline?Fan?are double benzyl groups with an18-membered lactone ring isolated from Stephania tetrandra S.Moore.Isoquinoline alkaloids are two important alkaloidal constituents in the plant powder.In recent years,the anti-tumor effects of Tet and Fan have attracted more and more attention.It is reported in a large number of documents that anti-tumor activity of Tet and Fan has a good anti-tumor activity and has a variety of anti-tumor mechanisms.In the previous study,our group found for the first time that azinbine had a novel mechanism of action in inducing autophagic death of hepatocellular carcinoma cells,and its structural modification in the previous period had a good in vitro anti-proliferative activity against hepatoma cell lines.Some of the derivatives are more active than the clinical drug Solafini.Domestic and foreign reports have been reported on the conventional structural modifications of galactomethyl and tetracycline,but liver-based glycosylation derivatives have not been reported.Based on this,this project used the anti-tetracycline and acetylcholine as the lead compounds.Fiest,the conventional sulfonamides and ester derivatives were design and synthesis.24 tetrandrine derivatives and 24 fangchinoline derivatives were obtained.Then the indirect glycosylation route was designed for Tetrandrine and fangchinoline,and 38 indirect glycosidated derivatives were obtained.The structure was characterized by ESI-MS,¹H-NMR and ¹³C-NMR.The in vitro anti-tumor activity of some of the synthesized derivatives was studied,and a preliminary mechanism study was performed on the compounds with better activity.The in vitro anti-tumor activity of some of the synthesized derivatives was studied,and a preliminary mechanism study was performed on the compounds with better activity.The results showed that the sulfonamide derivatives S-23 had a good inhibitory effect on proliferation of breast cancer cell lines with an IC₅₀0 value of 1.18?M.SJR series compounds showed good inhibitory activity against liver cancer cell line MHCC97L.The anti-cancer mechanism of S-23 on MDA-MB-231 cancer cells was further investigated using annexin V-FITC/propidium iodide staining assay.Compared with experimental control DMSO group,compound S-23 downregulated the expression of Bcl-2 and Bcl-xl,upregulate proapoptotic Bax level and activate PARP cleavage to induce apoptosis.