Design And Synthesis Of Anti-cancers Based On Xanthones Scaffold And The Mechanism Studies Thereafter

Objectives:Xanthones are chemicals with multiple pharmacological activities and its derivatives are widely distributed in plants and microorganisms.Based on the activity of antitumor and the value of development.In the current thesis,a series of xanthone compounds and their derivatives were synthesised,purified and checked by MS,NMR.The purpose of our experiments are tried for:The best synthesis method of xanthone compounds by microwave assisted method.The optimal connecting mode of DMXAA with Pyranoxanthone.The synthesis route of xanthone-NO donors.Test the activity of all the compounds in vitro against liver cancer and breast cancer and so on.The antitumor activity and mechanism of compound Xan-NO-30,P-D-6,LJ-1 and DMXAA combination in vitro and the structure-activity relationship and synergy mechanism.The intracellular targets and mechanisms and scientific evidences for the development of Xan-NO-30,P-D-6,LJ-1 and DMXAA to be a drug candidate or way for the treatment of liver cancer and mammary cancer.Methods:1.With microwave assisted technique,xanthone compounds were synthesized with substituted salicylic acid and substituted phenols as raw materials.Xanthone-NOs,DMXAA and Pyranoxanthone bridged by different length of carbon chain were also synthesized.2.Establishing MTT method for detecting proliferation inhibition activity against tumor cells in vitro and investigate the inhibitory activity of MDA-MB-231,MCF-7 and HepG2 tumor cells3.Establishing Annexin V/PI staining flow cytometry for analyzing the effects of Xan-NO-30,P-D-6,LJ-1 and DMXAA on cell cycle.4.Establishing flow cytometry and confocal laser assays for detecting Xan-NO-30,P-D-6,LJ-1 and DMXAA induced cell apoptosis.And the expression level of apoptosis-related proteins were tested by Western blot.5.Changes of mitochondrial membrane potential(MMP)after treatment with Xan-NO-30 and P-D-6 were detected by fluorescence probe JC-1.Results:In this study,we synthesized the chemicals of Xanthones and its derivatives.The experimental results showed that the best reaction conditions for the synthesis of Xanthones are as follows: Microwave assisted heating time: 40 min,temperature: 85 ?,substituted salicylic acid: substituted phenol 1: 1.2.37 Xanthones,45 Xanthone-NO compounds and 4 P-D compounds were synthesized by chemical synthesis and were verified by NMR and MS.Xan-NO-30,P-D-6,LJ-1 and DMXAA inhibited the proliferation of mammary cancer MDA-MB-231 cells and liver cancer Hep G2 cells by inducing apoptosis and showed good synergistic effect.Translocation of membrane-associated phospholipid phosphate-dylserines(PS),changes in cell morphology,activation of Caspase and cleavage of PARP were concomitant with this inhibition.Xan-NO-30 may also activates the ASK1-MAPK pathway to induce the apoptosis of HepG2.The involvement of the mitochondrial pathway in chemicals mediated apoptosis was suggested by observed disruptions in MMP.The compounds have much better activity of antitumor than the parent compound and have a potential of multi-target direction.Conclusion:In summary,the synthesis method was improved by microwave-assisted method.The final yield was improved greatly and increased significantly.We also showed the ability of Xan-NO-30,P-D-6,LJ-1 and DMXAA to inhibit the proliferation of liver cancer cells and mammary cancer cells by inducing apoptosis via mitochondrial pathways and disrupting mitochondrial oxidation reduction system.The results revealed that DMXAA and Pyranoxanthone formed an integration of heterozygotes with multiple target synergistic antitumor effect.It is the first time to connect the NO donors with Xanthone compounds.Compounds P-D-6 and Xanthone-NO-30 with multi-target and oriented function on anti-tumor and have good anticancer activity.The roles of molecular mechanism of antitumor with P-D-6 and Xanthone-NO-30 were also revealed?...