Study On Anti-tumor Multidrug Resistance Macrocyclic Diterpenes Of Euphorbia Kansui

The development of multidrug resistance(MDR)is one of the leading causes of treatment failure in the chemotherapy of malignant tumors.In recent years,the search for MDR modulators from natural products has attracted considerable interest of medicinal chemists.As a promising example,macrocyclic diterpenes isolated from the family Euphorbia,especially for jatrophanes,were found to be potential MDR modulators targeting Pgp.In our continuing study toward understanding the chemistry of the plants from the Euphorbia,7 jatrophane diterpenoids(1–13,7–9)and 10 ingenane diterpenoids(5–6,10–17)were isolated from Euphorbia kansui.All compounds were evaluated with breast cancer cells resistant to adriamycin,looking for lead compound about a new type of P-gp inhibitor that can reverse tumor cell resistance and enhance the sensitivity of tumor cells to chemotherapy drugs.In the first chapter of the thesis,introduces the research progress of macrocyclic diterpenes in P-gp inhibitors and the MDR chemical reversal agents,and illustrates the macrocyclic diterpenes as low toxicity and high efficiency MDR reversal agents.Then,a review of the research progress and pharmacological activity of macrocyclic diterpenes in Euphorbia kansui.In the second chapter,seventeen macrocyclic diterpenes were isolated and identified from 95% ethanol extract of the root tubers of Euphorbia kansui,including six new compounds and eleven known diterpenes.Their structures were determined by spectroscopic methods,especially 2D NMR and HRMS techniques.The relative configurations of the new compounds were determined with NMR.The absolute configurations of compound 1 and compound 2 were characterized by X-ray single crystal diffraction.In the third chapter of the paper,all compounds were evaluated for their reversal ADR resistant on MCF-7/ADR.Both jatrophane and ingenane have multidrug resistance reversal ability in MCF-7/ADR.Compound 2 exhibits a remarkable MDR reversal ability.Through this study,the structural diversity of macrocyclic diterpenes was enriched.E.kansui was successfully used as the research object of multidrug resistance.The structure–activity relationship(SAR)of two types of macrocyclic diterpene was discussed.The discovery of a lead compound that can be used as anti-tumor multidrug resistance reversal agents has laid a solid foundation.