Studies On The Chemical Constituents And Bioactivities Of The Stems Of Schisandra Incarnata And The Herbs Of Parasenecio Subglaber

This dissertation is made up of three parts.Chapter 1 elaborates the chemical constituents and biological activities of the stems of Schisandra incarnata.Chapter 2presents the chemical constituents and biological activities of the herbs of Parasenecio subglaber.Chapter 3 is a review about the research advance of natural sesquiterpene alkaloids from 1977 to 2018.Investigations on the chemical constituents of the stems of S.incarnata and the herbs of P.subglaber yielded 104 compounds,including 8 novel ones with unprecedented skeletons and 39 new ones with unreported structures.Their structures were elucidated on the basis of spectroscopic analyses（1D and 2D NMR,HRESIMS,IR,UV,CD）.The absolute configurations of the new compounds were confirmed by single-crystal X-ray diffraction.Some selected compounds were evaluated for their in vitro cytotoxic activities or immunosuppressive activities or neuroprotective effects.1.The chemical constituents and biological activities of the stems of S.incarnata The family Schisandraceae,placing under the tribe of llliciales（Magnoliiadae）,was divided into two genera,Kadsura and Schisandra.As reported,there are about 26species from this family have been used as traditional Chinese medicine for a long history.Some fruits from Schisandraceae show the effects of tranquilizing,invigorating and relieving cough and phlegm,and some roots,stems and leaves are beneficial to the treatment of traumatic injury and rheumatism.Considering the fact that many species of this family are rich source of structurally novel metabolites with compelling bioactivities,we explored the chemical constituents of the stems of S.incarnata obtained from Xingshan County in Hubei Province,China.As a consequence,43 compounds,including 1 unique schinortriterpenoid with a distinctive tricyclo[5.2.1.0^1,6]decane-bridged system,and12 other new ones with unreported structures,were isolated.The selected triterpenoids S2,S7,S8,S10,S13-S15,S17 and S20 were tested for their cytotoxicity against HepG2,PC3,Hela and HT-29,but no potential activity was detected.In addition,in vitro immunosuppressive activities of selected compounds S1,S2,S7,S8,S10,S13-S15,S17 and S20 were investigated.The majority of selected compounds exhibited different inhibition on ConA-induced T-cell proliferation and LPS-induced B-cell proliferation at the concentration of 100μM.And the most potent one is compound S13,which showing remarkable inhibition on the proliferation of T-cell with IC₅₀ value of 6.32μM（positive control CsA=0.02μM）and B-cell with IC₅₀ value of 11.49μM（positive control MMF=17.88μM）.Meanwhile,compared with the positive controls,all tested compounds showed no significant cytotoxicity against the murine spleen lymphocytes at the concentration of 100μM.2.The chemical constituents and biological activities of the herbs of P.subglaber The genus Parasenecio（Compositae）contains approximately 80 species in the word,about 50 of which are widespread in southwest and northwest of China.In Chinese folk medicine,26 species of this genus have been applied for curing bruises sprains and dysentery,relieving rheumatism and sore throat.In 2014,our research group studied the chemical constituents of P.rubescens and obtained 35 new sesquiterpenes with appreciable cytotoxicities.As an ongoing research on the species from Parasenecio,we investigated the phytochemistry of the herbs of P.subglaber from Xinning County in Hunan Province,China,and obtained63 compounds,including 7 novel sesquiterpene alkaloids with unprecedented eremophilane-indole skeleton,26 unreported sesquiterpenoids and 1 new triterpenoid.The cytotoxicity of selected compounds W2-W8,W10,W13-W15,W17-W19,W21-W23,W25,W28,W29,W31 and W46 against HepG2,PC3,Hela and HT-29were explored,but no significant activity was detected.The selected compounds W2,W3,W5-W7,W13,W17,W19,W21,W22,W28,W29,W31 and W46 were also evaluated for their neuroprotective activities against CoCl₂-induced hypoxic injury and H₂O₂-induced oxidative injury on SH-SY5Y cells.Only compound W22（10μM）in the CoCl₂-induced hypoxic injury model and W2（0.016 and 0.4μM）,W3（10μM）,W6（0.4μM）and W29（10μM）in the H₂O₂-induced oxidative injury model,improved cell viabilities by more than 10%compared with the negative control group.Additionally,the immunosuppressive effects of selected compounds W2-W8,W10,W13-W15,W17-W19,W21-W23,W25,W28,W29,W31 and W46 were studied.All tested compounds exhibited different inhibition on ConA-induced T-cell proliferation and LPS-induced B-cell proliferation at the concentration of 50μM.In particular,compounds W21,W22 and W29 showed moderate inhibition of LPS-induced B-cell proliferation with IC₅₀ values being 23.11,33.85 and 26.62μM,respectively（positive control MMF=17.88μM）.What’s more,compared with the positive controls,all evaluated samples showed no significant cytotoxicity against the murine spleen lymphocytes at the same concentration of 50μM.