Studies On The Chemical Constituents Of Three Medicinal Plants And The Mechanism Of Active Compound Dehydrocostus Lactone Induced Apoptosis In HeLa Cells

The chemical consitituents of medicinal plants are characteristic of diverse structures and biological activities,and low drug-resistance.There are more than 10,000 medicinal plants which distributed in China.Finding new natural products with important biological activity from medicinal plants and developing them as new drugs is our advantage,which is conducive to the promotion of modernization process of Chinese herb and also a focus in the field of pharmaceutical science.Alkaloids and terpenes are important natural products,which are widely distributed in various medicinal plants.They possessed complicated skeletons.Cordell G.A reported in 2011 that about 30,000 alkaloids were got from natural resource,of which 20,000 were obtained from plants including 1900 skeletons.Obviously,plants are important source of alkaloids.Terpenes are main constituents of essential oils in plants.Statistics show that about 23,000 terpenes were found.Alkaloids and terpenes also showed abundant biological activities.The discovery of famous bioactive compounds such as vincristine,colchicine,paclitaxel and artemisinin makes alkaloids and terpenes outstanding in the field of pharmacology,synthesis and natural products.In order to discover bioactive compounds from alkaloids and terpenes,we studied the chemical constituents of Winchia calophylla A.DC.,Ligularia przewalskii?Maxim.?and Senecio destomtanii in this dissertation,which are rich in the two groups of natural products.The biological activities of the isolated compounds were also evaluated.Meanwhile,we studied the mechanism of active compound dehydrocostus lactone?DHC?obtained from Saussurea lappa C.B.Clarke?Compositae?in the inhibition of He La cells,which provides reference for DHC as anticancer agent.102 compounds,including 30 monoterpenoid indole alkaloids,12 sesquiterpenes,10 triterpenoids,12 steroids,5 flavonoids,6 coumarin derivatives,24 benzene derivatives and 3 long-chain compounds,were obtained from the three plants using silica gel column,recrystallization and High Performance Liquid Chromatography?HPLC?,of which two?Wc 3 and Wc 8?were new.This is the first report of Wc 27 in W.calophylla.The structures of all compounds were determined based on spectroscopic data(HRESIMS,UV,¹H NMR,¹³ C NMR,¹H-¹H COSY,DEPT 135,HSQC,HMBC,NOESY and CD).Antifungal activities of some isolated compounds against Fusarium oxysporum f.sp niveum,Rhizoctonia solani,Fusarium oxysporum f.sp cubenis and Penicillium italicum in vitro was assayed.Among the tested compounds,Wc 2,7,10 and 11 revealed broad-spectrum antifungal effects.Wc 2 potently inhibited the growth of P.italicum and F.oxysporum f.sp cubenis with IC₅₀ values of 10 ?M and 11 ?M respectively,and Wc 7 siginificantly suppressed R.solani with IC₅₀ value of 11 ?M,which were more effective than methyl thiophanate?the positive control?.In addition,Sd 4,Sd 6 obtained from S.destomtanii,and Lp 1,Lp 12 obtained from L.przewalskii,also showed moderate antifungal activity.Moreover,we found that some of the isolated alkaloids displayed weak activity against acetylcholinesterase and the growth of tumor cell lines.It has been reported that DHC exhibited predominant antitumor activity in various human cancer cells such as hepatoma,lung cancer,oophoroma and cervical cancer,but the potential mechanism of DHC is still subtle.Therefore,we studied the mechanism of active compound DHC obtained from Saussurea lappa C.B.Clarke?Compositae?in the inhibition of He La cells.As demonstrated in this dissertation,DHC inhibited the activity of cytosolic thioredoxin reductase?TrxR1?in HeLa cells,which led to an accumulation of reactive oxygen species?ROS?and a destruction of the redox balance in cells.Meanwhile,DHC also caused decrease of intracellular total thiols,which elicited oxidative stress.The biological activities of DHC on the inhibition of cancer,inflammation,bacterium,fungi and other pathological processes were summarized at present dissertation.It offers useful information for further development of DHC in the discovery of new drugs.The dissertation enriches the study of the chemical constituents of the three plants.We hope that this thesis would provide useful references in the application of the plants in the development of effective drugs.Targeting TrxR1 with DHC revealed a new molecular mechanism of DHC and shed light on a new view of DHC as an antitumor agent.