Studies On The Chemical Constituents Of Eupatorium Chinense (Asteraceae)

This dissertation focuses on a systematic investigation of isolation,structural identification and preliminary biological activity of sesquiterpenoids from Eupatorium chinense.In the first chapter,the importance of natural products in drug innovation and development is illustrated with examples of marketed and investigational drugs derived from natural products.The advances of technologies in isolation and structural identification,which are driving natural product research,are also introduced.A mini review about chemical constituents and biological activities of the genus Eupatorium of the family compositae,especially the species E.chinense was presented.The second chapter describes the methodology used for the systematic study of E.chinense,including concise descriptions of the practices of quantum chemical calculations,absolute configuration determination,and other relavent experiments.The molecular network technique was used as an effective dereplication method to designate target compounds.In combination with the LC-MS guided isolation method,the separation and purification of sesquiterpenoids from the petroleum ether and dichloromethane fractions of E.chinense were performed by using various chromatographic methods including macroporous resin AB-8,MCI(CHP-20P),reversed-phase C-18 packing,Sephadex LH-20 gel,Toyopearl HW-40 F gel,silica gel,preparative and semi-preparative high performance liquid chromatography.In the third chapter,we describe structural characterization of the isolated compounds through integrated application of spectroscopic analysis of 1D,2D NMR data,ORD,IR,ECD,HR-ESIMS,etc.For compounds that are difficult to determine their relative conformations,the DFT NMR calculation combined with DP4+ method or customizable parameter’s DP4+ methods were used.Their absolute conformations were further confirmed by Cu Kα X-ray single crystal diffraction,time-density generalized electron circular dichroism(TDDFT ECD)calculation,modified Mosher’s method,or Snatzke’s method.A total of 125 compounds were finally identified,with 64 being new.Of all the isolated compounds,cadinane-type sesquiterpenes were isolated for the first time from E.chinense,and dimeric sesquiterpenes for the first time from the Eupatorium genus.The findings enrich the chemical diversity of compounds of the Eupatorium genus.Preliminary biological assay of the isolates against the tumor cell proliferation was also presented in this chapter.In the last chapter,a possible biosynthetic pathway of cadinane-type sesquiterpenes in E.chinense is postulated,and at the same time,the rules of changes between sterechemistry and NMR chemical shifts happening on some typical compounds are summarized.The preliminary structure activity relationship is also explored.The α,β unsaturated ketones/esters are identified as the key groups for the cytotoxic effect of sesquiterpenes,and the change of double bond position of sesquiterpenes was found to affect their cytotoxicities.At last,a summary of the thesis work is presented at the end of the chapter.