Abstract: The cytotoxicity of natural glycosides from Ginseng, semisynthetic analogues and related triterpenes of the dam- marane series, isolated from the leaves of the Far-East species of the genus Betula was studied in order to elucidate structure- activity relationships. Some of the compounds studied were active against the human lung carcinoma GLC 4 and adenocarci- noma COLO 320 cell lines. The natural glycosides displayed the lowest cytotoxicity. The triterpenes of the dammarane series used as starting aglycones for semisynthetic derivatives were moderately cytotoxic. The dammarane triterpenes possessing keto groups and their semisynthetic glucosides were the most active compounds tested. Cytotoxic effects of the dammarane glucosides were inversely proportional both to the number of sugars attached to the aglycones and to the number of hydroxy groups of the aglycones. The type of side chain and the config- uration of the hydroxy group at C-3 in aglycones did not have a significant influence on the cytotoxicity. Key words: Panax ginseng, Araliaceae, ginsenosides, chikuset- susaponin-LT8, Betula, Betulaceae, dammarane type triter- penes, betulafolienetriol, cytotoxicity. Introduction Ginseng(Panax ginseng C.A.Meyer),thefamousplantdrughas beenusedastraditionalmedicineinorientalcountriesformore than 5000 years. The chemical structures of ginsenosides, the ginsengsaponins,andtheirbiologicaleffectshavebeenwidely studied (1±7). The biological activities of the constituents of P. ginseng have been evaluated and it has been found that the ginsenoside-Rh 2 exhibitscytotoxicactivitieswhileotherginse- nosideslackthiseffect(3,7).Comparativestudiesoncytotoxic activities of ginseng saponins and their degradation products againstsomecancercelllineshavebeenperformed(6). Thescarcityofthenaturalginsenosideshadpromptedasearch for routes of synthesis from relatively accessible substances. The genuine sapogenins of the ginseng glycosides (= ginseno- sides) were structurally similar to some chemical constituents of leaves of the common birch Betula alba L. (Betulaceae). The triterpene of the dammarane series, betulafolienetriol [dam- mar-24-ene-3a,12b,20(S)-triol] (16), first isolated from the common birch Betula alba L. (Betulaceae) (8) and later identi- fiedintheleavesofFar-Eastspeciesofthegenus Betula,differed from the genuine sapogenin of the ginseng saponins, 20(S)- protopanaxadiol[dammar-24-ene-3b,12 b,20(S)-triol](10)inthe configurationatC-3only.Forthisreasonbetulafolienetriolwas used as a starting compound to prepare 20(S)-protopanaxadiol andsemisyntheticginsenosidesandtheiranalogues(9,10). It was our aim to elucidate the structural elements which were necessary for cytotoxicity and to get a clear picture of structure-activity relationships within this class of com- pounds, using a broad variety of saponins, aglycones as well asglycosides,naturallyoccurringandsemisynthetic. Materials and Methods Plant material The roots and leaves of cultivated Panax ginseng C. A. Meyer (Araliaceae) were commercially obtained from ªZhen-Shengº farm, Primorsky krai, Russia. The leaves of Betula platyphylla Sukacz., Betula mandshurica (Regel) Nakai, Betula costata Trautv. (Betulaceae) were collected near Octyabrsky settle- ment (Amurskaya oblast, Russia) and from Gryaznaya River ValleyandfromNarvaRiverValley(Primorskykrai,Russia)in the middle of June 1973±1978 and were identified by Prof. Dr.P.G.GorovoyandDr.V.I.Baranov,thePacificInstituteof Bioorganic Chemistry, Far East Division of the Russian Acad- emyofSciences,Vladivostok,Russia.Voucherspecimens[No: 1887 for Betula platyphylla Sukacz., Betula mandshurica (Regel) Nakai, Betula costata Trautv. and No: 5883 for Panax ginseng C. A. Meyer] were deposited at the Herbarium of the Institute of Biology and Soil, Far East Division of the Russian AcademyofSciences,Vladivostok,Russia. Extraction and purification of the natural ginsenosides Theginsenosides-Rg 1 1 ,-Re 2,-Rf 3,-Rd 5,-Rb 1 6,-Rb 2 7 ,-Rc 8, -Ro 9 were isolated from the 5±6 years old roots of Panax ginseng C.A.Meyer,accordingtotheconventionalmethodfor isolating plant glycosides with a slight modification (11). Ginsenoside F1 4 was isolated from the leaves of Panax ginseng C. A. Meyer by the same procedure. Their chemical structures (Fig. 1) were established on the basis of 13 C-NMR spectroscopicdata. PlantaMedica65(1999)30±34 GeorgThiemeVerlagStuttgart · NewYork Original Paper Cytotoxicity of Natural Ginseng Glycosides and Semisynthetic Analogues LyubovN.Atopkina 1, *,GalinaV.Malinovskaya 1 ,GeorgiB.Elyakov 1 ,NinaI.Uvarova 1 ,HermanJ.Woerdenbag 2,4 , AlbertKoulman 2 ,NieskoPras 2 ,andPierrePotier 3 1 PacificInstituteofBioorganicChemistry,FarEastDivisionoftheRussianAcademyofSciences,Vladivostok,Russia 2 DepartmentofPharmaceuticalBiology,UniversityCentreforPharmacy,Groningen,TheNetherlands 3 CentreNationaldelaPechercheScientifigue,InstitutedeChimiedesSubstancesNaturelles,Gif-sur-Yvette,France 4 Presentaddress:GroningenBiomolecularSciencesandBiotechnologyInstitute,UniversityofGroningen,Groningen,TheNetherlands Received:March11,1998;Revisionaccepted:June13,1998 30 Heruntergeladen von: University of Victoria. Urheberrechtlich geschützt.