鬼臼毒素及其衍生物

天然产物研究与开发 80 NATURALPRODUCTRESEARCHANDDEVELOPMENT 2004V01．16No．1 PODoPHYLLOTOXINANDITSDERIVATIVES ZHANGPei—nanl，LIZhao-fen92，ZHAOChang—qil* (1．BiologyDepartment，NorthzoestUniversity，Xi’an710069，China； 2．ShanxiMedicinalMaterialsCompany，Ⅺ’all710048，China) AbstractPodophyllotoxinisanaturalproductisolatedfromPodophyllurepeltatumandP．emodiandhas longbeenknowntopossessmedicinalproperties．Itscongenersandderivativesexhibitpronouncedbiological activitymainlyasstrongantiviralagentsandasantineoplasticdrugs．Thederivativesetol：的sideandteniposide havebeensuccmsfullyutilizedinthetreatmentofavarietyofmalignantconditions．Continuedresearchonthe Podophyllumlignansiscurrentlyfocusedonstructureoptimizationtogeneratederivativeswithsuperiorphar— macologicalprofilesandbroadertherapeuticscope，andthedevelopmentofalternativeandrenewableSOUrCesof podophyllotoxin． KeywordsPodophyllotoxinanditsglucosides；derivatives；anticancer Introduction TheplantsofPodophyllum，whichgrowintheHi— malayaregionofAsiaandinAmerica，aretraditional medicines．TheybelongtotheBerberidaceaefamily， andwereusedbythenativesofbothcontinentsas catharticsandanthelminthics⋯．Podophyllotoxin， whichshowshighantitumoractivity，isamaincon— stituentofthisgenus，hadalreadybeendescribedby Podwyrsmtzkiin1880[2|．Renewedinterestinthis genuswasgeneratedin1940，whenKaplan[3]demo- nstratedthecurativeeffectofpodophyllin，isolated fromthealcoholicextractsofthepoao挑yllumrhi— zomes，incondylomataacuminate．Butbecauseofits serioussideeffect，itcannotbeusedasantitumora— gentclinically．Subsequently，anumberofpodophyl— lotoxinderivativesandtheirglycosidesisolatedfrom theplantsofthePodophyllumspecieshaveshowna widerangeofbiologicalactivities．suchasEtoposide andTeniposidel4～5|．However．Theystillhavesev． erallimitationssuchas12Kx)rwatersolubility、metabol— icinactivationanddevelopmentofdrugresistance．So researchersaretryingtofindothernewderivativesof podophyllotoxinandtheirglucosidesthatcouldover— comesuchdeficiencies． 收稿Et期：2003．05．13修回日期：2003．06．16 OH R OH R=Me_{Etop。side P。d。phyll。t。1in R= 1 Mechanism ；Tenip。side Themechanismofpodophyllotoxinistoblockcelldi— vision．whichiSrelatedtoitsinhibitionofmicro— tubuleassemblyinthemitoticapparatus．However， etoposideandteniposidewereshownnottobein— hibitorsofmicrotubuleassembly，whichsuggested thattheirantitumorpropertieswereduetoanother mechanismofaction，viatheirinteractionwithDNA andinhibitionofDNAtopoisomeraseII． 2 Extraction Theplantkingdomhasprovidedawidevarietyof naturalproducts，SOextractingisaneffectivewayto obtainpodophyllotoxinanditsderivativesandgluco— sides．Podophyllotoxinmainlydistributedinthe 万方数据 2004、南1．16No．1 张培楠等：鬼臼毒索及其衍生物 81 speciesof Podophlloideae、DysosmaWoo&on、 SinopodophyllumYing、DiphylleiaMichx、and PodophullumL．Etc[6I．Uptodate．a10tofderiva— tiresandglucosideswereextracted．butmostofgly— cosidescontainonlyonesugar，theyalsohavethe problemofpoorsolubility．Inourresearchgroup，we havefoundsevennewGlycosidesfromSinopo- dophyllurnemodi(Wall．)Ying．Theyarerespective— ly：isopodophyllotoxin7’一O-fi—D-glucopyranosyl一(1— 6)一口一D—glucopyranoside(1)，picropodophyllotoxin7’一 O—l；8。D-glucopyranosyl一(1-6)一．|9一D-glucopyranoside (2)，methylepipodophyllate7’一O—p—D-glucopyranoyl一 (1-6)。p—D，glucopyranoside(3)，4一demethyl—picrop— odophyllotoxin7’一O-口一D—glucopyranoside(4)，4一 demethyl—epipodophyUotoxin7’一O一卢一D-glucopyrano- side(5)，picropodophyllotoxin7’一O一口一D-glucopyra— noside(6)and4，5一didemethyl—podophyllotoxin7’一O一 口一D-glucopyranoside(7)．Therootsandrhizomesof S．emodi(Wall．)YingwerecollectedfromtheQin． LingmountainareaChina．Compounds1-7wereob— tainedfromthen—butanolextraction．Thestructures wereidentifiedbasedonNMRspectraldataand chemicalevidence[7～8|． 0Me 1 OMe 2 OMe 3 H Me 1．isopodophyllotoxin7’一O一口一D—glueopyranosyl一(1·6)一口一D-glu— copyranoside 2．picropodophyllotoxin7’一O—p-D—glueopyranosyl-(1—6)一p-D—glu— copyranoside 3．methylepipodophyllate7’一O—B—D-glucopyranosyl一(1·6)母D— glucopyranoside 4 5 6 7 4．demethyl—picropodophyllotoxin7’一O-p_D-glucopyranoside 5．4-demethyl．epipodophyllotoxin7’一0一pINglueopyranoside 6．picropodoph：／rllotoxin7’一O-e-D—glueopyranoside 7 4．5-didemethyl—podophyllotoxin7’一0一pD-glueopymnoside 3 Synthesis Althoughthenaturalpodophyllinresinwasusedin folkmedicines，itwasnotuntilitsantitumoractivity wasconfirmedinthe1940sthatsyntheticstudiesof thepodophyllotoxinwereundertaken．Themaindeft— ciencyofthesecompoundsistheircytotoxicityfor normalcellsandhencesideeffectsderivedfromtheir lackofselectivityagainsttumorcells．Soitisneces— sarytoinvestigateandpreparenewmorepotentand 1esstoxicanalogs，thatis，withbettertherapeuticin— dices．Inthe1960s．Vp一16andVm一26wassemisyn— thesyzedbySandozCompanyofSwitzerlandSucces— sively．Inrecentyears，manynewderivativesand glucosidesweresynthesizedfromtheprecursorsof Vp一16andVm-26，suchasbodipy—etoposide；itwas synthesizedfromVp一16，andhasthesimilaractivity andhigherselectivitieswithVp一16． Upto date，manysynthesizedderivativesof poclophyllotoxincanovercomethedeficiencyof podophyllotoxinsuchasitscytotoxicityandpoorwa， tersolution．There&refourmainapproachesknown frompreviousliteratureforsynthesis[9]： (1)Elaborationofax—OXOester (2)Lactonizationofadihydroxyacid (3)Cyclizationofaconjugateadditionproduct (4)UtilizationofaDiels—Alderreaction Itiswellacceptedfromstructure—activitystudiesin thisfieldthatthetrails—lactonesaremorepotentas antineoplasticsthanthecis—lactones．Notonlythe configurationoftheDringisanimportantfactorfor highcytotoxicactivity，butalsoaquasi—axialarrange． meritoftheEringisnecessary．Onthisbasis，studies onlignanshavebeenaddressedtomodifythelactone moietyandprepareanalogswithheteroatomsatdif— ferentpositionsofthecyclolignanskeleton【10|． Ithasalsobeenrecognizedthat-substitutionatC4 positionisnecessarytothecompoundswithhighac— tivity．ShanghaiInstituteofPharmaceuticalIndustry hasestablishedamethodologytosynthesize4一substi— tutedderivativeofpodophytlotoxinstereoselectiv— ely[11]．Suchasthesynthesisof4一cyano-4．deoxy．4’。 demethylepipodophyllotoxin，whichisanimportant 万方数据 天然产物研究与开发 2004Vbl．16No．1 intermediateforsynthesizing4-carbonsubtituted derivative． 4 BiosynthesisofPodophyllotoxin Dewickandco-workersinexperimentselucidatedthe biosyntheticpathwayleadingtopodophyllotoxinthat involvedfeedingradiolabeliedprecursorsandfollow． ingtheincorporationoflabelintodifferentlignan metabolites．Morerecently，studieshaveconcentrat— edontheformationofenantiomericallypurecom． poundsbycellfreeextracts．Thefinalstepsinthe analysisofbiosyntheticpathwaysareidentificationof enzymescatalyzingindividualbioconversionsineell freesystems，andidentificationofgenescodingfor theseenzymes．Biosynthesisofpodophyllotoxinand relatedlignansis discussedin moredetailby Kuhlmann，etal[12]． Increaseofproductyields，byvariationofmedium andcultureconditionsorbyvaryingthechannelling ofprecursorsintoside-branchesofthebiosynthetic pathwaymolecularapproaches．Themethodofcell cultureispracticedinmanyplantspecies．Production ofpodophyllotoxinby￡：差型堡丝丝cellcultureswas firstattemptedbvKadkade[13]andhefoundthata combinationof2，4一Dandkinetininthemediumsup— portedthehighestamountofitsproduction．Red lightstimulatedtheproduction．Toincreasetheyield ofpodophyllotoxin，Woerdenbergeta1．inthe Netherlands[14|addeda complexofa precursor， coniferylalcohol，andp—cyclodextrintoPodophyllum． ．h．．．．．e．．．．x．．．．．．a．．．．．。n．．．．．d．．．．．．．r．．．．．u．．．．．．m．——cellsuspensioncultures[3-D-glucosideof coniferylalcohol，coniferin，wasamorepotentpre— cursorintermsoftheyieldoftheanticancercom— pound(0．055％)，butunfortunatelythiscompound isnotcommerciallyavailable．Thesameauthorsre— portedthatcellsuspensionculturesof．C．．．．．．．a．．．．．1．．．1．．．i．．．t．．．r．．．．．i．．s．．．．．．．．d．．．．．．r．．．u．．．．．．m．，．．——- —mon—dii(conifer)alsoaccumulatedpodophyllotoxin—p— D-glucoseThecallustissueinducedfromP．hexan— d—rumwasreportedbyHeyenga[15]toproduce podophyllotoxin，4’一demethyl—podophyllotoxinand podophyllotoxin．．4．．0．．glucosidewhenthecalluswasin·— cubatedinBsmediumcontaining2，4一D，gibberellic acidand6一benzylaminopurine．Thelevelsof podophyllotoxinanditsderivativesweresimilarto thoseinthemotherplant， 5 Conclusions Theintroductionofetoposideandteniposideintocan— cerchemotherapyisoneexampleofthewaybywhich startingfromoldfolkremedies，newsinglechemical entitiesoftherapeuticvaluearedeveloped．However therearestillmanyproblemstoberesolvedwhichin— volvedmanywindingsandloops． Referenees 1 StHhelinI-IF，yonWarburfgA．Thechemicalandbiologi— calroutefromPodophyllotoxintoetoposide．CancerRes， 1991．51：5～15 2 LarsBthulin．Podoph：'|rllotoxinderivatives：drugdiscovery anddevelopment．DrugDiscoveryToday，1996，8：343～ 351 3 KaplanIW．Condylomataacuminata．NewOrleansMed SurgJ，1942，94：388～390 4 Zhang，YL，GuoX，CheugYC，LeeKI-U．Synthesisand biologicalevaluationofnovd4-aminoderivativesofetopo— sidewithbetterpharmacologicalprofiles．MedCh绷， 1994，37：446～452 5 MarinaGordaliza．Cytotoxicaycloignansrelatedto岫 phyllotoxin．儿Farmaco，2001，56：297--304 6 wardRS．鬼臼毒及其抗肿瘤作用研究进展．国外医 药．植物药分册，1993，8(5)：206--210 7 ZhaoC．ThreeNewGlycosidesfromSinopodopullume— modi(WALL．)Ying．ChemPharmBull，2001，49 (11)：1474～1476 8 ZhaoC．TwoNewPodophyllotoxinGlycosidesfromSino- Ixdo加yZlureemodi(WALL．)Ying．ChemPharmBull， 2001，49：(6)773～775 9 CamiloCanel．Moleculesof InterestPodophyllotoxin． Phytochemitry，2000，54：115～120 10 GordalizaM，CastroMA，eta1．AntitumorPropertiesof PodophyUotoxinandRdatedCompounds．CurrentPhar— maceuticalDesign，2000，6：18 11Wang，ZG，IVIaWY，ZhangCN．StereoseleetiveSynthe— sisofNewPodophyllotoxinDerivative：4-cyano-4一deoxy一 4’demethylepipodophyllotoxin．ActaChimSinica， 1992，50：698～701 12 ArrooR尉．Plantcellfactoriesasasourceforanti—cancer lignans．PhotochemistryReviews，2002，1：27～35 13 KadkadePG．Growthandpodophyllotoxinproductionin 万方数据 张培楠等：鬼臼毒素及其衍生物 callustissuesofPodot旃yllumPeltatum．PlantScLett． 1982．25：107～115 14WoerdenbergHJ，eta1．Increasedpodophyllotoxinpro— ductioninPodophyllumhexandrumcellsuspensionculture afterfeedingconiferylalcoholasapcyclodextfincomplex． PlantCellReports，1990，9：9--100 15HeyengaAG，JohnALucas，eta1．Productionofturnout— inhibitorylignansincalluscultureofPodophyllumhexan— drum．PlantCellRep，1992，9：382～385 鬼臼毒素及其衍生物 张培楠1李朝峰2赵长琦1* (1．西北大学生命科学学院西安710069；2．陕西省药材公司西安710048) 摘要鬼臼毒素作为鬼臼属植物的主要活性成分，已经有广泛的研究报道。其同系物及衍生物具有 很强的抗肿瘤活性。依托泊甙、替尼泊甙已经成功地用于临床抗肿瘤治疗。优化结构、寻找新的鬼臼毒 素类化合物资源替代品，已成为当前进一步研究的主要方向。 关键词鬼臼毒素及鬼臼毒紊甙；衍生物；抗肿瘤 红景天提取物(RhodiodaroseaExtract) Salidroside；Rosavin 天津尖峰天然产物公司是一家专业从事天然植物提取、研究、开发、生产、销售的专业综合公司。目前是 国内最大的葡萄籽提取物生产厂家，同时推出红景天提取物。 红景天(Rhodiola)系景天科红景天属植物，藏语称“苏罗玛布”。系草本或亚灌木植物，因其含花色素， 根及根茎呈红色，浸液亦呈红色，又系景天科植物，故名红景天。红景天属植物大部分生长在海拔3500～ 5000米的山地、冰川、山梁草地或山谷岩石上，广泛分布于中亚、东亚西伯利亚及北美地区，我国的红景天资 源主要分布在东北、西北、华北及西南的一些地区。红景天产地用其作滋补强壮药，消除疲劳，抵御寒冷。皇 室将红景天作为贡品索取，乾隆时蒙古土尔扈特部从伏尔加河流域回归祖国时给皇帝的贡品中就有红景天。 对红景天资源研究与应用较早的国家是前苏联。上世纪60年代他们研究证实红景天的免疫补益作用 强于人参、刺五加。1976年他们将红景天用为“适应原”样药物投入市场，并用于宇航员、飞行员、潜水员、运 动员等消除疲劳、增加活力。 功效：抗衰老作用、抗缺氧作用、抗不良刺激作用、对机体双向调节作用、抗疲劳作用、抑制血糖升高作用 等。 产品特点： 本公司仔细研究国内红景天资源，找到了前苏联为宇航员、飞行员等研制保健品的红景天——玫瑰红景 天(Rhodiolarosea)。并且开发出红景天提取物以及不同的红景天苷(1—10％)和Rosavin(1～ 10％)提取物。 1、1--2％红景天苷、3％Rosavin的提取物(俄罗斯药典标准)基本保留红景天原料的基本成分，与红景天 原料具有同样的药理作用； 2、在低含量的提取物基础上又开发出高含量的单一成分的产品，10％红景天苷，10％Rosavin。 3、纯天然原料，高科技工艺，产品无污染，农药残留与有机溶剂残留低等特点。 4、工艺稳定，质量控制严格，质量稳定。 地址：天津市北辰科技园科园道 Tel：022—26721040 Fax：022—26721041 Http：／／www．jf-natural．eomE—mail：jf—natural@hotmail．com 万方数据 鬼臼毒素及其衍生物 作者： 张培楠， 李朝峰， 赵长琦 作者单位： 张培楠,赵长琦(西北大学生命科学学院,西安,710069)， 李朝峰(陕西省药材公司,西安 ,710048) 刊名： 天然产物研究与开发 英文刊名： NATURAL PRODUCT RESEARCH AND DEVELOPMENT 年，卷(期)： 2004,16(1) 被引用次数： 5次 参考文献(15条) 1.Stahelin HF;yon Warburfg A The chemical and biological route from Podophyllotoxin to etoposide 1991(5-15) 2.Lars Bthulin Podophyllotoxin derivatives:drug discovery and development 1996 3.Kaplan IW Condylomata acuminata 1942 4.Zhang;YL;Guo X;Cheng YC, Lee KHJ Synthesis and biological evaluation of novel 4-amino derivatives of etoposide with better pharmacological profiles[外文期刊] 1994 5.Marina Gordaliza Cytotoxic aycloignans related to podophyllotoxin[外文期刊] 2001 6.Ward RS 鬼臼毒及其抗肿瘤作用研究进展 1993(05) 7.Zhao C Three New Glycosides from Sinopodopullum emodi ( WALL. ) Ying[外文期刊] 2001(11) 8.Zhao C Two New Podophyllotoxin Glycosides from Sinopodophyllum emodi (WALL.) Ying 2001 9.Camilo Canel Molecules of Interest Podophyllotoxin[外文期刊] 2000 10.Gordaliza M;Castro MA Antitumor Properties of Podophyllotoxin and Related Compounds[外文期刊] 2000 11.Wang ZG;Ma WY;Zhang CN Stereoselective Synthesis of New Podophyllotoxin Derivative: 4-cyano-4- deoxy-4 '-demethylepipodophyllotoxin 1992 12.Arroo RRJ Plant cell factories as a source for anti-cancer lignans 2002 13.Kadkade PG Growth and podophyllotoxin production in callus tissues of Podophyllum Peltatum[外文期 刊] 1982 14.Woerdenberg HJ Increased podophyllotoxin production in Podophyllum hexandrum cell suspension culture after feeding coniferyl alcohol as a β-cyclodextrin complex 1990 15.Heyenga AG;John A Lucas Production of tumourinhibitory lignans in callus culture of Podophyllum hexandrum 1992 本文读者也读过(10条) 1. 高蓉.田暄.张兴.余向阳 鬼臼毒素类生物活性物质的研究概况[期刊]-农药学学报2000,2(1) 2. 贾红光.曹长年.陈建军.米琴.王彦广 鬼臼毒素类抗肿瘤药物的研究[期刊论文]-青海医学院学报2002,23(2) 3. 杨得锁.王晓玲.温普红.YANG De-suo.WANG Xiao-ling.WEN Pu-hong 鬼臼毒素的催化改性研究[期刊论文]-工业 催化2001,9(1) 4. 刘艳青.张守刚.程洁.肖杭.高蓉.LIU Yan-qing.ZHANG Shou-gang.CHENG Jie.XIAO Hang.GAO Rong 鬼臼毒素类 物质生物活性的研究[期刊论文]-医学研究生学报2006,19(3) 5. 王莉莉.周应军 抗癌物质鬼臼毒素及其衍生物研究进展[期刊论文]-国外医药（植物药分册）2006,21(1) 6. 权红.马和平.兰小中 鬼臼毒素的研究进展[期刊论文]-现代农业科技2009(23) 7. 朱承根.杨晶.李弟灶.赵亮.潘显道.熊瑜 天然抗肿瘤药鬼臼毒素及其衍生物研究进展[期刊论文]-药品评价 2004,1(4) 8. 张元 鬼臼毒素衍生物CIP-36抗肿瘤多药耐药作用机制研究[学位论文]2010 9. 牟英迪.林振广.刘宜辉 抗肿瘤药物替尼泊苷[期刊论文]-齐鲁药事2007,26(5) 10. 陆志科.余江帆.谢碧霞.LU Zhi-ke.YU Jiang-fan.XIE Bi-xia 抗肿瘤活性鬼臼毒素类似物的资源研究[期刊论 文]-中南林业科技大学学报2007,27(5) 引证文献(5条) 1.邓书端.赵兴玲.王巍.黄齐林.丁中涛.曹秋娥 八角莲不同部位鬼臼毒素分布的毛细管区带电泳研究[期刊论文]- 化学 2006(5) 2.张杰.周春山.刘韶.陈皓.杨超 鬼臼毒素抗胃癌细胞株SGC 7901作用的实验研究[期刊论文]-中南大学学报（医学 版） 2008(8) 3.万宗明.陈虹.曹波.王莹.牟洪军 大黄酸鬼臼毒素酯对人骨肉瘤细胞作用机制的研究[期刊论文]-中草药 2008(1) 4.权红.马和平.兰小中 鬼臼毒素的研究进展[期刊论文]-现代农业科技 2009(23) 5.陆志科.余江帆.谢碧霞 抗肿瘤活性鬼臼毒素类似物的资源研究[期刊论文]-中南林业科技大学学报 2007(5) 本文链接：http://d.g.wanfangdata.com.cn/Periodical_trcwyjykf200401023.aspx