Recent Studies on Natural Products as Anticancer Agents

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CurrentTopicsinMedicinalChemistry2004,4,241-265241RecentStudiesonNaturalProductsasAnticancerAgentsÁngelG.Ravelo*,AnaEstévez-Braun,HaydeeChávez-Orellana,ElisaPérez-Sacau,DulceMesa-SiverioInstitutoUniversitariodeBio-Orgánica“AntonioGonzález”,UniversidaddeLaLaguna,Avda.AstrofísicoFco.Sánchez2.38206.LaLaguna,Tenerife,SpainstAbstract:Cancerwillbethemajorcauseofdeathinthe21centuryandnaturalproductsshouldprovidenovelandmoreeffectiveanticanceragents.Thisreviewdealswithnewnaturalmoleculesliabletobecomeanticancerdrugs,aswellasrecentspecificstrategiesforaselectivetreatmentofcancer.Theintroductionpresentsthecurrentstateoftheartonanticancerresearch.Beside,inthefollowingsubheadingswesummarizeourresearchoncytotoxicnaturalquinonemethide-triperpenesandtheiranalogues.Wealsodiscussourresultsontheanti-tumourpromotingactivityofnaturalnaphthoquinonesandtheirderivatives.1.INTRODUCTIONmoleculelibrariescanbeusedtoidentifyandstudypreviouslyunknowntargets[17-18].Thetraditionalmedicinesystems,basedonplants,havebeenusedallovertheworldforthousandsofyears[1-4].Despitetheever-increasingdemandofnewnaturalTheseplantbasedsystemscontinuetoplayanessentialroleproducts,theirisolationandstructureelucidationstillremaininhealthcare.TheWHO(WorldHealthOrganization)alabor-intensiveprocess[8,19-20].Asanalternative,estimatesthatapproximately80%oftheworld’sinhabitantschemistsarenowenlistingthetoolsofsolid-phasecombi-relymainlyontraditionalmedicinefortheirprimaryhealthnatorialsynthesistoconstructlibrariesofnaturalproductcare[5-6].Toalargeextent,theuseofnaturalproductsinanaloguesandnaturalproductlikecompounds[21-23].Theredrugdesignrepresentsthenaturalevolutionofthisoldareexamplesofthisapproachbaseduponthenaturaltradition.Naturalproductshavehadamajorimpactasproductspaclitaxel[24]andepothilones[25-26].Nicolaoutemplatesordirecttreatmentsforcancersandinfective[27-29]introducedthisstrategyfortheconstructionofdiseases.Inthecancerarea,ofthe92drugscommerciallynaturalproduct–likelibrariesusingtheconceptofprivilegedavailablepriorto1983intheUnitedStates,orapprovedstructures,atermfirstproposedbyEvansetal.[30-31]toworldwidebetween1983and1994,approximately62%candescribeselectstructuraltypesthatbindtomultiple,berelatedtoanaturalproductorigin.Thisfigureignoresunrelatedclassesofproteinreceptorsashighaffinityligands.drugsofbiologicaloriginsuchasinterferon,orrecombinatelyGiventhesuccessofprivilegedstructuresinmedicinalproducedcytokines[7].Theinfluenceofnaturalproductsinchemistry,theapproachofNicolaou,andthesolid-phasedrugdiscoveryhasbeenrecentlyreviewedintwoexcellentsynthesisthatitentails,arenowleadingthisarea.papersbyCordell[8]andNewman[9],withsectionsWaldmannetal.[32-33]havedevelopedthe“domaindevotedtoantineoplasticsfromnaturalsources.concept”foramoreefficientsearchfordrugcandidates.ThisNaturalproductsalsoplayanimportantroleinchemicalconceptaimsatthegenerationofcompoundlibrarieswithabiology.Infact,naturalproductshavebeenextensivelyusedveryhighhitrate.The“domainconcept”isbasedontoelucidatecomplexcellularmechanisms,includingsignalstructurallyconservedyetgeneticallymobileproteintransductionandcellcycleregulation,leadingtothedomainsandthecorrespondingnaturalproductsselectedidentificationofimportanttargetsfortherapeuticinterventionduringevolution.Thebiologicallyactivenaturalproducts[10-11].Asaresultofrecentadvancesinbiology,thereexistsnowanincreasingdemandfornewnaturalproducts,orcanberegardedaschemicalentitiesthatwereevolutionarilynewnaturalproducts-likesmallmolecules.Specifically,theselectedandvalidatedforbindingtoparticularproteinfieldsofgenomicandproteomicspromisetherapiddomains.Therefore,theyarealreadybiologicallyvalidated,identificationoflargenumbersofgeneproductsforwhichandtheunderlyingstructuralarchitecturesofsuchnaturalsmallmoleculemodulatorswillbeofbothbiologicalandproductsmayprovidepowerfulguidingprinciplesformedicinalinterest[12-16].Moreover,thecombinationofcelldevelopmentofnewbioactivemolecules.Thedomainbiologyandhighthroughputtechnologyhasledtotheconceptregardsanaturalproductclassasastartingpointfordevelopmentofvariouscellularassaysinwhichsmallthedrugfindingprocessandthedevelopmentofcompoundlibrariesratherthanattemptingtosynthesizedenovo.*AddresscorrespondencetothisauthoratInstitutoUniversitariodeBio-Thetwoapproachesmentionedabove,privilegedOrgánica“AntonioGonzález”,UniversidaddeLaLaguna,Avda.structuresanddomainconcept,arealreadyobtainingAstrofísicoFco.Sánchez2.38206.LaLaguna,Tenerife,Spain;Fax:significantresultsandonecaneasilyforeseeafuturesuccess922318571;E-mail:agravelo@ull.esintheareaofcancertreatment.1568-0266/04$45.00+.00©2004BenthamSciencePublishersLtd. 242CurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2RaveloetalAlthoughplantshavealongrecordofuseinthecancertriterpeneshaverecoveredattentionafterthelastfindings.treatment[34],manyifnoalloftheclaimsontheefficacyofTheursolicacid(12),isolatedfrommanykindsofmedicinalsuchtreatmentsshouldbeviewedwithsomeskepticism.plants,hasinvitroanti-tumouractivity,possiblyattributableCancer,asanspecificdisease,ispoorlydefinedintermsoftomatrixmetalloproteaseinhibition[75-76].Ursolicacidisfolkandtraditionalmedicines[35].Evenmore,thereiscurrentlyundergoingpreclinicalinvestigationasapotentialcontroversyontheevaluationofthepotentialcancerchemopreventiveand/oranti-inflammatoryagent[77].chemotherapeuticefficacyofnaturalproductsandsomeUncarinicacidA(13)anditsisomer,uncarinicacidBresultsseemtodependonspecifictests[36].(14),bothwitholeaneskeleton,isolatedfromUncariarhynchophylla,areunderpreclinicalinvestigationinKoreaasFromnowonweshallfocusonanticanceragents;potentialanticanceragents[78].Thediterpenedysidiolidespecifically,weconsiderthoseappearingafterthereviewby(15)isthefirstnaturallyoccurringinhibitorofthedual-Newman[9].Afirstsetofstudiesarelistedasrefereencesspecificitycdc25proteinphosphatasefamily,whichplaysa[37-52].Butratherthangoingquicklythroughallofthem,crucialroleintheregulationofthecellcycle[79].Becausewewouldmentioninsomedetailafewadditionalworksofthispropertyandtheresultingantitumoractivity,thatillustratethemostrecentadvances.dysidiolidehasbeenofinteresttochemists,biologistsandb-lapachone(1)isanaturallyoccurringquinoneobtainedphamacologists[32,80-88].fromthelapachotree(Tabebuiaavellaneda).ThiscompoundArecentpaperreportsonthepreparationofpotent,orallyhasabroadspectrumofbiologicalactivitiesandpreclinicalactive,heterocycle-basedcombrestastinA-4analogues[89].studiesasanticancerdrugsareinadevelopmentalphase.TheCombrestatinA-4(16),isanaturalproductisolatedfromthepharmacokineticsofb-lapachoneshowstobebiexponentialSouthAfricantreeCombretumcaffrum.Thiscompoundwitharapiddistributionphaseafter40mg/kgIPadminis-exhibitsstrongantitubulinactivitybybindingtothetrationinnudemice.Maximumliverconcentrationforb-colchicinesbindingsiteoftubulin[90].CA-4doesnotshowlapachonewasobtainedat5minutespost-injection[53].Ininvivoefficacyagainstmurinecolon26adenocarcinoma,invitrob-lapachonewascytotoxicagainstavarietyofdrug-part,duetoitspoorpharmacokineticsresultingfromitshighsensitiveanddrugresistanttumourcelllines,includinglipophilicityandlowaqueoussolubility.ThereplacementofMDR1-overexpressingcelllines,camptothecin-resistantthecisdoublebondbya1,2-disubstitutedfive-membered(CPT-K5andU93/CR),andtheatypicalmultidrug-resistantheterocyclesuchasimidazole,oxazoleorpyrazole,provokesCEM/V-1cellline[54].b-lapachoneinducedapoptosisintheformationofanalogueswhichshowpotentoralantitumorhumanpromyelocyticleukaemiacells(HL-60),humanactivity“invivo”.prostatecancercells(DU-145,PC-3andLNCaP)[55,56],andMCF-7:WS8breastcancercells[57].ThecombinationTryprostatinA(17)andB(18)[91]havebeenisolatedasofb-lapachoneandpaclitaxelwashighlyeffectiveinsecondarymetabolitesfromthefermentationbrothofainhibitingtumoursurvivalinvitro[58].CoPharmahasmarinefungalstrainofAspergillusfumigatusBM939.Theselicensedworldwiderightstob-lapachone(year2001).compoundscompletelyinhibitedcellcycleprogressionofIsoasterriquinone(2)isoneofaseriesofasterriquinonetsFT210cellsintheG2/MphaseatafinalconcentrationofanaloguesisolatedfromthefungalspeciesAspergillus50mg/mLof(17)and12.5mg/mLof(18),respectively.candidus.Thepotentialuseofthesecompounds[59]intheOtherspecificstrategiesforaselectivetreatmentofcancertreatmentofcancerisbeingevaluatedinpreclinicalstudies(angiogenesis,antibody-directedenzymeprodrugtherapy,intheUSA(year2000).proteosomeinhibition,dualtopoisomeraseIandIIinhibition,Otherquinonesstudiedasanticanceragentsareetc)havealsobenefitedfromthediscoveryanduseofnaturalgeldanamycin(3),isolatedfromastrainofStreptomycesproducts.Thesewillbeconsiderednext.hygroscopicus[60],17-allylamino-17-demethoxygeldanamy-Theangiogenesis,i.e.thedevelopmentofnewbloodcin(4)[61-62],whichactastyrosinekinaseinhibitors,andvesselsfrompre-existingones,iscrucialtowoundrepair,irisquinone(5),isolatedfromtheseedsofIrislateapallasii,inflammation,andembryonicdevelopment.Aberrantangio-commonlyusedintraditionalChinesecancertherapies[63-genesisisbelievedtobeakeystepintumorgrowth,spread,64].(5)actsasradiosensitizerandmayalsohavechemo-andmetastasis[92-95].Vasculardevelopmentdependsonsensitisingactivity.Otherkindsofnaturalproductslikeendothelium-specificreceptortyrosinekinases,inparticularflavonoidsbaicalein(6)andbaicalin(7)isolatedfromthevascularendothelialgrowthfactorreceptors1-3Scutellariabaicalensis[65-66]areunderpreclinical(VEGFR1-3)andtheTie-2receptor[96-97].Alltheseinvestigationasanticanceragents.Thesecompoundshavereceptorshavebeenimplicatedintumorangiogenesis[98-beenshowntoinhibitthereplicationofthehumanTcell102],andantagonizationofTie-2,VEGFR-2orVEGF-D(aleukaemiavirus.ThepreclinicalstudiesonhumanovarianligandofVEFGR-3)inhibitstumorgrowthandtumorcancercellsofsylibin(8)continues[67].Quercetin(9),alsometastasisinvivo[101,103-104].ThefindingoflowknownasProsta-QÒ[68-69],hasbeenevaluatedinpatientsmolecularweightinhibitorsofthesereceptortyrosinekinaseswithprostatitisanditshowedantineoplasticeffects,althoughisoneofthemostpromisingapproachestothedevelopmentnephrotoxicitywasfoundasadverseevents[70-71].Theofnewalternativeantitumordrugs.Severalinhibitorsofcoumarinesculetin(10)isolatedfromArtemisiascopariaVEGFR-2areinclinicaltrials[103-104].Thecombination[72],continuespreclinicalstudiesasapotentialanticancerofVEGFR-2inhibitorswithTie-2antagonistsshoulddruginTaiwan(2001).ThediterpeneisolatedfromNocardiapotentiatetheiranti-angiogeniceffects[100].Furthermore,brasiliensisstrainIFM0406,calledbrasilicardinA(11),hasinhibitorsofVEGFR-3wouldsuppressthemetastasisofalsopotentialuseasananticanceragent[73-74].The RecentStudiesonNaturalProductsasAnticancerAgentsCurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2243lymphogenictumors.Todate,however,onlyafewcasesofThetopoisomerasesareessentialenzymesinthesmall-moleculeinhibitorsoftheTie-2andVEGFR-3regulationofDNAtopologywhicharerequiredforcellstoreceptorshavebeenreported[105-107].Waldmannetal.divideandproliferate[137].Theyrepresentimportantcellular[33,110]synthesizedalibraryof56nakijiquinoneanaloguestargetsforanumberofsuccessfulchemotherapeuticagents(19),theonlynaturalproductknowntobeinhibitorsofthe[137].Charltonetal.[138-139]undertookaprogramtoHer-2/Neureceptortyrosinekinases.StudiesareunderwaytodiscoverorallyactivedualinhibitorsoftopoisomeraseIandtesttheseanaloguesaspossibleinhibitorsofthetyrosineIIthatavoidMDR.Theysucceededwiththenovelangularkinasereceptorsinvolvedinangiogenesis.chiralbenzophenazine(24),acompoundselectedasacandidateforfurtherevaluation.ThiscompoundisstructurallyrelatedTheantibody-directedenzymeprodrugtherapy(ADEPT)toaremarkablefamilyofnaturalproducts,thecephalostatins,[111-112],firstdescribedbyBagshawe[113],isanewfirstisolatedfromthemarinetube-inhabitinginvertebratestrategyforaselectivetreatmentofcancer.Anon-toxicwormCephalodiscusgilchristi[140].prodrugisenzymaticallyconvertedintoacitotoxiccompoundselectivelyatthesurfaceofmalignantcellsbyemployinganFinally,inanefforttoenhanceaccesstoinformationenzyme-immunoconjugate.AsaproposedrequirementforavailableintheNationalCancerInstitute’s(NCI)anticancertheprodrug,thecorrespondingcytotoxiccompoundshoulddrug-screeningdatabase,anewwebsiteisaccessible(http://possesanIC50<10nM,[114](IC50:drugconcentrationspheroid.ncifcrf.gov)wherecomputationaltoolshavebeenrequiredfor50%inhibitionoftargetcells),andthequotientassembledforself-organizingmap-based(SOM)clusteroftheIC50oftheprodruginthepresenceoftherelatedanalysisanddatavisualization.Theseanalysesidentifiedenzyme(QIC50)shouldbeabove1000[115].Tietzeetal.relationshipsbetweenchemotypesofthescreenedagentsand[116],knowingthattheantibioticCC-1065(20)isolatedtheireffectsonfourmajorclassesofcellularactivities:fromSteptomyceszelensisisagoodtarget[117],synthesizedmitosis,nucleicacidsynthesis,membranetransportandthecompound(21).Thisnewpotentprodrugmeetsalltheintegrity,andphosphataseandkinase-mediatedcellcyclerequirementsforasuccessfuluseinADEPTandfirstpreclin-regulation[141].icalinvestigationsonmiceshowedpromisingresults[116].AlltheexamplescitedaboveillustratethecentralroleTheproteasomeisanintracellularmulticatalyticproteaseplayedbynaturalproductsindrugdevelopmentforthecomplexwhichincombinationwiththeubiquitinpathwaypreventionandtreatmentofcancer.Intheforthcomingplaysacentralroleinmajorcellularprocesses,suchasantigensectionsweshalldescribeourowneffortsinthisdirection.presentation,cellproliferationanddifferentiation,andWeelaborateontheisolationandchemistryoftwokindofapoptosis[118-121].Proteolysisoccursinabarrel-shapednaturalproducts,namely,quinone-methide-triterpenesandcorestructureknownas20Sproteasome,whichconsistofprenylnaphthoquinones.Thetriterpenicquinoneshavefourstackedringsarrayedinana7b7b7a7mode[122].Inalreadyshowninterestingcytotoxicactivitiesagainstvariouseukaryoticproteasomethreeb-subunitsofeachb-ringaretumourcelllines.WecarriedoutchemicalmodificationsenzymaticallyactivewithanN-terminalthreonineresidueasaimedatobtainingderivativesmoreactiveand/orselective,theactivenucleophileinvolvedinproteolysis[123],withaswellastoestablishstructure-activityrelationships.Thethreemoreorlessdistinctsubstratespecifities,thatisprenylnaphthoquinonesconstituteyetanotherimportantchymotrypsin-like(CL),trypsin-like(TL),andpeptidyl-groupofnaturalproductsstudiedincancerresearch.Besides,glutamyl-peptidehydrolase(PGPH)activities[124].Becausethequinonesrelatedtolapacholhaveanotablecancerofthephysiologicalroleofproteasomeincriticalintracellularpreventivepotential.Weshallpresenttheinhibitoryeffectofprocesses,thisenzymerepresentsapromisingtargetfordrugvariousnaturalprenylnaphthoquinones,aswellassomedevelopmentininflammatoryandautoimmunediseasesasderivativesoflapachol,ontheEpstein-Barrvirusearlywellasintumortherapy[125-127].Consequently,attentionantigen(EBV-EA)activationinducedby12-O-hasbeenpaidtothediscoveryofpotentandselectivetetradecanoylphorbol-13-acetate(TPA)asthepromoter.proteasomeinhibitorsbystructure-baseddesignornaturalproductscreeningapproaches.Mostofthesyntheticinhibitors2.NOR-QUINONE-METHIDE-TRITERPENESAND(consistingofpeptidealdehydes,boronatesandvinyl-NOR-CATECHOL-TRITERPENESWITHANTI-sulfones),aswellasthenaturalproductslactacystinandTUMOURACTIVITY.epoxymicins,inhibitinamoreorlessselectivemannertheTheCelastraceaespecieshavealongtraditionofuseinproteasomebyreactionwiththeN-terminalthreoninetraditionalmedicine,speciallyinAsiaandLatinAmericaresidue.Forarecentreviewonthetopicsee[128].[142-143].Inarecentreviewonplantsusedagainstcancer,AnotableexceptionisthehighlyselectiveandbasedontheresultsofaqueryoftheNAPRALERTdatabasecompetitiveproteasomeinhibitorTMC-95A(22),whichwasforplantsspecies,numerousCelastraceaespeciesbelongingisolatedfromthefermentationbrothofApiosporamontagneitoMaytenus,CelastrusandTripterygiumgenerahavebeenSaacTC1093,127anditssynthesishasattractedreferenced[144].considerableinterest[130-135].Moroderetal.[136]TheantitumoralpropertiesaremainlyattributedtosynthezisedthefirstTMC-95Aanalogue(23),andtheresultsaromaticandquinoidtriterpenoidswhichconstituteaobtainedsuggestthatnotallofthecomplexstructuralrelativelysmallgroupofunsaturatedandoxygenatedD:A-elementsofthenaturalproductarerequiredfortheinhibitionfriedonor-oleananes.Thesenor-triterpenoidpigmentsareofproteasome,thusmarkedlyfacilitatingthesynthesisofrestrictedtothefamilyoftheCelastraceae(includingTMC-95Arelatedcompounds.Hippocrataceae),althoughtheextendedquinonecharacteristic 244CurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2RaveloetalONROOOO(3)R=OCH3,GeldanamycinO(4)R=NHCH2CH=CH2,17-OH(allylamino)-17-demethoxyOOOHGeldanamycinMeONHCO(1)(2)3b-lapachoneIsoasterriquinoneOCONH2OHOO(5)IrisquinoneHOOOCH3OH3COOHOHOOHO(8)SylibinR5R6R4O(6)R=R=R=H;R=R=R=OHBaicaleinHO156234(7)R1=R5=R6=H;R2=R4=OH;R3=COOHOBaicalinHOR3R1(9)R1=R2=R4=R5=R6=OH;R3=HHOOHOOOR2OQuercetinHO(10)EsculetinHOOOHOOOCH3OOOHCOOHOHOOHHOHHONHCOCH3NH2HOHO(11)BrasilicardinAH(12)UrsolicacidHOHCOOHMeOHHORHOMeOOMeOH(13)R=trans-ferulicesterOOMeUncarinicacidA(14)R=cis-ferulicesterOUncarinicacidB(15)Dysidiolide(16)CombrestatinA-4(CA-4) RecentStudiesonNaturalProductsasAnticancerAgentsCurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2245Scheme1.(contd….)ROOHHNClNOONInd2HORNOHOHOOHOHO(17)R=OMe;TryprostatinAHOOH(18)R=H;TryprostatinB(19)Nakijiquinones(21)NH2NHNOHOOOHNHOHONOHNOHCONHNNOCH32NHHOONHOOONNHO(20)CC-1065(22)TMC-95ANH(23)TMC-95AanalogueZ=N-(benzyloxy-carboxyloxy)succinimideHONHNONOHMeOCONH2NHH3COONHOCONHCCH2N(Me)2NH(24)ChiralbenzophenazineOScheme1.Naturalmileculesliabletobecomeanticancerdrugs.ofnor-quinonemethidetriterpenesisalsopresentinan3029unusualtetracyclictriterpeneisolatedfromRussulaflavida(Agaricales)[145].Forthisreason,BrüningandWagner2720[146]coinedthegeneralname“celastroloids”forthisclassofE22compounds,whichareisolatedfromtherootsandare11thereforeregardedastaxonomicindicators.Thebasicskeleton1C13H2810ofthesecompoundsisrepresentedinFig.(1),which215invariablycontainsoxygenatedfunctionalitiesatC-2andC-A25263,theonlyexceptionbeingcelastranhydride[147]inwhichringAhasundergoneoxidativecleavage.OtherknownsitesofoxidationofthequinonemethidesystemareC-6andC-7.23OxidationatC-6affordstheclassof6-oxophenolicnor-triterpenoidswhereasoxidationatC-7resultsin7-oxoquinon-Fig.(1).Basicskeleton.emethides.Ontheothehand,triterpenoidquinonemethidesclassifiedunder14(15)-enequinonemethides,respectivelywithanadditionalunsaturationatC-14(15)containingaThemostcommonsiteofoxidationoutsidethequinon-rearrangedmethylgrouparealsoknownandtheseare.emethidesystemisC-29.Thismethylgroupisfrequently 246CurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2RaveloetalfoundoxidizedtoCH2OH,CO2HorCO2Me;subsequentInadditiontotheantitumoralactivity,somecelastroidsdecarboxylationyielding29-noranalogsisalsocommon.havealsoshownantimicrobialactivity[172-174].AlthoughOtherknownsitesofoxidationareC-15,C-21,C-22,C-23nocelastroidshassofarbeenpreparedbytotalsynthesis,itsandC-28.23-NoranalogsresultingfromdecarboxylationofpartialsynthesishasbeenattemptedforthepurposeofC-23oxidized6-oxophenolictriterpenoidsarealsoknown.unambiguousstructureconfirmation[165,175].ThemajorclassesofcelastroidsaredepictedinFig.(2).InthenextsectionsourresultsachievedusingnaturalAlthoughnoexperimentalproofhassofarbeenprovidedcelastroidsaswellasalibraryof63analoguesintheirforthebiosyntheticoriginofcelastroloids,theirco-occurrenceantitumouractivityevaluationarepresented.Theseanalogueswithfriedelanesinseveralplantsandincellcultureshashavebeenobtainedbyacylation,oxidation,extensionofthepromptedpostulationofbiosyntheticpathwaysimplicatingstructure,modificationsontheE-ring,andtreatmentswithpolpunonicacid,zeylanol,salaspermicacidandorthosphenicDDQ,NBSandmorpholine.Wheneverpossible,commentsacidaspossibleprecursors[148].onthestructure-activityrelationshipsthatcanbeinferredfromtheavailabledataareincluded.DrivenbyourinterestinbioactivemetabolitespresentinCelastraceaespeciesusedinSouthAmericanfolkmedicine,2.1.NaturalTriterpenequinoneswecarriedoutphytochemicalstudiesondiversespeciesmostofthemoftheMaytenusgenus(M.horrida,M.amazonica,Thequinones22b-hydroxytingenone(25),pristimerineM.macrocarpa,M.magellanica,M.disticha,M.(26),21-hydroxy-pristimerine(27)andtingenone(28),usuallychubutensis,M.boaria,M.blepharodes).Thebestresultstoarethemainsecondarymetabolitespresentintherootsofisolatethesecompoundswereobtainedusingtherootbark,Maytenusspecies.Therelativeabundancesdependspecificallyandemployingasoxhletapparatuswithn-hexanes:Et2O1:1onthespecies.Forinstance22b-hydroxi-tingenoneisthemainforextraction.ThepurificationofthemetaboliteswassecondarymetabolitepresentinM.amazonicaandM.macro-realizedusingcommonchromatographictechniquessuchascarpa[156-158],whilepristimerineisthemaincomponentsilicagelcolumn,sephadexLH-20column,preparativeofM.blepharodes[159]andM.scutioides[160].TheresultsTLC,andHPLC.Fromthesephytochemicalstudieswehaveofcytotoxicactivityofthesequinonemethidetriterpenoidselucidatedseveraltensofcelastroids[149-171],mostoftheirtogetherwithothernaturallyoccurring7-oxoand7-hydroxy-structuresbeingnewtotheliterature.ThedeterminationofquinonemethidetriterpenesareshowninTable1.theirstructureshasbeencarriedoutonthebasisofFromthedatashowninTable1,itiseasytoconcludeexhaustiveandrigorousspectroscopicstudies,includingthatcompoundstype7-oxo,or7-hydroxyquinonemethidesareNMRbidimensionalCOSY,ROESY,HSQCandHMBClessactivethanthecorrespondingquinonemethides.Probablyexperiments.TheabsoluteconfigurationofthesecompoundsthiscanbeexplainedasalostofconjugationthroughBhasbeendeterminedbymeansofX-rays,DCstudiesand/orring.Thecomparisonoftheactivitiesofcompounds(25-28)chemicalcorrelationswithothernor-triterpenoidsofknownshowsthatthedifferentfunctionalitiesinEringhaveabsolutestereochemistry.influencedtheiractivityandselectivity[151-152].OOOHOHOOHOQuinonemethides7-Oxoquinonemethides14(15)-EnequinonemethidesHOHOHOHOOPhenolic6-OxophenolicFig.(2).Majorclassesofcelastroids. RecentStudiesonNaturalProductsasAnticancerAgentsCurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2247R1R1R2R2R2R3OO7HOHOR4(25)R1=H;R2==O;R3=OH(29)R1=R3=H;R2=R4==O(26)R1=COOMe;R2=R3=H(30)R1=R3=H;R2==O;R4=OH(27)R1=COOMe;R2=OHb;R3=H(31)R1=H;R2=R4==O;R3=OH(28)R1=R3=H;R2==O(32)R1=H;R2==O;R3=R4=OHFig.(3).NaturallyoccuriringQuinonementhideTriterpenoids.Table1.CytotoxicActivityAgainstCulturedCellLines(IC50mM)of(25-32).(25)(26)(27)(28)(29)(30)(31)(32)P-3880.220.220.260.245.7311.411.105.50A-5490.540.270.260.6011.4711.412.2111.0HT-291.100.270.260.6011.4711.412.2111.0MEL-281.100.270.260.6011.4711.412.2111.0P-388:mouselymphoma(ATCC:CCL46);A-549:humanlungcarcinoma(ATCC:CL85);HT-28:humancoloncarcinoma(ATCC:HTB38);MEL-28:humanmelanoma(ATCC:HTB72).2.2.LibraryofAnaloguesofTriterpenequinonesacylgroups,oxidations,extensionofthestructure,additionsofnucleophiles,etc..InthenextsubheadingswepresenttheThedesignofthetriterpenequinoneanalogueswasbasedresultsobtainedwhencarryingoutthesetransformations.onthemodularstructureofthenaturalproducts.Thetriterpenoquinonesconsistoftwohydrophilicpartscentred2.2.1-AcylationReactionontheAandErings,whichcontainsH-bondacceptorandWhenperformingthisreaction,anddependingontheH-bond-donorgroups,respectively.Theyalsohaveanconditionsfollowed,twoselectivedifferentbehavioursofthehydrophobicpart,locatedontheB,CandDrings.Carbonquinonemethideswerefound.WeobtainedselectiveC-6atBringmayactasaMichaelacceptor.acylationsinC-3using1.5eqofthecorrespondingacylConsideringthisreactivityscheme,wedecidedtostudychloride,threeeqofdryEt3NindryCH2Cl2at0ºC.Usingtheinfluenceontheantitumouractivityofsomemodificationstheseconditions,differentacylderivativeswithseveralonthetriterpenemethideskeleton,liketheintroductiontheacylatingagentsofdifferentnatureandlipophiliccharacterH-bondacceptorHydrophobicpartOH-bondacceptorEHydrophilicpartOHCDOHydrophilicpartAH-bonddonorBHOHydrophobicpartH-bonddonorMichaelAcceptorFig.(4).Modularstructureoftriterpenequinones. 248CurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2Raveloetalwereprepared(Fig.(5)).Table2showsthecorrespondingepimersinC-6.Thethirdcompound(44)showedsimilar1valuesofcytotoxicactivity.HRMNthancompound(42),includingthesignalassignedtoH-6andthesurprisingpresenceofanethoxygroup.AcylationofthehydroxylgrouplocatedonC-3withthefollowingacylgroupsacetyl(33),lauroyl(36),andTheformationofthesecompoundscanbeexplainedbyadimethylcarbamoyl(37)producesonlyamarginaldecreaseofnucleophilicattackoftheacetategrouptotheC-6,whichactivity(2-3fold).Incontrast,therestofderivativeslosttheproducesthearomatisationoftheringA(Fig.(7)).Thisfactcytotoxicyty.Theextenttowhichfunctionalityistoleratedagreeswiththeobservedreactionmixturecolourchangefromdependsonthesizeanddirectionoftheelectroniceffect.Adarkorange(characteristicofquinones)topaleyellowdramaticlostofactivitywasobservedfortheisobutyryl(phenolicform).Thismechanismalsoexplainstheformationderivative(35),indicatingastericconstraintinthisregion.ofthetwoepimersastheresultofthetwopossibleattacksThisconjectureissupportedbythelostofcytotoxicityofthroughtheaorbfacesofthemolecule.Compoundsbenzoylanalogues[176].(42)and(43)donotpresentanacetategrouponC-6,andthusithastobeassumedanadditionalhydrolysisoraThetreatmentofnatural22-b-hydroxy-tingenone(25)intrans-esterificationoftheacetategrouptoyieldthepyridinewithanexcessofAc2Oaffordedthreecompoundscorrespondingalcohols.(42-44)(Fig.(6)).TheacetylatedmixturewaspurifiedbypreparativeTLCandthestructuralelucidationoftheseTheformationoftheethoxygroupwasattributedtothecompoundswasaccomplishedbyspectroscopicstudies.presenceofEtOHtracesexistingintheCHCl3usedwiththeThesestudiessuggestedthearomatisationofringAin(42)mixtureofreaction.Whenthereactionwasrepeatedusingwiththeformationofacatecholsystem,andthepresenceinanothersolventsuchasAcOEtthecorrespondingethoxyringBofavinylprotonandahydrogengeminaltoanderivativewasnotfound.Theobservedbstereochemistryforoxygenatedfunction.ThedispositionofthesegroupswastheethoxygroupwasratifiedbyROESYexperimentswhichestablishedbyHMBCexperimentswhilethestereochemistryshowedNOEeffectbetweentheOCH2CH3andMe-25.ThisofthehydroxylgrouponC-6wasdeterminedasain(42)stereochemistryagreeswithanucleophilicattacktothemainbecauseoftheNOEeffectdetectedbetweenH-6andMe-25.productthroughatypicalSN2process.SimilarresultswithCompound(43)showedthesamemolecularformulainothernaturalquinonessuchaspristimerine(26),21a-hydroxi-1HRMSthan(42)andsimilarHRMNspectrumtothoseofpristimerine(27),andtingenone(28)werealsoobtained.(42).ThemaindifferencewasinthesignalattributabletoH-Table3showstheantitumoralactivityforthephenolic6.TheNOEeffectbetweenH-6andMe-25wasnotobservedderivatives(42-52),togetherwiththeantitumoralactivityofinROESYexperimentsandthus(42)and(43)mustbeOO(33)R=COCH3(34)R=CO(CH2)2CH3(35)R=COCH(CH3)2OH1.5eqRCOClOH(36)R=CO(CH2)10CH33eqEt3NO(37)R=CON(CH3)2O(38)R=nicotinoyloxiCHCl/0oC22(39)R=CO-Ph(OMe)3RO(40)R=COp-NO2PhHO(41)R=SO2PHMe(25)Fig.(5).PreparationofC-3-acyl-derivatives.Tabla2.Cytotoxicactivityagainstculturedcelllines(IC50mM)of(33-41).P-388A-549HT-29Mel-28P-388A-549HT-29Mel-28250.220.541.101.10370.200.990.990.99330.521.041.041.04381.841.841.841.8434----2.032.03----39----1.597.94----35----10.210.2----4017.017.017.017.0360.401.621.621.62410.851.691.691.69P-388:mouselymphoma(ATCC:CCL46);A-549:humanlungcarcinoma(ATCC:CL85);HT-28:humancoloncarcinoma(ATCC:HTB38);MEL-28:humanmelanoma(ATCC:HTB72). RecentStudiesonNaturalProductsasAnticancerAgentsCurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2249R1R2R3HO(25)R1=H;R2==O;R3=OH(26)R1=COOMe;R2=R3=H(27)R1=COOMe;R2=OH;R3=HHO(28)R1=R3=H;R2==OR1R1R1R2R2R2R3R3R3HHHAcOAcOAcOAcOAcOAcOOHOHOCH2CH3(42)R1=H;R2==O;R3=OAc(43)R1=H;R2==O;R3=OH(44)R1=H;R2==O;R3=OH(45)R1=COOMe;R2=R3=H(46)R1=COOMe;R2=R3=H(47)R1=COOMe;R2=R3=H(48)R1=COOMe;R2=OAc;R3=H(49)R1=COOMe;R2=OH;R3=H(50)R1=COOMe;R2=OH;R3=H(51)R1=R3=H;R2==O(52)R1=R3=H;R2==OFig.(6).PhenolicderivativesobtainedundertreatmentwithAc2O/Py.OAcOAcOtrans-esterificationHOAcOAcOOAcOHOAcFig.(7).Probableformationofphenolicderivatives.cisplatinum,etoposide,vinblastineandtaxol,fouroftheoftheactivityofthefourstartingproducts(25),(26),(27)commonworld-wideanti-cancerdrugs.and(28),whichhaveonlystructuraldifferencesintheEring,showedthatthisEringhasasignificantrelationshipComparingtheactivityofcompounds(42),(43)and(44)withtheactivity.Thesameconclusionwasreachedfromthewiththestartingproduct(25),itwasobservedthattheactivitydataof(42),(45),(48)and(51).activityimprovedforthederivativepossessingahydroxygroupina-dispositiononC-6(42),whileitdrasticallyIngeneral,thebstereochemistryofthehydroxygroupdecreasedforthecorrespondingepimer(43).FortheetoxylocatedonC-6producesalostofantitumoralactivity.Thederivative(44)theactivitywassimilartothatof(25).Weastereochemistryleadstoactivitieshigherthanthoseoftheobtainedthebestresultswiththepristimerinederivatives.correspondingstartingmaterials.OnlyinthecaseofproductThus,compound(45)exhibitedthehighestantitumoral(45)(frompristimerine),thecelllineP-388selectivitywasactivityagainsttheP-388celllineswithanIC50=0.044mM,alsoincreased.Theresultsoftheetoxyderivativesdependon5-foldmorepotentthan(26).Theselectivityforthiscelllinethestartingmaterial.Compound(44),derivedfrom(25),wasalsoimproved,beingmuchlargerthanthatoftheshowedimprovedactivitiesforthecelllinesP-388,HT-29startingproduct(26).ThisresultwasbetterthanthoseandMEL-28,butnotforA-549.Compound(47),fromrecordedforcis-platinum,etoposideandtaxol,andregardingpristimerine(26),exhibitedanimprovementinselectivityselectivityitwasevenbetterthanvinblastine.ComparisonforP-388vs.MEL-28.Thisselectivitywasonefor(26), 250CurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2Raveloetalwhileitbecamefourforcompound(47),andeightifbromobenzoylchloride,obtainingthecorrespondingderi-comparingP-388vs.HT-29;Similarlycompound(50)alsovativesmixture(C6-OHa;C6-OHbandC6-OEtb),whichshowedanactivityimprovement.wereevaluatedforactivity.NoneofthemwasactiveandtheyexhibitedanIC50>10mg/ml.ForthesetypeofcatecholTable3.CytotoxicActivityinCulturedCellLines(IC50mM)derivatives,thesizeoftheacylgroupslocatedonringsAofderivatives(42-52).andEplayedanimportantroleintheactivity.Therewasnotasignificantelectroniceffectofthesubstituentsonactivityofthebenzoylatedderivatives,sinceweobtainedthesameCompoundsP-388A-549HT-29MEL-28activitywithdifferentsubstituentsinthearomaticring.250.220.541.101.102.2.2-ModificationsontheCarbonylandHydroxylGroupLocatedonRingE260.220.270.270.27Duetoourinterestinfindingstructure-activityrelation-270.260.260.260.26ships,modificationsofthetypeandnumberofhydrogen-280.240.600.600.60bonddonorsandacceptorspresentinringEof22b-hydroxy-tingenone(25)wereconducted.ModificationoftheC-21-420.170.430.860.86carbonylgroupwiththeformationoftheoximederivative4317.217.217.217.2(62)anditsreductiontohydroxygroup(64)(seeFig.(9)),andtransformationofthe22b-hydroxygroupintotheester-440.160.820.820.82acidderivative(65),undertreatmentwithsuccinicanhydride450.0440.180.180.18wereperformed.Thenwealteredthecarboxylicgrouptorenderderivatives(66)and(67).Thesubstitutionofthe462.222.222.222.22carbonylgroupwithanoximefunction(62)increasedtheactivityagainstthecelllinesA-549,HT-29andMel-28(2-470.210.841.680.84foldforA-549and4-foldfortheothertwocelllines).480.190.190.1916.0However,theselectivityoftheP-388celllinevsMel-28waslost.Aslightimprovementwasalsoobtainedwiththe4916.016.016.016.0acetylationof(62)togive(63).Thistendencywasalso500.150.150.150.19observedforthedihydroxylderivative(64),whichimproveditsactivitybutlostitscorrespondingselectivity.Whenthe510.230.230.230.23hydroxylgrouplocatedonC-22wastransformedintothe5219.019.019.019.0derivatives(65),(66)and(67)theresultswerenoteven.Thederivative(65)displayedanattractiveactivityandselectivityCis-platinum8.3316.6733.3333.33forthecelllineMel-28.TheactivityfortheP-388celllineEtoposide0.170.171.700.85oftheethylesternotablyimprovedwithrespectto(65)(12-fold),andalsowithrespectthestartingtriterpene(25)(3-Vinblastine0.0220.0220.0220.022fold).Likewisederivative(67)yieldedthesameIC50valuesTaxol0.590.0120.0120.012forthefourcelllines.Inshort,wehaveobtainedanalogueswithhigheractivityand/orselectivitythanthoseofetoposideP-388D1:Mouselymphoma(ATCCCCL-46);AT-549:Humanlungcarcinomaorcis-platinum(seeTable3).Itisthusshownthatwithonly(ATCCCCL-185);minorchanges,theactivityandtheselectivityforthecellHT-28:Humancoloncarcinoma(ATCCHTB-38);SK-MEL-28:HumanmelanomalinesP-388,(65),andMel-28,(66)werelargelyimproved.(ATCCHTB-72).TherelativecytotoxicactivitiesobtainedbythechangeofWealsostudiedthereactionwithotheracylatingagents,differentfunctionalgroupsonringE(seealsothevaluesforsuchasbenzoylchloride,p-nitrobenzoylchloride,andp-OOOORORORHHHROROROROROROOHOHOCH2CH3(53)R=p-Br-Bz(54)R=p-Br-Bz(55)R=p-Br-Bz(56)R=p-NO2-Bz(57)R=p-NO2-Bz(58)R=p-NO2-Bz(59)R=Bz(60)R=Bz(61)R=BzFig.(8).Benzoylatedderivatives. RecentStudiesonNaturalProductsasAnticancerAgentsCurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2251thenaturalnor-triterpenequinones(26-28)inTable4)oxidizeitwiththecommonreagentsforthistypeoffunction-togetherwiththefactthatmodificationsoftheA/Bringsalization:H2O2inalkalinemedium,tert-butylhydroperoxideaffectthecytotoxicactivity,seemtosuggestthattheprimaryorsodiumperborate,whichhavebeensuccessfullyusedinpharmacophoreresidesontheA/Brings,whereastheC-,D-,theepoxidationofbenzoquinones.WesucceededwithandEringsstabilizethequinonemethidesystemofthisDMDO,CAN,NCSandO2/K2CO3/MeOH[179,180].Theclassofcytotoxiccompounds.highestyieldswereobtainedwithDMDO,andthehighestselectivitywithO2/K2CO3/MeOH.2.2.3.OxidationReactionsCompound(25)wastreatedwithcericammoniumnitrateSeveralmethodsofoxidationthatallowedustoobtain(CAN)inaqueousacetonitrileandyieldedamixtureof1,2-dicarbonylcompoundswithanhydroxylormethoxycompounds(68)and(69)ina3:1ratio.ThestereochemistrygrouponC-4,keepingtheextendedconjugationofdoubleofthehydroxylgrouponC-4in(68)wassolvedbyabondspresentinringBwereperformed.WecouldnotROESYexperimentshowingaNOEeffectbetweentheMe-NHOHOHOHH(64)EOHOHOHNaBH4TracesOONH2CH3HClOHO(25)NOHOOHOHOHO(62)O(65)DCC,Py,EtOHNOAcOOHOEtOAcOHO(66)AcOOOHN(63)OAcO(67)ONHOHFig.(9).TransformationonEring.Table4.CytotoxicActivityinCulturedCellLines(IC50mM)ofderivatives(62-67).P-388A-549HT-29Mel-28P-388A-549HT-29Mel-28250.220.541.101.10630.160.160.160.16260.220.270.270.27640.230.230.230.23270.260.260.260.26650.931.870.930.22280.240.600.600.60660.080.440.440.44620.220.270.270.27670.130.130.130.33P-388D1:Mouselymphoma(ATCCCCL-46);AT-549:Humanlungcarcinoma(ATCCCCL-185);HT-28:Humancoloncarcinoma(ATCCHTB-38);SK-MEL-28:Humanmelanoma(ATCCHTB-72). 252CurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2RaveloetalR1R2ER3CHO(25)R1=H;R2==O;R3=OHA(28)R1=R3=H;R2==OHO(26)R1=COOMe;R2=R3=H(27)R1=COOMe;R2=OH;R3=HR1R2R1R2R3CHOR3CH25(68)R1=R=H;R2==O;R3=OHOO(70)R1=H;R2==O;R3=OH;R=Me25NOE(71)R1=R3=R=H;R2==O23OR(72)R1=R3=H;R2==O;R=MeO(74)R1=COOMe;R2=R3=R=HHONOE(75)R1=COOMe;R2=R3=H;R=Me(78)R1=COOMe;R2=OH;R3=H;R=Me(69)R1=H;R2==O;R3=OH(73)R1=R3=H;R2==O(76)R1=COOMe;R2=R3=HFig.(10).Oxidationofquinonemethidetriterpenes.23andMe-25.SimilarspectroscopicresultswereobtainedMe-23andMe-25.TheproductswithanOHgrouplocatedfortheminordiastereomer(69)whichisthecorrespondingonC-4turnedouttobelessstablethanthecorrespondingepimerinC-4of(68).ThenewhydroxygroupinthiscaseisoneswithOMegroup.locatedinthemorecongestedb-faceofthemolecule.Withtherestofthenaturalquinones(26-28),weSimilarresultswereobtainedwhen(25)wastreatedwithobtainedsimilarproducts.NCS,theyieldandtheratioofcompounds(68):(69)beingTable5showstheantitumoralactivityofcompoundshigherthanthoseobtainedwithCAN.Theratioofthese(25-28),(68),(70),(72),(75)and(78),togetherwiththediastereomerswasalsoincreasedto9:1usingDMDO.antitumoralactivityofetoposide.TherestofthederivativesThereactionswithO2andK2CO3/MeOHwerestereo-couldnotbeevaluatedbecausetheyresultedveryunstable,specific,becausejustonediastereomerwasproduced(70).rapidlydegradingwithtime.AllthesecompoundsexceptThepresenceofoxygenwasnecessarybecausewhenthe(68)haveactivitiessimilartothatofetoposide.Thereactionwasrepeatedunderinertatmosphereand,after24h,antitumoralactivityofdicarbonylcompounds(70),(72)andformationofthediketonecompoundwasnotdetected,and(75)forthecelllinesP-388,HT-29andMEL-28resultedthestartingmaterialremainedunaltered.ThestereochemistryhigherthanthoseofthecorrespondingstartingnaturalofthemethoxygroupwasestablishedasabyROESYproducts.Thebestresultwasobtainedforcompound(72),experiments,whichalsoshowedNOEeffectsbetweenthewhichshowedanIC50=60nMforthecelllineP-388.Table5.CytotoxicActivityinCulturedCellLines(IC50mM).P-388A-549HT-29MEL-28P-388A-549HT-29MEL28Etp0.170.171.700.85682.212.772.772.77250.220.541.101.10700.110.540.540.54260.220.270.270.27720.060.560.560.56270.260.260.260.26750.100.200.200.20280.240.600.600.60780.240.980.980.98P-388D1:Mouselymphoma(ATCCCCL-46);AT549:Humanlungcarcinoma(ATCCCCL-185);HT-29:Humancoloncarcinoma(ATCCHTB-38);SK-MEL-28:Humanmelanoma(ATCCHTB-72). RecentStudiesonNaturalProductsasAnticancerAgentsCurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2253NNOMeONH2N(79)ONH2ONOMeOHHNOEHONHO2NH2(80)O(70)OMeONH2NH2NOHNH2OOHOMeN(81)O(82)OHOMeFig.(11).Extensionofthestructure.Transformationofthequinonemethides(25,28,26and27)withaminoalcohols,wejustobtainedtheregioisomers(81)inthe1,2-diketones(70,72,75,78)hadonlyaslightand(82).Thestructureofcompounds(79-82)wasthoroughlyinfluenceintheselectivityforthecelllinesP-388vs.MEL-determinedbyoneandtwo-dimensionalNMRexperiments.28,sotheaverageselectivitywastwo-foldhigherthanthatDerivatives(79-82)wereevaluatedandthecorrespondingforthequinonemethides.ThelargestimprovementinthisresultsareshowninTable6,thesecompoundsresultedlessselectivitywasthatfromcompound(28)(selectivityP-388activethan(70).Theintroductionoftheoxazasystemwasvs.MEL-28equals2)tocompound(72)(selectivityP-388vs.moreeffective(81and82)thantheintroductionofthediazaMEL-28equals10).Theimportanceofthemethoxygroupring(79and80).Compounds(81)and(82)maintainedtheinC-4appearedaftercomparisonoftheactivityofcompoundssameselectivityforthecelllineP-388vs.Mel-28asthe(68)and(70);theactivitiesfor(70)(withOMe)arebetweenoriginal(70).Fromthisresultweconcludethattheincrease5and21-foldhigherthantheactivitiesfor(2)(withOH).insizeandtheabsenceofcarbonylgroupsinringAplayanThesedataallowtodrawthefollowingconclusion:theimportantroleintheactivity.modificationsonthecarbonsC-3andC-4oftheringA,Otherreactionstoextendthestructureofanortriterpene-keepingtheextendedconjugationofdoublebondspresentmethyilenquinone,namelythereactionsof22b-hydroxy-inringB,donotprovokeadramaticlostofcytotoxicity.tingenone(25)andpristimerine(26)witho-bromoanilwereThisfactsupportsthekeyroleoftheBring,whichtested.Thereactionof76mg(0.17mmol)of22b-possiblyactsasaMichaelacceptorintheinteractionwithhydroxytingenonewith1.5equivofo-bromoanilin20mLthetargetmolecule.ofdrybenceneatroomtemperatureyieldedthemixtureof2.2.4.ExtensionoftheStructureadductsshowedinFig.(12).Startingwiththe1,2-dicarbonylcompounds,weextendedTheseadductsarepresumablyformedbyaheteroDiels-thestructurefromringAbycondensationwithdiaminoorAlderreactionbetweentherichelectrondoublebondC3-C4aminoalcohols.Thesereactionsintroduce1,4-diazaor1,4-andthedicarbonylspresentino-bromoanil.Themajoroxazasystemswhichcharacterizeseveralbioactivecompoundscompound(83)isformedinthelesscongestedface,i.e.,theliketheantitumoralantibioticdactinomycinorclofazimine.aface.ThestereochemistryofthisadductwasestablishedbyROESYexperiments,whichshowedaNOEeffectbetweenFig.(11)showsthereactionsofdiketone(70)with1,2-Me-23andMe-25.Similarresultswereobtainedwhendiaminoanthraquinone,4,5-dimethyl-bencene-diamine,o-pristimerinewasused.Thesereactionswerealsoperformedaminophenolandaminoethanol.Inthecaseofthereactionsat0ºCtoseeiftheselectivitywasimproved,butitdidnot 254CurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2RaveloetalOHOOBrBrO(83)R1=H;R2==O;R3=OHOBr(85)R1=COOMe;R2=R3=HBrBrR1R2OBrBrBrR3O1HOHOO3OH(25)R1=H;R2==O;R3=OHBrO(26)R1=COOMe;R2=R3=HBrBr(84)R1=H;R2==O;R3=OH(86)R1=COOMe;R2=R3=HBrFig.(12).Reactionwitho-bromoanil.change.Table6showstheantitumoralactivityofcompounds2.2.5-AdditionalReactions(83-85).TherewasnotmuchgaininactivitywithrespecttoTheformationoftheenamineoftheC-21carbonylinthestartingproducts(compare83and84with25,andalso(25)usingmorpholine,tolueneandMolecularSieveswas85with26);however,theadductsbecomealittlemoreattempted,butweobtainedcompound(87).ThiscompoundselectiveagainstP-388andA-549.Thealmostidenticaldegreewaspresumablyformedbyaninitialnucleophilicadditionofactivityof(83)and(84)provedthattheactivitywasnotonthecarbonylgrouponC-2,followedbyaprototropythatrelatedtotheadductstereochemistry.Thisresultreinforcesinvolvesthehydrogen-11,therearrangementofMe-25,andtheimportanceofthecarbonylgrouponC-2andtheextendedthelostofhydroxygrouponC-2.(25)undertreatmentwithconjugationinringBsincetheextensionofthestructureNBSaffordedthestereoselectiveformationofjustonefromthecarbonsC-3andC-4donotimplyalostofactivity.ONNO,CHHO78OMolecular(87)OSievesDDQOCNCNOH(89)OHONBSBrOHOSHCH2PhHOHO(90)(88)SCH2PhFig.(13).Othertransformations. RecentStudiesonNaturalProductsasAnticancerAgentsCurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2255Table6.CytotoxicActivityinCulturedCellLines(IC50mM)of(79-85and90).P-388A-549HT-29MEL-28P-388A-549HT-29MEL287917.617.617.617.6830.140.141.160.58801.501.501.501.50840.140.141.160.58810.200.980.980.98850.140.280.560.56820.170.900.900.90900.220.221.790.90P-388:mouselymphoma(ATCC:CCL46);A-549:humanlungcarcinoma(ATCC:CL85);HT-28:humancoloncarcinoma(ATCC:HTB38);MEL-28:humanmelanoma(ATCC:HTB72).derivative(88).ThestereochemistryofthebromineatomDDQ.Wedidnotsuceedbut,instead,thederivative(89)wasestablishedasbbecauseoftheNOEeffectbetweenH-11wasobtained.AsoundhypothesisonhowthismayhaveandMe-27.Anothertypeoftransformationthatwastriedhappenedcannotbesuggested.Compounds(87),(88)andwastheextensionoftheconjugationundertreatmentwith(89)showedvaluesofIC50>10mg/ml.COOMeCOOMeOHOHOHOHOHOHOO(91)CHOO(92)O(93)OOOOHOHHOHOHOHOHOHOCHO(94)CHOO(95)COOHO(96)OOOOHOHOHHOHOHOMeOHOMeOCHO(97)COOHO(98)O(99)OOOOHOHOHHOHOHOMeOHOHOOHO(100)O(101)HO(102)Fig.(14).Naturallyoccurringcatecholtriterpenes. 256CurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2RaveloetalTabla7.CytotoxicactivityinCulturedCellLines(IC50mM)of(91-102).P-388A-549HT-29Mel-28P-388A-549HT-29Mel-289110.3710.3710.3710.37975.5511.1111.1111.11921.000.202.021.009820.1620.1620.1620.169311.4211.4222.8322.83992.152.152.152.159423.0423.0423.0423.041005.715.715.715.71950.540.541.071.071015.515.515.515.51965.195.195.195.191028.748.748.748.74P-388D1:Mouselymphoma(ATCCCCL-46);AT549:Humanlungcarcinoma(ATCCCCL-185);HT-29:Humancoloncarcinoma(ATCCHTB-38);SK-MEL-28:Humanmelanoma(ATCCHTB-72).Yetafollowingreactionwasthetreatmentwithphenyl-C8impliesareductionofactivitywhichwasalsoobservedmethanethiolasnucleophilicagent,theexpectedproduct(90)inthosecompoundsthathavelostMe-23andpresentawasobtained,whichappearstobeduetoaMichaeladditionhydrogeninstead,e.g.(100).YetanotherinterestingonC-6.Theadditionoccursinthelesshinderedfacesi-siofconclusionontheactivitystructurerelationshipappearedtheC5-C6doublebond,probablyduetothelargesizeofthefromthecomparisonofderivativeswithandwithoutaphenyl-methanethiol.Thecytotoxicactivitiesof(90)anditsmethoxygrouponC-3(e.g.96and98).Theactivityprecursor(25)weresimilar(Table6).Inasimilarwaytothedecreasedwiththepresenceofthemethoxygroup.Theformationof(90)discussedabove,thequinonemethidehighestactivitywasachievedwiththe6-oxo-catecholcouldactasaMichaelacceptorofthenucleophilicgroupstriterpenesthatpresentaC7-C8doublebondandwhenthepresentinthemoleculartarget(s)inthecell.OntheotherMe-23wasoxidizedtoaldehyde.Alossofactivitywashand,thehighlevelofactivityofderivativeswithstructureobservedwhenacarboxylicacidfunctionwaspresentinsteadtype(90)andasubstituentatC-6(asobtainedinacylationofthealdehyde.reactions)letuspointoutasecondpossibility;these2.3.1.ModificationsonPhenolicTriterpenescompoundscouldalsoreactwiththenucleophilicgroupspresentinthetargetbutvianucleophilicsubstitutiononC-Inanattempttoestablishtheroleofthedifferentgroups6.locatedinthearomaticringaswellasthecarbonylfunctionatC-6in6-oxophenolictriterpenes,wecarriedoutsome2.3.NaturalCatecholTriterpenessimplemodificationsonthemostactivenaturaltriterpeneThistypeofcompoundsalsoappearsintherootsofisolatedsofar(95).ThesereactionsareillustratedinFig(15).Maytenusspecies,butinlesserquantitiesthantheFromtheseresultsweobservedhowtheactivitydecreasedquinonemethides.Fig.(14)showsthestructureofseveralwiththeintroductionofmethoxygroups,whileitincreasedrepresentativenaturalphenolictriterpenesandTable7withtheintroductionofacetylgroups.Inallthesecases,thecontainsthecorrespondingcytotoxicactivities.lipophiliccharacterwasgreaterthanthatofcompound(95).FromtheresultspresentedinTable7,itcanbeseenthatAnalysingthesetwodifferentfunction-alities,itseemedthatthephenolictriterpenesarelessactivethanthecorrespondingtheactivitywasaffectedbytheelectroniceffectofthequinonemethidetriterpenes.Inthistypeofcompounds,thesubstituentsonringA.Thereplacementofasix-ringBforapresenceofacarbonylgrouponC-6seemstobecriticalforseven-ringBresultedinadramaticcytotoxicityloss,theactivity.Compoundswithouta6-oxofunctionpresentedlikewiseanactivitylosswasobservedwiththeheterocycliclowactivity(e.g.94and96).Inthecaseof6-oxo-phenolicderivative(107).triterpenes,theabsenceoftheconjugateddoublebondC7-Tabla8.CytotoxicactivityinCulturedCellLines(IC50mM)of(103-107).P-388A-549HT-29MEL-28P-388A-549HT-29MEL-28950.540.541.071.071059.589.589.589.581030.200.200.420.421065.065.065.065.061040.180.220.220.221071.081.082.171.08P-388:mouselymphoma(ATCC:CCL46);A-549:humanlungcarcinoma(ATCC:CL85);HT-28:humancoloncarcinoma(ATCC:HTB38);MEL-28:humanmelanoma(ATCC:HTB72). RecentStudiesonNaturalProductsasAnticancerAgentsCurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2257OOOOHOHOHMeOHOMeOMeOHO(106)CHOONMeONOMel/KCO(107)CHOCH232N2/CHCl3(105)ONH2NH2/C7H8OHHOHO(95)CHOOOAcO/pyO2OAcNOEHOAcAcOAcOAcOAcOCHOO(104)CHOO(103)Fig.(15).Modificationson(95).2.4.MechanismofAction(28),aswellasonthenucleotidesbasesadenine,guanine,cytosine,andthymine.ThemolecularmechanismcalculationsThemechanismofactionofthesetypeofcompoundssuggestedthatapossiblemodeofactionofquinone-methidehavenotbeenelucidatedyet.However,weadvanceainvolvesquasi-intercalativeinteractionofthecompoundsplausiblemechanismofactionforthequinonemethide.ThiswithDNA,followedbynucleophilicadditionoftheDNAmayinteractwithnucleophilicgroups(:Nu)ofthemolecularbasetotheC-6ofthetriterpenoid.targetviaMichaeladdition,orvianucleophilicadditiontoC-6in6-oxo-catecholtriterpenes,orvianucleophilic2.5.SummaryofStructure-activityRelationshipssubstitutionwiththe6-substituted-catecholtriterpenes.Consideringalltheavailableinformationonstructure-OurhypothesishasbeenrecentlyreinforcedbySetzeretactivityrelationships,wehavedistilledthefollowingrulesal[181].Theseresearcherscarryoutmolecularorbitalcalculationsusingsemi-empiricalPM3andHartee-Fock3-thatmaybeaccountedfortoforeseeoradvancethe21Gabinitiotechniquesonthequinonemethidetingenonecititoxicityofaproduct:HOHOOHOHOL'LeavinggroupHOOL2:Nu-Targt:Nu-Target:Nu-TargetMichaelAdditionNucleophilicAdditionNucleophilicSubstitutionFig.(16).Plausiblemechanismofaction. 258CurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2RaveloetalForQuinonemethidetriterpenes:·Withthe6-substitutedcatecholtriterpenes,thestereo-chemistryaenhancescitotoxicity.Novoluminous·PresenceoftheextendedconjugationofdoublebondsinsubstituentscanbepresentinringA.ringB.Therefore,smallstructuralmodificationmayleadto·PresenceofthecarbonylgrouponC-2.substantialimprovementinselectivityandseveralexamples·SmallestergroupsassubstituentonC-3.havebeenpresentedanddiscussed.·Thetypeandnumberofhydrogen-bonddonorsandAsaresultofthesestudiesseveralmetabolitesputacceptorspresentintheEringdonotmodifytheforwardabovehavebeenselectedbytheBiologicalcytotoxicityinasignificantway.EvaluationCommitteeforCancerDrugs(BEC/C)oftheNCIforpreliminarytestinginthehollowfiber-basedscreen.ForTriterpenecatechols:Thesetestshavebeendevelopedforthepreliminaryinvivo·PresenceonC-6ofacarbonylgrouporothersubstituentsassessmentofcancerchemotherapeuticefficacy[182].(e.g.OH,SCH2PH…..).3.NATURALNAPHTHOQUINONESPOSSESSING·Withthe6-oxoderivatives,thepresenceoftheC-7-C-8CANCERCHEMOPREVENTIVEACTIVITYdoublebond,orthepresenceofanelectronwithdrawingsubstituentinringA,orboth.Preventionisthemostreliablestrategyforremedyingalldiseases,includingcancer,andthepreventionhasbeenOOCHOOOOOH3HOROHOOHOHOOOCH3OOH(108)R==O(110)(111)(112)(109)R=OHOROOOOOOHORHOOHOR'OO(113)(114)R=R'=OH(117)(118)R=H(115)R=H;R'=OH(119)R=C(CH3)2OH(116)R=OMe;R'=HOOCH3OCH3HOOOHOOOOHOHOHOROCHOCHRO33(120)R=H(122)(123)(124)R=H(121)R=OH(125)R=OHOCH3OOOO(126)(127)Fig.(17).Naturallyoccurringnaphthoquinones. RecentStudiesonNaturalProductsasAnticancerAgentsCurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2259Table9.PercentageofEpstein-barrVirusEarlyAntigenInduction.aConcentration(molratio/TPA)Compounds1000500100101080(0)0(0)0(0)9.2(20)1090(0)0(0)0(0)53.7(70)1100(60)55.210010011132.7(70)63.888.11001120(70)32.957.393.81130(30)0(60)62.988.511436.1(60)88.410010011511.2(60)27.956.386.711683.8(70)92.010010011717.5(70)44.663.697.811821.3(70)30.770.6100.011919.2(70)36.679.5100.01201.9(70)24.265.294.61211.4(60)23.563.593.11229.9(70)28.770.1100.01235.9(70)27.772.695.012413.4(70)29.273.2100.01252.7(70)24.366.292.712617.7(70)33.976.4100.012712.1(70)30.273.6100.0b-carotene8.6(70)34.282.1100.0aMolratio/TPA(32pmol=20ng/mL),1000molratio=32nmol,500molratio=16nmol,100molratio=3.2nmol,and10molratio=0.32nmol.bValuesrepresentpercentagesofEBV-EAinductioninthepresenceofthetestcompoundrelativetothepositivecontrol(100%).ValuesinparanthesesrepresentviabilitypercentagesofRajicells;unlessotherwisestated,theviabilitypercentagesofRajicellsweremorethan80%.widelyanticipatedasaforemostparadigmforcancercontrol.tetradecanoylphorbol-13-acetate[185].TPA-typetumorCancerchemoprevention,coinedbySpornetal.in1976promoterssuchasphorbolesters,teleocidins,oraplysiatoxin+2[183],isdefinedasastrategyforcancercontrolbythecanactivatebothphospholipidandCa-dependentproteinadministrationofsynthethicornaturalcompoundscapableofkinaseC(PKC).PKCiswidelyacceptedasoneofthemajorhaltingorinhibitingtheonsetofcancer.intracellulartargetsofTPA-typetumorpromoters.MostcancerpreventionresearchisbasedontheconceptStudiesonTPAallowedtoestablishdetectionassaysofmultistagecarcinogenesis:initiation®promotion®usingitsbiologicalandphysiologicalactivities.Inthisprogression[184].Amongthesestages,incontrasttobothsense,ashort-terminvitroassayusingtheactivationofinitiationandprogressionstages,animalstudiesindicatethatEpstein–Barrvirus(EBV)genome-carryinghumanthepromotionstagetakesalongtimetooccurandmaybelymphoblastoidcellshasbeenusedtodetecttumourreversible,atleastinitsearlierstages.Therefore,thepromoters(e.g.12-O-tetradecanoylphorbol-13-acetate)andinhibitionoftumorpromotionisexpectedtobeanefficientanti-tumourpromoters.Thisassaysystemiscomposedofapproachtocancercontrol.PromotioninvolvesclonalEBV-non-producercellsastheindicator,n-butyrateastheproliferationoftheinitiatedcells,andconvertionofthemtrigger,TPAastheEBV-activatorandthetestsubstanceintopremalignanttumorcells.Duringthisphase,avariety[186-187].Epstein-Barrvirus(EBV)isanubiquitoushumanofintracellularsignallingpathwaysareactivated.Tumorgherpes-virusthatisassociatedwithseveralmalignanciespromotionresearchwasstartedwiththeidentificationofaanddiseases,togetherwithsometypesoflymphomasintumor-promotingconstituentincrotonoil,12-O-immunocompromisedhosts(e.g.,AIDSandpost-transplant 260CurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2Raveloetalpatients)[188].Differentkindsofnaturalproductshaveagentsofdifferentnatureandlipophiliccharacter(acetylshownanti-tumorpromotingactivity.Someexamplesarechloride,p-bromo-benzoylchloride,lauroylchlorideandcarotenoids[189],flavanoids[190],sesquiterpenes[191]anddiazomalonylchloride)usingasmallexcessofacylatinganthraquinones[192].Also,severalnaturalnaphthoquinonesagents,dryCH2Cl2andlutidineasbase.Derivatives(129),inhibittheEBV-EAactivation.Theyhavebeenisolated(130)and(131)showedactivitiessimilartothoseoffromdifferentplantspeciesbelongingtotheBignoniaceaelapachol,whiletheacetylderivative(128)turnedouttobefamily(Tabebuiarosae,T.avellanedae,Catalpaovata)moreactivethan(117).Itwasevenmoreeffectivethanb-[193,194]andtheAvicenniaceaefamily(Avicenniacarotene(seeTable10).Compound(128)hasstronganti-rumphiana,A.alba)[195].Thestructuresofthesetumorpromotingactivity,evenat10molratio/TPA(100%naphthoquinonesaredepictedinFig.(17)andtheresultsinhibitoryactivityat1000molratio/TPA,andmorethanreportedintheliteraturearesummarizedinTable9.75%and40%at500and100molratio/TPA,respectively),andpreservedhighviabilityofRajicells(morethan70%atCompounds(108-110),(112-113),(115),(117),(120-123)10to1000molratio/TPA).Thesedatasuggestthatand(125)werefoundtobemoreeffectivethanb-carotene,areplacingadonatinghydrogen-bondsubstituentonC-2withvitaminAprecursorthathasbeenintensivelystudiedinahydrogen-bondacceptorsubstituentincreasestheactivitycancerpreventionusinganimalmodels[196].Structuralwhentheacylgroupdoesnothavemorethantwocarbons.comparisonof(112),(113)and(115)withothernaphtho-quinonessuchas(110),(111),(114)and(116)indicatedthat3.2.ModificationsontheSideChaintheabsenceofsubstituentsontheAringandthepresenceofahydroxygroupontheCringmaybeimportantstructure-Compound(132)wasobtainedbyHooker’sactivityinformation.Lapachol(117)wasfoundtoshowoxidation.Theshorteningofthesidechainproduceda22inhibitoryactivitiesof55.4and36.4%at5x10and1x10structureflatterthanthatoflapachol(117),andthiseffectmolratio/TPA,respectively.Amongfuranonaphthoquinonescouldexplaintheobservedincreaseininhibitoryactivity.andtheiranalogs(121)and(125),withanOHgroupatC-3,Wealsomodifiedthedoublebondofthelateralchainoftheexhibitedpotentdose-dependentinhibitoryactivity(onsetof3derivative(128),whichisalreadymorepotentthanlapachol.inhibitionofactivationat1x10molratio/TPA;75,35and22(128)wastreatedwithMCPBAtoobtainthecorresponding7%inhibitionofactivationat5x10,1x10and1x10mol(+)epoxyderivative(133)in60%yield,whichunderratio/TPA,respectively).Compounds(120)and(123)displayedaboutthesameinhibitoryactivityaslapacholtreatmentwithHClO4,incatalyticamountsaffordedthe(117).Otherfurano-naphthoquinones(118-119)andtheircompound(134)in96%yield.Inaddition,thereactionofanalogs(122-124)werefoundtobelessactivethanlapachol(128)withNBSyieldedthehydroxy-halogenatedcompound(117).Ontheotherhand,boththelinear-typepyranon-(135)in94%yield.aphtoquinones(126)and(127)displayedaweakeractivityAllmodificationsofthesidechainresultinginthethanthatof(117).Therelatednaphthoquinones(108)andformationof(133),(134)and(135)increasetheinhibitory(109)showedsignificantdose-dependentinhibitoryeffects.activitywithrespecttolapachol(117),butnotwithrespectInparticular,theactivityof(108)was100-foldgreaterthantotheacetylatedcompound(128).Thisfactsuggeststhatthethatof(109),andgreateralsothanthatof(117).presenceofthedoublebondontheisoprenylsidechainisaBasedontheresultsobtainedinvitro,theinhibitoryeffectrequirementforhighactivity.Besides,thepresenceofanof(125)inaninvivotwo-stagecarcinogenesistestfocusingepoxygrouportwohydroxylgroupsonthecarbonsC12-C13onmouseskinpapilomasinducedbyDMBAasaninitiator,producedaneffectoninhibitoryactivitysimilartotheandTPAasapromoter,wasstudied.Thecontrolanimalspresenceofthedoublebond.Compound(136)wasformedshoweda100%incidenceofpapillomas10weeksafterbytreating(117)withchloranil.ThiscompoundhasaDMBA-TPAtumorpromotion,whiletreatmentwith(125)naphtholtype-structurewhoselateralchainhasbeenpossiblyalongwiththeinitiatorandpromoterremarkablyreducedtheproducedbyaheteroDiels-Alderreactionbetweentheo-percentageoftumor-carryingmiceto33%after10weeks.dicarbonylsystemofchloranilandthedoublebondC12-C13.Thenumberofpapillomas/mousewasreducedtoabout57%after20weeksfor(125)treatedmiceascomparedwith3.3.ModificationsontheC-1Carbonyluntreatedmice[195].Thereactionofcompound(117)withhydroxylamineFromthesestudies,oneconcludesthatnaphthoquinoneshydrochlorideproducedcompound(137)inaregioselectiverelatedtolapacholhaveanotablecancerpreventivepotential.form.ThisfactcanbeexplainedanalyzingthedifferentConsequently,effortsweremadetoobtainaseriesofresonancestructureswherethecarbonylgrouponC-4canderivativesresultingfrommodificationsonC-2,ontheside“pull”electronsfromtheoxygenatomlocatedonC-2.chain,andontheC-1carbonyl.WealsotriedtoobtainThestructureof(137)wasconfirmedbyanalysisofthetricyclicderivatives[176][197](SeeFig.(18)).TheresultsHMBCspectrum,whichshowedthreebondcouplingsarepresentedbelow.betweenthehydrogensH-11andthecarbonylgroupatd184.2.Compound(137),underacetylatingconditions,3.1.ModificationsoftheC-2HydroxyGroup:yieldedthecorrespondingacetylderivative(138).TheseIntroductionof–CORderivativesturnedouttobelessactivethancompound(117),Derivatives(128),(129),(130)and(131)wereobtainedwhichindicatesthatthecarbonylgroupplaysanimportantbytreatingcompound(117)withavarietyofacylatingrolefortheactivity. RecentStudiesonNaturalProductsasAnticancerAgentsCurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2261OOAcOOAcOHClO4OAcOHOO(134)OHO(133)OBrMCPBANBS(135)OHOCOOR(128)R=Me(129)R=OBrOHO(130)R=(CH2)10CH3(131)R=CHN2COEtNORORCOClORKMnO4(137)R=H(138)R=COCH3(132)O89OHO71NH2OH-HCl611103OH514O12OMeOH13H2SO4o-Chloranil(117)OO(136)MCPBAClClOOOClClO+OOOOOOHO(141)(42)OOOHO(119)(140)O(139)OHFig.(18).Modificationsonlapachol.3.4.TricyclicDerivativesTable2showstheresultsobtainedwhenthederivatives(139-142)werebiologicallyevaluated.AlltricyclicTreatmentof(117)withMCPBAviaanepoxidecompoundsweremoreactivethanlapachol,withtheintermediateyieldedseveralorthoquinones:theangularo-compoundsthatpresent5-memberringsbeingmoreeffectivedihydrofuranderivative(139),theangularpyranderivativethatthecorrespondingderivativeswith6-memberrings.(140),andthelineardihydrofuran1,4-naphthoquinone(119).Withrespecttotheseriesof6-memberrings,themostactiveDerivativeb-lapachone(141),anditsa-isomerderivativewastheonewithanhydroxygroup(140).compounds(139),(142),wereobtainedundertreatmentwithdilutedH2SO4via(140)and(141)haveachromophoricortho-quinonicsystemthecorrespondingcationicintermediate.structurallydifferentfromthatoflapachol.Inthese 262CurrentTopicsinMedicinalChemistry,2004,Vol.4,No.2RaveloetalTable10.PercentageofEpstein-barrVirusEarlyAntigenInduction.aConcentration(molratio/TPA)Compounds100050010010b11717.5(70)44.663.697.81280(70)22.756.082.112921.3(70)48.071.910013017.3(60)49.576.910013116.9(60)46.772.51001322.5(70)33.861.389.31334.7(70)35.262.490.21345.2(70)38.563.791.713514.7(60)45.971.610013623.6(60)50.373.910013719.9(70)47.868.510013820.7(70)49.773.710013910.5(60)42.266.294.814012.3(60)40.663.992.91197.7(60)40.865.092.514115.7(60)43.168.296.314214.6(60)41.764.094.7b-carotene8.6(70)34.282.1100aMolratio/TPA(32pmol=20ng/mL),1000molratio=32nmol,500molratio=16nmol,100molratio=3.2nmol,and10molratio=0.32nmol.bValuesrepresentpercentagesofEBV-EAinductioninthepresenceofthetestcompoundrelativetothepositivecontrol(100%).ValuesinparanthesesrepresentviabilitypercentagesofRajicells;unlessotherwisestated,theviabilitypercentagesofRajicellsweremorethan80%.compoundsthedegreesoffreedomofthesidechain[6]Farnsworth,N.R.;Akerele,O.;Bingel,A.S.;Soejarto,D.D.;Guo,disappear,beingthesemoleculespracticallyplanar.TheseZ.Bull.WHO,1985,63,965.[7]Cragg,G.M.;Newman,D.J.;Snader,K.M.J.Nat.Prod.1997,planarmoleculesturnedouttobeslightlymoreactivethan60,52-60.lapachol.Thebestresultinthetricyclicserieswasobtained[8]Cordell,G.A.Phytochemistry,1995,40,1585-1612.withthederivative(119),whichpresentsthe1,4-[9]Newman,D.J.;Cragg,G.M.;Snader,K.M.Nat.Prod.Rep.2000,naphthoquinonesystem.17,215-34.[10]Hinterding,K.;Alonso-Diaz,D.;Waldman,H.Angew.Chem.Int.Ed.1998,37,688-749.ACKNOWLEDGEMENTS[11]Hung,D.T.;Jamison,T.F.;Schreiber,S.L.Chem.Biol.1996,3,ThisworkhasbeenrealizedwithinanICICprogramand623-639.[12.]Lenz,G.R.;Hash,H.M.;Jindal,S.DrugDiscoveryToday2000,5,ithasbeenpartlyfundedbytheSpanishMCYT(PPQ2000,145-156.1655,C02-01).WethankPharmaMarS.A.andProf.[13]Razvi,E.S.;Leytes,L.J.Mod.DrugDiscovery2000,41-42.Tokudaforconductingthebiologicalassays.[14]Rosamond,J.;Allsop,A.Science2000,287,1973-1976.[15]Garret,M.D.;Workman,P.Eur.J.Cancer.1999,35,2010-2030.REFERENCES[16]Barry,C.E.;Slayden,R.A.;Sampson,A.E.;Lee,R.E.Biochem.Pharmacol.1999,59,221-231.[1]Chang,H.M.;But,P.P.H.PharmacologyandApplicationsof[17]Mayer,T.U.;Kapoor,T.M.;Haggarty,S.J.;King,R.W.;ChineseMateriaMedica,WorldScientificPublishing,SingaporeSchreiber,S.L.;Mitchison,T.J.Science,1999,286,971-974.1986,Vol1,2.[18]Silverman,L.;Campbell,R.;Broach,J.R.Curr.Opin.Chem.Biol.[2]Dev,S.;Environ.HealthPerspect.1999,107,783.1998,2397-403.[3]Kapoor,L.D.CRCHandbookofAyurvedicMedicinalPlants,CRC[19]Cordell,G.A.;Shin,Y.G.PureAppl.Chem.1999,71,1089-1094.Press,BocaRaton1990.[20]Corley,D.G.;Durley,R.C.J.Nat.Prod.1994,57,1484-1490.[4]Schultes,R.E.;Raffauf,R.F.TheHealingForest,Dioscorides[21]Watson,C.Angew.Chem.Int.Ed.1999,38,1903-1908.Press,Portland,1990.[22]Bertels,S.;Frorman,S.;Jas,G.;Bindseil,K.U.DrugDiscovery[5]Arvigo,R.;Balick,M.RainforestRemedies,LotusPress,TwinNat.1999,72-105.Lakes,1993.[23]Schreibers,S.L.Bioorg.Med.Chem.1998,6,1127-1152. 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