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Bioactive Molecules and Medicinal Plants
Bearbeitet vonKishan Gopal Ramawat, Jean-Michel MĂŠrillon
1. Auflage 2008. Buch. xxiii, 379 S. HardcoverISBN 978 3 540 74600 3
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Abstractâ Manyâ plant-derivedâ compoundsâ haveâ beenâ usedâ asâ drugs,â eitherâ inâtheirâ originalâ orâ semi-syntheticâ form.â Plantâ secondaryâ metabolitesâ canâ alsoâserveâ asâ drugâ precursors,â drugâ prototypes,â andâ pharmacologicalâ probes.â Re-centâ developmentsâ inâ drugâ discoveryâ fromâ plants,â includingâ informationâ onâapprovedâdrugsâandâcompoundsânowâinâclinicalâtrials,âareâpresented.âThereâareâalsoâseveralâplantâextractsâorââphytomedicinesââ inâclinicalâtrialsâforâtheâtreat-mentâofâvariousâdiseases.âInâtheâfuture,âplant-derivedâcompoundsâwillâstillâbeâanâessentialâaspectâofâtheâtherapeuticâarrayâofâmedicinesâavailableâtoâtheâphysician,âparticularlyâwithâtheâavailabilityâofânewâhyphenatedâanalyticalâmethodsâsuchâasâLC-NMR-MSâandâLC-SPE-NMRâtoâaccelerateâtheirâfutureâdiscovery.
Keywordsâ Naturalâ products,â Plant-derivedâ drugs,â Drugâ discovery,â Drugâdevelopment,â Drugâ precursors,â Drugâ prototypes,â Pharmacologicalâ probes,âNewâtherapeuticâagents,âClinicalâtrials,âAcceleratedâdiscoveryâtechniques
1.1â TheâRoleâof âPlantsâinâHumanâHistory
Overâtheâcenturiesâhumansâhaveâreliedâonâplantsâforâbasicâneedsâsuchâasâfood,âclothing,âandâshelter,âallâproducedâorâmanufacturedâfromâplantâmatricesâ(leaves,âwoods,âfibers)âandâstorageâpartsâ(fruits,âtubers).âPlantsâhaveâalsoâbeenâutilizedâforâadditionalâpurposes,ânamelyâasâarrowâandâdartâpoisonsâforâhunting,âpoisonsâforâmurder,âhallucinogensâusedâ forâ ritualisticâpurposes,â stimulantsâ forâendur-ance,âandâhungerâsuppression,âasâwellâasâinebriantsâandâmedicines.âTheâplantâchemicalsâusedâforâtheseâlatterâpurposesâareâlargelyâtheâsecondaryâmetabolites,âwhichâareâderivedâbiosyntheticallyâfromâplantâprimaryâmetabolitesâ(e.g.,âcarbo-hydrates,âaminoâacids,âandâlipids)âandâareânotâdirectlyâinvolvedâinâtheâgrowth,âdevelopment,âorâreproductionâofâplants.âTheseâsecondaryâmetabolitesâcanâbeâclassifiedâintoâseveralâgroupsâaccordingâtoâtheirâchemicalâclasses,âsuchâalkaloids,âterpenoids,âandâphenolicsâ[1].
RamawatâKG,âMĂŠrillonâJMâ(eds.),âIn: Bioactive Molecules and Medicinal PlantsChapterâDOI:â10.1007â/â978-3-540-74603-4_1,âŠâSpringerâ2008
Chapterâ1â âDrugâDiscoveryâfromâPlants
A.A.âSalim,âY.-W.âChinâandâA.D.âKinghornâ()
Divisionâof âMedicinalâChemistryâandâPharmacognosy,âCollegeâof âPharmacy,ââTheâOhioâStateâUniversity,âColumbus,âOHâ43210,âUSA,âe-mail:â[email protected]
A.A.âSalim,âY.-W.âChinâandâA.D.âKinghorn2
Arrowâ andâ dartâ poisonsâ haveâ beenâ usedâ byâ indigenousâ peopleâ inâ certainâpartsâofâtheâworldâwithâtheâprincipalâingredientsâderivedâfromâtheâgeneraâAco-nitumâ (Ranunculaceae),â Akocantheraâ (Apocynaceae),â Antiaris (Moraceae),âChondrodendronâ(Menispermaceae),âStrophanthusâ(Apocynaceae),âandâStrych-nosâ(Loganiaceae)â[2].âMostâcompoundsâresponsibleâforâtheâpotencyâofâarrowâandâdartâpoisonsâbelongâtoâthreeâplantâchemicalâgroups,ânamelyâtheâalkaloidsâ(e.g.,âstrychnineâfromâStrychnosâspecies),âcardiacâglycosidesâ(e.g.,âouabainâfromâStrophanthusâ species),â andâ saponinsâ (e.g.,â aâ monodesmosideâ glucosideâ fromâClematisâspecies)â[2].
Inâsomeâcultures,âtoxicâplantâextractsâwereâalsoâusedâforâmurderâandââtrialsâbyâordeal,ââwhereâaâpersonâaccusedâofâaâcrimeâwasâgivenâaânoxiousâbrew,âandâitâwasâbelievedâthatâ if â innocent,âthisâsuspectâwouldâsurviveâthisâordeal.âSomeâofâtheâplantsâwell-documentedâforâmurderâareâhenbaneâ(Hyoscyamus nigerâL.),âmandrakeâ(Mandragora officinarumâL.),âdeadlyânightshadeâ(Atropa belladonnaâL.),âandâsomeâDatura species,âallâofâwhichâbelongâtoâtheâfamilyâSolanaceaeâ[3].âCalabarâbeanâ (Physostigma venenosumâBalf.)âwasâ famousâ forâ itsâuseâ inâ trialsâbyâordealâbyâpeopleâwhoâlivedâonâtheâCalabarâCoast,âWestâAfricaâ[3].âCertainâplantsâformerlyâusedâforâarrowâpoisons,âsuchâasâseveralâAconitumâspecies,âhaveâalsoâbeenâusedâasâmedicinesâatâlowerâdosages,âforâtheirâanalgesicâandâanti-in-flammatoryâpropertiesâ[4].âInâfact,âmanyâcompoundsâisolatedâfromâpoisonousâplantsâwereâlaterâdevelopedâasâtherapeuticâdrugs,âdueâtoâtheirâdesirableâpharma-cologicalâactionsâ[5,â6].
Theâuseâofâhallucinogensâinâtheâpastâwasâusuallyâassociatedâwithâmagicâandâritual.âHowever,âtheseâhallucinogensâhaveâbeenâexploitedâasârecreationalâdrugsâandâ accordinglyâ mayâ leadâ toâ habituationâ problems.â Severalâ well-recognizedâplantsâthatâcontainâhallucinogenicâorâpsychoactiveâsubstancesâ(theâcompoundânamesâareâgivenâinâparentheses)âincludeâBanisteriopsis caapiâ(SpruceâexâGriseb.)âMorton (N,N-dimethyltryptamine),â Cannabis sativaâ L.â (Î9-trans-tetrahydro-cannabinol),âDatura speciesâ(scopolamine),âErythroxylum coca Lam. (cocaine),âLophophora williamsii (Salm-Dyck)â J.M.â Coult.â (mescaline),â Papaver som-niferum L.â(morphine),âandâSalvia divinorumâEplingâ&âJĂĄtiva (salvinorinâA)â[7,â8].âSeveralâofâtheseâplantsâareâalsoâusedâasâdrugsâdueâtoâtheirâdesiredâpharmaco-logicalâactivities,âandâsomeâofâtheâconstituentsâofâtheseâplantsâhaveâbeenâdevel-opedâintoâmodernâmedicines,âeitherâinâtheânaturalâformâorâasâleadâcompoundsâsubjectedâtoâoptimizationâbyâsyntheticâorganicâchemistryâ[5,â6].
Plantsâhaveâalsoâbeenâusedâ inâ theâproductionâofâstimulantâbeveragesâ (e.g.,âtea,â coffee,â cocoa,â andâ cola)â andâ inebriantsâ orâ intoxicantsâ (e.g.,â wine,â beer,âkava)âinâmanyâculturesâsinceâancientâtimes,âandâthisâtrendâcontinuesâtillâtoday.âTeaâ(Camellia sinensis Kuntze)âwasâfirstâconsumedâinâancientâChinaâ(theâearli-estâreferenceâisâaroundâCEâ350),âwhileâcoffeeâ(Coffea arabicaâL.)âwasâinitiallyâcultivatedâinâYemenâforâcommercialâpurposesâinâtheâ9thâcenturyâ[3].âTheâAztecânobilityâusedâtoâconsumeâbitterâbeveragesâcontainingârawâcocoaâbeansâ(Theo-broma cacaoâL.),âredâpeppers,âandâvariousâherbsâ[3].âNowadays,âtea,âcoffee,âandâcocoaâ areâ importantâ commoditiesâ andâ theirâ consumptionâ hasâ spreadâ world-wide.âTheâactiveâcomponentsâofâtheseâstimulantsâareâmethylatedâxanthineâde-rivatives,ânamelyâcaffeine,âtheophylline,âandâtheobromine,âwhichâareâtheâmainâconstituentsâofâcoffee,âtea,âandâcocoa,ârespectivelyâ[9].
Chapterâ1â DrugâDiscoveryâfromâPlants 3
Theâ mostâ popularâ inebriantsâ inâ societyâ todayâ areâ wine,â beer,â andâ liquorâmadeâ fromâ theâ fermentationâ ofâ fruitsâ andâ cereals.â Wineâ wasâ firstâ fermentedâaboutâ6000â8000âyearsâagoâinâtheâMiddleâEast,âwhileâtheâfirstâbeerâwasâbrewedâaroundâ 5000â6000âBCEâ byâ theâ Babyloniansâ [3].â Theâ intoxicatingâ ingredientâofâtheseâdrinksâisâethanol,âaâby-productâofâbacterialâfermentation,âratherâthanâsecondaryâplantâmetabolites.âRecentâstudiesâhaveâshownâthatâaâlowâtoâmoder-ateâconsumptionâofâredâwineâisâassociatedâwithâreductionâofâmortalityâdueâtoâcardiovascularâdiseaseâandâcancerâ[10].âThisâhealthâbenefitâhasâbeenâsuggestedâtoâbeâdueâtoâtheâpresenceâofâresveratrol,âaâhydroxylatedâstilbenoidâfoundâinâtheâskinâofâgrapesâ[11].âKava,âaâbeverageâmadeâfromâtheârootâofâPiper methysticumâRoxb.,âhasâbeenâaâpopularâintoxicatingâbeverageâinâPolynesiaâforâcenturiesâ[3].âKavaâisânotânormallyâconsumedâinâthisâmannerâinâtheâWesternâworld,âbutâhasâgainedâpopularityâasâaâbotanicalâdietaryâsupplementâtoâeaseâtheâsymptomsâofâstress,âanxiety,âandâdepressionâ[12].âAâstudyâhasâshownâthatâtheâanxiolyticâactiv-ityâofâkavaâextractâmayâbeâmediatedâinâpartâbyâtheâkavalactone,âdihydrokavainâ[13].âTheâconsumptionâofâkavaâhasâbeenâassociatedâwithâliverâtoxicity,âalthoughâthisâisâsomewhatâcontroversial.âRecently,âaâstudyâhasâshownâthatâtheâalkaloidâpipermethystine,â foundâmostlyâ inâ theâ leavesâandâstemsâofâPiper methysticum,âmayâbeâresponsibleâforâthisâtoxicityâ[14].
Plantsâ haveâ formedâ theâ basisâ ofâ sophisticatedâ traditionalâ medicineâ (TM)âpracticesâthatâhaveâbeenâusedâforâthousandsâofâyearsâbyâpeopleâinâChina,âIn-dia,âandâmanyâotherâcountriesâ[9].âSomeâofâtheâearliestârecordsâofâtheâusageâofâplantsâasâdrugsâareâfoundâinâtheâArtharvaveda,âwhichâisâtheâbasisâforâAyurvedicâmedicineâinâIndiaâ(datingâbackâtoâ2000âBCE),âtheâclayâtabletsâinâMesopotamiaâ(1700âBCE),âandâtheâEberâPapyrusâinâEgyptâ(1550âBCE)â[9].âOtherâfamousâlit-eratureâsourcesâonâmedicinalâplantâ includeââDeâMateriaâMedica,ââwrittenâbyâDioscoridesâbetweenâCEâ60âandâ78,âandââPenâTsâaoâChingâClassicâofâMateriaâMedicaââ(writtenâaroundâ200âCE)â[9].
Beforeâtheârealizationâthatâpharmacologicallyâactiveâcompoundsâpresentâinâmedicinalâplantsâareâresponsibleâforâtheirâefficacy,âtheââdoctrineâofâsignaturesââwasâ oftenâ usedâ toâ identifyâ plantsâ forâ treatingâ diseases.â Forâ example,â golden-rodâwithâaâyellowâhueâwasâusedâtoâcureâjaundice,âred-coloredâherbsâwereâusedâtoâ treatâ bloodâ diseases,â liverwortsâ wereâ usedâ forâ liverâ diseases,â pilewortsâ forâhemorrhoids,âandâtoothwortsâforâtoothacheâ[9].âInâ1805,âmorphineâbecameâtheâfirstâpharmacologicallyâactiveâ compoundâ toâbeâ isolatedâ inâpureâ formâ fromâaâplant,âalthoughâitsâstructureâwasânotâelucidatedâuntilâ1923â [9].âTheâ19thâcen-turyâmarkedâtheâisolationâofânumerousâalkaloidsâfromâplantsâ(speciesâinâparen-theses)â usedâ asâ drugs,â namely,â atropineâ (Atropa belladonna),â caffeineâ (Coffea arabica),âcocaineâ(Erythroxylum coca),âephedrineâ(Ephedra species),âmorphineâandâcodeineâ(Papaver somniferum),âpilocarpineâ(Pilocarpus jaborandiâHolmes),âphysostigmineâ(Physostigma venenosum),âquinineâ(Cinchona cordifolia MutisâexâHumb.),âsalicinâ(Salix species),âtheobromineâ(Theobroma cacao),âtheophyllineâ(Camellia sinensis),â andâ (+)-tubocurarineâ (Chondodendron tomentosum Ruizâ&âPav.)â[9].âFollowingâtheseâdiscoveries,âbioactiveâsecondaryâmetabolitesâfromâplantsâwereâlaterâutilizedâmoreâwidelyâasâmedicines,âbothâinâtheirâoriginalâandâmodifiedâformsâ[5,â6].
A.A.âSalim,âY.-W.âChinâandâA.D.âKinghorn4
Theâ correlationâ betweenâ theâ ethnomedicalâ usageâ ofâ medicinalâ plantsâ andâmodernâ medicinesâ discoveredâ fromâ thoseâ plantsâ hasâ beenâ studiedâ byâ Fabri-cantâandâFarnsworthâ[15].âBasedâonâtheirâanalysis,â88âsingleâchemicalâentitiesâisolatedâfromâ72âmedicinalâplantsâhaveâbeenâintroducedâintoâmodernâtherapy,âmanyâofâwhichâhaveâtheâsameâorâaâsimilarâtherapeuticâpurposeâasâtheirâorigi-nalâ ethnomedicalâ useâ [15].â Someâ ofâ theseâ plant-derivedâ compounds,â suchâ asâatropineâ(anticholinergic),âcodeineâ(coughâsuppressant),âcolchicineâ(antigout),âephedrineâ (bronchodilator),â morphineâ (analgesic),â pilocarpineâ (parasympa-thomimetic),âandâphysostigmineâ(cholinesteraseâinhibitor)âareâstillâbeingâusedâwidelyâasâsingle-agentâorâcombinationâformulationsâinâprescriptionâdrugsâ[5].
Nowadays,âplantsâareâstillâimportantâsourcesâofâmedicines,âespeciallyâinâde-velopingâcountriesâthatâstillâuseâplant-basedâTMâforâtheirâhealthcare.âInâ1985,âitâwasâestimatedâinâtheâBulletinâofâtheâWorldâHealthâOrganizationâ(WHO)âthatâaroundâ80â%âofâtheâworldâsâpopulationâreliedâonâmedicinalâplantsâasâtheirâpri-maryâhealthcareâsourceâ[16].âEvenâthoughâaâmoreârecentâfigureâisânotâavailable,âtheâWHOâhasâestimatedâthatâupâtoâ80â%âofâtheâpopulationâinâAfricaâandâtheâmajorityâofâtheâpopulationsâinâAsiaâandâLatinâAmericaâstillâuseâTMâforâtheirâprimaryâhealthcareâneedsâ [17].â Inâ industrializedâ countries,âplant-basedâ tradi-tionalâ medicinesâ orâ phytotherapeuticalsâ areâ oftenâ termedâ complementaryâ orâalternativeâmedicineâ(CAM),âandâtheirâuseâhasâincreasedâsteadilyâoverâtheâlastâ10âyears.âInâtheâUSAâalone,âtheâtotalâestimatedââherbalââsalesâforâ2005âwasâ$4.4âbillion,âaâsignificantâincreaseâfromâ$2.5âbillionâinâ1995â[18].âHowever,âsuchââbo-tanicalâdietaryâsupplementsââareâregulatedâasâ foodsâratherâ thanâdrugsâbyâ theâUnitedâStatesâFoodâandâDrugâAdministrationâ(USâFDA).
1.2â TheâRoleâof âPlant-DerivedâCompoundsââinâDrugâDevelopment
Despiteâtheârecentâinterestâinâdrugâdiscoveryâbyâmolecularâmodeling,âcombina-torialâchemistry,âandâotherâ syntheticâchemistryâmethods,ânatural-product-de-rivedâcompoundsâareâstillâprovingâtoâbeâanâinvaluableâsourceâofâmedicinesâforâhumans.âTheâimportanceâofâplantsâinâmodernâmedicineâhasâbeenâdiscussedâinârecentâreviewsâandâreportsâ[19â22].âOtherâthanâtheâdirectâusageâofâplantâsecond-aryâmetabolitesâinâtheirâoriginalâformsâasâdrugs,âtheseâcompoundsâcanâalsoâbeâusedâasâdrugâprecursors,âtemplatesâforâsyntheticâmodification,âandâpharmaco-logicalâprobes,âallâofâwhichâwillâbeâdiscussedâbrieflyâinâturnâinâthisâsection.
1.2.1 PlantSecondaryMetabolitesasDrugPrecursors
Someânaturalâproductsâobtainedâfromâplantsâcanâbeâusedâasâsmall-moleculeâdrugâprecursors,âwhichâcanâbeâconvertedâintoâtheâcompoundâofâinterestâbyâchemicalâ
Chapterâ1â DrugâDiscoveryâfromâPlants 5
modificationâorâfermentationâmethods.âTheâsemisyntheticâapproachâisâusuallyâusedâtoâresolveâtheâshortageâofâsupplyâdueâtoâtheâlowâyieldâofâcompoundsâfromâplantsâand/orâ theâhighâcostâofâ totalâ synthesis.âForâcompoundsâwithâcomplexâstructuresâandâmanyâchiralâcenters,âprotractedâmethodsâmayâbeâneededâforâtheirâsynthesis,âandâthusâtheseâmethodsâwouldânotâbeâfeasibleâeconomically.âTheâfol-lowingâexamplesâindicateâthatâsomeâsecondaryâmetabolitesâfromâplantsâareâuse-fulâdrugâprecursors,âalthoughâtheyâareânotânecessarilyâpharmacologicallyâactiveâinâtheirâoriginalânaturallyâoccurringâforms.
Croppingâofâtheâbarkâofâtheâslow-growingâPacificâyewâtree,âTaxus brevifoliaâNutt., isânotâaâfeasibleâmethodâtoâprovideâsufficientâamountsâofâtheâantitumorâdrugâpaclitaxelâ(1,âTaxol)âtoâmeetâtheâmarketâdemandâ(paclitaxelâwasâoriginallyâisolatedâinâonlyâ0.014â%âw/wâyieldâfromâtheâbarkâofâTaxus brevifolia)â[23].âEvenâthoughâthisâcompoundâcanâbeâproducedâbyâtotalâsynthesis,âthisâhasâprovenâtoâbeâ inefficientâ inâ affordingâ largeâ quantitiesâ ofâ paclitaxelâ [24,â 25].â Fortunately,â10-deacetylbaccatinâIIIâ(2)âcanâbeâisolatedâinârelativelyâlargeâamountsâfromâtheâneedlesâofâotherârelatedâyewâspecies,âsuchâasâTaxus baccata L.â(aârenewableâre-source),âandâcanâbeâconvertedâchemicallyâinâseveralâstepsâintoâpaclitaxelâ[26,â27].âDuringâtheâperiodâ1993â2002,âtheâmainâpharmaceuticalâmanufacturer,âBristol-MyersâSquibb,âadoptedâtheâsemisyntheticâmethodâdevelopedâbyâtheâHoltonâre-searchâgroupâtoâproduceâpaclitaxelâfromâ10-deacetylbaccatinâIIIâ[27,â28].âSinceâ2002,âBristol-MyersâSquibbâhasâproducedâpaclitaxelâusingâaâplantâcellâcultureâmethod,âwhichâwillâbeâmentionedâinâsectionâ1.4âofâthisâchapterâ[29].
Diosgeninâ (3),â aâ steroidalâ sapogeninâ obtainedâ fromâ theâ tubersâ ofâ variousâDioscorea speciesâthatâgrowâinâMexicoâandâCentralâAmerica,âcanâbeâconvertedâchemicallyâinâseveralâstepsâintoâprogesteroneâ(4),âaâhormoneâthatâcanâbeâusedâasâaâfemaleâoralâcontraceptiveâ[30].âOriginally,âprogesteroneâwasâisolatedâfromâsowâovariesâwithâaâveryâlowâyieldâ(20âmgâfromâ625âkgâofâovaries),âandâlaterâwasâsynthesizedâfromâcholesterolâwithâveryâlowâefficiencyâ[31].âProgesteroneâisâalsoâaâkeyâintermediateâforâtheâproductionâofâcortisoneâ(5),âanâimportantâanti-inflam-matoryâdrug.âProgesteroneâcanâbeâconvertedâintoâ11Îą-hydroxyprogesteroneâ(6)âbyâmicrobialâhydroxylationâatâC-11,âfollowedâbyâchemicalâreactions,âtoâproduceâ
A.A.âSalim,âY.-W.âChinâandâA.D.âKinghorn6
cortisoneâ(5)â[32,â33].âUntilânow,âdiosgeninâ(3)âisâstillâanâimportantâstartingâma-terialâforâtheâproductionâofâvariousâsteroidâhormones.
Oseltamivirâphosphateâ(7,âTamiflu)âisâanâorallyâactiveâneuraminidaseâinhibi-torâdevelopedâforâtheâtreatmentâandâprophylaxisâofâinfluenzaâvirusesâAâandâBâ[34,â35].âTheâstartingâmaterialâforâtheâoseltamivirâsynthesisâisâ(â)-shikimicâacidâ(8),âanâimportantâbiochemicalâintermediateâinâplantsâandâmicroorganismsâ[36].âPreviously,â shikimicâ acidâ wasâ extractedâ solelyâ fromâ theâ fruitsâ ofâ theâ shikimiâtreeâ(Illicium verum Hook.f.),âalsoâknownâasâstarâanise,âwhichâcontainsâaâlargeâamountâofâthisâcompoundâ[37].âLaterâon,âshikimicâacidâwasâobtainedâfromâtheâfermentationâofâgeneticallyâengineeredâEscherichia coliâ strains,âwhichâareâde-ficientâinâtheâshikimateâkinaseâgeneâ[38].âCurrently,âRoche,âtheâdrugâmanufac-turer,â stillâ reliesâonâbothâextractionâandâ fermentationâmethodsâ toâobtainâ tonâquantitiesâofâshikimicâacidâ[37].âSeveralâroutesâforâtheâproductionâofâoseltami-virâindependentâofâshikimicâacidâhaveâbeenâdevelopedâ[36,â39],âbutâtheseâalter-nativesâareâstillânotâcostâefficientâ[37].
1.2.2 PlantSecondaryMetabolitesasDrugPrototypes
Sneaderâhasâdefinedâaâdrugâprototypeâasââtheâfirstâcompoundâdiscoveredâinâaâseriesâofâchemicallyârelatedâtherapeuticâagentsââ[5].âAsâofâ1996,âfromâaâtotalâofâ244âdrugâprototypesâidentifiedâinâoneâanalysisâfromâminerals,âplants,âanimals,âmicrobes,âandâchemicalâsources,âplantâsecondaryâmetabolitesâcontributedâ56âofâtheseâ(23â%)â[5].âWithâadvancesâinâorganicâchemistry,âmedicinalâchemistsâstartedâpreparingâanalogsâfromâtheseâdrugâprototypesâtoâprovideâsaferâandâmoreâpotentâdrugs.âSometimes,ânewâcompoundsâwithânovelâpharmacologicalâpropertiesâhaveâ
Chapterâ1â DrugâDiscoveryâfromâPlants 7
beenâdevelopedâinâtheâprocessâofâdevelopingâsuchâderivatives.âInâtheâfollowingâexamples,âpodophyllotoxin,âcamptothecin,âandâguanidineâhaveâbeenâselectedâasâdrugâprototypesâwithâanalogsâhavingâtheâsameâpharmacologicalâactionâasâtheâparentâcompound,âwhileâatropineâisâaâdrugâprototypeâthatâhasâfurnishedâmanyâanalogsâthatâhaveâadditionalâpharmacologicalâproperties.
Severalâantineoplasticâcompoundsâisolatedâfromâplants,âsuchâasâpodophyl-lotoxinâ(9)âandâcamptothecinâ(10),âareâtooâtoxicâorânotâwaterâsolubleâenoughâforâclinicalâapplication,âandâanalogsâwithâhigherâtherapeuticâindicesâsuchâasâetopo-sideâ(11,âVepesid)âandâtopotecanâ(12,âHycamtin)âhaveâbeenâdevelopedâinâcon-sequenceâ[40,â41].âDueâtoâtheirâuniqueâmodesâofâanticancerâactivities,âthereâisâmuchâinterestâinâtheâclinicalâdevelopmentâofâfurtherâderivativesâofâpaclitaxelâ(1)âandâcamptothecinâ(10)âasâanticancerâtherapeuticâdrugsâ[28,â41â43].âAccordingâtoâaârecentâreview,âofâtheâ2255âcancerâclinicalâtrialsârecordedâasâofâAugustâ2003,â310â(orâ13.7â%)âandâ120â(orâ5.4â%)âofâtheâtrialsâinvolvedâtaxane-âandâcamptothe-cin-derivedâdrugs,ârespectivelyâ[43].âInâ2002,âitâwasâestimatedâthatâtheâcombinedâsalesâofâpaclitaxelâandâdocetaxelâ(bothâtaxanes),âandâtopotecanâandâirinotecanâ(bothâbasedâonâtheâparentâmoleculeâcamptothecin)âconstitutedâoverâ30â%âofâtheâtotalâglobalâsalesâofâcytotoxicâdrugsâ[44].
Guanidineâ(13)âisâaânaturalâproductâwithâgoodâhypoglycemicâactivityâisolatedâfromâGalega officinalisâL.,âbutâisâtooâtoxicâforâclinicalâuseâ[45].âManyâderivativesâofâguanidineâhaveâbeenâsynthesized,âandâmetforminâ(dimethylbiguanide)â(14)âwasâlaterâfoundâtoâbeâclinicallyâsuitableâforâtreatmentâofâtypeâIIâdiabetesâ[46].
Atropineâ(15)âisâanâartifactâofâtheâtropaneâalkaloidâ(â)-hyoscyamine,âwhichâracemizesâduringâ theâextractionâprocessâ fromâ itsâplantâofâoriginâ (Atropa bel-ladonna).â Atropineâ isâ aâ competitiveâ antagonistâ ofâ muscarinicâ acetylcholineâ
A.A.âSalim,âY.-W.âChinâandâA.D.âKinghorn8
receptorsâ(antimuscarinicâagent).âAtropineâ isâsometimesâusedâ inâtheâophthal-mologyâareaâasâaâmydriaticâagent,âandâhasâadditionalâ therapeuticâusesâasâanâantispasmodic.â Itâ isâalsoâusedâasâaâpremedicationâ forâanesthesia,â toâdecreaseâbronchialâandâsalivaryâsecretions,âandâtoâblockâtheâbradycardiaâ(lowâheartârate)âassociatedâwithâtheâadministrationâofâanestheticâdrugsâ[5].âBiologicalâandâphys-iologicalâ studiesâofâaâ largeânumberâofâsyntheticâatropineâanalogsâhaveâ ledâ toâtheâintroductionâofânewâdrugsâwithâdifferentâtherapeuticâapplicationsâthanâtheâparentâcompound.âExamplesâofâdrugsâderivedâfromâtheâbasicâatropineâskeletonâincludeâdroperidolâ(16,âantipsychotic),âipratropiumâbromideâ(17,âbronchodila-torâ forâ theâ treatmentâofâasthma),â loperamideâ (18,â antidiarrheal),âmethadoneâ(19,âaâmorphineâsubstituteâforâaddicts),âandâpethidineâ(20,âanalgesic)â[5].
1.2.3 PlantSecondaryMetabolitesasPharmacologicalProbes
Inâadditionâtoâtheirâdirectâcontributionâasâdrugsâorâdrugâprotopyesâtoâcureâhu-manâdisease,âsecondaryâmetabolitesâofâplantâorigin,âsuchâasâphorbolâestersâandâgenistein,âcanâbeâusedâasââpharmacologicalâprobes.ââPharmacologicalâprobesâhelpâresearchersâtoâunderstandâtheâmechanismâofâactionâofâintracellularâsignalâtransductionsâandâbiologicalâmechanismsârelatedâtoâhumanâdisease,âwhichâcanâaidâtheâdesignâofâbetterâdrugs.
Genisteinâ(21),âanâisoflavoneâfoundânaturallyâinâsoybeanâ(Glycine maxâMerr.),âisâanâinhibitorâofâvariousâproteinâtyrosineâkinasesâ(PTK),âwhichâareâessentialâenzymesâinvolvedâinâintracellularâsignalâtransductionâ[47].âGenisteinâhasâbeenâusedâtoâprobeâtheâinteractionâbetweenâPTKâandâcyclicânucleotide-gatedâ(CNG)âchannels,âwhichâareâimportantâinâmammalianâolfactoryâandâvisualâsystemsâ[48,â49].âByâobservingâtheâeffectâofâgenisteinâonâtheâCNGâchannelsâcontainingâeitherâhomomericâorâheteromericâsubunits,âspecificâsubunitsâcontainingâbindingâsitesâforâPTKsâcanâbeâidentifiedâ[48].âFurthermore,âtheâmechanismâofâinhibitionâofâtheâCNGâchannelsâbyâPTKsâhasâbeenâ studiedâwithâ theâaidâofâgenisteinâasâaâprobeâ[49].
Chapterâ1â DrugâDiscoveryâfromâPlants 9
PhorbolâisâaâtetracyclicâditerpenoidâplantâsecondaryâmetaboliteâisolatedâasâaâhydrolysisâproductâofâcrotonâoilâfromâtheâseedsâofâCroton tigliumâL.â[50].âVari-ousâ12,13-diestersâofâphorbolâhaveâtheâcapacityâtoâactâasâtumorâpromoters,âdueâinâpartâ toâ theirâ roleâasâproteinâkinaseâCâ (PKC)âactivatorsâ [51â53].âTheâmostâabundantâphorbolâ esterâderivativeâofâ crotonâoil,â 12-O-tetradecanoylphorbol-13-acetateâ(TPA)â(22),âhasâbeenâusedâinâbiomedicalâresearchâinâstandardâlabora-toryâmodelsâofâcarcinogenesisâpromotionâ[54â56].
1.3â RecentâDevelopmentsâinâDrugâDiscoveryâfromâPlants
Despiteâtheâlargeânumberâofâdrugsâderivedâfromâtotalâsynthesis,âplant-derivedânaturalâproductsâstillâcontributeâtoâtheâoverallâtotalânumberâofânewâchemicalâentitiesâ(NCE)âthatâcontinueâtoâbeâlaunchedâtoâtheâmarket.âSeveralâreviewsâonâdrugâdiscoveryâandâdevelopmentâfromânaturalâsourcesâ(plants,âmarineâfauna,âmicrobes)âhaveâbeenâpublishedârecentlyâ[42,â57â59].âTheâfollowingâsectionsâwillâcoverâ specificallyâ theâplant-derivedâdrugsânewlyâ launchedâ sinceâ2001âandâex-amplesâofâsomeâplant-derivedâcompoundsâcurrentlyâinâclinicalâtrials.
1.3.1 NewPlant-DerivedDrugsLaunchedSince2001
Inâtheâpastâ6âyears,âfiveânewâdrugsâderivedâfromânaturalâproducts,ânamely,âapo-morphineâ hydrochloride,â galanthamineâ hydrobromide,â nitisinone,â tiotropiumâbromide,âandâvarenicline,âhaveâbeenâapprovedâbyâtheâUSâFDA.âTheâfollowingâisâaâbrief âdescriptionâofâeachâdrugâandâtheirâtherapeuticâuse.
Galantamineâ(23,âRazadyne,âReminyl,âNivalin)âwasâfirstâmarketedâinâ2001âinâtheâUSAâforâtheâsymptomaticâtreatmentâofâpatientsâwithâearly-onsetâAlzheimerâsâ
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diseaseâ[58].âGalantamineâ(alsoâknownâasâgalanthamine)âisâanâalkaloidâthatâwasâinitiallyâisolatedâfromâtheâsnowdropâ(Galanthus woronowiiâLosinsk.)âinâtheâearlyâ1950s,âandâhasâsinceâbeenâfoundâinâotherâplantsâinâtheâfamilyâAmaryllidaceaeâ[60].âGalantamineâslowsâtheâprocessâofâneurologicalâdegenerationâbyâinhibitingâacetylcholinesteraseâasâwellâasâbindingâtoâandâmodulatingâtheânicotinicâacetyl-cholineâreceptorâ[60,â61].âDueâtoâtheâlimitedâavailabilityâofâtheâplantsâofâoriginâofâthisâcompound,âgalantamineâisânowâproducedâbyâtotalâsynthesis.
Nitisinoneâ (24,âOrfadin)âwasâapprovedâbyâ theâFDAâ inâ2002â forâ theâ treat-mentâ ofâ hereditaryâ tyrosinemiaâ typeâ 1â (HT-1)â [58].â HT-1â isâ aâ rareâ pediatricâdiseaseâ causedâ byâ aâ deficiencyâ ofâ fumarylâ acetoacetateâ hydrolaseâ (FAH),â anâenzymeâessentialâinâtheâtyrosineâcatabolismâpathway.âFAHâdeficiencyâleadsâtoâtheâaccumulationâofâtoxicâsubstancesâinâtheâbody,âresultingâinâliverâandâkidneyâdamageâ[62].âNitisinoneâisâaâderivativeâofâleptospermoneâ(25),âaânewâclassâofâherbicideâfromâtheâbottlebrushâplantâ[Callistemon citrinus (Curtis)âSkeels].âBothânitisinoneâ andâ leptospermoneâ inhibitâ 4-hydroxyphenylâ pyruvateâ dioxygenaseâ(HPPD),âtheâenzymeâinvolvedâinâplastoquinoneâandâtocopherolâbiosynthesisâinâplantsâ[63].âInâhumans,âinhibitionâofâHPPDâpreventsâtyrosineâcatabolism,âlead-ingâtoâtheâaccumulationâofâtyrosineâmetabolites,â4-hydroxyphenylâpyruvicâacidâandâ4-hydroxyphenylâlacticâacid,âwhichâcanâbeâexcretedâthroughâtheâurineâ[64].
Apomorphineâ(26,âApokyn)âwasâapprovedâbyâtheâFDAâinâ2004âasâanâinject-ableâdrugâforâtheâsymptomaticâtreatmentâforâParkinsonâsâdiseaseâpatientsâduringâepisodesâofââhypomobilityââ(e.g.,âpersonsâunableâtoâmoveâorâtoâperformâdailyâactivities)â [65].â Apomorphineâ isâ aâ syntheticâ derivativeâ ofâ morphineâ (27),â butâunlikeâmorphine,âapomorphineâdoesânotâhaveâopioidâanalgesicâproperties,âandâinsteadâisâaâshort-actingâdopamineâD1âandâD2âreceptorâagonistâ[66].
Tiotropiumâbromideâ(28,âSpiriva),âanâatropineâanalog,âwasâapprovedâbyâtheâFDAâinâ2005âforâtheâtreatmentâofâbronchospasmâassociatedâwithâchronicâob-structiveâpulmonaryâdiseaseâ(COPD),âincludingâchronicâbronchitisâandâemphy-semaâ[67].
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Vareniclineâ(29,âChantix),âbasedâonâtheâplantâquinolizidineâalkaloid,âcytisineâ(30),âhasâbeenâapprovedâbyâtheâFDAâsinceâ2006âasâanâaidâtoâsmokingâcessationâ[68â70].âCytisineâ(30),âanâalkaloidâisolatedâfromâCytisus laburnum L.,âhasâbeenâusedâtoâtreatâtobaccoâdependenceâinâEasternâEuropeâ(Bulgaria,âGermany,âPo-land,âandâRussia)âforâtheâlastâ40âyearsâ[71].âCigaretteâsmokingâhasâbeenâlinkedâtoâseveralâdiseasesâincludingâcardiovascularâdisease,âCOPD,âmanyâcancersâ(par-ticularlyâlung,âmouth,âandâesophageal),âandâpregnancy-relatedâcomplications.âVareniclineâ (29)â isâaâpartialâagonistâwithâaâhighâaffinityâ forâ theâÎą4β2ânicotinicâacetylcholineâreceptor,âandâisâaâfullâagonistâatâÎą7âneuronalânicotinicâreceptorsâ[70].
1.3.2 Examplesof Plant-DerivedCompoundsCurrentlyInvolvedinClinicalTrials
Althoughârelativelyâfewâplant-derivedâdrugsâhaveâbeenâlaunchedâontoâtheâmar-ketâtheâlastâ6âyears,âmanyâplant-derivedâcompoundsâareâcurrentlyâundergoingâclinicalâ trialâ forâ theâpotentialâ treatmentâofâvariousâdiseases.âTheâmajorityâofâsuchâdrugsâunderâclinicalâdevelopmentâareâ inâ theâoncologicalâarea,â includingânewâanalogsâofâknownâanticancerâdrugsâbasedâonâtheâcamptothecin-,âtaxane-,âpodophyllotoxin-,âorâvinblastine-typeâskeletonsâ[42].âExamplesâofâcompoundsâwithâcarbonâskeletonsâdifferentâfromâtheâexistingâplant-derivedâdrugsâusedâinâcancerâchemotherapyâwillâbeâdiscussedâbelow,ânamely,âbetulinicâacid,âceflato-nineâ (homoharringtonine),â combretastatinâA4âphosphate,â ingenol-3-angelate,âphenoxodiol,âandâprotopanaxadiol.âInâtheâantiviralâarea,âbevirimatâandâcelgosi-virâareâcurrentlyâundergoingâclinicalâtrialsâforâtheâtreatmentâofâhumanâimmuno-deficiencyâviralâ(HIV)âandâhepatitisâCâviralâ(HCV)âinfections,ârespectively.âCap-saicinâ isâ inâclinicalâ trialâ forâ theâ treatmentâofâsevereâpostoperativeâpain,âwhileâhuperzineâisâbeingâdevelopedâforâtheâtreatmentâofâAlzheimerâsâdisease.
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Betulinicâacidâ(31)âisâaâlupane-typeâtriterpeneâthatâisâwidelyâdistributedâinâtheâplantâkingdom,âandâthisâcompound,âalongâwithâvariousâderivatives,âhasâbeenâshownâ toâ haveâ anticancer,â antibacterial,â antimalarial,â anti-HIV,â anthelmin-thic,âanti-inflammatory,âandâantioxidantâpropertiesâ[72,â73].âInâ1995,âaâresearchâgroupâfromâtheâUniversityâofâIllinoisâatâChicagoâreportedâthatâbetulinicâacidâse-lectivelyâinhibitedâhumanâmelanomaâinâbothâin vitroâandâin vivoâmodelâsystems,âandâinducedâapoptosisâinâMel-2âhumanâmelanomaâcellsâ[74].âThisâcompoundâwasâ furtherâdevelopedâunderâ theâRapidâAccessâ toâ InterventionâDevelopmentâprogramâofâtheâUnitedâStatesâNationalâCancerâInstituteâ[75],âandâisâcurrentlyâundergoingâ phaseâ I/IIâ clinicalâ trialsâ forâ treatmentâ ofâ dysplasticâ melanocyticânevi,âaâpreliminaryâsymptomâthatâmayâleadâtoâmelanomasâofâtheâskinâ[76].
Bevirimatâ (32,âPA-457),âaâ semisyntheticâcompoundâderivedâ fromâbetulinicâacid,âisâbeingâdevelopedâbyâPanacosâPharmaceuticalsâ(Watertown,âMA,âUSA)âasâaânewâclassâofâantiretroviralâdrugâ[77].âBevirimatâblocksâHIV-1âmaturationâbyâ disruptingâ aâ lateâ stepâ inâ theâ Gagâ processingâ pathway,â causingâ theâ virionsâreleasedâ toâbeânoninfectious,â thusâ terminatingâ theâviralâ replicationâ [78].âThisâcompoundâisâcurrentlyâundergoingâphaseâIIâclinicalâtrials,âandâphaseâIIIâtrialsâareâexpectedâtoâcommenceâinâ2007â[77,â79].
Capsaicinâ (33)â isâ aâ capsaicinoid-typeâ amideâ thatâ causesâ theâ burningâ sen-sationâ inâ theâ mouthâ associatedâ withâ eatingâ chilliâ peppersâ [80].â Uponâ topicalâapplication,â capsaicinâ desensitizesâ theâ neuronsâ andâ lowersâ theâ thresholdâ forâthermal,âchemical,âandâmechanicalânociceptionâbyâdirectâactivationâofâtheâtran-sientâreceptorâpotentialâchannel,âvanilloidâsubfamilyâmemberâ1â[80,â81].âLow-concentrationâcapsaicinâ (0.025â0.075â%)âcreamsâandâdermalâpatchesâareânowâavailableâwithoutâprescriptionâtoârelieveâtheâpainâassociatedâwithâosteoarthritis,ârheumatoidâarthritis,âpostherpeticâneuralgia,âpsoriasis,âandâdiabeticâneuropathyâ[82].âAnesivaâ(SanâFransisco,âCA,âUSA)âhasâdevelopedâaâcapsaicinâformulationâforâinternalâuse,âforâtheâtreatmentâofâsevereâpostoperativeâpain,âpost-traumaticâneuropathicâpain,âandâmusculoskeletalâdiseases,âwhichâisâcurrentlyâundergoingâvariousâphaseâIIâclinicalâtrialsâ[83].
Chapterâ1â DrugâDiscoveryâfromâPlants 13
Ceflatonineâ (34),â aâ syntheticâ versionâ ofâ homoharringtonineâ producedâ byâChemGenexâPharmaceuticalsâ(MenloâPark,âCA,âUSA),âisâcurrentlyâundergo-ingâphaseâII/IIIâclinicalâtrialsâforâtheâtreatmentâofâpatientsâwithâchronicâmyeloidâleukemiaâthatâisâresistantâtoâtheâfirst-lineâtherapy,âGleevecâ[84].âHomoharringto-nineâisâanâalkaloidâisolatedâfromâtheâChineseâevergreenâtreeâCephalotaxus har-ringtoniaâK.âKoch.â[84].âHomoharringtonineâaffectsâseveralâcellularâpathways,âincludingâtheâregulationâofâgenesâassociatedâwithâapoptosisâandâangiogenesisâ[85].
Celgosivirâ(35,âMX-3253),âdevelopedâbyâMIGENIXâ(Vancouver,âCanada),âisâaâsemisyntheticâderivativeâofâtheâalkaloidâcastanospermineâ(36),âwhichâisâiso-latedâfromâtheâAustralianâtreeâCastanospermum australeâA.âCunninghamâexâR.âMudieâ[86,â87].âCelgosivirâisâanâÎą-glucosidaseâIâinhibitorâandâhasâshownâinâvitroâsynergyâwithâvariousâinterferonsâ[88].âCelgosivirâisâcurrentlyâundergoingâphaseâIIbâclinicalâtrialsâasâaâcombinationâtherapyâwithâpeginterferonâÎą2bâandâribavirinâforâtheâtreatmentâofâpatientsâwithâchronicâHCVâinfectionâ[89].
CombretastatinâA4âphosphateâ(37,âCA4P)âisâaâdisodiumâphosphateâprodrugâofâtheânaturalâstilbeneâcombretastatinâA4â(38)âisolatedâfromâtheâSouthâAfricanâtreeâCombretum caffrum Kuntzeâ[90].âCA4PâisâbeingâdevelopedâbyâOXiGENEâ(Waltham,âMA,âUSA)âtoâtreatâanaplasticâthyroidâcancerâinâcombinationâwithâotherâ anticancerâ drugsâ andâ alsoâ forâ myopicâ macularâ degeneration,â bothâ inâphaseâIIâclinicalâ trialsâ [91].âCombretastatinâ isâaâvascularâ targetingâagentâ thatâfunctionsâbyâdestroyingâexistingâtumorâvasculatureâbyâinducingâmorphologicalâchangesâwithinâtheâendothelialâcellsâ[90].
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HuperzineâAâ(39)âisâanâalkaloidâwithâaâpotentâacetylcholinesteraseâinhibitoryâactivityâisolatedâfromâtheâChineseâclubâmossâHuperzia serrataâ(Thunb.âexâMur-ray)âTrevis.â[92].âHuperzineâAâisâcurrentlyâavailableâinâtheâUSAâasâânutraceuti-calââorâ âfunctionalâ foodâ.âTheâNationalâ Instituteâonâ Aging,â atâ theâ NationalâInstitutesâofâHealthâ(Bethesda,âUSA)â[93],âinâcollaborationâwithâNeuro-Hitechâ(NewâYork,âNY,âUSA)â[94]âareâcurrentlyâevaluatingâtheâsafetyâandâefficacyâofâhuperzineâAâinâaâphaseâIIâclinicalâtrialâ[95].âAâprodrugâofâhuperzineâA,âZT-1â(40),â isâcurrentlyâbeingâevaluatedâbyâDebiopharmâ(Lausanne,âSwitzerland)âinâphaseâIIâclinicalâtrialsâforâtheâpotentialâtreatmentâofâAlzheimerâsâdisease,âandâhasâshownâefficacyâinâpatientsâwithâmildâtoâmoderateâsymptomsâ[96].
Ingenolâ3-angelateâ(41,âPEP005)âisâaâditerpeneâesterâ isolatedâfromâtheâme-dicinalâplantâEuphorbia peplusâL.,âaâspeciesâusedâtraditionallyâtoâtreatâskinâcon-ditionsâsuchâasâwartsâandâactinicâkeratosesâ [97].âPEP005âkillsâ tumorâcellsâviaâtwoâmechanisms:â(1)âbyâinducingâprimaryânecrosisâofâtumorâcells,âandâ(2)âbyâpotentlyâactivatingâPKC.âThisâisâalsoâassociatedâwithâanâacuteâT-cell-indepen-dentâinflammatoryâresponseâthatâisâcharacterizedâbyâaâpronouncedâneutrophilâinfiltrationâ[98].âPEP005,âdevelopedâbyâPeplinâ(Brisbane,âAustralia),âisâcurrentlyâundergoingâphaseâIIâclinicalâtrialsâasâaâtopicalâformulationâforâtheâtreatmentâofâactinicâkeratosisâandâbasalâcellâcarcinomaâ[99].
Morphineâ (27),â anâ opiateâ analgesicâ alkaloidâ isolatedâ fromâ Papaver som-niferum,â isâ aâdrugâ thatâ isâ stillâusedâwidelyâ todayâ forâ theâalleviationâofâ severeâpainâ[5].âMorphineâisâmetabolizedâintoâmorphine-3-glucuronideâandâmorphine-
Chapterâ1â DrugâDiscoveryâfromâPlants 15
6-glucuronideâ (42,â M6G)â inâ theâ humanâ body;â butâ ofâ theseâ twoâ metabolites,âonlyâM6Gâpossessesâanalgesicâactivityâ[100,â101].âM6GâisâbeingâdevelopedâbyâCeNeSâ (Cambridge,â UK)â asâ aâ treatmentâ forâ postoperativeâ pain,â andâ isâ cur-rentlyâundergoingâphaseâIIIâtrialsâinâEurope,âwithâphaseâIIIâclinicalâtrialsâinâtheâUSAâexpectedâtoâcommenceâinâ2007â[102].âTheâresultsâofâclinicalâtestingâtoâdateâhaveâshownâthatâM6Gâgivesâ theâsameâpostoperativeâpainârelief âasâmorphine,âbutâcausesâlessâpostoperativeânauseaâandâvomitingâ[102].
Phenoxodiolâ (43),â aâ syntheticâanalogâofâdaidzeinâ (44),â anâ isoflavoneâ fromâsoybeanâ(Glycine max Merr.),âisâbeingâdevelopedâbyâMarshallâEdwardsâ(NorthâRyde,â Australia)â forâ theâ treatmentâ ofâ cervical,â ovarian,â prostate,â renal,â andâvaginalâcancersâ[103].âPhenoxodiolâisâaâbroad-spectrumâanticancerâdrugâthatâin-ducesâcancerâcellâdeathâthroughâinhibitionâofâantiapoptoticâproteinsâincludingâXIAPâandâFLIPâ[104].âPhaseâIIIâclinicalâtrialsâofâphenoxodiolâasâaâtreatmentâforâovarianâcancerâhasâstartedâinâAustralia,âwithâphaseâIIâtrialsâcurrentlyâunder-wayâinâtheâUSAâ[105].
Protopanaxadiolâ (45),â aâ triterpeneâ aglyconeâ hydrolyzedâ fromâ variousâ Ko-reanâ ginsengâ (Panax ginsengâ C.â A.â Mey.)â saponinsâ [106],â hasâ beenâ shownâ toâexhibitâ apoptoticâ effectsâ onâ cancerâ cellsâ throughâ variousâ signalingâ pathways,âandâhasâalsoâbeenâreportedâtoâbeâcytotoxicâagainstâmultidrug-resistantâtumorsâ[106â108].âPanaGinâPharmaceuticalsâ(BritishâColumbia,âCanada)â isâdevelop-ingâ protopanaxadiolâ (Pandimex)â forâ theâ treatmentâ ofâ lungâ cancerâ andâ otherâsolidâ tumors,â andâ isâ currentlyâ undergoingâ phaseâ Iâ clinicalâ studyâ inâ theâ USAâ[109].âPandimexâhasâbeenâmarketedâ inâtheâPeopleâsâRepublicâofâChinaâunderâconditionalâapprovalâforâtheâtreatmentâofâadvancedâcancersâofâtheâlung,âbreast,âpancreas,âstomach,âcolon,âandârectumâ[110].
1.3.3 PlantExtractsCurrentlyInvolvedinClinicalTrials
Thereâ areâ newâ formsâ ofâ registeredâ plant-derivedâ medicinesâ (phytomedicines)âthatâareânotâsingleâchemicalâentities.âTheseâmoreâcomplexâdrugsâareâsubjectedâtoâqualityâcontrolâviaâextractâstandardizationâproceduresâinvolvingâeitherâorâbothâcompoundsâwithâknownâbiologicalâ activityâorâ inactiveââmarkerâ compoundsââ
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presentâinâhighâconcentrationâ[111].âTheâfollowingâareâexamplesâofâstandard-izedâplantâextractsâthatâhaveâundergoneâclinicalâtrialâforâtheâtreatmentâofâseveralâdiseases,âincludingâosteoarthritisâandâcancer,âandâasâaâpainâreliever.
DevilâsâClawâ(Harpagophytum procumbens DC.)âhasâbeenâusedâforâthousandsâofâ yearsâ inâ Africaâ forâ theâ treatmentâ ofâ fever,â rheumatoidâ arthritis,â andâ skinâconditions,âandâisâcurrentlyâavailableâasâanâalternativeâtreatmentâforâpainâandâosteoarthritisâ [112].â Harpagosideâ (46),â oneâ ofâ theâ majorâ componentsâ ofâ theâplant,âhasâbeenâshownâtoâsuppressâlipopolysaccharide-inducedâinducibleânitricâoxideâsynthaseâandâcyclooxygenaseâ(COX)-2âexpressionâthroughâinhibitionâofânuclearâfactor-ÎşBâactivationâ[113].âSeveralâclinicalâtrialsâhaveâshownâaâHarpag-ophytum procumbensâextractâcontainingâ50â60âmgâofâharpagosideâtoâbeâeffec-tiveâinâtreatingâpainâ[114].âThisâHarpagophytum procumbensâextractâisâcurrentlyâundergoingâphaseâIIâclinicalâtrialsâinâtheâUSAâforâtheâtreatmentâofâhipâandâkneeâosteoarthritisâ[115].
Flavocoxidâ(Limbrel),âaâproprietaryâblendâofânaturalâflavonoidsâfromâScu-tellaria baicalensis GeorgiâandâAcacia catechu Willd.,âisâbeingâmarketedâinâtheâUSAâbyâPrimusâPharmaceuticalsâ(Scottsdale,âAZ,âUSA)âunderâprescriptionâasâaââmedicalâfoodââtherapyâforâosteoarthritisâ[116].âAâmedicalâfoodâisânotâaâdrug,ânorâaâdietaryâsupplement,âandâ isâdefinedâbyâ theâFDAâasâaââformulatedâ foodâthatâisâconsumedâunderâtheâsupervisionâofâaâphysicianâandâisâintendedâforâtheâspecificâmanagementâofâaâdiseaseââ[117].âFlavocoxidâisâcurrentlyâundergoingâaâphaseâIâclinicalâtrialâinâtheâUSAâforâtheâtreatmentâofâkneeâosteoarthritis.âTheâactiveâcomponentsâofâflavocoxidâincludeâbaicalinâ(47)âandâcathechinâ(48),âtwoâflavonoidsâwithâanti-inflammatoryâandâantioxidantâpropertiesâ[118].âThisâprod-uctâworksâbyâinhibitingâtheâcyclooxygenaseâ(COX-1âandâCOX-2)âandâlipoxy-genaseâ(5-LOX)âenzymeâsystems,âtwoâmajorâinflammatoryâpathwaysâinvolvedâinâosteoarthritisâ thatâprocessâarachidonicâacidâ intoâ inflammatoryâmetabolitesâ[119].
Chapterâ1â DrugâDiscoveryâfromâPlants 17
GinkgoâextractsâareâproducedâfromâtheâdriedâleavesâofâtheâGinkgo bilobaâL.âtree,âaâuniqueâspeciesâwithânoâcloseâlivingârelatives,âthatâhasâbeenâdescribedâasâaââlivingâfossil.ââTheâstandardizedâginkgoâextractâ(EGbâ761)âcontainsâapproxi-matelyâ24â%âflavoneâglycosidesâ(primarilyâquercetin,âkaempferol,âandâisorham-netin)âandâ6â%âterpenoidâlactonesâ[2.8â3.4â%âginkgolidesâAâ(49),âBâ(50),âandâCâ(51),âandâ2.6â3.2â%âbilobalideâ(52)]â[120].âGinkgoâextractâisâusedâforâtheâtreat-mentâ ofâ early-stageâ Alzheimerâsâ diseaseâ (AD),â vascularâ dementia,â peripheralâclaudication,âandâtinnitusâofâvascularâoriginâ[121].âSeveralâreviewsâonâtheâstud-iesâofâginkgoâextractâforâtheâtreatmentâofâpatientsâwithâAlzheimerâsâdiseaseâandâdementiaâ haveâ beenâ publishedâ [122â124].â Inâ theâ USA,â Ginkgo biloba extractâ(240âmg/day)âisâcurrentlyâundergoingâphaseâIIIâclinicalâtrialsâtoâpreventâdemen-tiaâandâtheâonsetâofâAlzheimerâsâdiseaseâinâolderâindividualsâ[125].
Mistletoeâ(Viscum album L.)âextractâ(Iscador)âhasâbeenâusedâasâaâcomplemen-taryâtreatmentâinâcancerâpatientsâinâvariousâEuropeanâcountriesâ(e.g.,âAustria,âGermany,âSwitzerland,âandâtheâUnitedâKingdom)â[126].âInâtheâUSA,âmistletoeâextractâisâcurrentlyâundergoingâphaseâIIâclinicalâtrialsâasâaâsupplementalâtreat-mentâforâlungâcancerâpatientsâreceivingâconventionalâchemotherapyâ[127],âandâinâphaseâIâtrialsâasâaâcombinationâdrugâwithâgemcitabineâ(aâsyntheticâantitumorâdrug)âforâpatientsâwithâadvancedâsolidâtumorsâ[128].âMistletoeâextractâhasâbeenâshownâtoâhaveâcytotoxicityâagainstâtumorâcellsâandâimmunomodulatoryâactiv-ity,âbutâtheâmechanismâofâactionâisâpoorlyâunderstoodâ[126].âMistletoeâcontainsâaâcytotoxicâ lectinâ (viscumin)âandâseveralâcytotoxicâproteinsâandâpolypeptidesâ(viscotoxins)â thatâ haveâ beenâ shownâ toâ induceâ tumorâ necrosis,â increaseâ natu-ralâkillerâcellâactivity,âincreaseâtheâproductionâofâinterleukinsâ1âandâ6,âactivateâmacrophages,âinduceâprogrammedâcellâdeathâ(apoptosis),âandâprotectâDNAâinânormalâcellsâduringâchemotherapyâ[129â132].
Sativex,âdevelopedâbyâGWâPharmaceuticalsâ(Wiltshire,âUK),âisâaâstandard-izedâ extractiveâ ofâ Cannabis sativa L.â withâ anâ almostâ 1:1â ratioâ ofâ theâ canna-binoids,âÎ9-tetrahydrocannabinolâ(53)âandâcannabidiolâ(54),âforâtheâtreatmentâofâneuropathicâpainâinâpatientsâwithâmultipleâsclerosisâ [133].âInâ2005,âSativexâoromucosalâsprayâwasâapprovedâbyâHealthâCanadaâasâanâadjunctiveâtreatmentâforâ theâ symptomaticâ relief â ofâ neuropathicâ painâ inâ multipleâ sclerosisâ patientsâ[134].âInâtheâUSA,âSativexâbeganâphaseâIIIâclinicalâtrialsâforâmultipleâsclerosisâpatientsâinâ2006â[135].
A.A.âSalim,âY.-W.âChinâandâA.D.âKinghorn18
1.4â RecentâTrendsâandâFutureâDirections
Plant-derivedâandâotherânaturalâproductâsecondaryâmetabolitesâhaveâprovidedâmanyânovelâprototypeâbioactiveâmolecules,âsomeâofâwhichâhaveâledâtoâimpor-tantâdrugsâthatâareâavailableâonâtheâmarketâtoday.âInâspiteâofâthis,â inâtheâ lastâ10âyearsâorâso,âmostâlargeâpharmaceuticalâcompaniesâhaveâeitherâterminatedâorâscaledâdownâtheirânaturalâproductsâdrug-discoveryâprograms,â largelyâ inâfavorâofâperformingâcombinatorialâchemistry,âwhichâcanâgenerateâlibrariesâconsistingâofâmillionsâofâcompoundsâ[58,â136].âTheârolesâofâlargeâpharmaceuticalâcompa-niesâinâtheâfieldâofânaturalâproductsâhaveânowâbeenâtakenâoverâtoâsomeâextentâbyâsmallâbiotechnologyâcompanies,âwhichâareâspecializingâinâleadâidentificationâfromânaturalâproductâextractsâandâtheâdevelopmentâofâtheseâleadsâintoâdrugsâ[58,â137].âManyâofâtheâplant-derivedâdrugsâcurrentlyâundergoingâclinicalâtrialsâwereâobtainedâandâpromotedâbyâtheseâemergingââbiotechââcompanies,âsomeâofâwhichâwereâmentionedâinâtheâpreviousâsection.
Inâtheâpast,âdrugâdiscoveryâofâbioactiveâcompoundsâfromâplantsâwasâtime-consuming,âandâtheâprocessâofâidentifyingâtheâstructuresâofâactiveâcompoundsâfromâ anâ extractâ couldâ takeâ weeks,â months,â orâ evenâ years,â dependingâ onâ theâcomplexityâofâtheâproblem.âNowadays,âtheâspeedâofâbioassay-guidedâfraction-ationâ hasâ beenâ improvedâ significantlyâ byâ improvementsâ inâ instrumentationâsuchâ asâ high-performanceâ liquidâ chromatographyâ (HPLC)â coupledâ toâ massâspectrometryâ (MS)/MSâ (liquidâ chromatography,â LC-MS),â higherâ magneticâfield-strengthâ nuclearâ magneticâ resonanceâ (NMR)â instruments,â andâ roboticsâtoâautomateâhigh-throughputâbioassays.âTheâ introductionâofâcapillaryâNMRâ(cap-NMR)âspectroscopyâisâaârecentâmajorâbreakthroughâforâtheâcharacteriza-tionâofâcompoundsâthatâareâextremelyâlimitedâinâquantityâinâtheirâorganismsâofâoriginâ[138,â139].
Theâhighâsensitivityâofâtheâcap-NMRâprobeâhasâallowedâforâtheâcombina-tionâ ofâ NMRâ spectroscopyâ withâ otherâ analyticalâ âhyphenatedââ techniques,âsuchâasâLC-NMR-MSâandâLC-solidâphaseâextractionâ(SPE)-NMRâ[140,â141].âTheâLC-NMR-MSâtechniqueâgenerallyârequiresâdeuteratedâsolventsâduringâtheâchromatographicâseparation,âorâalternatively,âsolventâsuppressionâcanâbeâusedâforâ nondeuteratedâ solventsâ [141,â 142].â Inâ contrast,â theâ LC-SPE-NMRâ tech-niqueâ doesâ notâ requireâ deuteratedâ solventsâ duringâ theâ chromatographicâ sep-aration,âand,â furthermore,â itâ allowsâ forâ sampleâ enrichmentâ throughâ repeatedâchromatographicârunsâusingâSPEâbeforeâNMRâanalysisâ[140].âAâstate-of-the-artâintegratedâsystemâforâLC-NMR-MSâandâLC-SPE-NMR-MSâhasâbeenâdevel-opedâandâtheâhardwareâcanâbeâswitchedâfromâLC-NMR-MSâtoâLC-SPE-NMR-
Chapterâ1â DrugâDiscoveryâfromâPlants 19
MSâwithâminimalâ reconfigurationâ [140].âLC-SPE-NMRâinâcombinationâwithâHPLC-electrosprayâionizationâmassâspectrometryâ(ESIMS)âhasâbeenâusedâforâtheârapidâ identificationâofâcompoundsâpresentâ inâcrudeâextractsâofâplants,âasâexemplifiedâbyâtheâidentificationâofâsesquiterpeneâlactonesâandâesterifiedâphen-ylpropanoidsâ inâThapsia garganica L.â [143],âandâtheâcharacterizationâofâcon-stituentsâofâHarpagophytum procumbens [144].
Theâdevelopmentâofâautomatedâhigh-throughputâtechniquesâhasâallowedâforârapidâ screeningâ ofâ plantâ extracts;â thus,â theâ biologicalâ assayâ isâ noâ longerâ theârate-limitingâ stepâ inâ theâ drug-discoveryâ process.â Withâ advancesâ inâ dataâ han-dlingâsystemsâandârobotics,â100,000âsamplesâcanâbeâassayedâinâjustâoverâ1âweekâwhenâusingâaâ384-wellâformatâ[42].âScreeningâofâplantâextractâlibrariesâcanâbeâproblematicâdueâtoâtheâpresenceâofâcompoundsâthatâmayâeitherâautofluoresceâorâhaveâUVâabsorptionsâthatâinterfereâwithâtheâscreenâreadout,âbutâprefraction-ationâofâextractsâcanâbeâusedâtoâalleviateâsomeâofâtheseâtypesâofâproblems.âAlso,âmostâhigh-throughputâscreeningâassayâmethodsâhaveâbeenâdevelopedâwithâcom-putationalâ filteringâ methodsâ toâ identifyâ andâ removeâ potentiallyâ problematicâcompoundsâthatâcanâgiveâfalse-positiveâresultsâ[145].
Inâtheâfuture,âtheâroutineâuseâofâNMRââhyphenatedââtechniquesâwillâallowâforâquickââdereplicationââ(aâprocessâofâeliminatingâknownâandâactiveâcompoundsâinâtheâplantâextractsâthatâhaveâbeenâstudiedâpreviously),âandâhigh-throughputâscreeningâwillâpermitâ theâ rapidâ identificationâofâ theâactiveâ compoundsâ [140].âForâexample,âduplicateâSPEâplatesâcanâbeâgeneratedâduringâtheâHPLCâsepara-tion,â withâ oneâ plateâ usedâ toâ prepareâ samplesâ forâ high-throughputâ screening,âwhileâtheâotherâplateâisâkeptâasâaâreference.âTheâstructure(s)âofâcompoundsâinâwellsâofâtheseâplatesâthatâshow(s)âactivityâcanâbeâdeterminedâbyâcap-NMRâandâMS,â andâ knownâ compoundsâ canâ beâ ruledâ outâ quicklyâ basedâ onâ theirâ NMRâspectroscopicâandâMSâ information.â Inâ instancesâwhereâ theâactiveâ compoundâhasâaânewâstructure,â furtherâ isolationâcanâbeâcarriedâoutâ fromâtheâplantâma-terial,â providedâ thereâ isâ enoughâ sample.â Alternatively,â theâ compoundâ canâ beâsynthesizedâforâfurtherâbioassay,âandâcombinatorialâchemistryâcanâbeâusedâtoâdesignânewâanalogsâbasedâonâtheâparentâmolecules.
Adequateâ andâ continuousâ suppliesâofâplant-derivedâ drugsâareâ essentialâ toâmeetâtheâmarketâdemand.âForâcompoundsâthatâareâuneconomicalâtoâsynthesize,âandâonlyâavailableâinâaâsmallâquantitiesâfromâplants,âtheâuseâofâplantâcellâculturesâisâanâalternativeâproductionâmethod.âPlantsâaccumulateâsecondaryâmetabolitesâatâspecificâdevelopmentalâstages,âandâbyâmanipulatingâtheâenvironmentalâcon-ditionsâandâmedium,âmanyânaturalâproductsâhaveâbeenâsynthesizedâinâcellâcul-turesâinâlargerâpercentageâyieldsâthanâthoseâevidentâinâwholeâplantsâ[146,â147].âPaclitaxelâ(1)âhasâbeenâproducedâsuccessfullyâbyâplantâcellâfermentationâ(PCF)âtechnology,âand,âasâmentionedâearlier,âtheâsupplyâofâtheâimportantâanticancerâdrug,âpaclitaxel,âbyâitsâmanufacturer,âBristol-MyersâSquibb,âisânowâobtainedâbyâPCFâtechnologyâ[148â150].âOtherâplant-derivedâcompoundsâthatâcanâcurrentlyâbeâproducedâbyâcellâculturesâincludeâtheâCatharanthus alkaloidsâ[151],âdiosgeninâfromâDioscoreaâ[152],âandâthe Panax ginseng ginsenosidesâ[153].
Inâ conclusion,â plantsâ haveâ providedâ humansâ withâ manyâ ofâ theirâ essentialâneeds,âincludingâlife-savingâpharmaceuticalâagents.âInâtheâlastâ6âyears,âfiveânewâ
A.A.âSalim,âY.-W.âChinâandâA.D.âKinghorn20
plant-derivedâdrugsâhaveâbeenâlaunchedâontoâtheâmarket,âandâmanyâmoreâareâcurrentlyâundergoingâclinicalâtrials.âAsâaâvastâproportionâofâtheâavailableâhigherâplantâ speciesâ haveâ notâ yetâ beenâ screenedâ forâ biologicallyâ activeâ compounds,âdrugâdiscoveryâfromâplantsâshouldâremainâanâessentialâcomponentâinâtheâsearchâforânewâmedicines,âparticularlyâwithâ theâdevelopmentâofâhighlyâsensitiveâandâversatileâanalyticalâmethods.
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