Phytochemistry and medicinal plantsJ. David Phillipson *Centre
for Pharmacognosy, The School of Pharmacy, University of London,
29-39 Brunswick Square, London WC1N 1AX,
UKReceived14July2000;receivedinrevisedform1August2000AbstractA
truncated history of the contribution of plants to medicine is
given with reference to some of the lesswell known ancestors
oftheHarbornefamily.Sixofthetop20prescriptionsdispensedin1996werenaturalproductsandtheclinicaluseofdrugssuchasartemisinin,
etoposideandtaxol
hasoncemorefocussedattentiononplantsassourcesofnovel drugentities.
Highthrough-putroboticscreenshavebeendevelopedbyindustryanditispossibletocarryout50,000testsperdayinthesearchforcompoundswhich
have specicity of action against a key enzyme or a subset of
receptors. Bioassay-guided fractionation of plant extracts
linkedtochromatographicseparationtechniquesleadstotheisolationof
biologicallyactivemoleculeswhosechemical structurescanreadily be
determined by modern spectroscopic methods. The role of academics
in the search for new drugs is discussed by
referencetosomeofourresearchintonaturalproductswithactivityonthecentralnervoussystem,onpainreceptors,themalariaparasitePlasmodiumfalciparum,thewoundhealingpropertiesofthesapofspeciesofCroton(Dragon'sblood),andatraditionalChinesemedicineusedtotreateczema.ExpertiseinphytochemistryhasbeenessentialforthisresearchandthestrongleadshownbyPro-fessor
Jerey Harborne isgratefully acknowledged. #2001 Published by
Elsevier Science Ltd.Keywords: J.B. Harborne; Medicinal plants;
Phytochemistry; Academics; Newdrugs; Central nervous system;
Eczema; Malaria; Pain; Woundhealing1. IntroductionThe use of plants
as medicines goes backtoearlyman. Certainly the great civilisations
of the ancientChinese, Indians,
andNorthAfricansprovidedwrittenevidenceof man's
ingenuityinutilisingplants for thetreatment of a wide variety of
diseases. In
ancientGreece,forexample,scholarsclassiedplantsandgavedescriptionsofthemthusaidingtheidenticationpro-cess.
Theophrastushasbeendescribedbysomeasthefather of botany (Fig. 1)
but little, if anything, has beenrecordedonhisdistant
relativeJ.B.Theophrastus1whoextolledthevirtuesofmedicinalplantsandforecastthepossibility
of discovering avonoids. As Europe enteredthe dark ages much of
this information would have beenlost hadit not beenfor
themonasteries that actedascentres for the productionof medicinal
plants whichwere used to heal the suering of mankind. There is
stillmuchwecanlearnfrominvestigatingtheoldherbals,particularly
those less well known such as the oneattributed to the monk J.B.
Harbonus1.It wasnot until the19thcenturythat
manbegantoisolatetheactiveprinciplesofmedicinalplants and
oneparticularlandmarkwasthediscoveryofquininefromCinchonabarkbytheFrenchscientists
CaventouandPelletier (Fig. 2). Much less is known about the
isolationof quininebyJ.B. Caventou1andJ.B. Pelletier1.
Suchdiscoveries ledtoaninterest inplants fromthe NewWorld and
expeditions scoured the almost impenetrablejungles and forests in
the quest for newmedicines (Fig. 3).Oneof the lesserknownintrepid
explorerswas J.B. vanHarbon1who was never happier than when he was
abletohatchethiswaythroughthejunglestrippingothebarksfromeverytreeinsight.
Suchexpeditionswouldlast for years and it was not until the plants
arrived at awell equippedphytochemical laboratory that the
realdiscoveries could be made (Fig. 4). Laboratories such asthoseof
ProfessorJ.B. deHarbonney1becamecentresfor the isolationof the
active principles of medicinalplants fromaroundtheglobe. Years of
toil wouldberewarded by the isolation of numerous avonoids
whichwere welcomed by the cognoscenti as well as the
rapidlyexpanding
pharmaceuticalcompanies.0031-9422/01/$-seefrontmatter #
2001PublishedbyElsevierScienceLtd.PI I : S0031- 9422( 00) 00456-
8Phytochemistry56(2001)237243www.elsevier.com/locate/phytochem*
Tel.: +44-207-753-5800; fax +44-207-753-5909.E-mail address:
profjdp@msn.com1ThelecturepresentedmadereferencetoimaginaryforefathersofJerey
B. Harbone.2. Newdrugs fromnaturePrior toWorldWar 2, aseries of
natural productsisolated from higher plants became clinical agents
and anumber arestill inusetoday. QuininefromCinchonabark, morphine
and codeine from the latex of the opiumpoppy,
digoxinfromDigitalisleaves, atropine(derivedfrom()-hyoscyamine)
andhyoscine fromspecies oftheSolanaceaecontinuetobeinclinical use.
Theanti-biotic era dawned during and after World War 2 due toFig.
1. Theophrastus father of botany.Fig. 2. First of the alkaloid
chemists; Caventou, Pelletier and Quinine.238 J.D. Phillipson /
Phytochemistry 56 (2001) 237243the antibacterial eects of a whole
series of
naturalproductsisolatedfromspeciesofPenicillium,Cephalos-porium,
andStreptomyces. Inthepost-waryearstherewere relatively few
discoveries of new drugs from
higherplantswiththenotableexceptionofreserpinefromtheRauwolaspeciesheraldingtheageofthetranquillisersandalsovinblastineandvincristinefromCatharanthusroseus
which were eective in cancer chemotherapy.Fig. 3. Wresting the
Jungle's secrets.Fig. 4. The development of chemotherapy.J.D.
Phillipson / Phytochemistry 56 (2001) 237243 239Despite these
discoveries the impact of phytochem-istryonnewdrugdevelopment
wanedandinevitablytheinnovativepharmaceutical
industryturnedtosyn-thetic chemicals. Successful clinical agents
emergedfrommultidisciplinary researchteams inwhichphar-macologists
and synthetic chemists collaborated, e.g.atenolol (beta-blocker)
and captopril (ACE-inhibitor) fortreatment of hypertension,
salbutamol (adrenoceptorstimulant) for asthma andthe
benzodiazepines (hyp-notics and anxiolytics) for insomnia and
anxiety attacks.Duringrecentyears,theattentionofthepharmaceu-tical
industry has switchedonce more tothe
naturalworldandthismaybeillustratedbyreferencetothreeclinicaldrugs,taxol,etoposideandartemisinin(Phillip-son,
1999a). Taxol is obtainedfromthe barkof theWestern Pacic Yew, Taxus
brevifolia. The isolationandstructuredeterminationoftaxol
followedonfromexperiments that showed that a crude extract was
activeagainst cancer cells inlaboratorytests.
Althoughthisactivitywas discoveredintheearly1960's, it was notuntil
1971 thatthe structureelucidation of this
complexditerpenewasdetermined. In1979itwasreportedthatthe mode of
action was through promotion of theassembly of tubulin into
microtubules. Clinical trials didnot take place until the early
1980's and it was not untilthe 1990's that taxol andits
semisynthetic derivativetaxotere were showntobe clinically eective
againstbreast and ovarian cancers. The long period for
thedevelopmentoftaxolasaclinicalagent,itsdicultyinprocurement as a
natural product and the complexity ofitschemical structureall
attest tothedicultiesfacedby the pharmaceutical industry
indeveloping clinicalagents fromnatural
sources.Theresinpodophyllinobtainedfromtherootofthemayapple,
Podophyllumpeltatum, is toxic andis usedclinically to removewarts.
Themajorconstituentof theresinis
thelignanpodophyllotoxinwhichinhibits celldivision. Because of its
toxic properties it would seem tobe not worthwhile pursuing any
medicinal activitieseventhoughits eects oncell
divisionwouldindicatepotential use in cancer chemotherapy. However,
a semi-synthetic modied glucoside, etoposide, which has adierent
mode of action inhibiting topoisomerase II,hasfoundclinical
applicationinthetreatment of lungand testicular cancers.Artemisinin
is an unusual sesquiterpene endoperoxidethat has been isolated as
the active principle of theChinese antimalarial herb Artemisia
annua.
Clinicaltrialshavedemonstratedthatartemisininisaneectiveantimalarial
and can be used to treat infections of multi-drug resistant strains
of Plasmodium falciparumthe causeof human malignant cerebral
malaria. Semi-syntheticderivatives including artemether (the methyl
ether ofdihydroartemisinin) have improved pharmacokineticproperties
and are also of current clinical use. The activemoietyof
artemisininis 1,2,4-trioxaneandaseries ofsynthetic analogues
showremarkable activity againstPlasmodium species in vitro and in
vivo. Whether or notthese will prove to be eective clinical agents
or will leadto new clinical drugsis a matterfor future
research.Theprospectofnewdrugsandmedicinesfromplantsources is
discussedfurther withreferencetosomeofour research investigations
(Phillipson,1995,1999a,b).3. Will further newdrugs
bedevelopedfromnaturalproduct
research?Theclinicalapplicationsoftaxol,etoposideandarte-misinin
have helped to revive an interest in higher plantsas sourcesof
newdrugs(Phillipson,1999a).Despitethebelief thatthemajorityof
clinicaldrugs are syntheticinorigin,
itisinterestingtonotethat6outofthetop20pharmaceutical prescription
drugs dispensed in
1996werenaturalproductsandthatover50%ofthetop20drugs
couldbelinkedtonatural product research. Inrecent years the
development of sensitive
biologicaltestingsystems,mainlybyindustry,hasledtothepro-cedureofhighthrough-putscreening.
Suchscreensarecarriedoutroboticallyanditispossibleforapharma-ceutical
or biotechnological company to run 50,000biological testsperday.
Thetest screensarebasedonspecicenzymeswithinananimal ormicrobial
biosyn-theticpathwayoronreceptorsorsubsetsofreceptors.Newscreensarecontinuallybeingintroducedandbat-teries
of compounds, synthetic and natural, are tested asscreens
comeonline. Hence, banks of compounds
orextractsareneededforindustrial biological tests. It
isestimatedthattherearesome250,000speciesofhigherplants and the
majority of these have not been examinedin detail for their
pharmacological activities.
Specicplantsmayhavebeensubjectedtoparticulartests, e.g.for
cardiacactivity, but theyhavenot beenexaminedfor anyother type of
activity. The major screens forbiological activitiesofplant
extractshavebeencarriedoutinthesearchfornewanticancer,antiviralandanti-fertilitydrugs.
Thedevelopmentoftherapidscreeningtestsnowinuseinindustryhasmeantthatmanymoreplantscanbeevaluatedforawiderangeof
biologicalactivities.Unfortunatelytheresultsofsuchtestsdonotnecessarily
reach the public domain and are kept inlockedindustrial les.There
still remains anurgent needtodevelopnewclinical drugs and this can
be exemplied by thenumerous diseases which result from the
malfunction ofthecentral nervoussystem(CNS), e.g.
AlzheimersandParkinsons disease, epilepsy, migraine, pain,
schizo-phrenia, sleeping disorders. Natural products
alreadyhaveaproventrackrecordforCNSactivities, e.g.caf-feine,
codeine, morphine, nicotine, reserpine andit ispossible that there
are further suchdrugs still tobefound fromnature
(Phillipson,1999b).240 J.D. Phillipson / Phytochemistry 56 (2001)
237243Withthis inmind, we collaboratedwithtwomajorinternational
pharmaceutical companies, Glaxo (nowGlaxoWellcome) and Pzer. In one
investigation, some10 Chinese plants were assessed for their
activities
against18radioligand-receptorbindingassayswhichareimpli-catedwithCNS.Theotherinvestigationwasconcernedwith
pain and some 600 species of plant were tested. Thepain receptors
used were bradykinin II, neurokinin I, anda calcitonin gene related
peptide. Half of the plants wereselected from the ethnobotanical
literature as being usedfor the treatment of pain and the other
half were from arandom sample. The results showed that there were
morepositive hits for activity
inthebiologicalscreensfortheselectedgroup of plants
(Phillipson,1999b).4. MalariaIn1996it wasreportedthat
therewerebetween1.5and 2.7 million deaths annually and that the
majority ofthesewerechildren.
Thereareintheorderof500mil-lionnewincidences of malariaannually. It
is withoutdoubtoneofthemajorthreatstomankindandchemo-therapy is
hindered by the increase indrug resistantstrains, particularlyof
Plasmodiumfalciparum. Inthemid 1980's we posed the question `` Are
newanti-malarial drugs awaitingdiscoveryfromplants?'' Qui-nine, the
rst eective antimalarial drug is still inclinical use and the more
recently discovered
artemisininhasprovedtobeanincentiveforfurtherresearchintoplants.
Theonlymajorscienticpaperof antimalarialtesting of plant extracts
by the mid 1980's dated back to1947 when it was reportedthat some
600 species ofhigher plant representingsome 126families
hadbeentested against avian malarias. Several plants were
activebuttheresearchpointedtotwoparticularplantfamil-ies,
Simaroubaceae and Amaryllidaceae which hadnumerous active species.
It is pertinent toaskwhyittook more than 30 years for this research
to be followedthrough. The answer probably lies in the
techniqueswhich were available for carrying out this type
ofresearch. Avianmalarias wereusedbecausetheywerethe onlytests for
activityagainst
Plasmodiumspeciesapartfromthoseusingmonkeys.Theaviantestswhichusedlivechickensandducklingswerenotoriouslydi-cult
to carry out and were not thought to be
necessarilypredictiveofactivityagainstPlasmodiumspecieswhichaected
humans. These tests were not suitable forbioassay-guided
fractionation of plant extracts. Fur-thermore, the chemical
techniques available
werealsonotsuitableforthistypeofresearch.Inthe1940'sand1950's there
were not the sophisticated chromatographicseparation techniques
which are available today. Even
ifanactiveprinciplewereisolatedtherewerenoneofthespectroscopic
techniques available for structure deter-minationsuchas nuclear
magneticresonancespectro-scopy,
massspectrometryorX-raycrystallography.Bythemid1980'snotonlywerethesechemicaltechniquesavailable
but alsoit was possible totest for activityagainst P.
falciparuminvitroandtherewas areliabletest in mice against P.
berghei (Phillipson,1995).Followingthe leadfromthe 1947paper, we
testedactivitiesof 5 speciesof SimaroubaceaeagainstP.
falci-paruminvitroandutilisedbioassay-guidedfractiona-tiontechniques
toisolateaseries of activeterpenoids(quassinoids). Some 40
quassinoids became available forstructureactivity studies and this
led to the
preparationofsemi-syntheticandsyntheticanalogues.Despitecon-siderable
research eort, no new clinical drug was
devel-opedfromthiswork.Investigationofarangeofplantsused in
traditional medicine for the treatment of
malarialedtotheisolationofaseriesofothercompoundswithactivity
against P. falciparum including isoquinoline andindole alkaloids,
avonoids, mono-, di- and sesquiterpe-noids. These results
providedsome scientic
evidencewhichhelpedtowardsthejusticationofclaimsfortheuseofanumberoftraditional
medicinesandtheyalsoprovidedtemplate molecules for synthetic
approachestonewantimalarial drugs. Wideningtherangeof bio-logical
tests to include other species of
protozoademonstratedactivityofnaturalproductsagainstothertropical
diseaseswhichaectmankind, e.g. trypanoso-miasis and leishmaniasis
(Phillipson,1995 and 1999a).5. Dotraditional medicines
necessarilycontainasingleactiveingredient?The isolation and use of
natural products such asdigoxin, morphine and quinine has resulted
in replacingthe plant extracts used with single chemical
entities.Thereisabasicsuppositionthat anyplant possessingclinical
eectiveness must contain an active
principlewhichcancompletelyreplacetheplant extract.
Threeexamplesfromourresearchhaveshownthat thismaynot necessarily be
true
(Phillipson,1995).Artemisininiswithoutdoubtthepotentantimalarialactive
principle of Artemisia annua. Crude extracts of A.artemisia contain
a plethora of other compoundsincluding a series of avonoids and
some of theseenhance the activity of artemisinin against P.
falciparuminvitro. Whetherthesendingshaveclinical relevancehas not
been determined but they do lend support to
theviewthattheremaybesomeadvantagestothemedicaluse of extracts as
opposed to isolated single
entities.Dragon'sbloodisatermusedforthebloodredsapobtainedfromthe
barkof anumber of S. AmericanCroton species which are used for the
treatmentofwounds.Themajorconstituentsofthesaparepoly-mericanthocyanidinswhichco-occurwithmanyminorconstituents
including diterpenes and simple phenols.Chemical andbiological
investigationofthepropertiesJ.D. Phillipson / Phytochemistry 56
(2001) 237243 241ofDragon'sbloodledustoconcludethatthereisnotone
single woundhealing principle. Whenthe sapisusedtocoverawoundit
formsaprotectiveocclusivelayer whilst someof thesimplephenols act
as potentantimicrobial agents andother compounds exert
anti-inammatory eects.In the 1980's it was noted by clinical
dermatologists atGreat Ormond Street Hospital for Sick Children
inLondonthat someof theiryoungpatientswithsevereatopic eczemawere
showingsigns of improvement intheir disease state. These
improvements were not due tohospital
therapybuttotheco-administrationofatra-ditional Chinese medicine
(TCM). The patients hadvisitedaTCMpractitionerincentral
Londonandhadbeenprescribedamulti-herbalprescriptionfromwhichan
aqueous extract was prepared for oral use. In 1992, itwas reported
that a double blind placebo controlledclinical trial
ofatenherbmixturefororal
useinchil-drenwithnon-exudativeeczemaconrmedsubstantialclinical
benet as assessedbycurrentlyacceptedWes-tern orthodox medical
practitioners. Our scienticinvestigations utilising an
anti-inammatory/analgesictest withmiceshowedthat four of
thetenherbs pos-sessed signicant activity in the mice but they
proved tobeinactiveclinicallyinchildren. After
someconsider-ableinvestigationweconcludedthatnotonlywastherenosingleactiveingredient
but alsothat it requiredalltenherbstobepresent forclinical
eectiveness.
Therearemorethan12dierentbiologicalactivitiesfromtheherbs inthis
TCMprescriptionincludinganti-inam-matory, immuno-modulatory,
anti-allergic, sedative
andanti-pruritic.Thechemicalcompositionofthe10herbsis a
complexmixtureof natural productmolecules.6.
ConclusionsPlantscontinuetobeusedworld-wideforthetreat-mentofdiseaseandnovel
drugentitiescontinuetobedevelopedthroughresearchintotheir
constituents. Inthe developed countries, high-throughput screening
testsare usedfor bioassay-guidedfractionationleading
totheisolationofactiveprinciplesthatmaybedevelopedintoclinical
agents either as thenatural product or asynthetic modicationor
asynthesisedanalogue
withenhancedclinicalactionorreducedadversesideeects.Despitethemassivearsenalofclinicalagentsdevelopedbythepharmaceuticalindustrytherehasbeenanaver-sionbymanymembersofthepublicandherbal
reme-dies have proved to be popular as alternative orcomplementary
treatments of disease. There is a need toevaluateherbal treatments
byclinical trials usingcur-rentlyacceptedprotocols.
InthedevelopingcountrieslargenumbersoftheWorld'spopulationareunabletoaordpharmaceutical
drugs andtheycontinuetousetheir own systems of indigenous medicine
that aremainlyplant based. There is agreat needtoharnessscientic
and clinical research in order to investigate thequality, safetyand
ecacyof these
herbaltherapies.Theaimofthepharmaceuticalindustryistodevelopnovel
drugentities for the treatment of disease. Suchdrugs require
specicity of action and are, for e.g. aimedat a particular subset
of receptor. Although natural
pro-ductscontinuetosupplybanksofcompoundsfornewscreens,
thefocusofindustryiscurrentlyoncombina-torial synthesis for new
drug development. It must not beforgottenthat natural
productswhichresult frommil-lenniaof
biosyntheticpathwaysmodiedbyevolutionhavea
wellestablishedtrackrecordas medicinalagentsandpresent awiderangeof
structural diversity. Drugdevelopment throughnatural product
researchis notwithout its problems andthere is, for e.g.
aneedtoeliminatecommonnatural products suchas
saponins,tannins,etc.fromplantextractspriortotestingbybio-logical
screening procedures.Academics canplaya use-ful role inthis area of
research. They cannot
matchindustryinthewiderangeofscreensbuttheycanuseselective targets
and collaborate with industry. This typeof research needs a
multi-disciplinary approach and thisincludesexpertise in
phytochemistry.Itisapleasureandanhonourtopresentthislectureandtoacknowledge
the leadwhichProfessor JereyHarborne has giventoPhytochemistryover
somanyyears.
Iamoneofthosewhooweagreatdebttohimandtotheexamplewhichhehasset.Myownspeciali-sationofPharmacognosywasvirtuallywipedoutfromPharmacyundergraduatecurriculaandformanyyearshas
been considered to be an outmoded area
ofresearch.TechniquesinPhytochemistryhaverevolutio-nised our
ability to investigate the medicinal agentspresent in plants and
this is acknowledged by theindustrial interest in plants over
recent years. Thanks tothe hard work and tenacity of Jerey Harborne
we havebeenabletopublishresearcharticlesinPhytochemistryand to
continue working on the wealth of chemicaldiversity that existsin
the plantkingdom.AcknowledgementsIamgrateful
toParke,DavisandCompanyforper-missiontoreproducethegures
fromthebookGreatMomentsinPharmacy byG.A.Bender,Detroit,
North-woodInstitute Press, 2nd Edition, 1967.ReferencesPhillipson,
J.D., 1995. Amatterof somesensitivity. Phytochemistry38,
13191343.Phillipson, J.D., 1999a. Newdrugsfromnatureit
couldbeyew.Phytotherapy Research 13, 28.Phillipson, J.D., 1999b.
Radioligand-receptor bindingassays inthesearchfor
bioactiveprinciples fromplants. J. Pharm. Pharmacol.51, 493503.242
J.D. Phillipson / Phytochemistry 56 (2001)
237243DavidPhillipsonisEmeritusProfessorof Pharmacognosy at the
Centre forPharmacognosyandPhytotherapyatThe School of Pharmacy, The
Uni-versity of London. He was
formerlyProfessorandHeadofDepartmentofPharmacognosyat TheSchool
beforeretiring in 1994. In 1995, he wasappointedfor 6months at The
Chi-nese University of Hong Kong asWilson T.S. Wang
DistinguishedInternationalVisitingProfessor.HeisanHonoraryProfessorattheChineseAcademy
of Medical Sciences, Insti-tute of Medicinal Plant Development,
Beijing. For many years, he hasbeenanactivememberofthePhytochemical
SocietyofEuropeandbetween 1977 to 1988 heheld oces of Secretary,
Vice-Chairman
andChairman.Hisresearchinterestsincludethechemistryandbiologicalactivities
of plants used in traditional medicine. He has
receivedawardsfromthePhytochemicalSocietyofEuropeincludingtheTateand
Lyle Award (1992), Medal (1994) and Pergamon Prize
forcreativityinplant biochemistry(1996). In1989, he andfour
otherEuropeanscientists incollaborationwithProfessor Meinhart
Zenk(thenoftheUniversityofMunich)wereawardedtheKorberFoun-dation
Prize for achievement in European Science. The Pharma-ceutical
Societyof Great Britainpresentedhimwiththeir HarrisonMemorial medal
in 1999.J.D. Phillipson / Phytochemistry 56 (2001) 237243 243