Phytochemistry and Medicinal Plants

Phytochemistry and medicinal plants

J. David Phillipson *

Centre for Pharmacognosy, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK

Received 14 July 2000; received in revised form 1 August 2000

Abstract

A truncated history of the contribution of plants to medicine is given with reference to some of the less well known ancestors of

the Harborne family. Six of the top 20 prescriptions dispensed in 1996 were natural products and the clinical use of drugs such asartemisinin, etoposide and taxol has once more focussed attention on plants as sources of novel drug entities. High through-putrobotic screens have been developed by industry and it is possible to carry out 50,000 tests per day in the search for compounds

which have speci®city of action against a key enzyme or a subset of receptors. Bioassay-guided fractionation of plant extracts linkedto chromatographic separation techniques leads to the isolation of biologically active molecules whose chemical structures canreadily be determined by modern spectroscopic methods. The role of academics in the search for new drugs is discussed by reference

to some of our research into natural products with activity on the central nervous system, on pain receptors, the malaria parasitePlasmodium falciparum, the wound healing properties of the sap of species of Croton (Dragon's blood), and a traditional Chinesemedicine used to treat eczema. Expertise in phytochemistry has been essential for this research and the strong lead shown by Pro-

fessor Je�rey Harborne is gratefully acknowledged. # 2001 Published by Elsevier Science Ltd.

Keywords: J.B. Harborne; Medicinal plants; Phytochemistry; Academics; New drugs; Central nervous system; Eczema; Malaria; Pain; Wound

healing

1. Introduction

The use of plants as medicines goes back to earlyman. Certainly the great civilisations of the ancientChinese, Indians, and North Africans provided writtenevidence of man's ingenuity in utilising plants for thetreatment of a wide variety of diseases. In ancientGreece, for example, scholars classi®ed plants and gavedescriptions of them thus aiding the identi®cation pro-cess. Theophrastus has been described by some as thefather of botany (Fig. 1) but little, if anything, has beenrecorded on his distant relative J.B. Theophrastus1 whoextolled the virtues of medicinal plants and forecast thepossibility of discovering ¯avonoids. As Europe enteredthe dark ages much of this information would have beenlost had it not been for the monasteries that acted ascentres for the production of medicinal plants whichwere used to heal the su�ering of mankind. There is stillmuch we can learn from investigating the old herbals,

particularly those less well known such as the oneattributed to the monk J.B. Harbonus1.It was not until the 19th century that man began to

isolate the active principles of medicinal plants and oneparticular landmark was the discovery of quinine fromCinchona bark by the French scientists Caventou andPelletier (Fig. 2). Much less is known about the isolationof quinine by J.B. Caventou1 and J.B. Pelletier1. Suchdiscoveries led to an interest in plants from the NewWorld and expeditions scoured the almost impenetrablejungles and forests in the quest for newmedicines (Fig. 3).One of the lesser known intrepid explorers was J.B. vanHarbon1 who was never happier than when he was ableto hatchet his way through the jungle stripping o� thebarks from every tree in sight. Such expeditions wouldlast for years and it was not until the plants arrived at awell equipped phytochemical laboratory that the realdiscoveries could be made (Fig. 4). Laboratories such asthose of Professor J.B. de Harbonney1 became centresfor the isolation of the active principles of medicinalplants from around the globe. Years of toil would berewarded by the isolation of numerous ¯avonoids whichwere welcomed by the cognoscenti as well as the rapidlyexpanding pharmaceutical companies.

0031-9422/01/$ - see front matter # 2001 Published by Elsevier Science Ltd.

PI I : S0031-9422(00 )00456-8

Phytochemistry 56 (2001) 237±243

www.elsevier.com/locate/phytochem

* Tel.: +44-207-753-5800; fax +44-207-753-5909.

E-mail address: [email protected] The lecture presented made reference to imaginary forefathers of

Je�rey B. Harbone.

2. New drugs from nature

Prior to World War 2, a series of natural productsisolated from higher plants became clinical agents and anumber are still in use today. Quinine from Cinchona

bark, morphine and codeine from the latex of the opiumpoppy, digoxin from Digitalis leaves, atropine (derivedfrom (ÿ)-hyoscyamine) and hyoscine from species ofthe Solanaceae continue to be in clinical use. The anti-biotic era dawned during and after World War 2 due to

Fig. 1. Theophrastus Ð father of botany.

Fig. 2. First of the alkaloid chemists; Caventou, Pelletier and Quinine.

238 J.D. Phillipson / Phytochemistry 56 (2001) 237±243

the antibacterial e�ects of a whole series of naturalproducts isolated from species of Penicillium, Cephalos-porium, and Streptomyces. In the post-war years therewere relatively few discoveries of new drugs from higher

plants with the notable exception of reserpine from theRauwol®a species heralding the age of the tranquillisersand also vinblastine and vincristine from Catharanthusroseus which were e�ective in cancer chemotherapy.

Fig. 3. Wresting the Jungle's secrets.

Fig. 4. The development of chemotherapy.

J.D. Phillipson / Phytochemistry 56 (2001) 237±243 239

Despite these discoveries the impact of phytochem-istry on new drug development waned and inevitablythe innovative pharmaceutical industry turned to syn-thetic chemicals. Successful clinical agents emergedfrom multidisciplinary research teams in which phar-macologists and synthetic chemists collaborated, e.g.atenolol (beta-blocker) and captopril (ACE-inhibitor) fortreatment of hypertension, salbutamol (adrenoceptorstimulant) for asthma and the benzodiazepines (hyp-notics and anxiolytics) for insomnia and anxiety attacks.During recent years, the attention of the pharmaceu-

tical industry has switched once more to the naturalworld and this may be illustrated by reference to threeclinical drugs, taxol, etoposide and artemisinin (Phillip-son, 1999a). Taxol is obtained from the bark of theWestern Paci®c Yew, Taxus brevifolia. The isolationand structure determination of taxol followed on fromexperiments that showed that a crude extract was activeagainst cancer cells in laboratory tests. Although thisactivity was discovered in the early 1960's, it was notuntil 1971 that the structure elucidation of this complexditerpene was determined. In 1979 it was reported thatthe 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 and its semisynthetic derivativetaxotere were shown to be clinically e�ective againstbreast and ovarian cancers. The long period for thedevelopment of taxol as a clinical agent, its di�culty inprocurement as a natural product and the complexity ofits chemical structure all attest to the di�culties facedby the pharmaceutical industry in developing clinicalagents from natural sources.The resin podophyllin obtained from the root of the

mayapple, Podophyllum peltatum, is toxic and is usedclinically to remove warts. The major constituent of theresin is the lignan podophyllotoxin which inhibits celldivision. Because of its toxic properties it would seem tobe not worthwhile pursuing any medicinal activitieseven though its e�ects on cell division would indicatepotential use in cancer chemotherapy. However, a semi-synthetic modi®ed glucoside, etoposide, which has adi�erent mode of action inhibiting topoisomerase II,has found clinical application in the treatment of lungand testicular cancers.Artemisinin is an unusual sesquiterpene endoperoxide

that has been isolated as the active principle of theChinese antimalarial herb Artemisia annua. Clinicaltrials have demonstrated that artemisinin is an e�ectiveantimalarial and can be used to treat infections of multi-drug resistant strains of Plasmodium falciparum the causeof human malignant cerebral malaria. Semi-syntheticderivatives including artemether (the methyl ether ofdihydroartemisinin) have improved pharmacokineticproperties and are also of current clinical use. The activemoiety of artemisinin is 1,2,4-trioxane and a series of

synthetic analogues show remarkable activity againstPlasmodium species in vitro and in vivo. Whether or notthese will prove to be e�ective clinical agents or will leadto new clinical drugs is a matter for future research.The prospect of new drugs and medicines from plant

sources is discussed further with reference to some ofour research investigations (Phillipson, 1995, 1999a,b).

3. Will further new drugs be developed from naturalproduct research?

The clinical applications of taxol, etoposide and arte-misinin have helped to revive an interest in higher plantsas sources of new drugs (Phillipson, 1999a). Despite thebelief that the majority of clinical drugs are synthetic inorigin, it is interesting to note that 6 out of the top 20pharmaceutical prescription drugs dispensed in 1996were natural products and that over 50% of the top 20drugs could be linked to natural product research. Inrecent years the development of sensitive biologicaltesting systems, mainly by industry, has led to the pro-cedure of high through-put screening. Such screens arecarried out robotically and it is possible for a pharma-ceutical or biotechnological company to run 50,000biological tests per day. The test screens are based onspeci®c enzymes within an animal or microbial biosyn-thetic pathway or on receptors or subsets of receptors.New screens are continually being introduced and bat-teries of compounds, synthetic and natural, are tested asscreens come on line. Hence, banks of compounds orextracts are needed for industrial biological tests. It isestimated that there are some 250,000 species of higherplants and the majority of these have not been examinedin detail for their pharmacological activities. Speci®cplants may have been subjected to particular tests, e.g.for cardiac activity, but they have not been examinedfor any other type of activity. The major screens forbiological activities of plant extracts have been carriedout in the search for new anticancer, antiviral and anti-fertility drugs. The development of the rapid screeningtests now in use in industry has meant that many moreplants can be evaluated for a wide range of biologicalactivities. Unfortunately the results of such tests do notnecessarily reach the public domain and are kept inlocked industrial ®les.There still remains an urgent need to develop new

clinical drugs and this can be exempli®ed by thenumerous diseases which result from the malfunction ofthe central nervous system (CNS), e.g. Alzheimers andParkinsons disease, epilepsy, migraine, pain, schizo-phrenia, sleeping disorders. Natural products alreadyhave a proven track record for CNS activities, e.g. caf-feine, codeine, morphine, nicotine, reserpine and it ispossible that there are further such drugs still to befound from nature (Phillipson, 1999b).


With this in mind, we collaborated with two majorinternational pharmaceutical companies, Glaxo (nowGlaxo±Wellcome) and P®zer. In one investigation, some10 Chinese plants were assessed for their activities against18 radioligand-receptor binding assays which are impli-cated with CNS. The other investigation was concernedwith 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 in the biological screens for theselected group of plants (Phillipson, 1999b).

4. Malaria

In 1996 it was reported that there were between 1.5and 2.7 million deaths annually and that the majority ofthese were children. There are in the order of 500 mil-lion new incidences of malaria annually. It is withoutdoubt one of the major threats to mankind and chemo-therapy is hindered by the increase in drug resistantstrains, particularly of Plasmodium falciparum. In themid 1980's we posed the question `` Are new anti-malarial drugs awaiting discovery from plants?'' Qui-nine, the ®rst e�ective antimalarial drug is still inclinical use and the more recently discovered artemisininhas proved to be an incentive for further research intoplants. The only major scienti®c paper of antimalarialtesting of plant extracts by the mid 1980's dated back to1947 when it was reported that some 600 species ofhigher plant representing some 126 families had beentested against avian malarias. Several plants were activebut the research pointed to two particular plant famil-ies, Simaroubaceae and Amaryllidaceae which hadnumerous active species. It is pertinent to ask why ittook 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. Avian malarias were used because they werethe only tests for activity against Plasmodium speciesapart from those using monkeys. The avian tests whichused live chickens and ducklings were notoriously di�-cult to carry out and were not thought to be necessarilypredictive of activity against Plasmodium species whicha�ected humans. These tests were not suitable forbioassay-guided fractionation of plant extracts. Fur-thermore, the chemical techniques available were alsonot suitable for this type of research. In the 1940's and1950's there were not the sophisticated chromatographicseparation techniques which are available today. Even ifan active principle were isolated there were none of thespectroscopic techniques available for structure deter-mination such as nuclear magnetic resonance spectro-

scopy, mass spectrometry or X-ray crystallography. Bythe mid 1980's not only were these chemical techniquesavailable but also it was possible to test for activityagainst P. falciparum in vitro and there was a reliabletest in mice against P. berghei (Phillipson, 1995).Following the lead from the 1947 paper, we tested

activities of 5 species of Simaroubaceae against P. falci-parum in vitro and utilised bioassay-guided fractiona-tion techniques to isolate a series of active terpenoids(quassinoids). Some 40 quassinoids became available forstructure±activity studies and this led to the preparationof semi-synthetic and synthetic analogues. Despite con-siderable research e�ort, no new clinical drug was devel-oped from this work. Investigation of a range of plantsused in traditional medicine for the treatment of malarialed to the isolation of a series of other compounds withactivity against P. falciparum including isoquinoline andindole alkaloids, ¯avonoids, mono-, di- and sesquiterpe-noids. These results provided some scienti®c evidencewhich helped towards the justi®cation of claims for theuse of a number of traditional medicines and they alsoprovided template molecules for synthetic approachesto new antimalarial drugs. Widening the range of bio-logical tests to include other species of protozoademonstrated activity of natural products against othertropical diseases which a�ect mankind, e.g. trypanoso-miasis and leishmaniasis (Phillipson, 1995 and 1999a).

5. Do traditional medicines necessarily contain a singleactive ingredient?

The isolation and use of natural products such asdigoxin, morphine and quinine has resulted in replacingthe plant extracts used with single chemical entities.There is a basic supposition that any plant possessingclinical e�ectiveness must contain an active principlewhich can completely replace the plant extract. Threeexamples from our research have shown that this maynot necessarily be true (Phillipson, 1995).Artemisinin is without doubt the potent antimalarial

active 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. falciparumin vitro. Whether these ®ndings have clinical relevancehas not been determined but they do lend support to theview that there may be some advantages to the medicaluse of extracts as opposed to isolated single entities.Dragon's blood is a term used for the blood red sap

obtained from the bark of a number of S. AmericanCroton species which are used for the treatmentof wounds. The major constituents of the sap are poly-meric anthocyanidins which co-occur with many minorconstituents including diterpenes and simple phenols.Chemical and biological investigation of the properties


of Dragon's blood led us to conclude that there is notone single wound healing principle. When the sap isused to cover a wound it forms a protective occlusivelayer whilst some of the simple phenols act as potentantimicrobial agents and other compounds exert anti-in¯ammatory e�ects.In the 1980's it was noted by clinical dermatologists at

Great Ormond Street Hospital for Sick Children inLondon that some of their young patients with severeatopic eczema were showing signs of improvement intheir disease state. These improvements were not due tohospital therapy but to the co-administration of a tra-ditional Chinese medicine (TCM). The patients hadvisited a TCM practitioner in central London and hadbeen prescribed a multi-herbal prescription from whichan aqueous extract was prepared for oral use. In 1992, itwas reported that a double blind placebo controlledclinical trial of a ten herb mixture for oral use in chil-dren with non-exudative eczema con®rmed substantialclinical bene®t as assessed by currently accepted Wes-tern orthodox medical practitioners. Our scienti®cinvestigations utilising an anti-in¯ammatory/analgesictest with mice showed that four of the ten herbs pos-sessed signi®cant activity in the mice but they proved tobe inactive clinically in children. After some consider-able investigation we concluded that not only was thereno single active ingredient but also that it required allten herbs to be present for clinical e�ectiveness. Thereare more than 12 di�erent biological activities from theherbs in this TCM prescription including anti-in¯am-matory, immuno-modulatory, anti-allergic, sedative andanti-pruritic. The chemical composition of the 10 herbsis a complex mixture of natural product molecules.

6. Conclusions

Plants continue to be used world-wide for the treat-ment of disease and novel drug entities continue to bedeveloped through research into their constituents. Inthe developed countries, high-throughput screening testsare used for bioassay-guided fractionation leading tothe isolation of active principles that may be developedinto clinical agents either as the natural product or asynthetic modi®cation or a synthesised analogue withenhanced clinical action or reduced adverse side e�ects.Despite the massive arsenal of clinical agents developedby the pharmaceutical industry there has been an aver-sion by many members of the public and herbal reme-dies have proved to be popular as alternative orcomplementary treatments of disease. There is a need toevaluate herbal treatments by clinical trials using cur-rently accepted protocols. In the developing countrieslarge numbers of the World's population are unable toa�ord pharmaceutical drugs and they continue to usetheir own systems of indigenous medicine that are

mainly plant based. There is a great need to harnessscienti®c and clinical research in order to investigate thequality, safety and e�cacy of these herbal therapies.The aim of the pharmaceutical industry is to develop

novel drug entities for the treatment of disease. Suchdrugs require speci®city of action and are, for e.g. aimedat a particular subset of receptor. Although natural pro-ducts continue to supply banks of compounds for newscreens, the focus of industry is currently on combina-torial synthesis for new drug development. It must not beforgotten that natural products which result from mil-lennia of biosynthetic pathways modi®ed by evolutionhave a well established track record as medicinal agentsand present a wide range of structural diversity. Drugdevelopment through natural product research is notwithout its problems and there is, for e.g. a need toeliminate common natural products such as saponins,tannins, etc. from plant extracts prior to testing by bio-logical screening procedures. Academics can play a use-ful role in this area of research. They cannot matchindustry in the wide range of screens but they can useselective targets and collaborate with industry. This typeof research needs a multi-disciplinary approach and thisincludes expertise in phytochemistry.It is a pleasure and an honour to present this lecture

and to acknowledge the lead which Professor Je�reyHarborne has given to Phytochemistry over so manyyears. I am one of those who owe a great debt to himand to the example which he has set. My own speciali-sation of Pharmacognosy was virtually wiped out fromPharmacy undergraduate curricula and for many yearshas been considered to be an outmoded area ofresearch. Techniques in Phytochemistry have revolutio-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 Je�rey Harborne we havebeen able to publish research articles in Phytochemistryand to continue working on the wealth of chemicaldiversity that exists in the plant kingdom.

Acknowledgements

I am grateful to Parke, Davis and Company for per-mission to reproduce the ®gures from the book GreatMoments in Pharmacy by G.A. Bender, Detroit, North-wood Institute Press, 2nd Edition, 1967.

References

Phillipson, J.D., 1995. A matter of some sensitivity. Phytochemistry

38, 1319±1343.

Phillipson, J.D., 1999a. New drugs from nature Ð it could be yew.

Phytotherapy Research 13, 2±8.

Phillipson, J.D., 1999b. Radioligand-receptor binding assays in the

search for bioactive principles from plants. J. Pharm. Pharmacol.

51, 493±503.


David Phillipson is Emeritus Professor

of Pharmacognosy at the Centre for

Pharmacognosy and Phytotherapy at

The School of Pharmacy, The Uni-

versity of London. He was formerly

Professor and Head of Department of

Pharmacognosy at The School before

retiring in 1994. In 1995, he was

appointed for 6 months at The Chi-

nese University of Hong Kong as

Wilson T.S. Wang Distinguished

International Visiting Professor. He is

an Honorary Professor at the Chinese

Academy of Medical Sciences, Insti-

tute of Medicinal Plant Development, Beijing. For many years, he has

been an active member of the Phytochemical Society of Europe and

between 1977 to 1988 he held o�ces of Secretary, Vice-Chairman and

Chairman. His research interests include the chemistry and biological

activities of plants used in traditional medicine. He has received

awards from the Phytochemical Society of Europe including the Tate

and Lyle Award (1992), Medal (1994) and Pergamon Prize for

creativity in plant biochemistry (1996). In 1989, he and four other

European scientists in collaboration with Professor Meinhart Zenk

(then of the University of Munich) were awarded the Korber Foun-

dation Prize for achievement in European Science. The Pharma-

ceutical Society of Great Britain presented him with their Harrison

Memorial medal in 1999.


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Phytochemistry and Medicinal Plants