Phytochemistry 56 (2001) 237±243

www.elsevier.com/locate/phytochem

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 as
artemisinin, etoposide and taxol has once more focussed attention on plants as sources of novel drug entities. High through-put
robotic 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 linked
to chromatographic separation techniques leads to the isolation of biologically active molecules whose chemical structures can
readily 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 parasite
Plasmodium falciparum, the wound healing properties of the sap of species of Croton (Dragon's blood), and a traditional Chinese
medicine 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 particularly those less well known such as the one

The use of plants as medicines goes back to early
man. Certainly the great civilisations of the ancient
Chinese, Indians, and North Africans provided written
evidence of man's ingenuity in utilising plants for the
treatment of a wide variety of diseases. In ancient
Greece, for example, scholars classi®ed plants and gave
descriptions of them thus aiding the identi®cation pro-
cess. Theophrastus has been described by some as the
father of botany (Fig. 1) but little, if anything, has been
recorded on his distant relative J.B. Theophrastus1 who
extolled the virtues of medicinal plants and forecast the
possibility of discovering ¯avonoids. As Europe entered
the dark ages much of this information would have been
lost had it not been for the monasteries that acted as
centres for the production of medicinal plants which
were used to heal the su€ering of mankind. There is still
much we can learn from investigating the old herbals,
* Tel.: +44-207-753-5800; fax +44-207-753-5909.
E-mail address: profjdp@msn.com
1
The lecture presented made reference to imaginary forefathers of
Je€rey B. Harbone.
0031-9422/01/$ - see front matter # 2001 Published by Elsevier Science Ltd.
PII: S0031-9422(00)00456-8
attributed 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 one
particular landmark was the discovery of quinine from
Cinchona bark by the French scientists Caventou and
Pelletier (Fig. 2). Much less is known about the isolation
of quinine by J.B. Caventou1 and J.B. Pelletier1. Such
discoveries led to an interest in plants from the New
World and expeditions scoured the almost impenetrable
jungles and forests in the quest for new medicines (Fig. 3).
One of the lesser known intrepid explorers was J.B. van
Harbon1 who was never happier than when he was able
to hatchet his way through the jungle stripping o€ the
barks from every tree in sight. Such expeditions would
last for years and it was not until the plants arrived at a
well equipped phytochemical laboratory that the real
discoveries could be made (Fig. 4). Laboratories such as
those of Professor J.B. de Harbonney1 became centres
for the isolation of the active principles of medicinal
plants from around the globe. Years of toil would be
rewarded by the isolation of numerous ¯avonoids which
were welcomed by the cognoscenti as well as the rapidly
expanding pharmaceutical companies.
238 J.D. Phillipson / Phytochemistry 56 (2001) 237±243

Fig. 1. Theophrastus Ð father of botany.

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

2. New drugs from nature
Prior to World War 2, a series of natural products
isolated from higher plants became clinical agents and a
number are still in use today. Quinine from Cinchona
bark, morphine and codeine from the latex of the opium
poppy, digoxin from Digitalis leaves, atropine (derived
from (ÿ)-hyoscyamine) and hyoscine from species of
the Solanaceae continue to be in clinical use. The anti-
biotic era dawned during and after World War 2 due to
 J.D. Phillipson / Phytochemistry 56 (2001) 237±243 239

Fig. 3. Wresting the Jungle's secrets.

Fig. 4. The development of chemotherapy.

the antibacterial e€ects of a whole series of natural plants with the notable exception of reserpine from the
products isolated from species of Penicillium, Cephalos- Rauwol®a species heralding the age of the tranquillisers
porium, and Streptomyces. In the post-war years there and also vinblastine and vincristine from Catharanthus
were relatively few discoveries of new drugs from higher roseus which were e€ective in cancer chemotherapy.
240 J.D. Phillipson / Phytochemistry 56 (2001) 237±243
Despite these discoveries the impact of phytochem-
istry on new drug development waned and inevitably
the innovative pharmaceutical industry turned to syn-
thetic chemicals. Successful clinical agents emerged
from multidisciplinary research teams in which phar-
macologists and synthetic chemists collaborated, e.g.
atenolol (beta-blocker) and captopril (ACE-inhibitor) for
treatment of hypertension, salbutamol (adrenoceptor
stimulant) 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 natural
world and this may be illustrated by reference to three
clinical drugs, taxol, etoposide and artemisinin (Phillip-
son, 1999a). Taxol is obtained from the bark of the
Western Paci®c Yew, Taxus brevifolia. The isolation
and structure determination of taxol followed on from
experiments that showed that a crude extract was active
against cancer cells in laboratory tests. Although this
activity was discovered in the early 1960's, it was not
until 1971 that the structure elucidation of this complex
diterpene was determined. In 1979 it was reported that
the mode of action was through promotion of the
assembly of tubulin into microtubules. Clinical trials did
not take place until the early 1980's and it was not until
the 1990's that taxol and its semisynthetic derivative
taxotere were shown to be clinically e€ective against
breast and ovarian cancers. The long period for the
development of taxol as a clinical agent, its diculty in
procurement as a natural product and the complexity of
its chemical structure all attest to the diculties faced
by the pharmaceutical industry in developing clinical
agents from natural sources.
The resin podophyllin obtained from the root of the
mayapple, Podophyllum peltatum, is toxic and is used
clinically to remove warts. The major constituent of the
resin is the lignan podophyllotoxin which inhibits cell
division. Because of its toxic properties it would seem to
be not worthwhile pursuing any medicinal activities
even though its e€ects on cell division would indicate
potential use in cancer chemotherapy. However, a semi-
synthetic modi®ed glucoside, etoposide, which has a
di€erent mode of action inhibiting topoisomerase II,
has found clinical application in the treatment of lung
and testicular cancers.
Artemisinin is an unusual sesquiterpene endoperoxide
that has been isolated as the active principle of the
Chinese antimalarial herb Artemisia annua. Clinical
trials have demonstrated that artemisinin is an e€ective
antimalarial and can be used to treat infections of multi-
drug resistant strains of Plasmodium falciparum the cause
of human malignant cerebral malaria. Semi-synthetic
derivatives including artemether (the methyl ether of
dihydroartemisinin) have improved pharmacokinetic
properties and are also of current clinical use. The active
moiety of artemisinin is 1,2,4-trioxane and a series of
synthetic analogues show remarkable activity against
Plasmodium species in vitro and in vivo. Whether or not
these will prove to be e€ective clinical agents or will lead
to 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 of
our research investigations (Phillipson, 1995, 1999a,b).
3. Will further new drugs be developed from natural
product research?
The clinical applications of taxol, etoposide and arte-
misinin have helped to revive an interest in higher plants
as sources of new drugs (Phillipson, 1999a). Despite the
belief that the majority of clinical drugs are synthetic in
origin, it is interesting to note that 6 out of the top 20
pharmaceutical prescription drugs dispensed in 1996
were natural products and that over 50% of the top 20
drugs could be linked to natural product research. In
recent years the development of sensitive biological
testing systems, mainly by industry, has led to the pro-
cedure of high through-put screening. Such screens are
carried out robotically and it is possible for a pharma-
ceutical or biotechnological company to run 50,000
biological tests per day. The test screens are based on
speci®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 as
screens come on line. Hence, banks of compounds or
extracts are needed for industrial biological tests. It is
estimated that there are some 250,000 species of higher
plants and the majority of these have not been examined
in detail for their pharmacological activities. Speci®c
plants may have been subjected to particular tests, e.g.
for cardiac activity, but they have not been examined
for any other type of activity. The major screens for
biological activities of plant extracts have been carried
out in the search for new anticancer, antiviral and anti-
fertility drugs. The development of the rapid screening
tests now in use in industry has meant that many more
plants can be evaluated for a wide range of biological
activities. Unfortunately the results of such tests do not
necessarily reach the public domain and are kept in
locked industrial ®les.
There still remains an urgent need to develop new
clinical drugs and this can be exempli®ed by the
numerous diseases which result from the malfunction of
the central nervous system (CNS), e.g. Alzheimers and
Parkinsons disease, epilepsy, migraine, pain, schizo-
phrenia, sleeping disorders. Natural products already
have a proven track record for CNS activities, e.g. caf-
feine, codeine, morphine, nicotine, reserpine and it is
possible that there are further such drugs still to be
found from nature (Phillipson, 1999b).
 J.D. Phillipson / Phytochemistry 56 (2001) 237±243
With this in mind, we collaborated with two major
international pharmaceutical companies, Glaxo (now
Glaxo±Wellcome) and P®zer. In one investigation, some
10 Chinese plants were assessed for their activities against
18 radioligand-receptor binding assays which are impli-
cated with CNS. The other investigation was concerned
with pain and some 600 species of plant were tested. The
pain receptors used were bradykinin II, neurokinin I, and
a calcitonin gene related peptide. Half of the plants were
selected from the ethnobotanical literature as being used
for the treatment of pain and the other half were from a
random sample. The results showed that there were more
positive hits for activity in the biological screens for the
selected group of plants (Phillipson, 1999b).
4. Malaria
In 1996 it was reported that there were between 1.5
and 2.7 million deaths annually and that the majority of
these were children. There are in the order of 500 mil-
lion new incidences of malaria annually. It is without
doubt one of the major threats to mankind and chemo-
therapy is hindered by the increase in drug resistant
strains, particularly of Plasmodium falciparum. In the
mid 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 in
clinical use and the more recently discovered artemisinin
has proved to be an incentive for further research into
plants. The only major scienti®c paper of antimalarial
testing of plant extracts by the mid 1980's dated back to
1947 when it was reported that some 600 species of
higher plant representing some 126 families had been
tested against avian malarias. Several plants were active
but the research pointed to two particular plant famil-
ies, Simaroubaceae and Amaryllidaceae which had
numerous active species. It is pertinent to ask why it
took more than 30 years for this research to be followed
through. The answer probably lies in the techniques
which were available for carrying out this type of
research. Avian malarias were used because they were
the only tests for activity against Plasmodium species
apart from those using monkeys. The avian tests which
used live chickens and ducklings were notoriously di-
cult to carry out and were not thought to be necessarily
predictive of activity against Plasmodium species which
a€ected humans. These tests were not suitable for
bioassay-guided fractionation of plant extracts. Fur-
thermore, the chemical techniques available were also
not suitable for this type of research. In the 1940's and
1950's there were not the sophisticated chromatographic
separation techniques which are available today. Even if
an active principle were isolated there were none of the
spectroscopic techniques available for structure deter-
mination such as nuclear magnetic resonance spectro-
241
scopy, mass spectrometry or X-ray crystallography. By
the mid 1980's not only were these chemical techniques
available but also it was possible to test for activity
against P. falciparum in vitro and there was a reliable
test 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 for
structure±activity studies and this led to the preparation
of 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 plants
used in traditional medicine for the treatment of malaria
led to the isolation of a series of other compounds with
activity against P. falciparum including isoquinoline and
indole alkaloids, ¯avonoids, mono-, di- and sesquiterpe-
noids. These results provided some scienti®c evidence
which helped towards the justi®cation of claims for the
use of a number of traditional medicines and they also
provided template molecules for synthetic approaches
to new antimalarial drugs. Widening the range of bio-
logical tests to include other species of protozoa
demonstrated activity of natural products against other
tropical diseases which a€ect mankind, e.g. trypanoso-
miasis and leishmaniasis (Phillipson, 1995 and 1999a).
5. Do traditional medicines necessarily contain a single
active ingredient?
The isolation and use of natural products such as
digoxin, morphine and quinine has resulted in replacing
the plant extracts used with single chemical entities.
There is a basic supposition that any plant possessing
clinical e€ectiveness must contain an active principle
which can completely replace the plant extract. Three
examples from our research have shown that this may
not 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 compounds
including a series of ¯avonoids and some of these
enhance the activity of artemisinin against P. falciparum
in vitro. Whether these ®ndings have clinical relevance
has not been determined but they do lend support to the
view that there may be some advantages to the medical
use 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. American
Croton species which are used for the treatment
of wounds. The major constituents of the sap are poly-
meric anthocyanidins which co-occur with many minor
constituents including diterpenes and simple phenols.
Chemical and biological investigation of the properties
242 J.D. Phillipson / Phytochemistry 56 (2001) 237±243
of Dragon's blood led us to conclude that there is not
one single wound healing principle. When the sap is
used to cover a wound it forms a protective occlusive
layer whilst some of the simple phenols act as potent
antimicrobial 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 in
London that some of their young patients with severe
atopic eczema were showing signs of improvement in
their disease state. These improvements were not due to
hospital therapy but to the co-administration of a tra-
ditional Chinese medicine (TCM). The patients had
visited a TCM practitioner in central London and had
been prescribed a multi-herbal prescription from which
an aqueous extract was prepared for oral use. In 1992, it
was reported that a double blind placebo controlled
clinical trial of a ten herb mixture for oral use in chil-
dren with non-exudative eczema con®rmed substantial
clinical bene®t as assessed by currently accepted Wes-
tern orthodox medical practitioners. Our scienti®c
investigations utilising an anti-in¯ammatory/analgesic
test with mice showed that four of the ten herbs pos-
sessed signi®cant activity in the mice but they proved to
be inactive clinically in children. After some consider-
able investigation we concluded that not only was there
no single active ingredient but also that it required all
ten herbs to be present for clinical e€ectiveness. There
are more than 12 di€erent biological activities from the
herbs in this TCM prescription including anti-in¯am-
matory, immuno-modulatory, anti-allergic, sedative and
anti-pruritic. The chemical composition of the 10 herbs
is 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 be
developed through research into their constituents. In
the developed countries, high-throughput screening tests
are used for bioassay-guided fractionation leading to
the isolation of active principles that may be developed
into clinical agents either as the natural product or a
synthetic modi®cation or a synthesised analogue with
enhanced clinical action or reduced adverse side e€ects.
Despite the massive arsenal of clinical agents developed
by 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 or
complementary treatments of disease. There is a need to
evaluate herbal treatments by clinical trials using cur-
rently accepted protocols. In the developing countries
large numbers of the World's population are unable to
a€ord pharmaceutical drugs and they continue to use
their own systems of indigenous medicine that are
mainly plant based. There is a great need to harness
scienti®c and clinical research in order to investigate the
quality, 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. Such
drugs require speci®city of action and are, for e.g. aimed
at a particular subset of receptor. Although natural pro-
ducts continue to supply banks of compounds for new
screens, the focus of industry is currently on combina-
torial synthesis for new drug development. It must not be
forgotten that natural products which result from mil-
lennia of biosynthetic pathways modi®ed by evolution
have a well established track record as medicinal agents
and present a wide range of structural diversity. Drug
development through natural product research is not
without its problems and there is, for e.g. a need to
eliminate 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 match
industry in the wide range of screens but they can use
selective targets and collaborate with industry. This type
of research needs a multi-disciplinary approach and this
includes expertise in phytochemistry.
It is a pleasure and an honour to present this lecture
and to acknowledge the lead which Professor Je€rey
Harborne has given to Phytochemistry over so many
years. I am one of those who owe a great debt to him
and to the example which he has set. My own speciali-
sation of Pharmacognosy was virtually wiped out from
Pharmacy undergraduate curricula and for many years
has been considered to be an outmoded area of
research. Techniques in Phytochemistry have revolutio-
nised our ability to investigate the medicinal agents
present in plants and this is acknowledged by the
industrial interest in plants over recent years. Thanks to
the hard work and tenacity of Je€rey Harborne we have
been able to publish research articles in Phytochemistry
and to continue working on the wealth of chemical
diversity 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 Great
Moments 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.
 J.D. Phillipson / Phytochemistry 56 (2001) 237±243
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-
243
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.