I G E R I N N O VA T I O N S
1998
Natural Products from
Temperate Plants : the
way ahead for drug
discovery?
Robert J. Nash
Plant selection
Old remedies, new techniques
Chemical fingerprinting and isolation methodology
Potential for exploitation
I G E R I N N O VA T I O N S
1998
N AT U R A L P R O D U C T S F R O M T E M P E R AT E P L A N T S :
T H E WAY A H E A D F O R D R U G D I S C OV E RY ?
N AT U R A L P R O D U C T S F R O M T E M P E R AT E P L A N T S :
T H E WAY A H E A D F O R D R U G D I S C OV E R Y ?
Robert Nash
T
he discovery of new drugs, agrochemicals
HO
OH
or other biologically active compounds is
dependent on the ability to rapidly identify
and characterise active chemicals for commercial
development. Natural products have a vast
molecular diversity and functionality and they
CH 2OH
N
H
HO
OH
HOCH
OH
N
H
2
OH
HO
HOCH
2
HO
OH
O
N
H
OH
CH 2OH
O
OH
currently account for £9bn of annual sales in the
pharmaceutical
and
agrochemical
markets.
Conventionally, natural products have been tested as
crude extracts containing complex mixtures of
compounds which, if showing a desired activity,
require a process of purification and identification of
the active components which is lengthy and
inefficient. IGER has been developing expertise and
technology to rapidly isolate and identify plant
chemicals involved in animal and human health
problems, pest and pathogen resistance, etc. As a
result we have been able to identify many novel and
active natural products from common crops and
native UK plants (Figure 7.1). An expansion of this
research, involving an innovative strategic alliance
Figure 7.1 Bluebells (Hyacinthoides non-scripta) are the source
of dozens of novel biologically active alkaloids.
between IGER and Xenova Discovery Limited has
IGER will develop advanced chemical fingerprinting
begun which will combine the considerable
and isolation technologies which will be crucial to
experience in microbial drug discovery and
producing a library of high quality chemicals from
development at Xenova with IGER's botanical,
plants and other organisms. Within three years, the
horticultural and chemical expertise. Contrasting
combined library of purified natural products is
with traditional methodologies, the aim is to
expected
combine the diversity and bioactivity of natural
differentiated novel or rare compounds, at least
chemicals from plants, fungi and bacteria with the
2,500 of which will be of plant origin and isolated at
greater precision of screening a library of pure
IGER. The library will reduce the time necessary to
chemicals. The aim is therefore to purify specific
identify potential new drugs, have sufficient
components, which are likely to be rare or novel, and
quantities for re-supply of active chemicals and, for
then test these for activity in a wide range of
the plant compounds, there will be the ability for
biological assays.
scale up by selection and growing of plants and
to
comprise
extraction at IGER.
42
10,000
individually
I G E R I N N O VA T I O N S
1998
Plant selection
In recent studies on a handful of British species we
Much attention in the last two decades has focused
have found a large number of novel biologically
on tropical plants as sources of new natural products
active alkaloids. For example the Bluebell,
for potential pharmaceutical and agrochemical use.
Hyacinthoides
Recently however, temperate plants have provided
concentrations of dozens of new pyrrolidine,
most of the commercially interesting plant
piperidine and pyrrolizidine alkaloids and unusual
compounds identified. These include: etoposide
glycosides (Figure 7.1). Only one of these
(anti-cancer agent) from Podophyllum spp.,
compounds, DMDP, has been described previously
artemisinin (anti-malarial agent) from Artemisia
and that only from a tropical legume. DMDP has
annua (Annual Mugwort) and taxol from Taxus spp.
been patented as a nematocide and is in commercial
(Yew trees). Taxol as a treatment for ovarian cancer
production by extraction from the plant in Costa
is now in the top 30 best selling drugs. We propose
Rica. The commercial production of new products
to concentrate on plants grown in the UK because
from temperate plants has been shown to be a viable
production can then easily be scaled up for large
option by Bristol-Myers Squibb in the case of taxol,
scale extraction. Both wild and cultivated plants will
which is only a very minor component in the bark of
be selected for study. There is no doubt that, like
certain yew trees. However, it is now produced by
tropical plants, temperate plants also produce large
semi-synthetic modification of a related compound
numbers of biologically active metabolites for
found in greater abundance in needles of the
protection from herbivores and pathogens, and in
European Yew. Daffodils, with crop values of up to
response to wind and temperature damage. In
£500 per tonne, are also beginning to be cultivated in
additon, the seasonal nature of the selective
East Anglia for extraction of galanthamine for
pressures and short growing season may lead to
treatment of Alzheimer's disease. In addition to
changes in production of chemical defenses during
investigating new crops, IGER has a long history of
the year.
breeding varieties of clovers (Figure 7.2) and oats
non-scripta,
contains
high
N AT U R A L P R O D U C T S F R O M T E M P E R AT E P L A N T S :
T H E WAY A H E A D F O R D R U G D I S C OV E RY ?
Figure 7.2 Red clover has traditionally been used to treat coughs and also has anti-coagulant and anti-tumour activity. IGER's clover breeding
programme has considerable natural genetic diversity which will be reflected in both chemicals present and their quantities.
(Figure 7.3) and both of these species have been
43
I G E R I N N O VA T I O N S
1998
biologically-active tropane alkaloids in potato and
N AT U R A L P R O D U C T S F R O M T E M P E R AT E P L A N T S :
T H E WAY A H E A D F O R D R U G D I S C OV E RY ?
other solanaceous human food plants (Figure 7.4).
These alkaloids, despite being major components in
healthy potato tubers and aubergines, had been
missed by the many labs analysing these foods
because the analytical techniques traditionally used
on these plants were not able to detect them. Of
particular interest at the moment at IGER are plants
traditionally used to treat tuberculosis and leprosy,
such as Sea Pink, Wood Anemone and the Bluebell.
Because other drugs have been effective in almost
completely removing these related diseases from the
UK, these traditional remedies have been forgotten.
However, the increasing drug resistance of TB
means that there is a great urgency to find new ways
of combating the disease. One idea is based on the
fact that a sugar-like compound, rhamnose, is
incorporated into a crucial position in the cell wall of
Figure 7.3 There are claims that Oats contain compounds for
activity against colds, depression, muscular sclerosis and
shingles. Oats also have potent anti-oxidants of benefit to health
and possibly commercially important for healthy foods, however,
not all active components have been identified and they differ
amongst varieties bred at IGER.
HO
HN
HO
OH
O
OH
O
OH
OH
CH2OH
shown to have medicinal properties. To date, the
active chemicals remain largely unknown but the
new project will hope to identify and isolate them. In
the future therefore, these traditional crops may form
the basis of new commercial enterprises.
Old remedies, new techniques
There have been very few detailed studies of British
plants since powerful analytical techniques such as
gas chromatography and high pressure liquid
chromatography coupled to mass spectrometry (GCMS and HPLC-MS) have become available. There
are many examples of plants used in folk medicines,
or of toxic plants, for which the active principles
have not been identified. These new techniques
make the detection of novel chemicals much easier.
That new compounds can easily be found in plants
frequently analysed by other workers has been
shown by isolation of hitherto unsuspected
44
Figure 7.4 Healthy potato tubers contain tropane alkaloids and
glycosides which may be important components contributing to
human health and pest resistance but were only recently
discovered at IGER.
I G E R I N N O VA T I O N S
1998
natural products chemistry groups, despite the fact
The project will build detailed databases of chemical
information, which will help to avoid duplication of
compounds and will provide the most detailed
source of chemical information on British plants and
crops. This information will be valuable to other
commercial interests, including the animal feed and
human food industries.
Potential for exploitation
OH
This programme will combine the successful leading
OH
HO
edge expertise of IGER and Xenova to form the
HO
O
CH3
largest phytochemistry group in the UK. The
OH
CH 2OH
combination of the plant derived library with the
OH
HO
N
H
highly diverse fungal and bacterial chemical data
base already in existence at Xenova, will create what
CH3
is believed to be the world's biggest library of pure
natural products, and allow serious assessment of
Figure 7.5 Rhamnose analogues from plants such as Spring
squill (Scilla verna) may be useful in combating TB by indicating
ways of affecting microbial cell wall formation without affecting
human cells which do not use rhamnose.
chemicals from British plants as potential drugs (or
agrochemicals). Xenova Discovery will manage the
process of screening for biological activity, which
N AT U R A L P R O D U C T S F R O M T E M P E R AT E P L A N T S :
T H E WAY A H E A D F O R D R U G D I S C OV E RY ?
that biological systems are primarily water based.
will be required to assess viability of commercial
the disease-causing microorganism. In collaboration
with Dr George Fleet, at Oxford University's Dyson
Perrins Laboratory, we aim to use rhamnose
analogues, discovered in British plants (Figure 7.5),
as models for a synthetic chemistry programme
aimed at interfering with rhamnose formation.
Chemical fingerprinting and isolation
methodology
The advanced chemical characterization, which will
be used to define the structures of novel or
commercially
unavailable
chemicals
before
isolation, is a unique approach to natural products
products. Many active natural chemicals, such as the
alkaloids described here, are so complex that
synthesis from simpler compounds may be so
expensive that extraction from new crops could
prove to be more economically viable. It is hoped
that, in addition to small scale production at IGER
for the preliminary isolation work, new high value
crops may be developed for large scale production of
interesting compounds. Expertise and facilities at
IGER for taxonomy, plant physiology, horticulture
and agriculture and for chemical assessment and
purification will ensure rapid establishment of such
crops for extraction.
discovery. Water soluble (hydrophilic) components
will feature highly in the profiling and isolation
processes being developed, as these components
have not traditionally been fully exploited by other
Contact: [email protected]
45