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Natural products isolated from higher plants arid
microorganisms have been providing novel, clinically active drugs. The key to the success
of discovering naturally occurring therapeutic agents rests on bioassay-guided
fractionation and purification procedures.
Screening of both synthetic organic compounds
and extracts of natural products has had an impressive history of identifying active
agents. For example, there are about 50 commercially available anticancer drugs (excluding
endocrines) which have been approved to date by the USFDA, and significantly, the drugs
based on natural products represent almost 1/3 of these total approved agents. A most
recent addition is taxol (approved in 1992, and the semi-synthetic in 1995), a
natural product derived from the Pacific yew tree Taxus brevifolia, which is used
for the treatment of ovarian and breast cancer.
Malaysia has
about 12,000 species of flowering plants of which about 1,300 are said to be medicinal
(Burkill, 1935), and only about a hundred have been investigated fully for their
potential. The huge diversity of the Malaysian flora means that we can expect well
diversed chemical structures from their secondary metabolises, and chemical diversity is
one of the plus factors that makes natural products excellent candidates for any screening
programme.
The current trend of forest destruction for the sake of development means that
scientists and the science involved will have to progress even faster in order to get at
the potential natural products from the remaining forests. Universiti Kebangsaan Malaysia
(UKM) and other local universities and research institutes are embarking on their own
programmes which normally involves a concerted multidisciplinary approach in the discovery
of bioactive agents from plant-derived natural products. Certain novel strategies have
been carried out based on the expertise and funds available at their disposal and it is
imperative that a screening programme be implemented and administered accordingly with the
ultimate aim of discovering new chemicals from the Malaysian flora for use in the
pharmaceutical and related industries. This in turn will help in the development and
transfer of technology in the said industries which can only be achieved through
collaborative programmes with other better equipped countries.
THE EARLY YEARS
The use of plants as medicinals by the local
people have been well documented as early as in 1935 by Burkill, recent books and papers
on ethnobotany and ethnopharmacology are also available but not as comprehensive.
Medicinal plants were also available at that time in the markets or side walks, mostly in
crude form, sold by traditional medical practitioners. It was not until the 1950s that any
attempt was made to carry out scientific investigation on these medicinal plants although
awareness on the usefulness of such plants has been established for quite some time.
Projects undertaken at that time was simple and straightforward but effective which
involved surveys of plant species available in a certain designated area, their
ethnobotanical use, and laboratory testing for certain classes of compounds which were
already known to be effective drugs. So it was not surprising then that most of the
phytochemical surveys carried out concentrated on the testing of alkaloids in these plants
since alkaloids were already (generally) proven to be effective as drugs.
The first report of a phytochemical survey of plants in Malaysia was carried out by
Arthur in 1954, and this was followed by several more similar reports right up to the 90s
(Teo et al., 1990). This was, and still is, a proven strategic approach whereby
plants with alkaloids are chosen for further detailed investigation. Inadvertently, a
trend was set early on in Malaysia whereby most of the phytochemical work concentrated on
plants belonging to certain families or genus only because they contain alkaloids.
Some examples are the Annonaceae, Apocynaceae, Lauraceae, Menispermaceae, and
Rubiaceae. There was only one report ( Nakanishi et al.,
1965) which made use of bioactivity as a means of selecting plants for further
investigation but this was not fully utilised until the present time (Said et al., 1995a;
Latiff et al., 1995). Even the ethnobotanical data, though well documented, was not
fully utilised for this purpose.
The main reason was because present-day bioassays were not available at that time,
other bioactivity tests, if available, were deemed expensive. Furthermore, Malaysia did
not have enough manpower for a multidisciplinary approach and scientists at that time
worked more in isolation, a lack of funds also made sure that such projects remain a low
priority in a new nation.
Things began to improve when UNESCO got into the
picture in the early 70s, funds were made available for training of young scientists and
regional cooperation became more coordinated where networking was encouraged. Malaysia was
actively involved in the Regional Network for the Chemistry of Natural Products in
Southeast Asia and through this network our scientists were exposed to current trends and
situations in the natural products area by interacting with other networks, notably from
Australia (NCBINP), Sweden (IFS), and Pakistan (ISESCO).
THE PRESENT STATE OF
RESEARCH
The development of medicinal plants into therapeutic drugs takes several years and
millions of dollars are needed, hence making the process very capital-intensive the risks
are also high and the success rate not very good. Despite all this, natural products drug
discovery programmes are still in existence all over the world, mainly because of several
reasons:
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The high chemical diversity from natural products as compared to
synthethics, the potential of these natural products is largely unknown,
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The large number of terestrial and marine species yet uninvestigated, and the
back to nature syndrome.
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Modern technology and advancements made in this field in the last few years
has made such programmes attractive.
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High throughput screens and sensitive instrumentation for structure elucidation
has greatly reduced the amount of time (and also the amount of
sample) required for the first stage of the investigation.
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Biotechnology is also expected to play a major role in the production of natural
products through biosynthesis and bioengineering which will further reduce the dependence
on a large amount of plant samples and hence reduce the pressure of reducing the number of
biogenetic resources in our tropical forests. But at the same time recent developments in
the fields of combinatorial chemistry, high throughput screening, computational
capabilities and large data base management and manipulation are beginning to shift
interest away from natural products. Only time will tell whether this threath will become
a reality.
Malaysia, with her rich source of medicinal plants from the tropical forests, have
taken steps to increase the scientific knowledge of these plants by making available funds
for research beginring in 1985 with the IRPA (Intensification of Research in Priority
Areas) programme. IRPA is now in its third term (1996-2000) and one of the areas that have
been identified as a priority is the commercialisation of biotechnology, which also
takes into account the development and production of biopharmaceu ticals from plant
genetic resources. Bioprospecting and phytochemistry would at best equip the country with
the necessary knowledge and a build up of a good data base that can be used to venture
into the capital-intensive programme of drug development with the right foreign partners.
There is a need for equitable sharing not only in the profits that may come out
from such a venture but also the necessary transfer of research knowledge and technology
to the resource country. More than five groups are now funded by IRPA to do phytochemical
and bioscreening work but not all groups are fully equipped or have the luxury of a
multidisciplinary team. The overall direction is still not quite obvious other than that
determined in detail by that particular research group although coordination between the
different groups is good.
The emergence of phytomedicinals and nutraceuticals as an important
alternative means of health care world wide has also posed a dilemma: get involved with a
drug discovery programme which is very capital-intensive OR develop our own phytomedicinal
industry which is already in existence?
The phytomedicine market in Europe is huge with more
than US$6 billion in annual sales, and Germany alone accounting for half of the market
(Grunwald, 1995), while the US market is slightly less but with an annual growth of about
12% (Brevoort, 1996) makes phytomedicinals an attractive business venture. The Malaysian
phytomedicinal market is worth about RMI billion and efforts have been made by the Health
Ministry to make their products more acceptable for export. This calls for more scientific
input through research by the same groups mentioned earlier. Malaysia is both involved in
the development of phytomedicines and the discovery of therapeutic drugs from biogenetic
resources with the future in mind.
SOME NOTABLE EXAMPLES
The six universities and two research institutes that
are involved in natural products research meet annually to discuss their fmdings and seek
ways of improving the quality of their research . The Malaysian Natural Products
Society was formed in 1994 as a result of these meetings although the annual meetings
have been going on for the last twelve years. Other national committees have also been
formed to coordinate the many activities connected with medicinal plants, one of which is
responsible for the publication of a Malaysian Pharmacopea.
The University of Malaya was responsible for the
initial work on Malaysian medicinal plants because she was the only university then and
the activities at that institution has continued to flourish until the present time with
more than three groups actively involved. The earlier publications concentrated more on
phytochemical work especially on alkaloids (for example Kiang et al., 1964) and the
trend has continued over the years until the present time (Chan et al, 1966 , 1986;
Goh et al., 1985; Kam et al., 1993, 1996). Very little work has been
published on the bioactivity of all these alkaloids isolated although some of them are
known to have moderate cardiovascular effects (Chang et al., 1989), while tumor
promoting activities of some plant extracts were also investigated (lIham et al., 1996).
In a way, University of Malaya has gained a lot from their successful collaboration
with the Institut de Chimie des Substances Naturelles (CNRS-France) which started in 1982
and since renewed in 1993. This collaboration has resulted in more than 50 publications, 6
PhD theses and 1 patent. At the onset, however, the collaboration also concentrated only
on the alkaloid-bearing plants (Clivio et al, 1990; Jossang et al, 1991;
Montacnac et al., 1995) but the emphasis has since shifted to the present day trend
of bioassay-directed isolation of natural products (Omobuwajo et al., 1 996; Alias et
al., 1995).
The approach taken by the natural products group
from Universiti Kebangsaan Malaysia has always been a multi-disciplinary one
(Latiff et al., 1984) although the methods used were a bit different from their
approach today. The phytochemists did their own thing by isolating nice crystalline
compounds which were then sent for bioactivity studies, and most of the time these
compounds were not active. The exercise was more or less to tag the compounds with some
bioactivity studies. This approach was later reversed , phytochemical work was only done
on plant extracts that showed bioactivity and compounds were isolated through
bioassay-guided isolation techniques. Phytochemists were now required to do simple
benchtop bioassays (notably the brine shrimp lethality test) to help them isolate the
bioactive compounds which were then put through the other bioassays available to the
group.
At the same time, the group did not abandon the traditional way of selecting plants
through phytochemical screening (Said et al., 1990, 1995a, 1995b) which made
available plants that were not collected or recorded before, and with the etnobotanical
data available, the group was able to come in contact with a large number of plant
samples. The group has worked on the drug plant Mitragyna speciosa for some time
now and are still pursuing the bioactive compounds besides isolating some novel ones
(Houghton et al., 1991). Other notable examples are work on the anti-plasmodial
plants Alstonia anguslifolia (Said et al., 1992a; Wright et al., 1992) and
Dehaasia incrassata (Said et al., 1991, 1992b) which combined ethnobotanical data and
bioassays to isolate the chemical compounds. The group also has a special interest in the
Annonaceae because of the large number of plants in that family that are being used as
traditional medicine, the group also has a taxanomist that specilizes in the
Annonaceae.
Several species of Goniothalamus were investigated for their chemical components
(Din et al., 1990; Colgate et al., 1990; Said et al., 1995c) and also
for their bioactivity (Rawarian et al., 1994).
Other than having a multidisciplinary team, the
UKM group seems to be the only ones that are working on the chemistry of lichens which has
resulted in a series of papers on Malaysian lichens (Galloway, et al., 1994). Novel
compounds were isolated (Hamat et al., 1993; Samsudin et al., 1995), new
species discovered (Elix, et al., 1991; Din et al., 1995), but their
bioactivies have been shown to be not really significant (Din et al., 1992).
Other groups that have contributed significantly to the development of natural
products research in Malaysia, starting from the 1980's, are from Universiti Pertanian
Malaysia (UPM), Universiti Teknologi Malaysia (UTM), Universiti Sains
Malaysia, (USM) and the Forest Research Institute of Malaysia (FRIM). All are
deeply involved in phytochemical work but are currently developing their own bioassay
systems with the exception of USM which has a School of Pharmacy to complement the
chemical work. The group in UTM has concentrated mainly on phytochemical work especially
on the chemistry of the ginger family (Sirat et al., 1996; Sirat, 1994).
The group in UPM is also leaning towards
phytochemistry but have the simple bioassays at hand for some bioactivity work
(Hainzan et
al., 1994; Rahmani et al., 1995). With the presence of a pharmacy school, USM
is able to do some anti-malarial work (Ang et al., 1995) and has also been involved
in some tissue culture work for the production of high yielding medicinal plants (Chan et
al., 1995) The Forest Research Institute of Malaysia is dedicated to the production of
economically useful secondary forest products and has formed a Medicinal Plants Division
in 1995 for this purpose. Most of their work has concentrated on the essential oils
(Jantan et al., 1994, 1995) and their use in consumer products, but are currently
expanding into other classes of compounds and their bioactivities (Sahaari and Waterman,
1994; Connolly et al., 1996, Buchanan et al., 1996).
Special mention should also be given to Universiti Malaysia Sarawak (Unimas),
although new, have been actively involved with the natural products scene in Malaysia in
the last couple of years. They have developed an anti-termite screen (Sent et Al, 1994)
and are also involved in the development of other bioassays, besides being involved
indirectly with the identification of several anti-HIV components from the Calophyllum trees
of Sarawak (Pengsuparp et al.., 1996). The future focus of natural products
research will be on Sabali and Sarawak due to the floral diversity of the two states.
PROSPECTS AND REALITIES
Biotechnology and Natural Products
was the theme of the 37th Annual Meeting of the American Society of Pharmacognosy held
in July 1996 which indicates the importance of biotechnology playing a major role in the
search for biologically active natural products from plants and other sources. Although
natural products has the chemical diversity and has been proven to be useful templates,
their sustainable supply from the original biological source will always remain a problem.
Obtaining the biomes through bioengineering and the products themselves from biosynthesis
would be a more acceptable alternative. There have been many examples, but can
biotechnology meet the challenges in this particular problem when it has been successful
in others? Combinatorial chemistry can produce a variety of compounds and candidates for
testing but at the present state will not be able to offer the structural diversity that
natural products can.
Malaysia has a small pool of scientists to work on a large flora, as such will not
be able to focus on a restricted area of research in natural products without compromising
the freedom to do research. But, even after forty plus years of research on the natural
products of Malaysian flora, the nation has not produced any compounds of pharmaceutical
interest. Even in phytomedicinals, most of the raw materials are imported from India,
China and Indonesia, even though the market is getting bigger. There are few venture
capitalists that are willing to invest in the production of medicinal plants or for their
oils (Hunter, 1994), it is more lucrative (and sensible) to grow two of our biggest
agricultural commodities, rubber and oil palm.
Bioprospecting will remain an attractive
proposition as long as we have the floral diversity, but there is an urgent need to
produce something more tangible out of this exercise in order to sustain the interest and
commitment of the government because only they are the ones that would be willing to
invest on a capital-intensive project. The prospects are there, the infrastructure and
manpower is obtainable, the business realities will have to be looked into more
thoroughly.
CONCLUSION
Bioprospecting and the development of a natural products drug
discovery programme is something that the nation will have to address seriously. It is a
long term capital-intensive programme that may or may not bring any rewards, but with the
technology and advancements made in the last few years, the chances of success is good if
the genetic biodiversity of the country is taken into account. The programme will have to
focus not only on the national needs but also on the global demands where the market and
finance is ever present.
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