Taxol -
An anti-cancer drug obtained from the Pacific Yew -
Taxus brevifolia Nutt.
Adrian D Middleton
University of Sheffield - Certificate in Plant Studies - Extended Essay -
Summer 1997
NOTE - This essay was written in 1997. Science and medicine have
moved on since then, but I have not revisited the subject to update the
information, nor to check all internet links. The essay is offered in its
original form should anyone wish to bring the investigations up to date or to
follow up references in the bibliography. As time allows I will add and check
the links, and add links via the footnotes and bibliography.
Text
Footnotes
Bibliography
Why should a timber company with a reputation for ruthless exploitation of
the environment [1], have planted 280
million seedlings of a tree which was once considered worthless [2]? The thing that made the Weyerhaeuser company plant Yew trees is
Taxol - an anti-cancer drug with an annual market now worth a billion dollars [3].
Yew (Taxus sp.) has long been known to be poisonous. Deaths of people
and livestock have been recorded since the 4th century, and in the 18th century
they included women dying from its use as an abortificant [4]. The toxic component was named 'taxine', and was analysed in 1956
as a mixture of ten alkaloids including Taxine B which was identified as causing
cardiac arrest [5].
In spite of its toxicity, Yew is said to have been used medicinally by North
American tribes for rheumatism, fever and arthritis, and by the Japanese for
diabetes [6]. More recently it has been used in homoeopathy
for a variety of ills including cystitis, neuralgia, gout and rheumatism [7].
In the 1950s, many laboratories were screening plants in a search for new
drugs and one such search - looking at claims that the Madagascar Periwinkle
(now Catharanthus roseus) was effective against diabetes - had revealed
the Vinca alkaloids which have revolutionised the treatment of Leukaemia and
Hodgkin's Disease (a cancer of the lymph system). That discovery was made almost
by accident, but by 1960 the search for cancer drugs was made systematic by
testing plant extracts against a series of cultured cancer cells 'in vitro' -
i.e. 'in glass' - rather than on animals.
In 1960, Dr Monroe Wall left the US Department of Agriculture (USDA) to form
a Natural Products group at the Research Triangle Institute (RTI), North
Carolina, specifically aimed at evaluating drugs derived from plants. Here he
was joined by Dr Mansukh Wani and together they were involved in the discovery
of Camptothecin, an anti-cancer drug derived from Camptotheca acuminata,
a tree native to China [8].
At the same time (in 1960), Dr Jonathan Hartwell of the US National Cancer
Institute (NCI) had begun a formal screening program for plant samples collected
by the USDA, and in August 1963, a USDA botanist, Arthur S Barclay, with three
student assistants, collected samples in California, Washington and Oregon which
included parts from Taxus brevifolia, the Pacific Yew, an understorey
tree found in the mature western forests. Extracts from the Yew samples were
shown to be toxic to certain cancer cells, and in 1964 samples were sent to RTI
for investigation. Their results were encouraging, and the crude extracts were
refined and tested 'in vivo' on mice, using techniques which had previously
shown the value of the Vinca alkaloids. Without knowing either the formula or
the structure of the active component, Wall and Wani gave it the name 'Taxol' [9].
These early extractions produced 0.5g of Taxol from 12kg of dried bark - a
yield of 0.004%. The amounts available were therefore limited - it was not
available in pure form until 1969 [10], and its structure
was not described until 1971 - again by Wall and Wani [11].
Taxol was shown to have a complex structure found in a range of
compounds collectively known as 'taxanes'. Figure 1 (right) shows Taxol's
structure compared to other taxanes including Taxine B. It is described as "a
complex diterpene [comprising] a taxane ring system with a four-membered oxetane
ring and an ester side chain at position C-13" [12]. The
'taxane ring' structure comprises 3 rings (A, B and C) which form a folded
structure bringing rings A and C almost parallel, the 'oxetane' ring (ring 'D')
being attached to carbons 4 and 5 of ring C. The ester chain was later shown to
be essential to the cytotoxicity of Taxol and of its analogues [13]. The complexity and asymmetry of the structure suggested that
synthesis would be difficult.
Until the late 1970s the NCI showed little interest in Taxol because of the
difficulty of the extraction process, and the limited supply of both the source
material and the extract. Early work suggested that it inhibited mitosis (cell
division) in a similar way to the Vinca alkaloids and other experimental agents
such as Maytansine. In the latter case, though it was effective in the
laboratory, Maytansine had failed in clinical trials in the late 1970s due to
its general toxicity [14]. Similar fears arose with Taxol
but in 1977 Taxol was finally accepted for clinical development.
Here it is worth a diversion into the mechanism of mitosis, since it was the
discovery in 1979 of the unique action of Taxol which led to renewed interest in
the drug.
Figure 2 (right) shows some of the key stages in cell division,
the process needed for growth and the replacement of tissue, which becomes out
of control in cancers.
For most of a cell's life it is performing a function such as the production
of proteins. In this state it is not dividing - it is within the 'Interphase' -
sometimes called the G0 or Quiescent Phase (not shown in the diagram). The DNA
enclosed within the nucleus is diffuse and at work in the process of protein
synthesis.
In preparation for division, the DNA replicates in the S (Synthesis) phase,
and after a time 'gap' (G2) condenses to form the chromosomes visible through
the microscope. This is the start of the M (Mitosis) phase - the actual cell
division.
Mitosis is itself divided into smaller phases shown in Figure 2. In the
'Prophase' a structure called the spindle forms within the cell. It is made of
'microtubules' which are spiral chains of 'tubulin' molecules. Other clusters of
microtubules form two 'organising centres' which migrate to the opposite ends of
the cell within the 'Metaphase'. The tubulin for these structures comes from the
dismantling of other internal cell structures.
In the Metaphase, the microtubules of the spindle attach to the pairs of
'chromatids' which form the chromosomes, and the chromosomes arrange themselves
along a plane in the centre of the cell - the 'metaphase plate'. Moving into the
'Anaphase', the spindle pulls the chromatids away from the metaphase plate - one
element from each chromasome going to each half of the cell.
In the 'Telophase' - the final stage of Mitosis, the spindle disperses, the
tubulin being needed for its other jobs within the cell, and a new nuclear
membrane forms around the cluster of chromatids in each half of the cell. At the
same time, the cell body divides along the line of the metaphase plate forming
two separate cells. Finally, the DNA of each nucleus 'de-condenses' as the cell
enters the G1 or Resting Phase.
From G1, the cell either moves back to the Synthesis phase - if it is
actively dividing - or into the G0 phase if it is to perform its function within
the body.
Various anti-cancer drugs, including Colchicine, Maytansine and the Vinca
alkaloids stop the cell division process by preventing the formation of the
spindle. These 'Spindle Poisons' act on the actively dividing cells within the
cancer, and are especially effective in diffuse cancers such as Leukaemia. Since
this action affects any rapidly dividing cells including those in the digestive
tract and in hair follicles, such agents can have a variety of side effects
including nausea and hair loss [15]. Microtubules are also
involved in the structure and function of nerve cells, and their disruption can
cause neurological side effects which can be dose limiting [16].
In 1978, Fuchs and Johnson [17] showed that Taxol also
blocked the mitosis cycle in the G2/M phase - apparently like the other spindle
poisons. The following year, Susan Horwitz showed that the mechanism was in fact
different from the other spindle poisons since Taxol did not prevent the
formation of microtubules, but prevented their de-polymerisation by binding to
and stabilising their structure [18]. Microscopic
examination of cells exposed to Taxol shows their cytoplasm packed with parallel
bundles of microtubules [19] which prevent successful
division and disrupt the cell function. It was not until 1995 that the binding
site of Taxol on the tubulin structure was identified [20],
but the discovery of a unique mode of action opened the field for new work and
potential new uses.
Several lines of research began in the early 1980s, some in the clinical
application of the drug, some in the supply of Taxol, and others in the
synthesis of both Taxol - now given the generic name Paclitaxel [21] - and of analogues.
The first obstacle to be overcome was that Taxol is not a polar molecule and
is not water-soluble. A suitable medium was therefore needed, and this was found
in a mixture of Cremophor EL - a derivative of Castor Oil - and ethanol. This
had been used with other insoluble drugs, but Taxol required a higher proportion
of Cremophor and in early trials, beginning in 1983, this resulted in many
hypersensitivity reactions and some deaths [22]. These
problems were reduced by varying the dose rate and by pre-medication with
steroids.
The second problem was the supply of Taxol. In the early days several mature
trees, each up to 100 years old, were needed to provide enough drug to treat one
patient [23]. This caused a clash between conservationists
and the researchers - the habitat of the Pacific Yew was already under threat by
logging, and the extraction process involved destroying the trees. There were
fears that the Pacific Yew would be wiped out - with echoes of the case of
Maytansine, where the NCI had harvested the entire known adult population of the
South American shrub (Maytenus krukovit) in which the drug was found [24], though ultimately the drug had failed to fulfil its early
promise.
Over the next ten years, timber companies such as Weyerhaeuser carried out
research into the growth of the Yew, and the conditions which favoured the
formation of Taxol. Though Taxol was found in all parts of the plant, the
highest concentrations were in the bark and in trees growing in shaded areas -
the conditions found in mature forests. There was also considerable variation
between individual trees and over the seasons. Within this research, other
taxanes were identified. Some were found with higher concentrations in the
needles, and their presence in a renewable part of the tree led to a major
breakthrough in France - the development of the first active analogue of
Taxol.
Dr Pierre Potier and his team worked from an extract of 10-deacetyl baccatin
III (DAB III), a non-cytotoxic taxane found in the needles of the European Yew
Taxus baccata - see Figure 1. By adding a side chain to the taxane ring
structure they obtained a new compound - which they named Docetaxel - which was
more potent that Taxol, and which was more soluble. Within the same research,
they also succeeded in producing Taxol from DAB III, and in 1986 the drug
company Rhône-Poulenc Rorer submitted patents both for this semi-synthetic
Taxol, and also for the new drug Taxotere or Docetaxel [25].
These patents were granted in 1989 [26].
By now, in the late 1980s after successful Phase II trials, Taxol was known
to be active against some ovarian cancers including those resistant to other
treatments, and NCI were looking for an industrial partner to develop the drug
and to improve the supply. In 1989 Bristol-Myers Squibb entered into a
Co-operative Research and Development Agreement (CRADA) with NCI whereby BMS
ensured the supply in exchange for patent and marketing rights. In fact BMS did
not produce Taxol - which by now was their registered name. It was produced by a
chemical company called Hauser Chemical.
Between the early 1980s and 1991, 70,000kg of bark were collected by the
USDA, and 0.5kg Taxol was produced each year. In 1991, collections of bark from
public lands rose to 400,000kg, with a similar amount collected from private
land [27]. Between 1991 and 1992 production increased from
5,000 to 50,000 vials per month, and Hauser improved their extraction process
from 1kg per 16,000kg of bark to 1kg per 7,500kg [28]. The
increased supply made the drug available for treatment as well as research and
in 1992 Taxol produced from Pacific Yew bark was approved in the US for the
treatment of ovarian cancer. UK trials also began in 1992 [29], in July 1993 Sweden became the first European country to
approve the use of Taxol, and in October 1993, the European Union recommended
the licensing of Taxol for use in the EU [30].
Clinical developments continued with the discovery of Taxol's effectiveness
against breast cancer (1991) and some lung cancers and head and neck cancers
(1992) [31]. As with many other forms of chemotherapy, the
trials also included Taxol used with other drugs. One successful combination was
with platinum based drugs such as Cisplatin and Carboplatin [32]. Cisplatin, which was also used in treating ovarian cancer, and
other platinum drugs act by damaging DNA during its replication. The use of two
drugs with different actions can enhance their separate effects but careful
trials are needed to avoid adverse interactions. In the case of Taxol and
Cisplatin it was found that Taxol had to be administered before Cisplatin to
enhance the cytotoxic effects and to reduce adverse side effects.
Another important 'combination' was Taxol administered with radiotherapy.
Radiation has been used to treat many tumours, and has been used in conjunction
with chemotherapy since the 1960s [33]. Cells are most
sensitive to radiation while in the G2 and M phases of mitosis, and since the
effect of Taxol is to 'freeze' the cells in this state, it was felt that Taxol
might increase the effect of the radiation. This was found to be the case both
in the laboratory [34] and in clinical trials including
trials on solid tumours which contain a lower proportion of actively dividing
cells, and are therefore more difficult to treat [35].
In the late 1980s the value of Taxol and the issue of Yew bark became major
news items in the US especially in the Pacific states. In October 1991 five
people were charged with the theft of Yew Bark from live trees [36], and bark collecting had become a source of income for local
communities. One reported conversation in the 'line of battered pick-up trucks
outside the Taxol-extraction plant in Cottage Grove, Oregon' ran "The bark's
real loose. You just stick in a screwdriver and peel them like sausages. I got
to get it now. Pretty soon there won't be any left." [37]
This lack of control led to the passing of the Pacific Yew Act in 1992 which
placed limits on the collection. It placed a duty on the loggers to allow
collection before areas were clear felled, and introduced measures to minimise
waste and to allow for regeneration of the trees [38].
Meanwhile other sources were being investigated.
A semi-synthetic form of Taxol was licensed by BMS and went into production
in 1993 using DAB III extracted from needles and twigs of the European Taxus
baccata and Himalayan T. wallichiana - the DAB III extract was
produced by an Italian company called Indena. Because of the different
production method, a separate drug application had to be filed (in 1993) [39]. Clinical trials began in early 1994 [40], and approval to market the semi-synthetic version was given
later in 1994. Also in 1994, the US FDA approved Taxol for use against breast
cancers [41]. In August 1995 it was reported that BMS had
not harvested any Yew bark for over a year, though it was still using bark
collected earlier [42].
Semi-synthetic Taxol reached the US market in late 1995, and is now the main
source of Taxol. It is based on renewable resources which include yew clippings
and specially grown yew seedlings including those planted by Weyerhaeuser.
The advantage of semi-synthesis is that nature has already done some of the
difficult chemistry by building the more complex parts of the chemical
structure. Other researchers took a more fundamental approach and began with
simpler and more readily available raw materials. In the UK, a team at Leicester
University succeeded in building a basic taxane structure from glucose (in 1985)
and later attempted semi-synthesis using a taxane - 'taxacin' - extracted from
Taxus baccata clippings collected from the hedges of Longleat House [43].
Total synthesis was finally achieved by two teams - by Robert Holton's team
at Florida State University in December 1993 and by Kyriacos Nicolaou's team at
Scripps Research Institute (La Jolla, California) in January 1994. Both teams
published their results in 1994 [44].
Holton's team started their process using camphor, while Nicolaou succeeded
in building and combining the separate ring structures. An alternative approach
taken by Dr Paul Wender of Stanford University began with Pinene, a major
component of turpentine obtained from Pine trees, which has the same
'handedness' as Taxol and a 'bicyclic terpene' structure related to camphor.
Pinene could be converted to the taxane core of Taxol in eight stages [45], but the latest reports found (dated 1995) do not suggest that
the process has been taken as far as producing Taxol [46].
In all cases the process is complex, and even at an early stage it was
acknowledged that total synthesis was unlikely to become commercially viable in
the short term. Total synthesis was however seen as a major breakthrough, and as
a valuable research tool to investigate new and possibly more effective
compounds.
A more practical approach was felt to be industrial scale cultures of tissue
from the Yew. Some of the first papers and patents relate to cultures of
separate cells [47], while others relate to callus cultures
in which plant fragments were grown in a nutrient medium [48]. In all cases, the aim has been to provide an industrial scale
of production, preferably on a continuous basis, to produce either Taxol, a
pre-cursor such as DAB III, or some new active compound. To do this the tissue
has to be provided with appropriate conditions and nutrients, and much research
has been done on increasing the production of the required secondary metabolites
[49]. Equally, the required product has to be extracted from
the growth medium since, if not removed, the increasing concentration reduces
the rate of production and reduces the viability of the process [50]. In the last two years (1995-April 1997) the yield of large
scale plant cell cultures for Taxol have been increased 100-fold [51].
In all of these processes, none of which are yet used commercially, the
plant's own mechanisms are being used to produce the product. Other research
therefore looked at the plant to find out how this production might be improved.
Since one of the higher concentrations of Taxol (after the bark) is within the
roots of Yew, one proposed approach has been to stimulate the root growth in
cultures - a process known as 'hairy root culture'. This can be induced by
genetic transformation using a DNA fragment - a 'plasmid' - from
Agrobacterium, which affects the regulation of auxins within the tissue,
and thus the form of the root growth [52].
The variations in Taxol concentration within the Yew tissues also show that
it is not highest in new growth, but - as with many 'secondary' metabolites - it
is associated with the differentiation of tissues in the 'late exponential
growth' and 'stationary' phases [53] - callus cultures in
contrast comprise largely undifferentiated tissue. Attempts were therefore made
to encourage such differentiation in cultures - a process known as 'somatic
embryogenesis' whereby plant fragments or individual cells are developed into
fully differentiated shoots within a growth medium. This process has been used
for many years to propagate plants, but only more recently (1985) has it been
demonstrated in conifers. A patent filed in 1993 [54]
proposes this as a means of producing Taxol.
An earlier patent, filed in 1992 by Roy Stahlhut of the ESCA Genetics
Corporation [55], proposed the production of Taxol and
taxanes in Yew tissue by inducing galls in which the compounds are concentrated.
As with hairy root culture, the galls - crown galls - are induced by introducing
strains of Agrobacterium (e.g. A. tumefaciens) into the plant
tissue. Several techniques are mentioned in the patent including simply wounding
the seedling using a needle dipped in the Agrobacterium culture, and
using a particle gun to fire microspheres of plastic, cellulose or starch into
the cambium. In the preamble to the patent it is noted that the biosynthetic
pathways in a gall may differ from normal tissue, hence it was satisfying for
the researchers to find not only that taxanes were produced in the galls, but
that they were produced in higher concentrations and more rapidly that in normal
tissue - it appears that the taxane production also takes place within the main
growth phase rather than later. The proposal in the patent is that the galls can
be harvested from the living tree as a renewable source of the drug.
Agrobacterium is also used as a 'vector' in genetic engineering to
introduce tailored DNA fragments - 'genes' - into plants as varied as grape
vines, alfalfa and maize [56]. Its use demonstrates that
genetic material can be transferred between organisms in a controlled
environment, and it is now known that this process also occurs in nature.
A possible example was found in 1992 [57] when Dr Gary
Strobel, of Montana State University, was inspired (supposedly by 'walking
around a favourite mountain lake') to search the Yew trees for fungi [58]. Strobel's team isolated a new 'endophytic' fungus from inner
bark samples taken from a Yew tree in Montana's Glacier National Park. Initially
known as 'Montana BA', the fungus was cultured and was found to produce Taxol
which could be extracted from the culture medium. It seemed that the fungus
shared the capability to produce Taxol with its host, possibly by the transfer
of genetic material, though it remains unclear where the ability originated. The
fungus, now named Taxomyces andreanae (after Andrea Stierle, one of the
original team), and the extraction process were patented [59] and caused a flurry of optimistic reports in scientific
journals [60].
Since then, the rights to develop the fungus have been acquired by Cytoclonal
Pharmaceuticals Inc. who specialise in fungal genetic engineering [61], and it is reported that they have now isolated the gene
complex responsible for synthesis of the Taxol ring structure [62].
Further similar finds have been reported since, including another fungus,
Pestalotiopsis microspora, which also produces Taxol [63]. An interesting aspect is that the production of Taxol occurs
in the fungus when isolated not only from a Yew (T. wallichiana), but
also from the Bald Cypress, Taxodium distichum. P. microspora is a
disease of various trees, and is reported to be a threat to a rare member of the
Yew family - the 'Stinking Yew' or 'Florida Nutmeg' (Torreya taxifolia)
[64]. A recent patent [65] also reports
the production of taxanes, including Taxol, by a bacteria ('a novel bacteria of
the genus Erwinia') isolated from Taxus canadensis.
The 76 patents approved between January 1996 and June 1997 [66] show that Taxol is still a major topic of research and
development, and the valuation of the 1997 market at a billion dollars shows
that it is major earner for the drug companies.
On the clinical side [67], Taxol's original approval was
for ovarian cancer which had failed to respond to other treatments. Similarly
the approval in 1994 for breast cancer was for 'refractory' cancers, not as a
first line therapy. Phase II and III trails were started in 1995 for the use of
Taxol as a first line therapy for both ovarian and breast cancer [68] - some results have been published this year [69] but no further approvals have been reported.
Trials also started in 1995 for its use on non-small cell lung cancers, and
head and neck cancers [70], and a recent paper (1997)
reported results of a Phase II trial on non-Hodgkin's lymphoma [71] - a cancer of the lymph system which is far less responsive to
treatment than Hodgkin's Disease. Other papers cover a range of other trials -
e.g. for small cell lung cancer [72], and for pancreatic and
gastric cancers [73]
Recent technical developments may also lead to new applications. Already in
1997, a patent has been granted to Kyriacos Nicolaou and his team for water
soluble Taxol derivatives - essentially a water soluble 'pro-drug' which is
converted within the body to the normal Taxol structure [74].
Another significant area of interest is in overcoming the inability of
complex molecules such as Taxol to pass through the 'blood-brain' barrier. This
natural line of defence not only prevents dangerous chemicals passing into the
brain tissue, but also excludes drugs which may affect diseases of the central
nervous system. One approach is to use a substance which passes through the
barrier, and which occurs naturally in the brain, to 'carry' a drug molecule.
One such substance is known as DHA, a fatty acid, in which the glycerol molecule
can be replaced by other compounds. Pre-clinical trials have started using DHA
to carry dopamine, a neuro-transmitter, and laboratory experiments have attached
DHA to Taxol. The company Neuromedica intend to file an 'investigational new
drug application' for DHA-Taxol within 1997 [75].
In June of this year, an alternative approach to the blood-brain barrier was
published [76] in which the Taxol (or some other anti-cancer
drug) would be ferried to the site of a brain tumour within a lipid coated
'micro-bubble'. Similar 'liposomes' are being used experimentally to carry DNA
fragments for gene therapy since they can fuse with cells and carry their
contents directly into the cell structure [77].
Ovarian cancer remains as the main fully approved use of Taxol, now often in
combination with platinum compounds. It is however still not a cure for the
cancer. Ovarian cancer is especially difficult to treat - it is known as the
'silent disease' since it only shows any symptoms late in its development [78] - and though Taxol/Cisplatin has been shown to extend a
patients life expectancy by over 50%, this is still only from 24 to 37 months
(on average) [79]. These figures were reported in a paper
considering the cost effectiveness of the treatment.
The cost of such treatments and the involvement of large drug companies has
been a continuing issue both for natural products and for synthetic materials.
Some reports [80] suggest that when Taxol became openly
available BMS had made little contribution to its development - they relied on
research provided by NCI and funded by the US government - and that BMS made an
excessive profit. Though the market price was $4.87 per milligram (about $9000
for a complete treatment), Hauser Chemical sold the drug to BMS for only $0.25
per milligram.
Further controversy has arisen over whether companies can 'trademark' a
natural product [81] and more recently over the issues
surrounding the patenting of natural genetic sequences [82].
Whatever view one takes, it is currently inevitable that a drug with the
potential of Taxol should become a commercial commodity, and that a large
proportion of the $1bn spent on Taxol in 1997 will be profit for BMS. Hauser
Chemical no longer make Taxol for BMS - their contract was cancelled in 1994 as
BMS moved to the semi-synthetic product. They do however still make Taxol, and
after several 'lean' years they are currently gearing up for December 1997 when
BMS lose their exclusive rights to the product. Hauser and a European partner
then plan to market a generic form of the drug especially in Europe and Eastern
Europe [83].
Taxol has achieved its high profile in spite of not 'curing' any disease,
though many people with few other options have 'lived longer with less
discomfort' [84]. One may wonder whether the success of
Taxol has been one of marketing and pure research as much as of medicine and
human benefit - and therefore whether such a development has really been
worthwhile. The alternative view would be that without such research and
development we will never succeed in finding any 'cures'.
The discovery of the Vinca alkaloids in the 1950s, and their development to
'cure' many patients with leukaemia and Hodgkin's Disease [85] encouraged the systematic search which discovered Taxol.
Between 1960 and 1980 the search only found two successful drugs - Taxol and
Camptothecin [86] - out of 114,000 separate extracts from
35,000 plant species, and this NCI project was discontinued in 1982. A new
project was initiated in 1988 by the NCI Natural Products Branch, and now runs
in collaboration with other world-wide groups and emphasises both the
involvement of local indigenous people, and that these people should benefit
from any commercial developments [87]. A number of companies
have also sprung into being to exploit this field, including Shaman
Pharmaceuticals who specialise in plants used by traditional healers [88], and EcoPharm, formed by Gary Strobel, who are working with Eli
Lilly to examine plant based microbes [89]. In some cases,
as with EcoPharm, the new emphasis is on the drugs needed to treat the
complications of AIDS.
The story of Taxol is now based in the chemical laboratory and the hospital
(and the board room) rather than in the forest, but across the world the search
for new medicines from plants continues.
Meanwhile, in the mountains of the western United States there is a tree
which has had its fifteen minutes (or twenty years) of fame, and which may once
again be destined to become brush-wood. It has however emphasised the potential
value of products from nature, both in themselves and as models for other
developments, and therefore the need to conserve the diversity of our natural
resources.
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Footnotes
Bibliography
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Taxol was shown to have a complex structure found in a range of
compounds collectively known as 'taxanes'. Figure 1 (right) shows Taxol's
structure compared to other taxanes including Taxine B. It is described as "a
complex diterpene [comprising] a taxane ring system with a four-membered oxetane
ring and an ester side chain at position C-13" [12]. The
'taxane ring' structure comprises 3 rings (A, B and C) which form a folded
structure bringing rings A and C almost parallel, the 'oxetane' ring (ring 'D')
being attached to carbons 4 and 5 of ring C. The ester chain was later shown to
be essential to the cytotoxicity of Taxol and of its analogues [13]. The complexity and asymmetry of the structure suggested that
synthesis would be difficult.