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Chemistry


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Common Yew (Taxus baccata)

A sprig of yew (Taxus baccata) in a separating funnel, together with the molecular structure of taxine A.

A sprig of yew (Taxus baccata) in a separating funnel, together with the molecular structure of taxine A.

In the days just before Christmas, you can often find yew branches in Christmas wreaths, where their red ‘berries’ contrast with the green leaves perfectly. The yew has been called “tree of life” for its longevity and more recently also because it was found to contain anticancer drug-related compounds. However, it is also called the “tree of death”, because it is highly poisonous for humans and livestock. Are the compounds of life and death related, or is it another case of “It’s not yew, it’s me.”? (Sorry, poor pun… (NF))

Fig. 1: Common yew (Taxus baccata) in a separating funnel together with the molecular structure of taxine A in ball-and-stick representation.

Fig. 1: Common yew (Taxus baccata) in a separating funnel together with the molecular structure of taxine A in ball-and-stick representation.

1. The main picture and Fig. 1 both show a yew branch in a separation funnel, together with the molecular structure of one of yew’s key components, taxine A, in two different molecular representations. The separating funnel gets used in science laboratories to separate immiscible solvent phases, allowing the extraction of compounds from solutions, for example from plant extracts or reaction mixtures. One solvent phase is usually water (with or without additives) and the other an organic solvent such as ethyl acetate or dichloromethane. The solvents and the compound mixture are placed in the closed separation funnel and mixed by shaking, followed by time where the two phases are allowed to separate according to their densities. Water-soluble (hydrophilic) compounds end up in the aqueous phase while the rest (hydrophobic and lipophilic) ends up in the organic phase. Fig. 2 shows the two phases in a separation funnel. The organic solvent phase here is ethyl acetate, which is less dense than water and so makes up the top layer. Here this phase contains coloured compounds from a fungal extract.

Fig. 2: A separating funnel in action, showing the molecular structure of taxine B in the organic layer.

Fig. 2: A separating funnel in action, showing the molecular structure of taxine B in the organic layer.

The common yew, also named European or English yew (Taxus baccata), is one of the evergreen trees found mainly in old church yards or cemeteries in Europe. If you are wondering why they are so common there, the better question is possibly why they are not widespread in forests anymore. The wood of yew trees has been used for music instruments and longbows since at least the Bronze Age (in Britain, from ca. 2,300 to 800 BC). Demand for yew grew dramatically over time: English medieval records show a serious shortage of yew so that archers had to be allowed to use other wood for practice bows. Ships coming to an English port had to bring several bow staves of yew to be allowed into the port and trade their merchandise. During the late 16th century the tree disappeared from many forests in Europe. Today it is appreciated by gardeners as a slow growing evergreen shrub, and a range of cultivars with different shades of green needles are available. It is particularly suitable for hedging and topiary, making it a key plant in traditional English gardens; it has also been used to make a three-dimensional maze in the gardens of Longleat House.

Some plants of Taxus baccata are thought to be not just hundreds but thousands of years old and it is thus among the longest-living plants in Europe. The oldest known yew tree in the British Isles is the Fortingall Yew in Perthshire, Scotland, which is thought to be around 2,000 years old. Not only are these trees slow-growing and long-lived, fossil records indicate that yew trees have existed for more than 200 million years with little evolutionary change.

Most parts of the yew tree are highly poisonous except the red “berries” surrounding the seeds (botanically, these are not really berries, but this goes beyond this blog post). The Celts and ancient Germanic tribes knew about the poisonousness of the yew, which played an important part in their mythology. In addition, they used the yew sap to make their arrows poisonous for hunting.

2. Attempts to isolate and identify the toxic compound started in the early 19th century and the white powder that was obtained after extraction was named taxine. As often the case with natural compounds, i.e. those extracted from plants, fungi or animals, a number of very similar molecules can be produced by a single organism and in 1956 it was realised that there are several taxines present in the leaves of the common yew (Toxicon 2001, 39, 175-185).

Fig. 3: The molecular structures of taxines A and B, highlighting the isoprene units in red and green

Fig. 3: The molecular structures of taxines A and B, highlighting the isoprene units in red and green

Chemists call these molecular families “derivatives” and tend to give them letters, e.g. taxine A, B, C… Fig. 3 shows taxine A (also shown as a space-fill structure in the main image and in ball-and-stick representation in Fig. 1) and B (also in Fig. 2), the main taxines in the common yew leaves. Taxine B is found in much higher concentrations. For taxanes, as this group of derivatives is commonly called, more than 100 have been discovered to date, and these have been extracted from various yew species. If you want to see more taxane structures, have a look at the following link.

Chemically, taxanes are diterpene molecules. You might have come across diterpenes in our post on Euphorbia spp. a little while ago, where we showed how they are built from four isoprene units (C5H8). In the structure of taxine B (Fig. 3) we have coloured the joined isoprene units in festive colours, alternating red and green.

Taxol (later renamed paclitaxel after the name Taxol was trademarked for the formulation, including solvents, marketed as a drug, Fig. 4), another taxane, was discovered as a very active compound in a large-scale screen of plant extracts to identify whether they might kill cancer cells. The extract came from the bark of a Pacific yew tree (Taxus brevifolia). Despite the promising screening results, for years there was a shortage of paclitaxel, because Pacific yew trees are not common and their range is restricted to the West coast of North America. This held back the extensive testing new pharmaceuticals have to undergo before they can be introduced as drugs to patients, not to mention the problems with securing a regular supply for treating patients in the longer run.

Fig. 4: The structures of taxol, docetaxel and 10-deacetylbaccatin III

Fig. 4: The structures of taxol/paclitaxel, docetaxel and 10-deacetylbaccatin III

Paclitaxel is extremely difficult to make by chemical synthesis, because of its 11 chiral centres (highlighted by an asterix in Fig. 4). At each chiral carbon centre, two different arrangements in space are possible for the four groups connected, making them non-superimposable mirror images. (For more about chirality, have a look at the post on roses.) It can be difficult to selectively synthesise just one form of a chiral compound, and this becomes increasingly complicated as the number of chiral centres goes up. However, by 1992 thirty research groups worldwide had taken up the challenge of developing its total synthesis. The first results were published in 1994, and others have been reported since. But even today, no synthetic route that is economically viable is known.

Nevertheless, paclitaxel and its semi-synthetic analogue docetaxel, are used to treat patients with various cancers, e.g. lung, ovarian, prostate, breast and head and neck cancer. The solution to the supply problem was again found in nature. The common yew may have actually rescued her sister tree, the Pacific yew, from becoming extinct in the hunt for paclitaxel by producing a valuable precursor for a semi-synthesis in its leaves. This precursor, 10-deacetylbaccatin III (shown in Fig. 4), provides the complete right hand side of paclitaxel, including 9 of the 11 chiral centres. 10-Deacetylbaccatin III can be isolated in large quantities from the needles of the common yew and in the UK large amounts of clippings are collected in parks and gardens to extract this compound. Other routes of production are being explored and used, such as cell fermentation in a culture of Taxus brevifolia, securing the supply of paclitaxel through biotechnology, rather than chemical routes.

Yew (Taxus baccata), together with some common laboratory equipment - a separating funnel, a conical flask and a sample bottle.

Yew (Taxus baccata), together with some common laboratory equipment – a separating funnel, a conical flask and a sample bottle.

3. (Short so you can have your Christmas lunch…) The intriguing discovery that paclitaxel had a new mode of preventing the proliferation of cancer cells inspired fields beyond cancer research. This goes beyond the chemistry of taxanes, but if you would like to read more about this mechanism, have a look at Nature Reviews 2004, 4, 253-265. Despite the hydroxyl (OH) groups surrounding its complicated core, paclitaxel is very lipophilic and the compound needs to be injected in a solvent mixture that causes side effects. These solubility issues can be addressed by changing how the drug is delivered and this has been reviewed in J. Nanomed. Nanotechnol. 2013, 4, 100164 and Anticancer Research 2010, 30, 903-910.

Ongoing research projects are using structure-activity relationships and developing new paclitaxel derivatives, which should have higher activity, greater specificity, better solubility or indeed all of the above. Some of the strategies have been summarised in a review : The Chemical Record 2001, 1, 195–211.

The common yew is not just a pretty ornament in your Christmas wreath, but also contains a valuable weapon in the fight against cancer – food for thought perhaps in this season of good will, and a useful conversational snippet if you happen to see friends and family. Have a great break!

Contributors: Katja Fisch (research, photographs, writing), Natalie Fey (molecular structures, editing).