European yew

Environmental groups objected to this practice, and many demonstrations were staged. A solution was eventually found when the needles of the European yew tree Taxus baccata) provided a source for the paclitaxel precursor without destroying the bark. 

Early production of 1 kg of paditaxel required extraction from about 13,000kg of the Pacific yew tree bark. This process was refined, and pacli-taxel is now produced by a semisynthetic route. The starting material, 10-deacetyl baccatin 111 (10-DAB), is obtained from the needles of Taxus baccata (European yew) or T. wallichiana (Himalayan yew). The yield is around 1000 kg of needles to produce 1kg of 10-DAB. 

When studying the Pacific yew s close relative, the European yew, chemists made an exciting discovery that led to the second solution. 

The needles and twigs of the European yew contain 10-deacetylbaccatin III, shown at the bottom of the page. A few reaction steps can transform 10-deacetylbaccatin III into TAXOL . Instead of destroying an entire Pacific yew tree for a single treatment of TAXOL , scientists can now use the needles from a European yew. The parent tree is not harmed. 

A brilliant example for the industrial-scale application of plant cell fermentation is the new process for the production of the anticancer drug paclitaxel developed by Bristol-Myers Squibb (see Figure 15.1). It starts with clusters of paclitaxel producing cells from the needles of the Chinese yew, T. chinensis, and was introduced in 2002. The API is isolated from the fermentation broth and is purified by chromatography and crystallization. The new process substitutes the previously used semisynthetic route. It started with lO-deacetylbaccatin(III), a compound that contains most of the structural complexity of paclitaxel and can be extracted from leaves and twigs of the European yew, T. baccata. The chemical process to convert 10-deacetylbaccatin(III) to paclitaxel is complex. It includes 11 synthetic steps and has a modest yield. 

The alkaloid ester paclitaxel (7.93) is a natural product derived from the western yew (Taxus brevifolia) and European yew (Taxus baccata). This agent functions as a mitotic spindle by causing excessive tubulin polymerization. Paclitaxel has demonstrated considerable clinical utility in ovarian and breast cancer. 

Paclitaxel is an alkaloid ester derived from the Pacific yew (Taxus brevifolia) and the European yew (Taxus baccata). The drug functions as a mitotic spindle poison through high-affinity binding to microtubules with enhancement of tubulin polymerization. This promotion of microtubule assembly by paclitaxel occurs in the absence of microtubule-associated proteins and guanosine triphosphate and results in inhibition of mitosis and cell division. 

Docetaxel is a semisynthetic taxane derived from the European yew tree. Its mechanism of action, metabolism, and elimination are identical to those of paclitaxel. It is approved for use as second-line therapy in advanced breast cancer and non-small cell lung cancer, and it also has major activity in head and neck cancer, small cell lung cancer, gastric cancer, advanced platinum-refractory ovarian cancer, and bladder cancer. Its major toxicities are listed in Table 54-4. 

Figure 7.4 European yew tree Taxus baccata) close-up of leaves.

With the successful development and commercial manufacture of semi-synthetic Taxol , tile destruction of the Pacific yew tree forests was halted. However, this successful move away from an essentially non-renewable source (extraction of the Pacific yew tree bark) to a renewable source (harvested European yew tree leaves and twigs to obtain 10-DAB, followed by syntliettc transformation to Taxol ) still presented significant environmental challenges. The use of 13 different solvents. 

Lignans were found in the Taxus extracts prepared from bark, heart-wood, needles, roots, or other parts. In the studies on European yew T. bac-cata L. carried out by Das et al., the extracts were prepared by extracting from the needles rather than the heartwood of the plant using a solvent system CL Ck-MeOH (1 1) [70-73], although in the studies on Turkish T. baccata, the extracts were prepared by applying EtOH to the needles and twigs of the plant [74-76]. So far, after many studies of T. baccata... 

One of the most intensely studied Taxus species, due to its biological activities, is T. baccata L. The needles of this plant have shown hepato-protective, tranquilizing and sedative properties, presumably related to the benzodiazepine-like activity of its biflavones. In contrast to the European yew T. baccata, the Himalayan yew T. wallichiana has a long history of use in medicines, as well as in coloring materials and as incense [86]. 

Chemists synthesize molecules for many reasons. Sometimes a natural product, a compound isolated from natural sources, has useful medicinal properties, but is produced by an organism in only minute quantities. Synthetic chemists then prepare this molecule from simpler starting materials so that it can be made available to a large number of people. Taxol (Section 5.5), the complex anticancer compound isolated in small amounts from the bark of the Pacific yew tree, is one such natural product. It is now synthesized commercially from a compound isolated from the leaves and needles of the European yew. 

Few data are also available on the concentration of alkaloids in different plant parts. The red aril surrounding the seeds does not contain taxoids, and the alkaloids, at least in the European yew, seem to be concentrated mainly in the needles, where their concentration can be higher than 1% on dry weight basis [29], The alkaloid contents varies greatly during the course of the year, and is higher in winter [29], It was recognized early that taxine from different yews is different [5], but the complexity and instability of taxine has so far prevented its full characterization in species different from the European yew. Furthermore, no data on the concentration of taxine in the other species have been reported. 

Paclitaxel and docetaxel are taxane plant alkaloids with antimitotic activity (see Table 124-12). Paclitaxel was isolated from the bark of the Pacific yew tree, Taxus brevifolia, but is now produced semisyntheti-cally from the needles of the European yew, Taxus baccata. Docetaxel is a semisynthetic taxoid extracted from 10-deacetyl baccatin III, a noncytotoxic precursor found in the renewable needle biomass of yew plants. ... 

TAXOL (Paclitaxel) was first isolated from the bark of the Pacific Yew, Taxus brevifolm Nutt., family Taxaceae. Because of its value, supplies were difficult to obtain. Attempts to address the supply issue have involved semisynthesis from baccatin III or 10-deacetylbaccatin III which are taxanes found in the needles of the common European Yew Taxus baccMa L. Other approaches have involved the use of fungal and tissue culture. 

The supply problem was partially solved through improvements in the extraction process from Pacific yew, but a more radical solution was achieved by French groups under the leadership of Pierre Potier in Paris and Andrew Greene in Grenoble. They discovered that the needles of the European yew, Taxus baccata, contained a structural relative of taxol called 10-deacetylbaccatin III to the extent of around 1 g per 3 kg of needles. This natural product could be converted to taxol in four chemical steps in a process discovered by Robert Holton in the USA. Since the European yew grows relatively rapidly, the needles could be harvested and the supply of taxol was thus assured. 

Paclitaxel (Taxol ) is an anti-cancer agent originally obtained from Pacific yew tree bark. The complexity of the molecule makes chemical synthesis from simple compounds economically unfeasible. For instance, one of the most efficient semisyntheses starts from 10-deacetylbaccatin III, a more abundant taxoid obtained from needles of the European yew tree (Scheme 8.16) [67,68], However, the process is still long, requiring 11 chemical transformations. 

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