Taxol baccata

A fine example of such a semi-synthesis is the preparation of the anti-cancer drug paclitaxel (Taxol ), a relatively scarce compound from Taxus brevifolia. Here, the natural and better accessible 10-deacetylbaccatin III, isolated from the leaves of Taxus baccata, provides the complicated ring system of paclitaxel, including all substituents with the right stereostructure (Scheme 5.1). In just four reaction steps [5] paclitaxel is obtained from 10-deacetylbaccatin III. 

Taxol was the most triumphant new anticancer drug developed in the last few decades. It resulted from a drive to screen thousands of synthesized compounds and plant extracts, financed by the National Cancer Institute (Georg et al. 1994, Suffness 1995, Goodman and Walsh 2001). Taxol is extracted from the bark of the Pacific yew tree, or Taxus brevifoli, found in the Pacific Northwest, and has been proven effective against intractable breast and ovarian cancers. It is now produced by semi-synthetic methods from the needles of the common ornamental tree English Yew, or Taxus baccata. We will discuss taxol in greater detail in Chapter 2. 

With an increasing number of novel lead candidates that enter into preclinical development, considerable resources are needed to identify impurities. LC/MS-based approaches provide integrated sample cleanup and structure analysis procedures for the rapid analysis of impurities. This advantage was demonstrated during the preclinical development of TAXOL . LC/MS played an important role for the identification of impurities contained in extracts and process intermediates from Taxus brevifolia and T. baccata biomass. Because drugs derived from natural sources often have a very diverse set of structural analogs, it is important to determine which... 

It has been estimated that six 6-inch-diameter trees would have to be sacrificed for enough Taxol to treat one woman suffering from ovarian cancer. Considering that the number of potential patients in the late 1980s numbered approximately 12,000, an eventual limitation of Taxol was possible. Fortunately, the problem was solved in the early 1990s by the partial synthesis of Taxol from a precursor produced in needles and twigs from the more renewable Taxus baccata. 

From Taxus baccata (Taxaceae) the alkaloid taxol has been isolated. Taxol also affects the architecture of microtubules in inhibiting their disassembly (312). Nonalkaloidal compounds to be mentioned in this context include the lignan podophyllotoxin (312). In conclusion, any alkaloid which impairs the function of microtubules is likely to be toxic, because of their importance for a cell, and, from the point of view of defense, a well-working and well-shaped molecule. 

These taxol-type compounds have already been described by Suffness and Cordell (3). The various substances extracted from the bark of T. baccata, T. watlichiana, or T. brevifolia differ only in the nature of the substituents R, Rj, and Rji R, may be a free hydroxyl group or a xylose derivative (/4), R2 a hydroxyl, acetyl (taxol), or hydroxybutyrate group (74), and R3 a phenyl (taxol) (2), tiglate (cephalomannine) 28), or hexanoate group (74). 

Despite the existence of a large number of taxol derivatives, only taxol itself has given rise at present to significant pharmacological and biological studies. However, some work employing the mixture taxol—cephalomannine 115) (more easily extracted from the bark of T. baccata than taxol itself) as well as derivatives having a xylose residue attached to the taxane skeleton may be cited 116). 

VanHaelen-Fastre, R. Diallo, B. Jaziri, M. Faes, M.-L. Homes VanHaelen, M. High-speed countercurrent chromatography separation of taxol and related diterpenoids from Taxus baccata. J. Liq. Chromatogr. 1992, 15, 697 - 706. 

A chief problem in the early development of taxane pharmaceuticals was the establishment of a steady and dependable supply. Taxanes are present in low quantities in plants. In contrast, taxines are relatively abundant in plants (especially in Taxus baccata and Taxus cuspidate), they can serve as an alternative starting material for semisynthetic production of paclitaxel derivatives. The major taxines are taxine A and taxine There is a significant structural resemblance between taxine B and taxanes (Fig. 1). Both groups share the main taxane ring moreover, the C-5 side chain of the taxines has a close spatial position to the C-13 side chain of the taxanes (the latter is essential for antitumor activity). A biosynthetic hypothesis involved the intermediacy of a C-5 to a C-13 ester transfer it was also demonstrated that taxine B can be converted into a baccatin V derivative. Taxines do not show antitumor activity, whereas the cardiotoxicity of taxol is lower compared to taxines but is undesirable for... 

Diterpenes (C20) can be linear as in the phytol part of chlorophyll or mono- to tetracyclic.87 Very well researched are the tricyclic taxanes of which taxol A from the Taxus baccata tree inhibits cell division and has found use in anticancer treatment. Certain labdanes inhibit blood platelet aggregation and kaurane norditer-pene glycosyl ester atractylosides from the Mediterranean thistle block the ATP/ADP translocation - such diterpenes are very toxic when ingested. Ubiquitous plant-derived kaurane-type diterpenes are the plant hormones (gibberellins) or defense substances (phytoalexins). 

The diterpene taxol is used as a potent chemotherapeutic agent in cancer treatment. The hmited supply of the drug from the natural source, the bark of the Pacific Yew (Taxus brevifolia), was overcome by a semisynthetic approach. Taxol is presently manufactured by coupling the advanced naturally occurring taxoid 10-deacetylbaccatin 111, isolated from needles of the more abundant Tdxus baccata, to a synthetic side-chain precursor. 

Phytotherapy Research (United Kingdom), 1996, 10/SUPPL. 1 (S25-S26) Properties and medieal use of flavonolignans (Silymarin) from Silybum marianum. Kersey RG, Vanee NC, Taxol and cephaomanine from Taxus baccata needles.In JNP59[2] 117-123.1996. 

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. 

Such fingerprints of mass spectral fragmentation have been useful in dereplication and in identification of family similarities. For instance, a family of 18 different naturally occurring taxol analogs were each identified from crude extracts of Taxus brevifolia and Taxus baccata by a procedure primarily based on analysis of their behavior under LC-MS-MS conditions (33). Fourteen different molecular ions were obtained for the eighteen compounds, but after the four or five fragmentations depicted in Fig. 4, each compound exhibited an identical template ion of 327 m/z, representing the ionized taxol core. 

Forgacs, E. Use of porous graphitized carbon column for determining taxol in Taxus baccata. Chroma-tographia, 1994, 39, 740-742... 

The most enthusiastic reports concern the diterpenoids paclitaxel, Taxol (from Taxus brevifolia) and docetaxel, Taxotere (from Taxus baccata) having unique tri- or tetracyclic 20 carbon skeletons extracted from the bark of yew. This tree was known as a toxic plant for animals and humans for centuries. Monroe E. Wall and Mansukh C. Wani, at the Research Triangle Park (Chapel Hill, USA), identified the active principle of the yew tree in 1971. In 1979, Susan Horwitz of the Department of Molecular Pharmacology, Albert Einstein College of Medicine (New York) suggested that paclitaxel s mechanism of action was different from that of any previously known cytotoxic agent. She observed an increase in the mitotic index of P388 cells and an inhibition of human HeLa and mouse fibroblast cells in the G2 and M phases of the cell cycle. 

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