Discovery of Paclitaxel

Dioscurides writes in his pharmacology teachings (De Materia Medico) that yews in Narbonia (the present-day arrondissement of Narbonne) are so poisonous that people even resting in their shade come to harm and may often die. In the Middle Ages, yew extracts were used for the treatment of epilepsy. 

126 Memorial to King Ambiorix in Tongeren (a town in what is now Belgium). The Eburones lived 54 BC in a dual kingship under the rule (sub imperio) of Ambiorix and Catuvolcus. The Eburones were a Celtic tribe, whose territory lay between the rivers Rhine and Maas, the Rhineland, the northern Ardennes and the Eifel. 

The red and sweetish aril is however non-poisonous. It may be preserved as a jam, so long as the poisonous seeds are removed carefully. 

128 The highly functionalised, tetracyclic W-desacetylbaccatin Hi was likewise found in the Pacific yew, and proved iater to be the key intermediate for partial syntheses. 

Phase I clinical studies began in 1983. Problematic from the beginning, however, was the supply of paclitaxel. A 100-year old yew has around 3 kg of bark, out of which 300 mg of paclitaxel can be isolated. Bristol-Myers-Squibb (BMS) patented a process for the extraction of paclitaxel from the yew bark. In 1992, there were harvested just 1,400 tonnes of bark, from which 139 kg of paclitaxel could be isolated. A year later already, paclitaxel came on to the market under the trade name Taxol . 

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The non-rational and unplanned exploitation of the natural resources may result in the loss of important medicinal species. The non-rational exploitation of Taxus brevifolia is a clear example. This specie was threatened with the discovery of paclitaxel and it became necessary to found another renewable source of this metabolite [1]. The agronomical practices are an alternative to avoid the devastation of medicinal plants. Growing medicinal plants instead of collect them from nature has several advantages because it is possible to control the presence of pathogens, temperature, soil conditions and humidity, among others, in order to ensure the optimum growth and secondary metabolites production. 

Cancer is a disease, which has been known since antiquity. The discovery of paclitaxel and the development of Taxofl are milestones in natural product synthesis and also in cancer research. 

Since the discovery of vesicular structures, termed liposomes, by Alec Bangham, a tremendous amount of work on applications of liposomes has emerged. The use of small unilamellar liposomes as carriers of drugs for therapeutic applications has become one of the major fields in liposome research. The majority of these applications are based on the encapsulation of water-soluble molecules within the trapped volume of the liposomes. Long circulating poly(ethylene glycol) (PEG) modified liposomes with cytotoxic drugs doxorubicin, paclitaxel, vincristine, and lurtotecan are examples of clinically applied chemotherapeutic liposome formulations (1,2). 

As will be mentioned further in this chapter, the discovery of the anticancer drug, paclitaxel (21), was soon followed by sourcing issues due to the low yield of this compound in the source plant, Taxus brevifolia Nutt. This led to the semisynthesis of paclitaxel (21), from a precursor molecule, 10-deacetylbaccatin III, readily available from the leaves of Taxus baccata L., a renewable source with high yields of this compound.Docetaxel (37) is a second taxane class anticancer drug and is a semisynthetic derivative of paclitaxel (21). ... 

A major advantage of the natural products approach to drug discovery is that it is capable of providing complex molecules that would not be accessible by other routes. Compounds such as paclitaxel (Taxol, 8) or rapamycin (10) would never be prepared by standard "medicinal chemistry" approaches to drug discovery, even including the newer methods of combinatorial chemistry. Likewise, the new approach of combinatorial biosynthesis, although an important one, is unlikely in the near future to yield new compounds of the complexity of paclitaxel and camptothecin. 

Natural products have served as a major source of drugs for centuries, and about half of the pharmaceuticals in use today are derived from natural products. Quinine, theophylline, penicillin G, morphine, paclitaxel, digoxin, vincristine, doxorubicin, cyclosporin, and vitamin A all share two important characteristics they are cornerstones of modem pharmaceutical care, and they are all natural products. The use of natural substances, particularly plants, to control diseases is a centuries-old practice that has led to the discovery of more than half of all modem pharmaceuticals. 

In this chapter, we describe an account of our research on the chemistry and biology of paclitaxel and taxoid anticancer agents (taxoid = taxol-like compound). The topics covered in this chapter include (i) the development of a practical and efficient method for the semisynthesis of paclitaxel and docetaxel using chiral 3-hydroxy-P-lactams as synthetic intermediates, (ii) structure-activity relationship (SAR) studies of various taxoids that led to the discovery of the extremely potent second-generation taxoids, and (iii) biological and conformational studies with the use of fluorine-containing taxoids as probes. ... 

Our SAR study of paclitaxel analogues on their ability to activate macrophage, inducing the production of NO and TNF, has revealed stark differences in the structural requirements for cytotoxicity vs. macrophage activation. The results warrant a great deal of further study on the possible alternative or auxiliary mechanism of action for paclitaxel and taxoids, which might lead to the discovery of a new series of taxoid anticancer agents with unique mechanism of action. 

Small molecules modulating microtubule assembly have played major roles as tools in microtubule research, in a manner closely related to their chemotherapeutic interest [1], Tubulin was first purified in the last century as the colchicine-binding protein proposed to be the subunit of cellular microtubules [2], More recently, a colchicine derivative was employed to help crystallization and determine the structure of tubulin by X-ray diffraction [3], The colchicine, vinblastine [4] and paclitaxel [5] sites are main drug binding sites of tubulin, to which many other substances bind. The discovery of microtubule stabilization by paclitaxel [6] prompted its clinical development [7] and a burst of research on new MSAs, as well as the generalized use of paclitaxel or docetaxel as convenient reagents to assemble (see Fig. 1), stabilize or detect microtubules in the laboratory. One example is the development... 

Natural products have provided some of the most effective drugs for the treatment of cancer, including such well-known drugs as paclitaxel (Taxol Bristol-Myers Squibb) adriamycin, vinblastine, and vincristine. Natural products have also provided many compounds that have led to the discovery of new biochemical mechanisms. This review summarizes the major natural products in clinical use today and introduces several new ones on the cusp of entering clinical practice. The review is organized by mechanism of action, with compounds that interact with proteins discussed first, followed by compounds that interact with RNA or DNA. 

In the early seventies, the discovery of the antitumor properties of paclitaxel [25] and the detection of large amounts of ecdysones [26] in yew tissues shifted the attention of the scientific community toward other constituents of the yew, and the number of papers devoted to taxine plummeted. However, interest was revived in the early nineties by the possibility of using taxine... 

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