Taxol discovery

Wall and Wani (22) are the pioneers in taxol discovery. To date, around 400 taxoids have been isolated from the Taxus species. Taxus alkaloids were reviewed recently in the book Taxus, genus Taxus edited by Itokawa and Lee (23). Biologic... 

Wall, M.E. and Wani, M.C., Camptothecin and taxol discovery to clinic (13th Bruce F.Caine Memorial Award lecture). Cancer 55,753, 1995. 

Wall ME, Wani MC. Campothecin and taxol discovery to clinic. Cancer Res 1995 55 753-60. 

Wall ME, Wani MC (1994) Taxol Discovery to Clinic. In Wagner H, Farnsworth NR (ed) Economic and Medicinal Plant Research. Academic Press, Ltd., London, p 299... 

Since the discovery of the anticancer potential of Taxol , a complex compound isolated from the bark extract of the Pacific yew tree, more than 20 years ago, there has been an increasing demand for the clinical application of this compound. First, the promising results of the 1991 clinical trials in breast cancer patients were announced, and soon after Bristol-Myers-Squibb trade-marked the name Taxol and used it as an anticancer drug. At that point, the only source of the drug was the bark of the endangered yew tree. Fortunately, it was soon discovered that a precursor of Taxol could be obtained from an extract of the tree needles instead of the bark. 

Since the discovery of the high anticancer activity of taxol, much attention has been drawn to its asymmetric synthesis. The total synthesis stood for more than 20 years as a challenge for organic chemists. The compound taxoids are diterpenoids isolated from Taxus species and have a highly oxidized tricyclic carbon framework consisting of a central eight-membered and two peripheral six-membered rings (see Fig. 7-2).21... 

Guenard D, Gueritte-Voegelein F, Potier P, Taxol andTaxotere Discovery, chemistry and strucmre-activity relationships. Accounts Chem Res 26 160—167, 1993. 

There are several books on the history of the development of taxol, which is one of the most remarkable stories in product development. In fact, it inspired the 1992 motion picture Medicine Man, starring Sean Connery as a research botanist looking for a cancer cure in the Brazilian rain forest. For a time, it became a moral drama pitting the needs of patients of intractable ovarian and breast cancer against the passions of environmentalists to preserve an obscure Pacific yew tree. Suffness and Wall are two of the principals in this story, and they wrote (1995) It [Taxol] is not an obvious winner till the very end, and there were a number of times till the very end when it seemed highly likely that it would not be put into development at all, or that once it had been accepted, it would be dropped. More than 30 years passed between the discovery of taxol, with its potential as an anticancer drug, and its approval by the Food and Drug Administration (FDA) for clinical use. 

Nobel e-Museum. 2002. Nobel Lectures. Stockholm Nobel Foundation, http //www.nobel.se/. Suffness, M. and M. E. Wall. 1995. Discovery and Development of Taxol. In Taxol Science and Applications, Suffness, M., ed., Boca Raton, FL CRC Press. 

The story of the discovery of taxol illustrates one of the major problems in seeking pharmaceutical agents among the himdreds of thousrmds of NPs made by plants. An effective, valuable chemical might be formd but a practical, economic source of the chemical might not be. Indeed, a natural source of a very important drug could be very bad news for threatened habitats. How that problem might be resolved is discussed later. 

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. 

Another important method of drug discovery is the random screening of vast numbers of compounds. Each year, for example, the National Cancer Institute screens some 20,000 compounds for anticancer activity. One successful hit was the compound Taxol, shown in Figure 14.4. This compound has significant activity against several forms of cancer, especially ovarian cancer. 

Gurnard D, Gueritte-Voegelein F and Potier P (1993) Taxol and taxotere discovery, chemistry, and structure-activity relationships. Account Chem Res 26, 160-167. 

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. ... 

A plant neurotoxin that is receiving much current publicity because of its effectiveness in the chemotherapeutic treatment of at least one form of cancer is taxol, a complex molecule that belongs to the class of taxine alkaloids. Taxol occurs in most tissues of Taxus breviofolia, the western yew tree, and is isolated from the bark of that tree (once considered a nuisance tree in forestry, but in short supply following discovery of the therapeutic value of taxol until alternate sources were developed). Ingestion of taxol causes a number of neurotoxic effects, including sensory neuropathy, nausea and gastrointestinal disturbances, and impaired respiration and cardiac function. It also causes blood disorders (leukopenia and thrombocytopenia). The mechanism of taxol neurotoxicity involves binding to tubulin, a protein involved in the assembly of microtubules, which assemble... 

The approval of Taxol for marketing in December 1992 was the culmination of 35 years of work. During this period of time the National Cancer Institute (NCI) and the U.S. Department of Agriculture (USDA) collaborated to collect, identify, and screen U.S. native plant material for antitumor activity. The year 1992 also marked, coincidentally, the discovery of the Ice Man in the Italian Alps. This Bronze Age man, who died 5300 years ago, was found in possession of a pure copper axe set in a yew wood handle and an unfinished 6-foot yew bow. Obviously, the yew tree has played a number of important roles for humans throughout history. 

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