Docetaxel anticancer agents

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. ... 

Paclitaxel (Taxol Bristol Myers Squibb 14) and its semisynthetic analog docetaxel (15) are two of the most important anticancer agents of the last 25 years. Paclitaxel was isolated originally by Wall and Wani from Taxus brevifolia (23) and named taxol this name was later trademarked by Bristol-Myers... 

The taxanes originally were extracted from the bark of the Pacific Yew tree and have found widespread use as anticancer agents. The structurally related taxanes, docetaxel and pacUtaxel, bind to and stabilize polymerized microtubules. Cells that enter mitosis in the presence of paclitaxel attempt to assemble a spindle apparatus, however the inhibition of depolymerization renders this structure unable to properly position chromosomes at the metaphase plate. Therefore, although kinetochores bind to microtubules, there is insufficient tension to inactivate the SAC. Paclitaxel-treated cells become blocked in mitosis, and eventually die by the mechanisms just described. Currently, there... 

For centuries, plants have been a unique source of therapeutically significant alkaloids and they continue to be excellent sources of drugs. Furthermore, alkaloids of natural origin serve as a model for the semisynthesis or the synthesis of derivatives which have improved pharmacokinetic properties, a higher efficacy and/or less toxicity. One of the most recent examples is the isolation of the anticancer agent, called taxol, from the stem bark Of the Pacific yew tree Taxus brevifolia in 1971 by Wani and co-workers [1] and the development, a few years later, of docetaxel, a semisynthetic derivative obtained from 10-deacetyl-baccatin III [2]. 

Commercial evidence also supports the case for natural products. Of the 20 best-selling non-protein drags in 1999, nine were either derived from or developed as the result of leads generated by natural products (e.g., simvastatin, lovastatin, ciprofloxacin, clarithromycin and cyclosprin) with combined annual sales of greater than US 16 billion. Newer developments based on natural products include the antimalarial drag artemisinin, and the anticancer agents taxol, docetaxel and camptothecin. In addition to the historical success in dixig discoveiy, natural products are likely to continue to be sources of new commercially viable... 

Docetaxel, taxoid anticancer agent was extracted from plasma and analyzed on a Cig column (A = 227nm) with paclitaxel as IS [1394]. Good peak shapes and resolution were obtained in 12-min analysis using a 43/57 acetonitrile/water (20 mM aimnonium acetate pH 5) mobile phase. Control standards were run from 5 to lOOOng/mL with a reported quantitation limit of 5ng/mL. 

Although paclitaxel was reported to be effective against ovarian and breast cancers resistant to other first-line anticancer drugs in clinics, the patients often relapsed and did not respond to these antimmor agents, including pachtaxel, anymore. Unfortunately, docetaxel was also inactive toward paclitaxel-resistant tumors. 

Salminen E, Bergman M, Huhtala S, Jekunen A, Ekholm E. Docetaxel, a promising novel chemotherapeutic agent in advanced breast cancer. Anticancer Res 2000 20(5C) 3663-8. 

The study of natural products, or Nature s Combinatorial Library , has had a long history as a source of drugs, and plants have historically been at the forefront of natural product drug discovery. In the anticancer area, for example, vinblastine and vincristine, etoposide, paclitaxel (Taxol), docetaxel, topotecan, and irinotecan, among others, are all plant-derived natural products or modified versions of plant compounds, while antimalarial therapy would be much poorer without quinine and artemisinin and the drugs derived from these plant products. This chapter provides an overview of the major medicinal agents that are themselves natural products isolated from plants or are chemical modifications of such lead compounds. It covers the therapeutic areas of cancer, HIV, malaria, cardiovascular, and central nervous system (CNS) diseases. Natural plant products have also made contributions in areas such as immunomodulatory and antibiotic activities," and the reader is referred to the cited reviews for information on these areas. 

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