Taxol® Taxoid anticancer

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. ... 

The second chapter addresses new facets of the medicinal chemistry of the important anticancer drug Taxol (paclitaxel). Ojima and coworkers explore, in particular, the structure-activity relationship associated with the 3-phenylisoserine side chain, synthetically exploiting their P-Lactam Synthon Method . Their research has led to, among other things, a series of noteworthy second-generation taxoid anticancer agents. 

Some naturally occurring or semisynthetic non-Taxol taxoids can restore MDR tumor cells sensitivity toward paclitaxel and other anticancer drugs. These taxoids are usually weakly cytotoxic thus, they are ideal candidates for combined use with cytotoxic agents. 

This chapter gives an account of our research on the use of fluorine, exploiting the unique nature of this element, in the medicinal chemistry and chemical biology of taxoid anticancer agents (i.e., Taxol-like compounds). 

Scheme 12.26 Efficient DKR process for the synthesis of the side chain for taxoid anticancer drugs, including taxol and Taxotere.

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... 

In one study (60) aimed at identifying and quantifying, from various plant extracts, new compounds related to the anticancer drug taxol, polyclonal antibodies were raised using 2-succinyl taxol-bovine serum albumin (Fig. 9) as the immunogen. These antibodies were then used to develop an enzyme-linked immunosorbent assay (ELISA) that was specific for the taxol family. This taxol ELISA assay was used to monitor solvent partitions and chromatographic fractions of extracts of Taxus brevifolia from different sources. Five different ELISA-positive taxoids were isolated, one of which was previously unreported. 

Paclitaxel (Taxol, NSC-125973), obtained from Taxus species, is a diterpene with intense antitumoral activity because of its tmique mode of action on the microtubular cell system. It is one of the most successful anticancer drugs developed in the past 50 years. Due to several difficulties associated with obtaining Taxol and related taxoids firom plants growing in nature, plant cell cultures are considered to be the most favorable and environmentally sustainable approach for its production of at an industrial level. Some pharmaceutical companies, such as the... 

Paclitaxel and docetaxel, as very powerful anticancer drugs, proved to be a life saver for thousands of patients with various types of cancer. However, these drugs are expensive and difficult to synthesize and cause undesirable side effects as well as drug resistance, and their natural sources are limited. These mean that to remain taxol as an inexpensive drug in the pharmaceutical markets, separadmi of other biologically active compounds from renewable sources and new methods of synthesis or biotechnological cultivation techniques of plant cell and tissues to supply new generation of taxoids would be demanded. 

Exposito, O., Bonfill, M., Moyano, E., Onrubia, M. et al (2009) Biotechnological production of taxol and related taxoids current state and prospects. Anticancer Agents Med. Chem., 9, 109-121. 

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