Commercialization taxol

However, during the clinical tests and commercialization of Taxol, a supply crisis developed because of its scarce origin—the bark of Pacific yew. To extract enough Taxol for one patient, stem bark from three 50 year old trees had to be stripped. Then BMS supported NCI financially for collaborative efforts to overcome the supply crisis. In return, BMS obtained exclusive rights to commercialize Taxol in the U.S. market for 10 years. 

Besides their essential roles in nature, isoprenoids are of commercial importance in industry. Some isoprenoids have been used as flavors, fragrances, spices, and food additives, while many are used as pharmaceuticals to treat an array of human diseases, such as cancer (Taxol), malaria (artemisinin), and HIV (coumarins). In contrast to the huge market demand, isoprenoids are present only in low abundance in their host organisms. Thus, isolation of the required isoprenoids consumes a large quantity of natural resources. Furthermore, owing to their structural complexity, total chemical synthesis is often not commercially feasible. For these reasons, metabolic engineering may provide an alternative to produce these valuable isoprenoids [88,89]. 

In separate instances involving the drug products Taxol and BuSpar, which are not included in the 22 described above, the generic applicants began commercial marketing without waiting for a district... 

Phase 1 clinical trials using Taxol began in 1983, and it soon became clear that the quantities required for the clinical phases, as well as the projected commercial... 

Much of the basis of the BMS CRADA proposal was built on the ability of BMS to tap into the tremendous synthetic knowledge contained in Robert Holton s research group at Florida State University (FSU). This research group had been actively studying the chemistry of Taxol and had made significant strides toward a total synthesis and a viable semi-synthetic pathway from 10-DAB. A licensing agreement between BMS and FSU was created, and in 1992 the first commercially viable semi-synthetic route from 10-DAB to Taxol was discovered [13]. 

With this process finally developed, the yield of Taxol was increased to the point that the synthesis became commercially viable in preparation for market launch of Taxol in 1993. 

With the successful development and commercial manufacture of semi-synthetic Taxol , tile destruction of the Pacific yew tree forests was halted. However, this successful move away from an essentially non-renewable source (extraction of the Pacific yew tree bark) to a renewable source (harvested European yew tree leaves and twigs to obtain 10-DAB, followed by syntliettc transformation to Taxol ) still presented significant environmental challenges. The use of 13 different solvents. 

Paclitaxel is an antitumor drug, with a low oral bioavailability (6%) [96] due to poor water solubility, hydrophobicity (log P = 4), and its high affinity to P-gp and CYP3A4. A novel SMEDDS of paclitaxel increased the bioavailability by up to 1.5-fold in comparison to the commercial micellar solution taxol. Concomitant intake of cyclosporine A, a known P-gp inhibitor, further increased paclitaxel bioavailability (1.8-fold in comparison to taxol) [97]. 

Paclitaxel (Taxol) is a diterpenoid compound that contains a complex taxane ring as its nucleus (Figure 62.1). The side chain linked to the taxane ring at carbon 13 is essential for its antitumor activity. Modification of the side chain has led to identification of a more potent analogue, docetaxel (Taxotere), which has clinical activity against breast and ovarian cancers. Originally purified as the parent molecule from yew bark, paclitaxel can now be obtained for commercial purposes by semisynthesis from 10-desacetylbaccatin, a precursor found in yew leaves. It also has been successfully synthesized from simple off-the-shelf reagents in a complex series of reactions. 

The first two DES to be commercialized incorporated sirolimus (rapamycin Rapamune , Wyeth Pharmaceuticals, Inc, Collegeville, Pennsylvania, U.S.A.), an immunosuppressive agent used for the prevention of transplanted organ rejection, or paclitaxel (Taxol , Bristol-Myers Squibb, Princeton, New Jersey, U.S.A.) an agent with an extensive history as an anti-cancer therapy. 

The bark of the cascara tree of the northwestern region of the United States yields cascara, a laxative used in medicine. Several hundred tons of bark are harvested annually. One of the most promising anti-carcinogenic compounds to be discovered in the last 25 years was found in the bark and wood of the Pacific Yew tree from the Pacific Northwest of the United States. This compound, taxol, was found to be quite effective by the National Cancer Institute for the treatment of breast and ovarian cancers. The compound is now produced by partial synthetic routes and is available commercially under the generic name, paclitaxel. 

The asymmetric oxidation of indene to the corresponding epoxide (Equation 24) is carried out commercially by Sepracor on a small scale. Chiral indene oxide is an intermediate in the synthesis of crixivan (an HIV protease inhibitor). Reaction is carried out at 5°C with moderately high turnover numbers in the presence of an exotic donor ligand ( P3NO , 3-phenylpropylpyridine N oxide) and sodium hypochlorite as the terminal oxidant. A similar epoxidation of a simple cis olefin (Equation 25) leads to an enantiomerically pure amino-alcohol used in the synthesis of taxol, a potent anticancer drug. 

Small peptide phage libraries have been used to screen for binding to organic molecules to identify consensus motifs that are then compared to known protein sequences to eventually determine biologically relevant interactions. Rodi et al. (80) screened a commercially available 12-mer library L6 fused to phage pill coat protein for its binding with a biotinylated derivative of taxol supported onto streptavidin-coated petri dishes (Fig. 10.15). The isolated sequences after one, two, and three rounds of selection and amplification were compared for common structural motifs. Two 5-mer motifs were identified, and a search in protein databases found six binding candidates for taxol (Fig. 10.15). More sophisticated... 

Figure 5.1 Examples of terpenoids that are of commercial importance or whose functional role in plants has recently been investigated. Isoprene may stabilize membranes at high temperatures. Camphor, artemisinin and paclitaxel (taxol) are valuable pharmaceuticals. The other three compounds appear to be involved in plant defence pulegone is toxic to herbivores polygodial is a herbivore feeding deterrent and (3 )-4,8-dimethyl-1,3,7-nonatriene, a Cn homoterpene, functions to attract herbivore enemies to herbivore-damaged plants.

Chemists synthesize molecules for many reasons. Sometimes a natural product, a compound isolated from natural sources, has useful medicinal properties, but is produced by an organism in only minute quantities. Synthetic chemists then prepare this molecule from simpler starting materials so that it can be made available to a large number of people. Taxol (Section 5.5), the complex anticancer compound isolated in small amounts from the bark of the Pacific yew tree, is one such natural product. It is now synthesized commercially from a compound isolated from the leaves and needles of the European yew. 

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