Paclitaxel, origin

One well-known, and particularly complex, member of the diterpene (C20) family of natural products is paclitaxel, originally isolated from the Pacific yew tree, Taxus brevifo-lia. Paclitaxel functions as an antimicrotubule agent used in the treatment of a range of cancers including breast, lung, and ovarian tumors (trade names abraxane Taxol, Bristol-... 

There are natural targets whose syntheses have important practical applications. For example, paclitaxel (marketed as Taxol by Bristol-Myers Squibb) is an anticancer compound originally isolated from the bark of a species of yew tree, but for a long time it seemed that natural sources would not be sufficient to meet the need. Consequently, many chemists developed synthetic approaches to paclitaxel from readily available materials, although these are not yet fully practical for manufacturing. The quest continues, and a semisynthetic route has been developed starting with a compound isolated from yew needles that can be harvested without destroying the tree. An alternative approach has employed plantcell cultures in bioreactors to produce paclitaxel from yew needles (see Chapter 7 for discussion of related matters). 

Paclitaxel (Taxol, Bristol-Myers Squibb) is a chemotherapy drug for ovarian cancer, breast cancer, and certain lung cancers. It was discovered by the US National Cancer Institute in the 1960s. Originally, it was extracted from the bark of the North American yew tree (Taxus brevifo-lia). Clinical tests had necessitated the harvesting of the bark, and this method damaged the trees irreversibly. 

Paclitaxel is a taxane that was originally derived from the bark of the yew tree. Paclitaxel is used in cytotoxic chemotherapy for malignant disease. 

Paclitaxel (21), formerly known as taxol , is a nitrogen-containing diterpenoid compound isolated from the bark of Taxus brevifolia Nutt. (Pacific yew). As an anticancer agent, paclitaxel acts as a tubulin stabilizer and leads to cell cycle arrest.Since paclitaxel was originally isolated from the bark of the slow-growing species, 77 brevifolia, sourcing was a major obstacle in the development of this drug and its introduction into the market.However, as described later in this chapter, this has now been overcome. 

Paclitaxel (21) was originally obtained from the bark of the Pacific yew, Taxus brevifolia Nutt. However, as the tree takes 200 years to mature, stripping the bark to produce this compound for the market was not sustainable. A better source of naturally occurring paclitaxel has not been found in other species and the total synthesis, on the other hand,... 

Conversely, in these same Italian patients, low RRMl mRNA levels were significantly associated with improved survival (15.5 vs. 6.8 months p = 0.002) (45). No differences were found according to RRMl status in patients treated with paclitaxel/carboplatin or vinorelbine/cisplatin as part of the original phase III randomized trial (46). 

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 coupling of baccatins 76 and 77 with IV-benzoyl-P-lactam 11 and the V-f-Boc-P-lactam 12 followed by deprotection using Zn in AcOH afforded taxoids 78-81 in fair to good yields. These taxoids possess strong to modest cytotoxicity against our standard five human cancer cell lines (Table 12). The microtubule disassembly inhibitory activity of these new taxoids was also evaluated. Taxoid 78 (SB-T-1011) exhibits activity same to or better than that of paclitaxel. Results are listed in Table 12. The attachment of the AT-acylphenylisoserine residue at the C-14 position (taxoids 80 and 81) instead of the original C-13 position results in ca. 10-fold decrease in cytotoxicity, but 80 still retains 10 nM level (IC50) cytotoxicity. 

Many anticancer agents have their origins in pharmacognosy, including paclitaxel, etoposide, and the camptothecin analogues, topotecan and irinotecan, to name just a few. The dolastatins are a unique class of compounds isolated from the Indian Ocean sea-hare Dolabdla auricularia that are referred to as depsipeptides,... 

Originally developed as part of a large-scale effort headed by the United States National Cancer Institute to investigate chemotherapeutic agents from natural sources, paclitaxel was approved by the FDA in 1992 as an antineoplastic agent to treat metastatic ovarian cancer after failure of first-line or subsequent chemotherapy (37). Further studies demonstrated efficacy in other solid tumors (38). In addition, paclitaxel was shown to inhibit T- and B-cell proliferation when tested for transplant-rejection application (39,40) and has demonstrated inhibition of matrix-metalloproteinase synthesis in studies conducted to test its utility for rheumatoid arthritis (41). 

The extension of the C-13 side chain to its homologated one furnished poorly active paclitaxel and docetaxel analogs in tubulin assembly assay. The authors assumed that the poor activity of the analogs may have originated from their different conformations from that of paclitaxel in water. 

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... 

Paclitaxel causes disturbances in cardiac rhythm, but the relevance of these effects has not been fully elucidated. Originally, aU patients in trials of paclitaxel were under continuous cardiac monitoring, owing to the risk of hypersensitivity reactions, and cardiac disturbances were therefore more likely to be detected. Many trials limited eligibility to patients without a history of cardiac abnormalities and to those who were not taking medications likely to alter cardiac conduction. The incidence of cardiac dysrhythmias in the population under study not treated with paclitaxel is unknown, and it is therefore not always possible to attribute dysrhythmias to paclitaxel in these patients. The Cremophor EL vehicle does not appear to be implicated in the incidence of dysrhythmias, although hypotension associated with hypersensitivity reactions may occur (13). 

---