Anticancer taxol

Chemistry of taxol, anticancer diterpenoid with oxethane cycle as a part of fused system 98PAC331. 

Camptothecin was discovered as an active anticancer drug isolated from the bark of Camptotheca acuminata. The anticancer activity of camptothecin was discovered in the 1960s by the National Cancer Institute (NCI) as part of a systematic effort to screen for novel anticancer agents derived from natural products. Monroe Wall and Mansuhk Wani identified the chemical structure of camptothecin. They also identified the chemical structure of taxol, again under the auspices of the NCI. Susan Hoiwitz was contracted by the NCI to elucidate the anticancer mechanisms of camptothecin. She found in the early 1970s that camptothecin induced DNA breaks and attested DNA and RNA synthesis. However, it is approximately 12 years later, only after DNA topo-isomerase I (Topi) had been identified in human cells, that Leroy Liu and his coworkers found that Topi was the cellular target of camptothecin [reviewed in [1]. 

The epothilones are natural products containing a 16-membered lactone ring that are isolated from mycobacteria. Epothilones A-D differ in the presence of the C(12)-C(13) epoxide and in the C(12) methyl group. Although structurally very different from Taxol, they have a similar mechanism of anticancer action and epothilone A and its analogs are of substantial current interest as chemotherapeutic agents.36 Schemes 13.59 to 13.66 summarize eight syntheses of epothilone A. Several syntheses of epothilone B have also been completed.37... 

The significance of P-gp, however, in affecting absorption and bioavailability of P-gp substrate drugs can be seen in studies in knockout mice that do not have intestinal P-gp. The gene responsible for producing that protein has been knocked out of the genetic repertoire. Those animals evidenced a sixfold increase in plasma concentrations (and AUC, area under the plasma concentration-time curve) of the anticancer drug paclitaxel (Taxol) compared to the control animals [54]. Another line of evidence is the recent report... 

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). 

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... 

The 5-fluorouracil (5-FU) and NONOate conjugates (Fig. 1.7) were prepared and their cytotoxicity was tested [90]. The median effect doses of the conjugates for DU145 and HeLa cancer cell lines were 2-4-fold lower than that of 5-FU. In another study by Wink et al, the cytotoxicity of cisplatin was enhanced about 60-fold after NONOate pretreatment for 30 min [91]. The enhancement of cytotoxicity of 5-FU/NONOate conjugates and cisplatin-NONOate combination has shown that there is a synergistic effect between anticancer drugs and NO. Another study by Jia et al. demonstrated that the cytotoxicity of Taxol was enhanced by S-nitrosocaptopril (Fig. 1.7) [92]. This effect is primarily mediated via the increased influx of Taxol by NO into intracellular compartments, while NO-induced cytotoxicity cannot be excluded. 

As an example, we present in Exhibit 10.8 the synthesis of paditaxel (Taxol, Bristol-Myers Squibb), an important anticancer drug for breast and ovarian cancer and Kaposi sarcoma. It illustrates the complexity in the synthesis of drug molecules. 

Cragg GM, Schepartz SA, Sufftiess M, Grever MR. (1993) The taxol supply crisis. New NCI policies for handling the largescale production of novel natural product anticancer and anti-HIV agents. J Nat Prod 56 1657-1668. 

Kingston DGl. (1994) Taxol The chemistry and strnctnre-activity relationships of a novel anticancer agent. Trends Biotechnol 12 222-227. 

In recent years, however, some of the greatest emphasis has been placed on the search for anticancer and antiviral agents derived from natural products. Success in that area has not heen as great as that achieved in other helds. Since 1960, only seven plant-derived drugs have heen approved by the FDA for use as anticancer agents. Four of those drugs, vinblastine, vincristine, etoposide, and teniposide, were discovered in the 1950s. The last three—Taxol , topotecan, and irinotecan—were discovered and approved much more recently. 

Perhaps the most exciting story about an anticancer agent derived from a natural product is that of Taxol . That story begins in 1958, when the National Cancer Institute began a program to screen natural products for substances that might have anticancer activity. The... 

Taxol is an anticancer drug obtained from the Pacific yew tree (Taxuxbrevifolia). (Mix/ Phanie/Photo Researchers, Inc.)... 

Taxol is an anticancer drug obtained from species of yew, and has the partial structure shown. R represents a splendidly complex terpenoid group. 

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. 

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