Taxol antitumor activity

F.14 Paclitaxel, which is extracted from the Pacific yew tree Taxus brevifolia, has antitumor activity for ovarian and breast cancer. It is sold under the trade name Taxol. On analysis, its mass percentage composition is 66.11% C, 6.02% H, and 1.64% N, with the balance being oxygen. What is the empirical formula of paclitaxel ... 

Figure 4.19 Antitumoral activity of paclitaxel (Taxol), docetaxel (Taxotere), and CFs-acetyl-docetaxel. ° ...

Epothilones are naturally occurring cytotoxic macrolides, which were initially isolated from a mycobacterium. Their antitumor activity is similar to that of the clinically established taxoids (Taxol, Taxotere), by interrupting the dynamic mechanism of microtubule assembly/disassembly via microtubule stabilization. In contrast to taxoids, epothilones are remarkably efficient against multidrug resistant cells. 

Deutsch, M., J. A. Glinski, M. Hernandez, R. D. Haugwitz, V. L. Narayanan, M. Suffness, and L H. Zalkow. 1989. Synthesis of congeners and prodrugs. 3. V foter-soluble prodrugs of taxol with potent antitumor activity. J. Med. Chem32 788-792. 

Ueda, Y., et al. 1993. Novel water soluble phosphate prodrugs of taxol(R) possessing in vivo antitumor activity. Bioorg Med Chem Lett 3 1761. 

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. 

Paclitaxel is a low-molecular-weight, lipophilic compound which is FDA-approved for anticancer therapy. (This compound is referred to in the research literature by both its generic name paclitaxel and the registered tradename Taxol [Bristol-Myers Squibb Co., N.Y., N.Y.].) Paclitaxel has been shown to exert antitumor activity against many cell lines (ref. 596-599). Paclitaxel... 

W.C. Rose, Taxol a review of its preclinical in vivo antitumor activity, Anticancer Drugs 3 (1992) 311-321. 

The approval of Taxol for marketing in December 1992 was the culmination of 35 years of work. During this period of time the National Cancer Institute (NCI) and the U.S. Department of Agriculture (USDA) collaborated to collect, identify, and screen U.S. native plant material for antitumor activity. The year 1992 also marked, coincidentally, the discovery of the Ice Man in the Italian Alps. This Bronze Age man, who died 5300 years ago, was found in possession of a pure copper axe set in a yew wood handle and an unfinished 6-foot yew bow. Obviously, the yew tree has played a number of important roles for humans throughout history. 

The discovery of Taxol is a fruit of a National Cancer Institute (NCI)-sponsored project on identification of antitumor agents from natural resources. Bioassay-guided fractionation led to the isolation of this unique compound from Taxus bre-vifolia (pacific yew). Wani et al. also identified another famous antitumor natural product camptothecin. Unlike camptothecin, which was abandoned in the phase of clinical trial because of its severe toxicity, Taxol was almost discarded at the preliminary phase because it only exhibited moderate in vitro activity toward P388, a murine leukemia cell line that was used in the standard evaluation system by NCI researchers at that time. However, it was rescued by a subsequent finding of its strong and selective antitumor activities toward several solid tumors, and more... 

Maththew, A. E. MejiUano, M. R. Nath, J. P. Himes, R. H. SteUa, V. J. Synthesis and evaluation of some water-soluble prodmgs and derivatives of taxol with antitumor activity. J. Med. Chem., 1992, 35 145-151. 

Murugkar, A. Padhye, S. Guha-Roy, S. Wagh, U. Metal complexes of Taxol precursor 1. Synthesis, characterization and antitumor activity of the copper complex of 10-deacetylbaccatin thiosemicarbazone. Inorg. Chem. Commun., 1999, 2 545-548. 

Distefano, M. Scamhia, G. Ferhni, C. GaUo, D. De, Vincenzo, R. Filippini, P Riva, A. Bombardelli, E. Mancuso, S. Antitumor activity of paclitaxel (Taxol) analogues on MDR-posititive human cancer cells. Anticancer Drug Des., 1998, 13 489 99. 

This methodology also enables stereospecific synthesis of the side-chain of taxol [56]. The A-benzoyl-3-phenylisoserine side chain at C-13 of the taxol molecule is essential for its antitumor activity. The stereoselectivity in this reaction depends on the geometry of the silyl ketene acetal (Eq. 77). The reaction of the (E)-ketene acetal with (i )-27 produces the anti adduct with high stereoselectivity anttsyn = 98 2, 92 % de anti). In contrast, the reaction of the (Z)-silyl ketene acetal with S)-27 produces the enantiomerically pure syn adduct (symanti = > 99 1, > 99 % de syn). Aus, our methodology provides the first practical and efficient route for the preparation of both diastereomers of an a-hydroxy /3-amino ester. The syn adduct 52 is transformed to the desired A-benzoyl-(27 ,35)-phenylisoserine methyl ester by hydrogenolysis over a palladium catalyst then the Schotten-Baumann reaction. 

A chief problem in the early development of taxane pharmaceuticals was the establishment of a steady and dependable supply. Taxanes are present in low quantities in plants. In contrast, taxines are relatively abundant in plants (especially in Taxus baccata and Taxus cuspidate), they can serve as an alternative starting material for semisynthetic production of paclitaxel derivatives. The major taxines are taxine A and taxine There is a significant structural resemblance between taxine B and taxanes (Fig. 1). Both groups share the main taxane ring moreover, the C-5 side chain of the taxines has a close spatial position to the C-13 side chain of the taxanes (the latter is essential for antitumor activity). A biosynthetic hypothesis involved the intermediacy of a C-5 to a C-13 ester transfer it was also demonstrated that taxine B can be converted into a baccatin V derivative. Taxines do not show antitumor activity, whereas the cardiotoxicity of taxol is lower compared to taxines but is undesirable for... 

Since 1955, the American National Cancer Institute (NCI) has conducted a massive search for compounds with antitumor activity, with successes including the Vinca alkaloids from the Madagascar periwinkle and taxol from the Pacific yew tree. This highlight [1] covers a family of steroids also discovered by the NCI efforts. 

Mathew AE, Mejillano MR, Nath JP, Himes RH, Stella VJ (1992) Synthesis and Evaluation of Some Water-Soluble Prodrugs and Derivatives of Taxol with Antitumor Activity. J Med Chem 35 145... 

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