Taxol Metabolites

The metabolism of taxol and other taxoid drugs has been reviewed (341-343), and this section will thus primarily cover the synthesis of taxol metabolites. The major identified metabolites of taxol in the rat were found in the bile, and two of these were the phenolic metabolites 

1 have all been identified in human feces (345). A study of taxol metabolites in rat bile by LC-MS identified nine metabolites, seven of which were hydroxylated compounds with the other two being a deacetyltaxol and a baccatin derivative (346). The metabolites were not 

The metabolites 9.1 and 9.2 were both synthesized by Georg and her collaborators by standard methods, using an appropriate / -lactam to prepare 9.1 from baccatin III and converting taxol to a protected 2-debenzoyltaxol and then acylating it to prepare 9.2 347). The 3 -metabolite 9.1 was about twice as active as taxol in a tubulin-assembly assay, but was sevenfold less cytotoxic than taxol to B-1 melanoma cells. The metabolite 9.2 was about 40 times less cytotoxic than taxol to LI210 leukemia cells. The synthesis of the major human metabolite 9.3 was described earlier in section 4.2.1. 

The major human metabolites of docetaxel were found to be the side-chain oxidation products 9.5, 9.6, and 9.7 348), and these were synthesized by Commer on and his colleagues by appropriate conversions of an N-debenzoyl 10-deacetytaxol derivative 349). 

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Poon, G. K. Wade, J. Bloomer, J. Clarke, S. E. Maltas, J. 1996. Rapid screening of taxol metabolites in human microsomes by liquid chromatography/electrospray ionization-mass spectrometry. Rapid Commun. Mass Spectrom., 10,1165-1168. 

The novel marine natural product laulimalide (65), a metabolite of various sponges, has received attention as a potential antitumor agent due to its taxol-like ability to stabilize microtubules. There has been considerable synthetic effort toward 65, culminating within not more than 2 years in as many as ten... 

Taxol (Paclitaxel) 137, a natural product derived from the bark of the Pacific yew, Taxus brevifolia [213-215], and the hemisynthetic analogue Docetaxel (Taxotere) 138, two recent and promising antitumour agents, have been the matter of extensive in vivo and in vitro animal metabolic studies. The major metabolites of taxol excreted in rat bile [216] were identified as a C-4 hydroxylated derivative on the phenyl group of the acyl side chain at C-13 (139), another aromatic hydroxylation product at the mefa-position on the benzoate group at C-2 (140) and a C-13 deacylated metabolite (baccatin III, 142) the structure of six minor metabolites could not be determined. The major human liver microsomal metabolite, apparently different from those formed in rat [217], has been identified as the 6a-hydroxytaxol (141) [218, 219]. A very similar metabolic pattern was... 

The very good yields of especially the bridgehead alkoxy derivatives 231 and the excellent regioselectivity with which they can be transformed to other skeletons plus the fact that a spirocyclopropane moiety is a mimic of and can in fact be considered as a masked gem-dimethyl substituent [28, 112] makes these products versatile precursors of certain natural products. In fact, one may conceive new approaches to the total syntheses of taxol [113-115] and of mediter-raneol [116]. Both strategies rely on the MIMIRC reaction of lithium cycloalka-dienolates [117] with the a-chloro acrylate 1-Me to produce a tricyclic precursor to the appropriate bicyclo [n.2.1]alkanedione derivative, which are key structural units of several diterpenes and their metabolites. 

The diterpenoid taxol (Figure 1.12) was first isolated from the pacific yew tree (Taxus brevifolia) in the late 1960s. Its complete structure was elucidated by 1971. Difficulties associated with the subsequent development of taxol as a useful drug mirror those encountered during the development of many plant-derived metabolites as drug products. Its low solubility made taxol difficult to formulate into a stable product, and its low natural abundance required large-scale extraction from its native source. 

An alternative route of taxol production under investigation entails the use of plant cell culture techniques. Plant cell culture is considered to be an economically viable production route for plant-derived drugs, if the drug commands a market value in excess of 1000 2000/kg. While many commonly used plant-derived metabolites fall into this category, plant cell culture has not... 

Whiterup, . M., S. A. Look, M. W. Stasko, T. J. Ghiorzi, G. M. Muschik, and G. M. Cragg. 1990. Taxus spp. needles contain amounts of taxol comparable to the bark of Taxus brevifolia analysis and isolation. J. Nat. Prod. 53 1249-1255. Wickremesinhe, E. R. M. and R. N. Arteca. 1998. Taxus species (yew) in vitro culture, and the production of taxol and other secondary metabolites. In Bajaj, Y. P. S. (ed.). Biotechnology in Agriculture and Forestry 41. Medicinal and Aromatic Plants X. Springer-Verlag. New York. p. 415-442. 

Most of the important antitumor compounds used for chemotherapy of tumors are microbially-produced antibiotics. These include actinomycin D, mitomycin, bleomycins and the anthracyclines, daunorubicin and doxorubicin. The recent successful molecule, taxol (=paclitaxel), was discovered in plants but also is a fungal metabolite. It is approved for breast and ovarian cancer and is the only antitumor drug known to act by blocking depolymerization of microtubules. In addition, taxol promotes tubulin polymerization and inhibits rapidly dividing mammalian cancer cells. It also inhibits fungi such as Pythium, Phytopthora and Aphanomyces spp. by the same mechanism. ... 

Monsarrat, B. Mariel, E. Cros, S. Gares, M. Guenard, D. Gueritte, V. Wright, M. Taxol metabolism. Isolation and identification of three major metabolites of taxol in rat bile. Drug Metab. Dispos. 1990, 18, 895-901. 

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