Paclitaxel, structure

Figure 2. Conformation of paclitaxel based on the X-ray structure of docetaxel and proposed for nonpolar aprotic organic solvents (structure A) and the conformation based on the X-ray structure of paclitaxel (structure B) and proposed for aqueous solvents.

Boge, T. C. Heperle, M. Vander Velde, D. G. Gunn, C. W. Grunerwald, G. L. Georg, G. I. The oxetane conformational lock of paclitaxel structural analysis of D-secopa-clitaxel. Bioorg. Med. Chem. Lett., 1999, 9 3041-3046. 

Boge TC, Hepperle M, Vander Velde DG, Gunn CW, Grunewald GL, Georg GI (1999) The Oxetane Conformational Lock of Paclitaxel Structural Analysis of D-secopaclitaxel. Bioorg Med Chem Lett 9 3041... 

Takahashi and coworkers have used INOC for synthesis of the chiral CD rings paclitaxel, which is an antitumor agent. Synthetic strategy starting from 2-deoxy-D-ribose is demonstrated in Scheme 8.22.110 The precursor of INOC was prepared by 1,2-addition of a,(3-unsaturated ester to ketone. INOC and subsequent reductive cleavage by H2/Raney Ni afford the desired CD ring structure. 

The answer is c. (Hardman, pp 1260—1262.) Paclitaxel is a large structural molecule that contains a 15 membered taxane ring system. This anti cancer agent is an alkaloid derived from the bark of the Pacific yew tree. Its chemotherapeutic action is related to the microtubules in the cell. Paclitaxel promotes microtubule assembly from dimers and causes microtubule stabilization by preventing depolymerization. As a consequence of these actions, the microtubules form disorganized bundles, which decreases... 

Structure 1 vinblastine, 2 vincristine, 3 maytansine, 4 rhizoxin and 5 paclitaxel (Taxol)... 

Fig. 2.1 Structures of the naturally occurring mictrotubule stabilizing compounds paclitaxel, epothilones A and B, discodermolide, and eleutherobin.

Since the discovery of vesicular structures, termed liposomes, by Alec Bangham, a tremendous amount of work on applications of liposomes has emerged. The use of small unilamellar liposomes as carriers of drugs for therapeutic applications has become one of the major fields in liposome research. The majority of these applications are based on the encapsulation of water-soluble molecules within the trapped volume of the liposomes. Long circulating poly(ethylene glycol) (PEG) modified liposomes with cytotoxic drugs doxorubicin, paclitaxel, vincristine, and lurtotecan are examples of clinically applied chemotherapeutic liposome formulations (1,2). 

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 extraordinary biological activity of epothilones has spurred interest of scientists around the world. Indeed, several epothilones and many derivatives are currently in different phases of clinical trials for the treatment of various forms of cancer. Also the synthetic community has given a great deal of attention to these remarkable compounds, probably more than to any other compound in the last ten years. This is not very surprising, because in comparison to paclitaxel (which until recently was one of the main success stories of natural products research), the epothilones have a relatively simple structure, which allows easier modification, and they display higher in vitro activity as well as better pharmacokinetic properties. 

Fig. 1. Chemical structure of the taxanes. The chemical structures of docetaxel and paclitaxel. From ref. 5.

Three classes of plant-derived drugs, the vinca alkaloids (vincristine, vinblastine, and vinorelbine), the epipodo-phyllotoxins (etoposide and teniposide and the tax-anes (paclitaxel and taxotere), are used in cancer chemotherapy. These classes differ in their structures and mechanisms of action but share the multidrug resistance mechanism, since they are all substrates for the multidrug transporter P-glycoprotein. 

A brilliant example for the industrial-scale application of plant cell fermentation is the new process for the production of the anticancer drug paclitaxel developed by Bristol-Myers Squibb (see Figure 15.1). It starts with clusters of paclitaxel producing cells from the needles of the Chinese yew, T. chinensis, and was introduced in 2002. The API is isolated from the fermentation broth and is purified by chromatography and crystallization. The new process substitutes the previously used semisynthetic route. It started with lO-deacetylbaccatin(III), a compound that contains most of the structural complexity of paclitaxel and can be extracted from leaves and twigs of the European yew, T. baccata. The chemical process to convert 10-deacetylbaccatin(III) to paclitaxel is complex. It includes 11 synthetic steps and has a modest yield. 

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