Paclitaxel chemical structure

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

FIGURE 62.1 Chemical structures of paclitaxel (taxol) and its more potent analog, docetaxel (taxotere). 

Bollag et al. (88)at the Merck Research Laboratories discovered that the epothilones stabilize microtubule assembly and thus inhibit cell division by the same mechanism as that of paclitaxel (see above). This observation, together with their less complex chemical structure, increased water solubility, more rapid action in vitro, and effectiveness against multidrug-resistant tumor cells, has prompted... 

Thin-layer chromatography (TLC) is mainly applied in micropreparative taxoids separation [2-4]. Silica gel 6OF254 preparative plates are usually applied for this purpose. The problem of taxoids separation involves not only their similar chemical structure (e.g., paclitaxel versus cephalomannine) but also, due to different coextracted compounds usually encountered in crude yew extracts (polar compounds such as phenolics and nonpolar ones such as chlorophylls and biflavones), the separation is very difficult. The common band of paclitaxel and cephalomannine was satisfactorily resolved from an extraneous fraction in isocratic elution with ethyl acetate as a polar modifier [4] and n-heptane-dichloromethane as the solvent mixture and it was of suitable purity for high-performance liquid chromatography (HPLC) quantitative determination. 

Fig. 4. Anticancer drugs paclitaxel and docetaxel. Both compounds can be obtained by chemical structure modification of baccatin III or 10-deacetyl baccatin III...

Natural products are generally complex chemical structures, whether they are cyclic peptides like cyclosporin A, or complex diterpenes like paclitaxel. Inspection of the structures that are discussed in Section IV is usually enough to convince any skeptic that few of them would have been discovered without application of natural products chemistry. Recognition and appreciation of the value of natural prod-uct-like models in improving efficiency in so-called diver-sify-orienfed synfhesis has already been mentioned. 

Figure 8.2 Conjugation of paclitaxel to PEG enhances solubility in water. Chemical structures of paclitaxel (Taxol , (a)) and Taxol 2 -PEG ester (b).

Among the worldwide total of 30000 known natural products, about 80% stems from plant resources. The number of known chemical structures of plant secondary metabolites is four times the number of known microbial secondary metabolites. Plant secondary metabolites are widely used as valuable medicines (such as paclitaxel, vinblastine, camptothecin, ginsenosides, and artemisinin), food additives, flavors, spices (such as rose oil, vanillin), pigments (such as Sin red and anthocyanins), cosmetics (such as aloe polysaccharides), and bio-pesticides (such as pyrethrins). Currently, a quarter of all prescribed pharmaceuticals compounds in industrialized countries are directly or indirectly derived from plants, or via semi-synthesis. Furthermore, 11% of the 252 drugs considered as basic and essential by the WHO are exclusively derived from plants. According to their biosynthetic pathways, secondary metabolites are usually classified into three large molecule families phenolics, terpenes, and steroids. Some known plant-derived pharmaceuticals are shown in Table 6.1. 

Fig. 3.10 These complicated chemical structures can only come from plants—the molecular formulas of vincristine and paclitaxel. (Authors own work)...

Most alkaloids have basic properties coimected with a heterocyclic tertiary nitrogen. Notable exceptions are colchicine, caffeine, and paclitaxel. Most alkaloids are biosynthetically derived from amino acids such as phenylalanine, tyrosine, tryptophan, ornithine, and lysine. Alkaloids represent a wide variety of chemical structures. About 20000 alkaloids are known, most being isolated from plants. But alkaloids have also been found in microorganisms, marine organisms such as algae, dinoflagellates, and puffer fish, and terrestrial animals such as insects, salamanders, and toads. 

Docetaxel differs from paclitaxel at two positions in its chemical structure. It has a hydroxyl functional group on C-10 (see Fig. 101.1) whereas paclitaxel has an acetate ester, and a tert-butyl carbamate ester exists on the phenylpropionate side chain instead of the benzyl amide in paclitaxel. The C-10 functional group change causes docetaxel to be more water soluble than paclitaxel. 

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. 

The use of 19F NMR for a variable temperature (VT) NMR study of fluorinated taxoids is obviously advantageous over the use of H NMR because of the wide dispersion of the l9F chemical shifts that allows fast dynamic processes to be frozen out. Accordingly, F2-paclitaxel 65 and F-docetaxel 66 were selected as probes for the study of the solution structures and dynamic behavior of paclitaxel and docetaxel, respectively, in protic and aprotic solvent systems.77 The inactive 2, 10-diacetyldocetaxel (73) was also prepared to investigate the role of the 2 -hydroxyl moiety in the conformational dynamics.89 While molecular modeling and NMR analyses (at room temperature) of 73 indicate that there is no significant conformational changes as compared to paclitaxel, the 19F NMR VT study clearly indicates that this modification exerts marked effects on the dynamic behavior of the molecule.77... 

Figure 6.27 Product ion spectrum of the [M+NFL ion of paclitaxel and correspondence of ions to specific substructures diagnostic of the compound, used as a template for structure identification of paclitaxel impurities. (Reprinted with permission from Kerns et al., 1994. Copyright 1994 American Chemical Society.)...

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