Docetaxel structure

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... 

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). 

In this chapter, we describe an account of our research on the chemistry and biology of paclitaxel and taxoid anticancer agents (taxoid = taxol-like compound). The topics covered in this chapter include (i) the development of a practical and efficient method for the semisynthesis of paclitaxel and docetaxel using chiral 3-hydroxy-P-lactams as synthetic intermediates, (ii) structure-activity relationship (SAR) studies of various taxoids that led to the discovery of the extremely potent second-generation taxoids, and (iii) biological and conformational studies with the use of fluorine-containing taxoids as probes. ... 

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 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.

F2-10-Ac-docetaxel (74) was first studied in a polycrystalline form by the RFDR technique. Based on the standard simulation curves derived from molecules with known F-F distances (distance markers), the F-F distance of two fluorine atoms in 74 was estimated to be 5.0 0.5 A (Figure 6). This value corresponds quite closely to the estimated F-F distances for the conformers B and C (F-F distance is ca. 4.5 A for both conformers) based on our RMD studies for F2-paclitaxel (65) (vide supra). This means that the microcrystalline structure of 74 is consistent with the hydrophobic clustering conformer B or C, but not with the conformer A in which the F-F distance is ca. 9.0 A. 

P-Hydroxy-10-deacetylbaccatin III (75, 14P-OH-DAB) was first isolated from the needles of the Himalayan yew tree (Taxus wallichiana Zucc.) and its structure was determined by X-ray crystallographic analysis in 1992.93 Because of an extra hydroxyl group at the C-14 position, 14P-OH-DAB (75) has much higher water solubility than DAB (3), the key precursor of paclitaxel and docetaxel. We envisaged that new taxoids derived from 75 would improve water solubility and bioavailability, and also reduce hydrophobicity-related drug resistance. These improved... 

A molecular modeling study shows that the conformation of pseudo-docetaxel 80 overlaps well with that of docetaxel based on the X-ray crystal structure,84 except that the two hydrophobic groups, phenyl at C-3 and rert-butoxycarbonyl group at C3 -N, have exchanged their positions almost perfectly. The ability of pseudo-... 

It is very important to clarify the minimum structural requirements for paclitaxel and taxoids to exhibit anticancer activity by looking at simplified structure analogues. Along this line, we have investigated the role of the A ring by synthesizing novel nor-seco analogues of paclitaxel and docetaxel.37,96... 

Small molecules modulating microtubule assembly have played major roles as tools in microtubule research, in a manner closely related to their chemotherapeutic interest [1], Tubulin was first purified in the last century as the colchicine-binding protein proposed to be the subunit of cellular microtubules [2], More recently, a colchicine derivative was employed to help crystallization and determine the structure of tubulin by X-ray diffraction [3], The colchicine, vinblastine [4] and paclitaxel [5] sites are main drug binding sites of tubulin, to which many other substances bind. The discovery of microtubule stabilization by paclitaxel [6] prompted its clinical development [7] and a burst of research on new MSAs, as well as the generalized use of paclitaxel or docetaxel as convenient reagents to assemble (see Fig. 1), stabilize or detect microtubules in the laboratory. One example is the development... 

One of the first effects of taxanes in microtubules observed was the fact that the structure of the paclitaxel-induced microtubules is different from that of the microtubules assembled in its absence [18]. Moreover, paclitaxel is able to change the structure of preformed docetaxel-induced assembled microtubules within a time range of the order of tens of seconds, indicating a fast exchange of taxanes in the site [41]. 

Before these investigations, most of the models of the paclitaxel-tubulin interaction had been directly extrapolated from the conformations of paclitaxel found either in polar [60] or non-polar media [61] and from the single crystal X-ray structure of docetaxel (Fig. 10a) [58],... 

Fig. 1 Structures of the taxanes paclitaxel (PTX, taxol) and docetaxel (DTX, taxotere)...

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