The Taxol Pharmacophore

A third approach to the taxol pharmacophore was developed by Giannakakou et al 503), who compared the effects of taxol and various epothilone analogs on the polymerization of native tubulin and of modified tubulins carrying / -tubulin mutations near the taxol-binding... 

In summary, we are at an interesting point in our understanding of the taxol pharmacophore. At least two rather different hypotheses have been suggested for the pharmacophore of taxol, and it will be interesting to see how future work clarifies this situation. If the initial results described above are supplemented with new results from the use of physical methods such as solid state NMR and additional computations, it is reasonable to expect that a final model of the taxol pharmacophore could be developed and used in a predictive way to create new and improved taxol analogs. 

Several attempts have been made to define the key pharmacophore of taxol. Much of the chemical work reported in the previous sections was carried out with a view to determining structure-activity relationships for taxol and its analogs and thus to defining the pharmacophore in chemical terms. Some of this work can be summarized as in structure 15.4.1 below, where the key structure-activity relationships of taxol are shown. 

Fuji K, Watanabe Y, Ohtsubo T, Nuruzzaman M, Hamajima Y, Kohno M (1999) Synthesis of Extremely Simplified Compounds Possessing the Key Pharmacophore Units of Taxol, Phenylisoserine and Oxetane Moieties. Chem Pharm Bull 47 1334... 

Winkler JD, Axelsen PH (1996) A Model for the Taxol (Paclitaxel)/Epothilone Pharmacophore. Bioorg Med Chem Lett 6 2963... 

Based on analysis of electronic crystallography and NMR data for the bindings of Taxol and epothilone A to tubulin subunits, it was proposed that they did not share a common pharmacophore (similar binding mode and sites) as hypothesized for a long time, because they bind to their receptors uniquely and independently. Also, the T-shape conformation of Taxol binding to tubulin was supported from this study. 

Fig. 1 The 3D vision of pharmacologically active molecules (here taxol) provides the medicinal chemist with a complex information from which a pharmacophore has to be deduced to generate analogs with more adequate pharmocokinetic and toxicological properties.

The discovery of the tubulin-assembly properties of these natural products have raised the obvious questions as to whether they bind to the same binding site as taxol and whether there is thus a common pharmacophore that can be deduced for all these compounds. These questions have been addressed in various ways. The first attempt at developing a common pharmacophore was by Winkler and Axelsen 499), who simply compared the structures of taxol and epothilone and proposed a pharmacophore based on regions of structural similarity. 

He L, Jagtap PG, Kingston DGI, Shen H-J, Orr GA, Horwitz SB (2000) A Common Pharmacophore for Taxol and the Epothilones Based on the Biological Activity of a Taxane Molecule Lacking a C-13 Side Chain. Biochemistry 39 3972... 

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