Microtubule Stabilizers and Promotors of Microtubule Assembly

7.04.3.1 Paclitaxel and Related Taxanes

Paclitaxel 84, the first member of this class to be identified, was isolated in 1971 from the bark of the pacific yew (Taxus brevifolia) (Figure 38).187 This compound has been the object of a tremendous amount of interest over the years.188 The taxanes and related microtubule-stabilizing agents target the dimer of alpha- and beta-tubulin, binding in a hydrophobic cleft on the beta form (Figures 39 and 40). This binding promotes the formation of, and imparts unusual stability to, the microtubule.189 The chemistry and structural biology of this interaction have been objects of considerable study using a range of techniques, particularly photoaffinity labeling.190 Not surprisingly, these experiments show that the site targeted by microtubule-stabilizing drugs is distinct and well separated from the site at which other mechanistic classes of microtubule-interacting agents bind to the target. More recently, an electron diffraction structure of oligomeric alpha-beta-tubulin prepared in the presence of paclitaxel confirmed the presence of the drug in the site suggested by the earlier labeling experiments.191 The low resolution (c. 4 A) of the structure means that structure-based drug design based on it is not yet possible.

The discovery of the potent anticancer properties and subsequent elucidation of the mechanism of action of paclitaxel firmly established this compound as a leader in the treatment of difficult cancers. The last decade has seen paclitaxel and related taxanes emerge as aggressive frontline therapies for advanced tumors, including breast, lung, and ovarian carcinomas. Initially the development of paclitaxel for chemotherapy was slowed by poor availability of the natural product. However, the discovery that paclitaxel could be prepared semisynthetically from a more abundant natural product, baccatin III 83, alleviated this problem.192

Hundreds of synthetic and semisynthetic analogs in the taxane class have been prepared. From this effort, an understanding of the structural components required for antimitotic activity has been developed. It is clear from this SAR that the core structure of the taxanes is required for the maintenance of potency. Furthermore, much of the

Small acyl and H RETAIN activity

AcO O

Reduction INCREASES activity

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