FIGURE 8.3 Semisynthesis of taxanes.

Although paclitaxel and docetaxel are widely used for the therapy of a variety of solid tumors and are being investigated clinically for numerous other cancers, they have some limitations. The main ones are the impossibility of oral administration and the frequent development of resistances mediated by tubulin mutation, leading to weaker interactions, or by overexpression of the Pgp-170 transport pump, leading to efflux from the cell. Another problem is the need to associate them with formulation vehicles to allow their administration. Thus, paclitaxel, very insoluble in water, is generally formulated using polyoxyethylated castor oil (Cremophor EL) while docetaxel, more soluble in water, is formulated using Tween 80 and ethanol. Cremophor EL is responsible for many hypersensitivity reactions and Tween 80, albeit less toxic than Cremophor, may also be responsible of some toxic effects.35 These problems have stimulated the search for new taxoids, several of which are under clinical evaluation.36 Among the firstgeneration analogs, we will mention BMS-188797 and BMS-184476, which have improved pharmacokinetic properties. More substantial variations can be observed in ortataxel, where the aromatic rings of paclitaxel have been replaced by other lipophilic substituents and the hydroxyl at the bridgehead position is part of a cyclic carbonate structure. Ortataxel shows increased potency with respect to paclitaxel and is the first orally active taxoid. Another structurally related, orally active, semisynthetic taxane is BMS-275183. Both ortataxel37 and BMS-27518338 have reached clinical trials for solid tumors.

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