SAR of 14-substituted taxanes

The success of paclitaxel and docetaxel as anticancer agents stimulated the search of innovative analogs endowed with more favorable pharmacol. profile. Ortataxel, lead of the class of 14-hydroxy taxoids, represents a milestone in such a research. Although the 14-substitution plays an important role in the biol. of Taxanes, an extensive SAR for this position was believed not possible due the lacking of natural occurring 14-substituted taxoids and of chem. methodologies for the modification of position 14. During our studies to solve the supply of 14-hydroxytaxoids we have developed the chem. of the enolate of 13-oxo-7-protected baccatin. Such a chem. gave us a powerful tool for modifying position 14, opening new perspectives in the Taxane chem. By quenching the enolate with different electrophiles, we have generated a wide no. of 14-functionalized taxoids. In vitro and in vivo data confirmed the importance of 14-substitution and permitted the selection of new candidates