DESIGN, SYNTHESIS AND BIOLOGICAL-ACTIVITY OF PROTAXOLS

TAXOL1-6 is a product isolated from the Pacific yew tree (Taxus brevif olia) and is a potent microtubule-stabilizing agent which has recently been approved for treatment of otherwise intractable ovarian cancer. Despite taxol's therapeutic promise, its aqueous insolubility (<0.004 mg ml-1) hampers its clinical application. Here we report the design, synthesis and biological activity of a series of taxol-releasing compo unds (protaxols) with improved pharmacological properties. These prodr ugs were designed to increase their aqueous solubility and allow for t axol release under basic or physiological conditions. We demonstrate t he stability of these prodrugs at pH less-than-or-equal-to 7 and their ability to release taxol in a basic medium. Taxol-like microtubule-st abilizing activity7-9 appears after the release of taxol. In vitro the se prodrugs have cytotoxic properties against tumour cell lines compar able to those of taxol; moreover, human plasma catalyses the release o f active taxol. These protaxols have greater potential as anticancer a gents than the parent compounds taxol and taxotere (Fig. 1a).