Seite - (000224) - in Biomedical Chemistry: Current Trends and Developments

promoiety dependency. Thus, the permeability of the 5’-L-valyl prodrug was roughly 2- and 5-fold higher than the permeability of 5’-L-isoleucyl and 5’-leucyl floxuridine prodrugs, respectively (Landowski, 2005a). The metabolic conversion of floxuridine to 5-fluorouacil (5-FU) following systemic delivery has been shown to be detrimental to the therapeutic efficacy of floxuridine. The mechanism of action of these two drugs are well understood, where the toxicity of 5-FU is predominantly caused by 5-FU incorporation into RNA. Unlike 5-FU, floxuridine is specifically incorporated into DNA, which leads to the minimization of adverse effects. It is important to highlight that floxuridine has shown to inhibit cell proliferation 10- to 100-fold more than 5-FU. However, floxuridine is rapidly converted to 5-FU in many tissues (including the liver) by the enzyme thymidine phosphorylase (Tsume, 2008). As a consequence, higher doses of floxuridine are required to maintain clinical efficacy, which leads to greater toxicity. Therefore, protection of floxuridine prodrugs against this enzyme is essential to enhance therapeutic efficacy at low doses and obviate toxicity. All amino acid ester prodrugs examined by Landowski and co- workers were stable to glycosidic bond cleavage by thymidine phosphorylase. It is therefore possible to conclude that modification of one or both of the free hydroxyl groups on the sugar moiety provide protection from glycosidic bond cleavages. The rate of conversion of the prodrugs to the parent drug after transport would determine floxuridine disposition and therapeutic action (Landowski, 2005a). As previously reported to structure, stereochemistry and the site of esterification of the amino acid promoiety affect the rates of activation of floxuridine prodrugs. Therefore, the wide range of variations for prodrug structure suggests that the hydrolysis rate can be tailored to produce a prodrug with the desired half-life (Landowski, 2005a; Vig, 2003). The roughly 5- to 12-fold higher activity in Caco-2 cell homogenates compared with pH 7.4 buffer suggests the predominance of enzymatic bioconversion of the prodrugs. The results obtained for the leucyl ester prodrugs indicate that they would not be suitable candidates. In comparison, isoleucyl ester prodrugs of floxuridine are enzymatically