Seite - (000225) - in Biomedical Chemistry: Current Trends and Developments

more stable than the valyl ester floxuridine prodrugs and the reference drug valacyclovir (Landowsky, 2005b). The combined results of the in vitro studies suggest that isoleucyl monoesters of floxuridine may be potentially promising candidates for improving oral bioavailability of floxuridine in vivo. The prodrugs given orally could improve the intestinal uptake of floxuridine as well as shield it from unwanted degradation (Landowsky, 2005b). Various dipeptides and peptidomimetics have also been tested to characterize the hPEPT1 transporter and improve its affinity, and mono amino acid ester prodrugs have been evaluated as hPEPT1 substrates (Landowsky, 2005a; 2005b; Song, 2005). Based on those reports, six amino acids were chosen to be N-terminal amino acids of the dipeptide and paired with three others to test the hypothesis that molecular sizes may structurally affect its ester bond stability (Tsume, 2008). In this study, dipeptide prodrugs appeared to be less stable in pH 7.4 buffers than the corresponding mono amino acid ester prodrugs. Since no mono amino acid ester prodrug degradation products were detected, it is quite likely that the dipeptide monoester prodrugs degrade through parallel pathways, as previously suggested for some anti-viral dipeptide prodrugs. Although gemcitabine is clinically effective in the treatment of advanced or metastatic pancreatic cancer, it also exhibits various side effects which are attributed to its inability to distinguish between normal or target cells. It is known that gemcitabine exerts its antiproliferative activity via multiple mechanisms of action. It is initially phosphorylated intracellularly by deoxycytidine kinase and subsequently by nucleotide kinases to its active metabolites, gemcitabine diphosphate and gemcitabine triphosphate. The influence of gemcitabine on DNA synthesis has been strongly correlated with the gemcitabine triphospate intracellular concentration. However, extensive degradation of gemcitabine by cytidine deaminases to an inactive metabolite adversely affects gemcitabine activity (Huang, 1991; Song, 2005). To overcome this disadvantage, Song and co-workers reported the synthesis of amino acid ester prodrugs of gemcitabine and evaluated their affinity to oligopeptide transporterts (hPEPT1), which are overexpressed in the gastrointestinal tract and recently known to be expressed in tumor cells (Song, 2005; Vig, 2003). The promoieties used