Seite - (000223) - in Biomedical Chemistry: Current Trends and Developments

the delivery of peptidomimetic anticancer agents (Gonzalez, 1998; Nakanishi, 2000; Vig, 2003). Anticancer drugs are primarily cytotoxic agents and exert their antitumor activity by interfering with some aspects of DNA replication, repair, translation or cell division. However, these agents are not “magic bullets”, as they do not destroy tumor cells while sparing the normal cells (Sinhababu, 1996). The prodrug strategy is once again used with anticancer agents as a way to alleviate their toxicity. Different prodrug strategies have been employed to not only to improve solubility, transport and pharmacokinetic properties, but also to enable selective activation in target tissues. As a means to reduce the toxic effects of these agents, prodrugs designed for selective activation in target tissues are by far the most efficient and attractive option. However, an enzyme or transporter that is exclusively or preferentially expressed in these tissues is a prerequisite for selective targeting (Landowski, 2006; Sinhababu, 1996). There are numerous studies of amino acid derivatives of the clinically-effective anticancer agents floxuridine (Vig, 2003) and gemcitabine (Song, 2005) concerning the activation of the prodrug. Unlike the desired rapid activation required for valacyclovir, extensive intestinal activation of floxuridine and gemcitabine prodrugs would lead to severe intestinal toxicity. In this regard, Song and Landowski demonstrated that amino acid ester prodrugs provided resistance to deamination of gemcitabine (Song, 2005) and to floxuridine cleavage (Landowski, 2005a), respectively. The studies developed with the amino acid esters of fluxoridine were consistent with previous findings: 5’-L-valyl floxuridine was the most efficiently transported floxuridine prodrug, exhibiting the highest PEPT1-mediated transport and permeability across Caco-2 monolayers. The length and stereochemistry of the amino acid moiety side chain influences the transport efficiency of floxuridine prodrugs. The slightly more branched isoleucyl side chain reduced the transport of these prodrugs to half, but the branching at γ carbon (as in leucine) side chain decreases this transport even further. The permeability of 5’-monoester prodrugs of floxuridine across Caco-2 monolayers was significantly higher than that of the parent drug and also reflected a profound