Seite - (000226) - in Biomedical Chemistry: Current Trends and Developments

in this study were the aliphatic amino acids L-valine, D-valine, and L- isoleucine, as well as the aromatic amino acids L-phenylalanine and D- phenylalanine. The results obtained were once again consistent with the previously mentioned findings with amino acid prodrugs. All gemcitabine prodrugs (Fig. 3.1.7) showed a greater affinity to the oligopeptide transporter compared with the parent drug and the preference for the 5’-monoester and L-configuration persist. The prodrugs rates of hydrolysis were also observed to be affected by the structure, stereochemistry and site of esterification of the promoiety (Song; 2005). Figure 3.1.7: Amino acid-gemcitabine prodrug (R = L-Val, L-Ile, L-Phe, D-Val, D-Phe). The chemical stability and rapid enzymatic bioconversion characteristic of the 5’-L-valyl-gemcitabine derivative suggests it potential in enhancing oral absorption of gemcitabine. On the other hand, the 5’-L- isoleucyl-gemcitabine showed a slow bioconversion in Caco-2 cells and in human plasma, as well as an unusual resistance to cytidine deaminase deactivation. This way a longer systemic circulation half-life is possible which may facilitate the targeting of cells over expressing hPEPT-1 transporter (Song, 2005). Spontaneous cyclization of oligopeptides and prodrugs with amino acids in solution does not easily occur without the intervention of specific enzymes, with the exception of dipeptides that easily cyclize to piperazine-2,5-diones or diketopiperazines (DKP, 1). The DKP scaffold is widely found in compounds of biological interest and could serve as a drug template with appropriately arrayed pharmacophores (Gomes, 2007). The major role of DKP in prodrug design falls in the domain of approach (ii): by linking adequate dipeptide carriers to a drug, a prodrug can be created which undergoes a strictly chemical cyclization- elimination process via intramolecular aminolysis of the dipeptide moiety to a DKP, with simultaneous departure of the free parent drug