Bifunctional and Unusual Amino Acid β- or γ-Ester Prodrugs of Nucleoside Analogues for Improved Affinity to ATB0,+ and Enhanced Metabolic Stability: An Application to Floxuridine

Floxuridine (FUdR, 5-fluoro-2-deoxyuridine) was widely used in patients with tumor. But the poor activity and severe side effects have been observed in the clinic, which resulted from increased degradation cleavage of FUdR to 5-FU by thymidine phosphorylase and reduced transporter-mediated entry into cells. In this study, we have synthesized a series of L-aspartic acid beta-esters and L-glutamic acid gamma-esters of FUdR to improve the metabolic stability of FUdR and target FUdR to cancer cells via amino acid transporter ATB(0,+) which was exclusively up-regulated in some cancerous tissue. The uptake mechanism, stability, in vitro/in vivo antiproliferation action, pharmacokinetics, and tissue distribution were studied. The combined results showed the unusual 5'-beta-L-Asp-FUdR possessed a better tumor inhibition rate and a better metabolic stability than FUdR through a ATB(0,+)-mediated prodrug approach. The present study provided the first proof-of-concept of exploiting ATB(0,+) for tumor-selective delivery of nucleoside analogues in the form of prodrug.