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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 effect has 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 β-ester and L-glutamic acid γ-ester of FUdR to improve the metabolic stability of FUdR and target FUdR to cancer cells via amino acid transporter ATB0,+ which was exclusively up-regulated in some cancerous tissue. The uptake mechanism, stability, in vitro/in vivo anti-proliferation action, pharmacokinetics and tissue distribution were studied. The combined results showed the unusual 5'-β-L-Asp-FUdR possessed a better tumor inhibition rate and a better metabolic stability than FUdR through a ATB0,+-mediated prodrug approach. The present study provided the first proof-of-concept of exploiting ATB0,+ for tumor-selective delivery of nucleoside analogues in the form of prodrug.