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 β-esters and l-glutamic acid
γ-esters 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 antiproliferation 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.