American Chemical Society
jm0c00149_si_003.pdb (365.87 kB)

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

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posted on 2020-09-18, 11:04 authored by Yongbing Sun, Yu Ke, Chunshi Li, Jian Wang, Liangxing Tu, Lvjiang Hu, Yi Jin, Hao Chen, Jianping Gong, Zhiqiang Yu
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.