Abstract |
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.
|
Authors | Yongbing Sun, Yu Ke, Chunshi Li, Jian Wang, Liangxing Tu, Lvjiang Hu, Yi Jin, Hao Chen, Jianping Gong, Zhiqiang Yu |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 63
Issue 19
Pg. 10816-10828
(10 08 2020)
ISSN: 1520-4804 [Electronic] United States |
PMID | 32882127
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Amino Acid Transport Systems
- Amino Acids
- Antimetabolites, Antineoplastic
- Esters
- Prodrugs
- Floxuridine
|
Topics |
- Amino Acid Transport Systems
(chemistry)
- Amino Acids
(chemistry)
- Animals
- Antimetabolites, Antineoplastic
(chemistry)
- Area Under Curve
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Drug Stability
- Esters
(chemistry)
- Floxuridine
(chemistry)
- Half-Life
- Humans
- Prodrugs
(chemistry, pharmacokinetics, pharmacology)
|