Bifunctional and Unusual Amino Acid β- or γ-Ester Prodrugs of Nucleoside Analogues for Improved Affinity to ATB^0,+ and Enhanced Metabolic Stability: An Application to Floxuridine

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 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′-β-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.

Identified Isosteric Replacements of Ligands’ Glycosyl Domain by Data Mining

“…Isosteric replacement of ribose groups is a classic practice in medicinal chemistry. For example, the modification of the ribose of nucleosides has led to the discovery of several drugs ( Figure 1 ) such as the cancer therapeutic Floxuridine (FUdR, 5-fluoro-2-deoxyuridine), 28 where the 2′-hydroxyl of 5-fluoro-uridine is absent. Cytarabine (Ara-C) is a stereoisomer of cytidine with the d -ribose, 29 replaced with d -arabinose.…”

Identification of Isosteric Replacements of Glycosyl Domain of Ligands by Data Mining

“…Isosteric replacement of ribose groups is a classic practice in medicinal chemistry. For example, the modi cation of ribose of nucleosides, has led to the discovery of several drugs (Figure 1): such as cancer therapeutics Floxuridine (FUdR, 5-uoro-2-deoxyuridine) [27] where the 2'-hydroxyl of 5-uoro-uridine is absent. Cytarabine (Ara-C) is a stereoisomer of cytidine with the D-ribose [28], replaced with D-arabinose.…”

Modulation of Naturally Occurring Linear Dipeptide Chirality to Reduce the Affinity for Oligopeptide Transporter 1 and Increase Intestinal Stability for an Enhanced Colon-Targeting Effect in the Treatment of Inflammatory Bowel Disease: An Application of trans-4-l-Hydroxyprolyl-l-serine

“…This indicates that linear dipeptides consisting of both a d - and d -amino acid and a cis orientation of the peptide bond may not be transported by PEPT1 in the upper GI tract . Furthermore, an increase in stability in the GI tract when the natural amino acid is replaced with its counterpart non-natural amino acid is observed, because multiple proteolytic enzymes in the GI tract have a preference for the naturally occurring linear dipeptide with the l -configuration and trans orientation of the peptide bond. , Until now, the modulation of the chirality of naturally occurring linear dipeptides has not been proposed to improve the colon-targeting ability, taking advantage of the fact that the membrane transport mediated by PEPT1 and the hydrolysis mediated by enzymes in the intestine may differ among stereoisomers.…”