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.,Journal of Medicinal Chemistry

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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.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-03 , DOI: 10.1021/acs.jmedchem.0c00149
Yongbing Sun ₁ , Yu Ke ₁ , Chunshi Li ₂ , Jian Wang ₂ , Liangxing Tu ₁ , Lvjiang Hu ₁ , Yi Jin ₁ , Hao Chen ₁ , Jianping Gong ₁ , Zhiqiang Yu ₃

Affiliation

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.

中文翻译：

核苷类似物的双功能和不常见的氨基酸β-或γ-酯类前药，可改善对ATB0 +的亲和力和增强的代谢稳定性：对氟尿苷的应用。

氟尿苷（FUdR，5-氟-2-脱氧尿苷）被广泛用于肿瘤患者。但是在临床上已经观察到活性差和严重的副作用，这是由于胸苷磷酸化酶将FUdR降解为5-FU的降解裂解增加，以及转运蛋白介导的进入细胞的减少。在这项研究中，我们合成了一系列FUdR的l-天冬氨酸β-酯和l-谷氨酸γ-酯，以改善FUdR的代谢稳定性，并通过氨基酸转运蛋白ATB ^0，+将FUdR靶向癌细胞。在某些癌组织中完全上调。摄取机制，稳定性，在体外/体内研究了抗增殖作用，药代动力学和组织分布。综合结果表明，通过ATB ^0，+介导的前药方法^，异常的5'-β- 1 -Asp-FUdR具有比FUdR更好的肿瘤抑制率和更好的代谢稳定性。本研究中所提供的第一个证明的概念利用ATB的^0，+为前药形式的核苷类似物的肿瘤选择性递送。

更新日期：2020-10-08

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