Bacterial cytidine deaminases as versatile activators of fluoropyrimidine nucleoside prodrugs

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-06-10 DOI:10.1016/j.ejmech.2025.117860

Viktorija Preitakaitė , Arūnas Kazlauskas , Agota Aučynaitė , Kamilė Butkutė , Ringailė Lapinskaitė , Nina Urbelienė , Audrius Laurynėnas , Rolandas Meškys

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Abstract

A platform for modification of 5-fluoropyrimidine nucleosides as potential prodrugs has been developed utilizing bacterial-derived cytidine deaminases (CDAs) for activation. It has been demonstrated that CDA_EH, CDA_F14, and CDA_Lsp effectively convert 5-fluoropyrimidine analogs into 5-fluoro-(2′-deoxy)uridine exhibiting cytotoxic effects. Prodrug activation, leading to reduced viability in CDA-expressing cells, has been observed in HCT116, MCF7, and U87MG cancer cell lines. This framework allows the evaluation of various N⁴-acyl/alkyl-5-fluorocytidines, 4-alkylthio-5-fluorouridines, 4-alkoxy-5-fluoro- and 4-alkoxy-5-fluoro-2′-deoxyuridines for their potential use in enzyme-prodrug therapy. Overall, the developed platform provides valuable guidance on selecting both enzyme and prodrug components for the development of effective enzyme-prodrug strategies.

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细菌胞苷脱氨酶作为氟嘧啶核苷前药的多功能激活剂

利用细菌衍生胞苷脱氨酶（CDAs）进行活化，开发了一个修饰5-氟嘧啶核苷作为潜在前药的平台。研究表明，CDA_EH、CDA_F14和CDA_Lsp有效地将5-氟嘧啶类似物转化为5-氟-（2'-脱氧）尿嘧啶，具有细胞毒作用。在HCT116、MCF7和U87MG癌细胞系中观察到药物前激活导致表达cda的细胞活力降低。该框架允许评估各种n4 -酰基/烷基-5-氟胞嘧啶、4-烷基硫-5-氟尿嘧啶、4-烷氧基-5-氟-和4-烷氧基-5-氟-2'-脱氧尿嘧啶在酶前药物治疗中的潜在用途。总的来说，开发的平台为选择酶和前药成分提供了有价值的指导，为开发有效的酶-前药策略提供了指导。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.