Fast Release of Carboxylic Acid inside Cells.

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem Pub Date : 2025-02-17 DOI:10.1002/cmdc.202500056

Pascal Moser, Renaud Zelli, Leandro J Dos Santos, Mickaël Henry, Kevin Sanchez-Garcia, Yvan Caspar, Florian C Marro, Benoit Chovelon, Jaione Saez Cabodevilla, Sandrine Ollagnier de Choudens, Eric Faudry, Yung-Sing Wong

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引用次数: 0

Abstract

Delivering carboxylic acid functions into cells is challenging due to their poor permeability across lipophilic membranes at physiological pH, where they are ionized. Masking carboxylic acids as esters improves cell entry, but once inside the cell, its rapid release is essential to maintain spatiotemporal control which can be beneficial for therapeutic and diagnostic applications. This study evaluates the 2-hydroxyethyl-dithio-benzyl ester functional group which undergoes selective and rapid cleavage of the disulfide bond by thioredoxin (Trx), triggering rapid self-immolation of the thio-benzyl ester releasing the carboxylic acid. Fluorescence-based assays using the pro-fluorescent BODIPY structure have demonstrated the rapid intracellular release of carboxylic acids within minutes in both eukaryotic and prokaryotic cells. The approach was tested on antibiotics, and among them, levofloxacin ester prodrug, having the 2-hydroxyethyl-dithio-benzyl ester functional group, showed significantly enhanced antimicrobial activity against resistant and intracellular bacteria compared to its methyl ester analogue.

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细胞内羧酸的快速释放。

由于羧酸在生理pH值下被电离，其通过亲脂膜的渗透性较差，因此将羧酸功能传递到细胞中是具有挑战性的。将羧酸掩藏为酯可以改善细胞进入，但一旦进入细胞，其快速释放对于维持时空控制至关重要，这对治疗和诊断应用是有益的。本研究评价了2-羟乙基二硫代苄基酯官能团，该官能团经历了硫氧还蛋白（Trx）选择性和快速切割二硫键，引发硫代苄基酯快速自我牺牲释放羧酸。使用前荧光BODIPY结构的荧光分析表明，真核细胞和原核细胞在几分钟内快速释放羧酸。结果表明，具有2-羟乙基二硫代苄基酯官能团的左氧氟沙星酯前药与甲酯类似物相比，对耐药菌和细胞内细菌的抑菌活性显著增强。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

期刊介绍： Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.