离子通道和转运体在细胞增殖和程序性细胞死亡等各种生物过程中起着关键作用。最近，我们报道了通过谷胱甘肽（GSH）激活的2,4-二硝基苯磺酰保护的N1，N3-二己基-2-羟基异异苯酰胺（1）能形成离子通道，并通过耗尽癌细胞内的GSH储备诱导细胞凋亡。然而，这些合成转运系统在癌细胞中引起细胞凋亡的详细分子事件仍需揭示。沿着这个方向，我们使用1H核磁共振（NMR）基于代谢组学的非靶向全局代谢谱分析，研究了乳腺癌细胞MCF-7中的细胞代谢物和相关代谢途径的改变。通过对MCF-7细胞暴露在1下的谱图进行评估，并与未经处理的（对照组）细胞的谱图进行对比，鉴定了14个显著变化的代谢物。这些代谢物主要属于抗氧化防御、能量代谢、氨基酸生物合成和脂质代谢途径，其中包括GSH、o-磷酸胆碱、苹果酸和天门冬氨酸等。这些结果将帮助我们深入了解1介导的MCF-7细胞细胞毒性的分子机制，并最终有助于鉴定潜在的新型治疗靶点，以实现更有效的癌症管理。版权所有 © 2023 Elsevier B.V. 保留所有权利。

Ion channels and transporters play key roles in various biological processes, including cell proliferation and programmed cell death. Recently, we reported that 2,4-dinitrobenzene-sulfonyl-protected N1,N3-dihexy-2-hydroxyisophthalamide (1) forms ion channels upon activation by glutathione (GSH) and results in the induction of apoptosis by depleting the intracellular GSH reservoir in cancer cells. However, the detailed molecular events leading to the induction of apoptosis by these synthetic transport systems in cancer cells still need to be uncovered. Along these lines, we investigated the alterations in cellular metabolites and the associated metabolic pathways by performing untargeted global metabolic profiling of breast cancer cells - MCF-7 - using 1H NMR-based metabolomics. The evaluation of spectral profiles from MCF-7 cells exposed to 1 and their comparison with those corresponding to untreated (control) cells identified 14 significantly perturbed signature metabolites. These metabolites belonged mostly to antioxidant defence, energy metabolism, amino acid biosynthesis, and lipid metabolism pathways and included GSH, o-phosphocholine, malate, and aspartate, to name a few. These results would help us gain deeper insights into the molecular mechanism underlying 1-mediated cytotoxicity of MCF-7 cells and eventually help identify potential novel therapeutic targets for more effective cancer management.Copyright © 2023 Elsevier B.V. All rights reserved.