Synthesis and evaluation of smart drugs with integrated functions for identifying and treating oxidative microenvironments associated with cellular ferroptosis
Abstract Ferroptosis is a novel form of cell death driven by oxidative damage, and is implicated in various pathological conditions, including neurodegenerative diseases, retinal damage, and ischemia‐reperfusion injury of organs. Inhibiting ferroptosis has shown great promise as a therapeutic strate...
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| Format: | Article |
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Wiley
2025-06-01
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| Series: | Smart Molecules |
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| Online Access: | https://doi.org/10.1002/smo.20240048 |
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| author | Yibo Zhang Rui Cai Yu Ding Jiangye Zhang Changxu Ning Jiangcheng Zeng Zhongxiang Zhou Shisheng Wang Yueqing Li Xiuhan Guo |
| author_facet | Yibo Zhang Rui Cai Yu Ding Jiangye Zhang Changxu Ning Jiangcheng Zeng Zhongxiang Zhou Shisheng Wang Yueqing Li Xiuhan Guo |
| author_sort | Yibo Zhang |
| collection | DOAJ |
| description | Abstract Ferroptosis is a novel form of cell death driven by oxidative damage, and is implicated in various pathological conditions, including neurodegenerative diseases, retinal damage, and ischemia‐reperfusion injury of organs. Inhibiting ferroptosis has shown great promise as a therapeutic strategy for these diseases, underscoring the urgent need to develop effective ferroptosis inhibitors. Although Ferrostatin‐1 (Fer‐1) is a potent ferroptosis inhibitor, its susceptibility to oxidation and metabolic inactivation limits its clinical utility. In this study, the accumulation of peroxides and the resulting oxidative damage in the cellular microenvironment during ferroptosis were utilized to design Ferrostatin‐1 prodrugs with reactive oxygen species‐responsive features. This approach led to the development of a series of ferroptosis inhibitors that were capable of recognizing oxidative damage in diseased areas, allowing for targeted release and improved stability. The novel compounds demonstrated significant inhibitory effects and selectivity against RSL‐3‐induced ferroptosis in HK‐2 cells, with compound a1 exhibiting an EC50 of 15.4 ± 0.7 μM, outperforming Fer‐1. These compounds effectively identify the oxidative microenvironment associated with ferroptosis, enabling the targeted release of Fer‐1, which prevents lipid peroxide accumulation and inhibits ferroptosis. This strategy holds promise for treating diseases related to ferroptosis, offering a targeted and intelligent therapeutic approach. |
| format | Article |
| id | doaj-art-df15da4b07374c7d8818445ebfd18e75 |
| institution | OA Journals |
| issn | 2751-4587 2751-4595 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Smart Molecules |
| spelling | doaj-art-df15da4b07374c7d8818445ebfd18e752025-08-20T02:38:15ZengWileySmart Molecules2751-45872751-45952025-06-0132n/an/a10.1002/smo.20240048Synthesis and evaluation of smart drugs with integrated functions for identifying and treating oxidative microenvironments associated with cellular ferroptosisYibo Zhang0Rui Cai1Yu Ding2Jiangye Zhang3Changxu Ning4Jiangcheng Zeng5Zhongxiang Zhou6Shisheng Wang7Yueqing Li8Xiuhan Guo9Department of Pharmaceutical Engineering School of Chemical Engineering State Key Laboratory of Fine Chemicals Dalian University of Technology Dalian Liaoning ChinaInstrumental Analysis Center Dalian University of Technology Dalian Liaoning ChinaDepartment of Pharmacy Dalian Rehabilitation Recuperation Center Dalian ChinaDepartment of Pharmaceutical Engineering School of Chemical Engineering State Key Laboratory of Fine Chemicals Dalian University of Technology Dalian Liaoning ChinaDepartment of Pharmaceutical Engineering School of Chemical Engineering State Key Laboratory of Fine Chemicals Dalian University of Technology Dalian Liaoning ChinaDepartment of Pharmaceutical Engineering School of Chemical Engineering State Key Laboratory of Fine Chemicals Dalian University of Technology Dalian Liaoning ChinaDepartment of Pharmaceutical Engineering School of Chemical Engineering State Key Laboratory of Fine Chemicals Dalian University of Technology Dalian Liaoning ChinaDepartment of Pharmaceutical Engineering School of Chemical Engineering State Key Laboratory of Fine Chemicals Dalian University of Technology Dalian Liaoning ChinaDepartment of Pharmaceutical Engineering School of Chemical Engineering State Key Laboratory of Fine Chemicals Dalian University of Technology Dalian Liaoning ChinaDepartment of Pharmaceutical Engineering School of Chemical Engineering State Key Laboratory of Fine Chemicals Dalian University of Technology Dalian Liaoning ChinaAbstract Ferroptosis is a novel form of cell death driven by oxidative damage, and is implicated in various pathological conditions, including neurodegenerative diseases, retinal damage, and ischemia‐reperfusion injury of organs. Inhibiting ferroptosis has shown great promise as a therapeutic strategy for these diseases, underscoring the urgent need to develop effective ferroptosis inhibitors. Although Ferrostatin‐1 (Fer‐1) is a potent ferroptosis inhibitor, its susceptibility to oxidation and metabolic inactivation limits its clinical utility. In this study, the accumulation of peroxides and the resulting oxidative damage in the cellular microenvironment during ferroptosis were utilized to design Ferrostatin‐1 prodrugs with reactive oxygen species‐responsive features. This approach led to the development of a series of ferroptosis inhibitors that were capable of recognizing oxidative damage in diseased areas, allowing for targeted release and improved stability. The novel compounds demonstrated significant inhibitory effects and selectivity against RSL‐3‐induced ferroptosis in HK‐2 cells, with compound a1 exhibiting an EC50 of 15.4 ± 0.7 μM, outperforming Fer‐1. These compounds effectively identify the oxidative microenvironment associated with ferroptosis, enabling the targeted release of Fer‐1, which prevents lipid peroxide accumulation and inhibits ferroptosis. This strategy holds promise for treating diseases related to ferroptosis, offering a targeted and intelligent therapeutic approach.https://doi.org/10.1002/smo.20240048ferroptosis inhibitoroxidative microenvironmentrecognizingspace‐time controlled release |
| spellingShingle | Yibo Zhang Rui Cai Yu Ding Jiangye Zhang Changxu Ning Jiangcheng Zeng Zhongxiang Zhou Shisheng Wang Yueqing Li Xiuhan Guo Synthesis and evaluation of smart drugs with integrated functions for identifying and treating oxidative microenvironments associated with cellular ferroptosis Smart Molecules ferroptosis inhibitor oxidative microenvironment recognizing space‐time controlled release |
| title | Synthesis and evaluation of smart drugs with integrated functions for identifying and treating oxidative microenvironments associated with cellular ferroptosis |
| title_full | Synthesis and evaluation of smart drugs with integrated functions for identifying and treating oxidative microenvironments associated with cellular ferroptosis |
| title_fullStr | Synthesis and evaluation of smart drugs with integrated functions for identifying and treating oxidative microenvironments associated with cellular ferroptosis |
| title_full_unstemmed | Synthesis and evaluation of smart drugs with integrated functions for identifying and treating oxidative microenvironments associated with cellular ferroptosis |
| title_short | Synthesis and evaluation of smart drugs with integrated functions for identifying and treating oxidative microenvironments associated with cellular ferroptosis |
| title_sort | synthesis and evaluation of smart drugs with integrated functions for identifying and treating oxidative microenvironments associated with cellular ferroptosis |
| topic | ferroptosis inhibitor oxidative microenvironment recognizing space‐time controlled release |
| url | https://doi.org/10.1002/smo.20240048 |
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