A novel integrated diagnostic and therapeutic ferroptosis inhibitor based on a phenothiazine scaffold with ROS-Responsive strategy

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2025-04-11 DOI:10.1016/j.bmc.2025.118195

Jiangye Zhang , Rui Cai , Changxu Ning , Zhongxiang Zhou , Yibo Zhang , Shisheng Wang , Yueqing Li , Xiuhan Guo

{"title":"A novel integrated diagnostic and therapeutic ferroptosis inhibitor based on a phenothiazine scaffold with ROS-Responsive strategy","authors":"Jiangye Zhang , Rui Cai , Changxu Ning , Zhongxiang Zhou , Yibo Zhang , Shisheng Wang , Yueqing Li , Xiuhan Guo","doi":"10.1016/j.bmc.2025.118195","DOIUrl":null,"url":null,"abstract":"<div><div>Ferroptosis is a newly discovered form of cell death that is closely related to the occurrence of various diseases, such as neurodegenerative diseases, cardiovascular and cerebrovascular ischemic damage, and organ fibrosis. Therefore, the discovery of new active compounds with ferroptosis inhibitory activity is regarded as a new strategy for the clinical treatment of these diseases. In this study, a multifunctional prodrug molecule PNX-B2 with a phenoxazine structure was designed based on the oxidative microenvironment characteristic of ferroptosis. PNX-B2 can recognize the ferroptosis-associated oxidative conditions and simultaneously release compounds with ferroptosis-inhibitory activity. Moreover, it integrates diagnostic and therapeutic functions and offers a fluorescent indication of the ferroptosis microenvironment. PNX-B2 has demonstrated excellent ferroptosis-inhibitory activity with an EC<sub>50</sub> value of 1.7 nM. This intelligent multifunctional compound shows great potential as a novel clinical agent for ferroptosis inhibition and presents broad prospects for future development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"124 ","pages":"Article 118195"},"PeriodicalIF":3.0000,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0968089625001361","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Ferroptosis is a newly discovered form of cell death that is closely related to the occurrence of various diseases, such as neurodegenerative diseases, cardiovascular and cerebrovascular ischemic damage, and organ fibrosis. Therefore, the discovery of new active compounds with ferroptosis inhibitory activity is regarded as a new strategy for the clinical treatment of these diseases. In this study, a multifunctional prodrug molecule PNX-B2 with a phenoxazine structure was designed based on the oxidative microenvironment characteristic of ferroptosis. PNX-B2 can recognize the ferroptosis-associated oxidative conditions and simultaneously release compounds with ferroptosis-inhibitory activity. Moreover, it integrates diagnostic and therapeutic functions and offers a fluorescent indication of the ferroptosis microenvironment. PNX-B2 has demonstrated excellent ferroptosis-inhibitory activity with an EC₅₀ value of 1.7 nM. This intelligent multifunctional compound shows great potential as a novel clinical agent for ferroptosis inhibition and presents broad prospects for future development.

Abstract Image

查看原文本刊更多论文

基于吩噻嗪支架和 ROS 反应策略的新型综合诊断和治疗铁蛋白沉积抑制剂

Ferroptosis是一种新发现的细胞死亡形式，与神经退行性疾病、心脑血管缺血性损伤、器官纤维化等多种疾病的发生密切相关。因此，发现具有抑制铁下垂活性的新活性化合物被认为是临床治疗这些疾病的新策略。本研究基于铁死亡的氧化微环境特点，设计了一种具有吩恶嗪结构的多功能前药分子PNX-B2。PNX-B2可以识别与铁中毒相关的氧化条件，同时释放具有抑制铁中毒活性的化合物。此外，它集成了诊断和治疗功能，并提供了铁下垂微环境的荧光指示。PNX-B2具有良好的抑铁活性，EC50值为1.7 nM。该智能多功能化合物作为一种新型的临床上抑制铁下垂药物具有很大的潜力，具有广阔的发展前景。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.