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

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 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.