A Druglike Ferrostatin‐1 Analogue as a Ferroptosis Inhibitor and Photoluminescent Indicator
Jiangkun Yan, Luo Bao, Huicong Liang, Zhao Li, Min Liu, Lingxiu Kong, Xuejing Fan, Chunhui Liang, Tongtong Liu, Xinyu Han, K H Wang, Chuanbin Shen, Wanyang Sun, Xin J. Zhou, Bo Chu, Michael J. McGlinchey, Ximing Xu, Xue Qiu, Yong Wang
Abstract
Redox-based diagnostic and therapeutic applications have long suffered from a shortage of suitable drugs and probes of high specificity. In the context of anti-ferroptosis research for neurological diseases, the inaccessibility of a blood-brain barrier (BBB) permeable small molecular ferroptosis inhibitor, and the lack of specific ferroptosis probes, seriously impeded a deeper understanding of the mechanism of ferroptosis and the development of clinically applicable drugs. We report herein a novel 1,3,4-thiadiazole-functionalized druglike ferrostatin analogue entitled Ferfluor-1 with superior anti-ferroptosis potency, favorable BBB permeability and in vivo activity against stroke and Parkinson's disease. Moreover, the exclusive pseudo-excited-state intramolecular proton-transfer (ESIPT) property of Ferfluor-1 via a long-distance hydrogen-bonding network makes it the first sensitive ratiometric photoluminescent probe to detect phospholipid hydroperoxides and a specific indicator for the fluctuation of ferroptosis. These unprecedented advantages not only make Ferfluor-1 a potential tool for ferroptosis-related diagnostic and therapeutic applications in the central nervous system, but also pave the way to developing new theragnostic agents for precision redox detection and regulation.