1. Academic Validation
  2. Discovery of novel diphenylbutene derivative ferroptosis inhibitors as neuroprotective agents

Discovery of novel diphenylbutene derivative ferroptosis inhibitors as neuroprotective agents

  • Eur J Med Chem. 2022 Mar 5;231:114151. doi: 10.1016/j.ejmech.2022.114151.
Yuying Fang 1 Qingyun Tan 1 Huihao Zhou 1 Qiong Gu 2 Jun Xu 3
Affiliations

Affiliations

  • 1 Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
  • 2 Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China. Electronic address: [email protected].
  • 3 Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China. Electronic address: [email protected].
Abstract

Ferroptosis is a regulated and iron-dependent cell death. Ferroptosis inhibitors are promising for treating many neurological diseases. Herein, with phenotypic assays, we discovered a new diphenylbutene derivative Ferroptosis inhibitor, DPT. Based on this hit, we synthesized fourteen new diphenylbutene derivatives, evaluated their Ferroptosis inhibitory activities in HT22 mouse hippocampal neuronal cells, and found that three compounds exhibited improved inhibitory activities compared with DPT. Among these active compounds, compound 3f displayed the most potent anti-ferroptosis activity (EC50 = 1.7 μM). Further studies demonstrated that 3f is a specific Ferroptosis inhibitor. And we revealed that different from the classic Ferroptosis inhibitors, 3f blocked Ferroptosis by increasing FSP1 protein level. Moreover, 3f can penetrate blood-brain barrier (BBB). In a rat model of ischemic stroke, 3f effectively mitigated cerebral ischemic injury. Therefore, we are confirmed that 3f, as a novel Ferroptosis inhibitor with a new scaffold, is promising for further development as an agent against neurological diseases.

Keywords

Diphenylbutene; FSP1; Ferroptosis inhibitor; Neuroprotective; Structural modification.

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