Antiferroptotic Activity of Phenothiazine Analogues: A Novel Therapeutic Strategy for Oxidative Stress Related Disease

Jun Liu, Indrajit Bandyopadhyay, Lei Zheng, Omar M. Khdour, Sidney M. Hecht

Research output: Contribution to journalArticlepeer-review

Abstract

Ferroptosis is an iron-catalyzed, nonapoptotic form of regulated necrosis that has been implicated in the pathological cell death associated with various disorders including neurodegenerative diseases (e.g., Friedreich's ataxia (FRDA), Alzheimer's disease, and Parkinson's disease), stroke, and traumatic brain injury. Recently, we showed that lipophilic methylene blue (MB) and methylene violet (MV) analogues both promoted increased frataxin levels and mitochondrial biogenesis, in addition to their antioxidant activity in cultured FRDA cells. Presently, we report the synthesis of series of lipophilic phenothiazine analogues that potently inhibit ferroptosis. The most promising compounds (1b-5b) exhibited an improved protection compared to the parent phenothiazine against erastin- and RSL3-induced ferroptotic cell death. These analogues have equivalent or better potency than ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1), that are among the most potent inhibitors of this regulated cell death described so far. They represent novel lead compounds with therapeutic potential in relevant ferroptosis-driven disease models such as FRDA.

Original languageEnglish (US)
Pages (from-to)2165-2173
Number of pages9
JournalACS Medicinal Chemistry Letters
Volume11
Issue number11
DOIs
StatePublished - Nov 12 2020
Externally publishedYes

Keywords

  • Ferroptosis
  • Friedreich's ataxia
  • antiferroptotic activity
  • lipid peroxidation
  • methylene blue
  • methylene violet

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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