Discovery and optimization of 2-(trifluoromethyl)benzimidazole derivatives as novel ferroptosis inducers in vitro and in vivo

• Published in: European journal of medicinal chemistry 2023-01, Vol.245, p.114905-114905, Article 114905
• Main Authors: Fang, Yuying, Tan, Qingyun, Zhou, Huihao, Xu, Jun, Gu, Qiong
• Format: Article
• Language: English
• Subjects: Anti-cancer; Ferroptosis inducer; Structural modification; System Xc
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114905

Ferroptosis is implicated in diverse human diseases. Ferroptosis inducers hold great potential for cancer therapy. The existing ferroptosis inducers, however, lack structural diversity, and only a few of them are suitable for in vivo applications. Herein, by phenotypic screenings, we discovered a new ferroptosis inducer FA-S, a 2-(trifluoromethyl)benzimidazole derivative, from which a series of its analogs were designed and synthesized to improve the activity. This produced the most potent compound FA16 with single-digit micromolar activity of ferroptosis induction and satisfactory metabolic stability. Further studies demonstrated that FA16 induced ferroptosis by inhibiting cystine/glutamate antiporter (system Xc−). It is noteworthy that analogue FA16 has more favorable metabolic stability than the classic system Xc− inhibitor erastin, which is not suitable for in vivo studies. FA16 significantly inhibited tumor growth in the HepG2 xenograft model by inducing ferroptosis. This work provides new ferroptosis inducers with a novel scaffold, but also a promising lead for hepatocellular carcinoma treatment. Our work reveals a suitable in vivo ferroptosis-inducing tool to explore the mechanisms underlying ferroptosis and the relevance of ferroptosis to pathogenesis of human diseases. [Display omitted] •A novel scaffold for ferroptosis inducers was discovered through phenotypic screening.•Thirty-one 2-(trifluoromethyl)benzimidazole derivatives were designed and synthesized for ferroptosis induction.•FA16 is a specific ferroptosis inducer with satisfactory metabolic stability.•FA16 induces ferroptosis by inhibiting cystine/glutamate antiporter (system xc−).•This work provides a suitable in vivo ferroptosis-inducing tool that is also a lead against hepatocellular carcinoma.