Diversity-Oriented Synthesis toward the Discovery of Ferrocenophane-Appended GPX4 Inhibitors as Potent Ferroptosis Inducers with Drug Likeness

Novel drug-like Ferroptosis inducers with distinct chemotypes and enhanced potency are needed to overcome Cancer therapy resistance. In this study, we reported a new series of ferrocenophane-appended GPX4 inhibitors as highly effective ferroptosis-inducing Anticancer agents by leveraging the "one-stone-kills-two-birds" strategy. Through diversity-oriented synthesis and structure-activity relationship investigations, the [3]-ferrocenophane derivative ML210-ansaFc emerged as a standout candidate, demonstrating remarkable cytotoxicity and superior Ferroptosis selectivity in Cancer cells versus ML210. Mechanistic studies revealed, for the first time, the ROS-generating capability of bridged ferrocenes at the molecular and cellular levels, underscoring the dual functionality of ansa-ferrocenes in driving Ferroptosis. ML210-ansaFc exhibited robust tumor growth suppression in 3D spheroid models, coupled with favorable drug-like properties, highlighting its potential as a therapeutic agent for intractable cancers. This work could pave the way for the development of metallocene-based chemotypes with diverse spatial configurations for the treatment of multiple diseases.