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.