Structural optimization and biological evaluation of ferrocene-appended RSL3 derivatives as potent ferroptosis inducers

Ferroptosis inducers with novel chemical scaffolds are promising for overcoming cancer therapy resistance. In this study, we conducted structural optimization and biological evaluation of ferrocene-appended RSL3 derivatives as potent ferroptosis inducers for anticancer treatment. Through structure-activity relationship studies, compound A6 stands out with stronger antiproliferative ability (IC₅₀ ≈ 3–5 nM) and higher ferroptosis selectivity than RSL3. Mechanistic studies confirmed the dual-function role of ferrocene acting as both a structural scaffold to maintain the inhibition of GPX4 and a reactive oxygen species (ROS) generator to enhance the vulnerability to ferroptosis of cancer cells. Importantly, significant tumor shrinkage and optimal safety profile of A6 in xenograft model demonstrates its potential for treating aggressive cancers. This study of developing ferrocene-appended ferroptosis inducers via structural optimization expands the toolbox for metal-based therapies against oxidative stress-related pathologies.