Easily Available, Amphiphilic Diiron Cyclopentadienyl Complexes Exhibit in Vitro Anticancer Activity in 2D and 3D Human Cancer Cells through Redox Modulation Triggered by CO Release

A straightforward two‐step procedure via single CO removal allows the conversion of commercial [Fe(2)Cp(2)(CO)(4)] into a range of amphiphilic and robust ionic complexes based on a hybrid aminocarbyne/iminium ligand, [Fe(2)Cp(2)(CO)(3){CN(R)(R’)}]X (R, R’=alkyl or aryl; X=CF(3)SO(3) or BF(4)), on up to multigram scales. Their physicochemical properties can be modulated by an appropriate choice of N‐substituents and counteranion. Tested against a panel of human cancer cell lines, the complexes were shown to possess promising antiproliferative activity and to circumvent multidrug resistance. Interestingly, most derivatives also retained a significant cytotoxic activity against human cancer 3D cell cultures. Among them, the complex with R=4‐C(6)H(4)OMe and R’=Me emerged as the best performer of the series, being on average about six times more active against cancer cells than a noncancerous cell line, and displayed IC(50) values comparable to those of cisplatin in 3D cell cultures. Mechanistic studies revealed the ability of the complexes to release carbon monoxide and to act as oxidative stress inducers in cancer cells.