Isocyanide Incorporation Expands the Anticancer Potential of Diiron(I) Aminocarbyne Complexes

ABSTRACT Diiron(I) bis‐cyclopentadienyl complexes with a bridging aminocarbyne ligand feature an organometallic scaffold with established anticancer potential. Aiming to expand the structure‐activity relationships, seven new compounds were synthesized by incorporating isocyanide ligands: [Fe 2 Cp 2 (CO)(CNFc)(μ‐CO){μ‐CNMe(R)}]CF 3 SO 3 (Fc = [Fe(Cp)(η 5 ‐C 5 H 4 )], R = Me, 2a ; cyclohexyl = Cy, 2b ; p ‐methoxyphenyl = Anis, 2c ; Cp = η 5 ‐C 5 H 5 ) and [Fe 2 Cp 2 (CO) x (CNR′) (1‐x) (μ‐CO){μ‐CNMe(R)}]CF 3 SO 3 (R = Cy, R′ = Anis, x = 1, 3b or x = 2, 4b ; R = Anis, R′ = Cy, x = 1, 3c or x = 2, 4c ). The products were isolated in 70%–85% yields and characterized by IR, NMR spectroscopy, and single crystal X‐ray diffraction in one representative case. They display submillimolar water solubility, amphiphilic or moderately lipophilic character, and remarkable inertness in physiological‐like solutions. While the ferrocenyl derivatives 2a–c exhibited only modest activity, 3 and 4 displayed potent cytotoxicity across a panel of six cancer cell lines, with IC 50 values in the low micromolar range in most cases and in the nanomolar range for the NTERA‐2 testis cell line. Moreover, 3b–c showed significant selectivity toward cancer cells and, along with 4b–c , retained a remarkable cytotoxic effect in 3D cell spheroids. Complexes 3b–c were effective in targeting cellular TrxR and increasing cellular ROS production.