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

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: [Fe₂Cp₂(CO)(CNFc)(μ-CO){μ-CNMe(R)}]CF₃SO₃ (Fc = [Fe(Cp)(η⁵-C₅H₄)], R = Me, 2a; cyclohexyl = Cy, 2b; p-methoxyphenyl = Anis, 2c; Cp = η⁵-C₅H₅) and [Fe₂Cp₂(CO)_x(CNR')_(1-x)(μ-CO){μ-CNMe(R)}]CF₃SO₃ (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 IC₅₀ 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.