Mitochondria-Disrupting Aminocarbyne−DMAP Diiron(I) Complexes Perturb Iron Homeostasis with Marginal ROS Contribution in Cancer Cells

Abstract

Five diiron complexes, [Fe2Cp2(CO)(dmap)(μ-CO){μ-CN(Me)(R)}]CF3SO3 (3a-e), were synthesized from readily available tris-carbonyl precursors and characterized. The complexes display ≈10−4 M aqueous solubility, amphiphilicity, and 50−74% of intact complex remaining after 72 h in DMEM-d/CD3OD solution. All compounds exhibit potent activity in MDA-MB-231, A2780, A2780R, HeLa, HCT116, PANC-1, and U87MG cancer cell lines. The most active derivatives, 3c and 3d, are 5- to 30-fold more potent than cisplatin. In 3D HCT116 spheroids enriched in cancer stem cell-like populations, 3a-e showed IC50 approximately one order of magnitude lower than cisplatin. Notably, 3c and 3d retained activity in HCT116 cells under hypoxia. Subcellular fractionation revealed predominant association of 3c and 3d with membrane fractions. Treatment with 3c and 3d induced downregulation of transferrin receptor 1 (TfR1), G1 phase arrest (57−60% vs 45% in control cells) and mitochondrial dysfunction. In contrast, flow cytometry and radical scavenger experiments indicate a limited contribution of reactive oxygen species.