Anti‐Cancer Iron(II) Complexes of Pentadentate N‐Donor Ligands: Cytotoxicity, Transcriptomics Analyses, and Mechanisms of Action

Two cytotoxic iron(II) complexes [Fe(L)(CH 3 CN) n ](ClO 4 ) 2 (L=qpy for Fe‐1 a , Py 5 ‐OH for Fe‐2 a ) were synthesized. Both complexes are stable against spontaneous demetalation and oxidation in buffer solutions. Cyclic voltammetry measurements revealed the higher stability of Fe‐2 a (+0.82 V vs Fc) against Fe II to Fe III oxidation than Fe‐1 a (+0.57 V vs Fc). These two complexes display potent cytotoxicity at micromolar level against a panel of cancer cell lines ( Fe‐1 a =0.8–3.1 μ M ; Fe‐2 a =0.6–3.4 μ M ), and induce apoptosis that involves caspase activation. Transcriptomic and Connectivity Map analyses revealed that the changes of gene expression induced by Fe‐1 a and Fe‐2 a are similar to that induced by ciclopirox, an antifungal compound whose mode of action involves formation of intracellular cytotoxic iron chelates. Both Fe‐1 a and Fe‐2 a caused cellular nuclear DNA damage, as revealed by Comet assay and H2 AX immunofluorescence experiments. The cytotoxicity is associated with production of reactive oxygen species (for Fe‐1 a ), cell cycle regulation, and stress kinase pathways. The relative contributions of these to the overall cytotoxic mechanism is significantly affected by the structure of penta‐ N ‐donor ligand.