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

Abstract

Two cytotoxic iron(II) complexes [Fe(L)(CH3CN)n](ClO4)2 (L=qpy for Fe-1 a, Py5-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 FeII to FeIII 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 μm; Fe-2 a=0.6–3.4 μm), 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.