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

Two cytotoxic iron(II) complexes [Fe(L)(CH3CN)(n)](ClO4)(2) (L=qpy for Fe-1a, Py-5-OH for Fe-2a) were synthesized. Both complexes are stable against spontaneous demetalation and oxidation in buffer solutions. Cyclic voltammetry measurements revealed the higher stability of Fe-2a (+0.82 V vs Fc) against Fe-II to Fe-III oxidation than Fe-1a (+0.57 V vs Fc). These two complexes display potent cytotoxicity at micromolar level against a panel of cancer cell lines (Fe-1a=0.8-3.1 mu m; Fe-2a=0.6-3.4 mu m), and induce apoptosis that involves caspase activation. Transcriptomic and Connectivity Map analyses revealed that the changes of gene expression induced by Fe-1a and Fe-2a are similar to that induced by ciclopirox, an antifungal compound whose mode of action involves formation of intracellular cytotoxic iron chelates. Both Fe-1a and Fe-2a caused cellular nuclear DNA damage, as revealed by Comet assay and H2AX immunofluorescence experiments. The cytotoxicity is associated with production of reactive oxygen species (for Fe-1a), 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.