title: 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)(CH3 CN)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 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 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.
authors.affiliation: State Key Laboratory of Synthetic Chemistry, Department of Chemistry and Chemical Biology Centre, The University of Hong Kong, Pokfulam Road, Hong Kong (PR China).
authors.forename: Wai-Lun
authors.initials: WL
authors.lastname: Kwong
authors.forename: Chun-Nam
authors.initials: CN
authors.lastname: Lok
authors.forename: Chun-Wai
authors.initials: CW
authors.lastname: Tse
authors.forename: Ella Lai-Ming
authors.initials: EL
authors.lastname: Wong
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Che
mesh_terms: D017209:Apoptosis; D018929:Cell Culture Techniques; D004249:DNA Damage / Q000235:genetics*; D020869:Gene Expression Profiling; D006367:HeLa Cells; D006801:Humans; D007501:Iron / Q000737:chemistry*; D008024:Ligands; D017382:Reactive Oxygen Species; D059467:Transcriptome
chemical_list: D008024:Ligands; D017382:Reactive Oxygen Species; D007501:Iron
keywords: DNA damage; apoptosis; cytotoxicity; iron complexes; transcriptomics