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Metal complexes provide a versatile platform to develop novel anticancer pharmacophores, and they form stable compounds with N-heterocyclic carbene (NHC) ligands, some of which have been shown to inhibit the cancer-related selenoenzyme thioredoxin reductase (TrxR). To expand a library of isostructural NHC complexes, we report here the preparation of Rh III -and Ir III (Cp*)(NHC)Cl 2 (Cp* = η 5 -pentamethylcyclopentadienyl) compounds and comparison of their properties to the Ru II -and Os II (cym) analogues (cym = η 6 -p-cymene). Like the Ru II -and Os II (cym) complexes, the Rh III -and Ir III (Cp*) derivatives exhibit cytotoxic activity with half maximal inhibitory concentration (IC 50 ) values in the low micromolar range against a set of four human cancer cell lines. In studies on the uptake and localization of the compounds in cancer cells by X-ray fluorescence microscopy, the Ru and Os derivatives were shown to accumulate in the cytoplasmic region of treated cells. In an attempt to tie the localization of the compounds to the inhibition of the tentative target TrxR, it was surprisingly found that only the Rh complexes showed significant inhibitory activity at IC 50 values of ∼1 μM, independent of the substituents on the NHC ligand. This indicates that, although TrxR may be a potential target for anticancer metal complexes, it is unlikely the main target or the sole target for the Ru, Os, and Ir compounds described here, and other targets should be considered. In contrast, Rh(Cp*)(NHC)Cl 2 complexes may be a scaffold for the development of TrxR inhibitors.

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Redox‐active Cu(II) complexes are able to form reactive oxygen species (ROS) in the presence of oxygen and reducing agents. Recently, Faller et al. reported that ROS generation by Cu(II) ATCUN complexes is not as high as assumed for decades. High complex stability results in silencing of the Cu(II)/Cu(I) redox cycle and therefore leads to low ROS generation. In this work, we demonstrate that an exchange of the α‐amino acid Gly with the β‐amino acid β‐Ala at position 2 (Gly2→β‐Ala2) of the ATCUN motif reinstates ROS production (•OH and H2O2). Potentiometry, cyclic voltammetry, EPR spectroscopy and DFT simulations were utilized to explain the increased ROS generation of these β‐Ala2‐containing ATCUN complexes. We also observed enhanced oxidative cleavage activity towards plasmid DNA for β‐Ala2 compared to the Gly2 complexes. Modifications with positively charged Lys residues increased the DNA affinity through electrostatic interactions as determined by UV/VIS, fluorescence, and CD spectroscopy, and consequently led to a further increase in nuclease activity. A similar trend was observed regarding the cytotoxic activity of the complexes against several human cancer cell lines where β‐Ala2 peptide complexes had lower IC50 values compared to Gly2. The higher cytotoxicity could be attributed to an increased cellular uptake as determined by ICP‐MS measurements.

Dinuclear RhIII(Cp*) and IrIII(Cp*) complexes demonstrated potent in vitro anticancer activity while exhibiting low toxicity in haemolysis studies and in vivo zebrafish models.

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The development of the metallodrug pull-down as a metalloproteomic technique has enabled the identification of the protein targets of metal-based anticancer agents.

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