The promise of the metal(arene) structure as an anticancer pharmacophore has prompted intensive exploration of this chemical space. While N-heterocyclic carbene (NHC) ligands are widely used in catalysis, they have only recently been considered in metal complexes for medicinal applications. Surprisingly, a comparatively small number of studies have been reported in which the NHC ligand was coordinated to the Ru II (arene) pharmacophore and even less with an Os II (arene) pharmacophore. Here, we present a systematic study in which we compared symmetrically substituted methyl and benzyl derivatives with the nonsymmetric methyl/benzyl analogues. Through variation of the metal center and the halido ligands, an in-depth study was conducted on ligand exchange properties of these complexes and their biomolecule binding, noting in particular the stability of the M−C NHC bond. In addition, we demonstrated the ability of the complexes to inhibit the selenoenzyme thioredoxin reductase (TrxR), suggested as an important target for anticancer metal−NHC complexes, and their cytotoxicity in human tumor cells. It was found that the most potent TrxR inhibitor diiodido(1,3-dibenzylbenzimidazol-2-ylidene)(η 6 -p-cymene)ruthenium(II) 1b I was also the most cytotoxic compound of the series, with the antiproliferative effects in general in the low to middle micromolar range. However, since there was no clear correlation between TrxR inhibition and antiproliferative potency across the compounds, TrxR inhibition is unlikely to be the main mode of action for the compound type and other target interactions must be considered in future.

Ru(arene) compounds have many desirable features making them promising candidates for further development in anticancer drug research. While a lot of emphasis has been placed on the modification of the ancillary ligands, there are not many examples of arene ligands bearing functional groups. Herein, we report the preparation of [Ru(arene)(8-oxyquinolinato)Cl] complexes with the arene being a protected form of the amino acid l-phenylalanine and 8-oxyquinolinato ligand substituted with halogens. With this approach we aimed to alter the pharmacological properties of the complexes and address issues with the aqueous solubility of the analogous p-cymene complexes. The complexes were shown to be stable in DMSO and water and reacted readily with l-histidine and 9-ethylguanine as protein and DNA models, respectively. Assaying the antiproliferative activity in cancer cells gave IC values in the low μM range. While the lipophilicity of the p-cymene analogues correlated well with their in vitro cytotoxicity, the potency of the complexes with the l-phenylalanine-derived arene was independent of lipophilicity.

Organoruthenium compounds have been widely investigated for their anticancer activity. Here we use one of the classic ligand classes found in organometallics, i.e., N-heterocyclic carbenes (NHC), and coordinate them to the Ru­(η6-p-cymene) scaffold as N,C-bidentate ligands substituted with a pyridyl moiety. Introduction of different substituents gave compounds with a wide variety of properties. We investigated their stability in solution and in the presence of biomolecules, in vitro anticancer activity, and cellular uptake to rationalize their biological properties in dependence on the structure. A clear effect of their structure on the stability in water and DMSO was found for some derivatives, which was reflected in the reactivity to biomolecules that was determined with selected representatives of the compound classes. The antiproliferative activity of the compounds was widely dependent on the lipophilicity of the N,C-bidentate ligand, but as cellular accumulation studies revealed, lipophilicity does not provide the full picture and additional effects must be responsible for the anticancer activity.

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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.

Metal-based anticancer agent development can be improved with advanced metallomics methods that allow for quick and efficient screening of metallodrugs for their metabolites in biological media. Cellular accumulation in in vitro settings is not always correlated with cytotoxicity; and protein binding, particularly with albumin and transferrin, can have an important influence on metallodrug transportation, selectivity, and efficacy. We contrast the time-dependent cellular accumulation of both cisplatin and the pre-clinically investigated RAPTA-C in terms of cell uptake and speciation in culture medium via CE-ICP-MS analysis. Despite RAPTA-C being administered at 40-fold higher dose than cisplatin, owing to its much higher IC value, the accumulation over time was only 10-fold higher. An optimised CE-ICP-MS method, through the coating of the capillary to prevent protein-capillary surface interactions, resulted in superior resolution and metal-protein adduct identification. It was then used for extracellular speciation in conjunction with [tris(acetylacetonato)cobalt(iii)] as an internal standard. RAPTA-C was found to be more inert to extracellular reactions than cisplatin which could be used to rationalise the observed cellular uptake patterns. While for cisplatin both transferrin and albumin were identified as the main binding partners, RAPTA-C was found to react nearly exclusively with albumin. Moreover, this behaviour was time-dependent and our results also demonstrate that cancer cells have an influence on metal species distribution in the cell culture medium over time.

The combination of more than one bioactive moiety in a multitargeted anticancer agent may result in synergistic activity of its components. Using this concept, bioorganometallic compounds were designed to feature a metal center, a 2‐pyridinecarbothioamide (PCA), and a hydroxamic acid, which is found in the anticancer drug vorinostat (SAHA). The organometallics showed inhibitory activity in the nanomolar range against histone deacetylases (HDACs) as the key target for SAHA. In particular, the Rh complex was a potent inhibitor of HDAC6 over HDAC1 and HDAC8. Whereas this complex was highly cytotoxic in human cancer cells, it showed low toxicity in hemolysis studies and zebrafish, demonstrating the role of the metal center. For this complex a slightly reduced expression of vascular endothelial growth factor receptor 2 (VEGFR2) was established, which was upregulated by SAHA. This finding indicates that the new organometallics display different modes of action than their bioactive components.

The combination of more than one bioactive moiety in a multitargeted anticancer agent may result in synergistic activity of its components. Using this concept, bioorganometallic compounds were designed to feature a metal center, a 2‐pyridinecarbothioamide (PCA), and a hydroxamic acid, which is found in the anticancer drug vorinostat (SAHA). The organometallics showed inhibitory activity in the nanomolar range against histone deacetylases (HDACs) as the key target for SAHA. In particular, the Rh complex was a potent inhibitor of HDAC6 over HDAC1 and HDAC8. Whereas this complex was highly cytotoxic in human cancer cells, it showed low toxicity in hemolysis studies and zebrafish, demonstrating the role of the metal center. For this complex a slightly reduced expression of vascular endothelial growth factor receptor 2 (VEGFR2) was established, which was upregulated by SAHA. This finding indicates that the new organometallics display different modes of action than their bioactive components.