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.
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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