Investigations
on incorporating an N-flanking
anthracenyl moiety to [Rh(Cp*)(NHC)Cl2] complexes surprisingly
led to the formation of an intramolecular C–C bond between
the Cp* and anthracenyl moieties, with additional auxiliary interactions
between the metal and the anthracenyl ring system. In silico modeling supports a reaction mechanism whereby Rh(η4-tetramethylfulvene) intermediates undergo metallocycloaddition and
the abstraction of a chlorido ligand, affording unique cationic complexes
that feature Rh centers coordinated by a nonadentate ligand with exclusively
carbon donor atoms. Some Rh–C interactions were extremely weak
but nevertheless exhibited covalent bonding character. These weak
Rh–C interactions were readily displaced by stronger electron
donors, and the nonadentate ligand reverted to the heptadentate coordination
mode observed in the intermediate. As far as we are aware, this study
provides the first conclusive evidence of complexes bearing a single
nonadentate κ9-coordinating ligand that features
only carbon donors bound to a metal center.
N-Heterocyclic carbene (NHC) ligands
are widely investigated in
medicinal inorganic chemistry. Here, we report the preparation and
characterization of a series of half-sandwich [M(L)(NHC)Cl2] (M = Ru, Os, Rh, Ir; L = cym/Cp*) complexes with a N-flanking anthracenyl
moiety attached to imidazole- and benzimidazole-derived NHC ligands.
The anticancer activity of the complexes was investigated in cell
culture studies where, in comparison to a Rh derivative with an all-carbon-donor-atom-based
ligand (5a), they were found to be cytotoxic with IC50 values in the low micromolar range. The Ru derivative 1a was chosen as a representative for stability studies as
well as for biomolecule interaction experiments. It underwent partial
chlorido/aqua ligand exchange in DMSO-d
6/D2O to rapidly form an equilibrium in aqueous media.
The reactions of 1a with biomolecules proceeded quickly
and resulted in the formation of adducts with amino acids, DNA, and
protein. Hen egg white lysozyme crystals were soaked with 1a, and the crystallographic analysis revealed an interaction with
an l-aspartic acid residue (Asp119), resulting in the cleavage
of the p-cymene ligand but the retention of the NHC
moiety. Cell morphology studies for the Rh analog 3a suggested
that the cytotoxicity is exerted via mechanisms different from that
of cisplatin.
Ru(η-arene) compounds carrying bioactive flavonol ligands have shown promising anticancer activity against tumor cells via a multitargeting mode of action, i.e., through interaction with DNA and inhibition of topoisomerase IIα. By introducing a novel arene ligand based on the amino acid l-phenylalanine (Phe), we aimed to alter the pharmacological properties of the complexes. We report here a series of novel Ru(η-arene)Cl complexes with different substituents on the phenyl ring of the flavonol which should maintain the multitargeting capability of the parent η- p-cymene (cym) complexes. Studies with selected examples revealed stability in aqueous solution after quickly forming aqua complexes but rapid decomposition in pure DMSO. The reactions with protein and DNA models proceeded quickly and resulted in cleavage of the flavonol or adduct formation, respectively. The compounds were found to be cytotoxic with significant antiproliferative activity in cancer cells with IC values in the low μM range, while not following the same trends as observed for the cym analogues. Notably, the cellular accumulation of the new derivatives was significantly higher than for their respective cym complexes, and they induced DNA damage in a manner similar to that of cisplatin but to a lesser extent.
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