Heptadentate, Octadentate, Or Even Nonadentate? Denticity in the Unexpected Formation of an All-Carbon Donor-Atom Ligand in RhIII(Cp*)(Anthracenyl-NHC) Complexes.

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.

Anthracenyl Functionalization of Half-Sandwich Carbene Complexes: In Vitro Anticancer Activity and Reactions with Biomolecules.

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-d6/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.

A Bioactive l-Phenylalanine-Derived Arene in Multitargeted Organoruthenium Compounds: Impact on the Antiproliferative Activity and Mode of Action.

RuII(η6-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 RuII(η6-arene)Cl complexes with different substituents on the phenyl ring of the flavonol which should maintain the multitargeting capability of the parent η6- 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 IC50 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.

Anticancer Ru and Os complexes of N-(4-chlorophenyl)pyridine-2-carbothioamide: Substitution of the labile chlorido ligand with phosphines.

Half-sandwich MII(cym)Cl (cym = Î·6-p-cymene; M = Ru, Os) complexes of pyridinecarbothioamide (PCA) ligands have demonstrated potential as orally active anticancer agents. In order to investigate the impact of the substitution of the labile chlorido ligand with phosphorous donor ligands on the antiproliferative properties, the triphenylphosphine (PPh3) and 1,3,5-triaza-7-phophaadamantane (pta) analogues were prepared and characterized by spectroscopic techniques and the molecular structures of several complexes were determined by X-diffraction analysis. Interestingly, the molecular structures contained the PCA ligand deprotonated, presumably driven by the reduction in overall charge of the complex. Density Functional Theory (DFT) calculations suggested minor energy differences between the protonated and deprotonated forms. The aqueous stability and the reactivity with the amino acids l-histidine and l-cysteine were investigated by 1H NMR spectroscopy of representative examples. The most potent anticancer agents featured Ru or Os centers and a PPh3 ligand and showed IC50 values in the submicromolar range against four cancer cell lines. This suggests that the antiproliferative activity was mainly dependent on the lipophilic properties of the phosphine ligand with PPh3 having a significantly higher clog P value than pta.

Triazolyl- vs Pyridyl-Functionalized N-Heterocyclic Carbene Complexes: Impact of the Pendant N-Donor Ligand on Intramolecular C-C Bond Formation.

Organometallic Rh(Cp*) (Cp* = η5-pentamethylcyclopentadienyl) complexes with monodentate N-heterocyclic carbene (NHC) ligands bearing a pendant anthracenyl substituent have been shown to undergo intramolecular C-C coupling reactions. Herein, two bidentate NHC ligands substituted with pyridyl or triazolyl donor groups were prepared along with the corresponding MII/III (M = RuII, OsII, RhIII, IrIII) complexes. While the Rh(Cp*) complex featuring an NHC-triazole bidentate ligand underwent the equivalent reaction as the monodentate Rh(NHC) complex, i.e., it formed a polydentate ligand, the pyridyl-pendant derivative was unequivocally shown to be unreactive. This contrasting behavior was further investigated by density functional theory (DFT) calculations that highlighted significant differences between the two types of Rh(III) complexes with pendant pyridyl or triazolyl N-coordinating groups. Modeling of the reaction pathways suggests that the initial formation of a dicationic Rh(III) species is unfavorable and that the internal ligand transformation proceeds first by dissociation of the coordinated N atom of the pendant group from the Rh center. After the formation of a neutral η4-fulvene ligand via combined proton/single electron transfer, a cycloaddition occurs between the exo-ene bond of fulvene and the 9' and 10' positions on the pendant anthracenyl group. The resulting experimental UV-visible spectrum recorded in methanol of the polydentate triazolyl-based Rh species revealed the loss of the vibronic coupling typically associated with an anthracenyl functional group. Moreover, TD-DFT modeling indicates the presence of an equilibrium process whereby the N-coordination of the pendant triazolyl group to the RhIII center appears to be highly labile. Charge decomposition analysis (CDA) of the DFT-modeled species with the dissociated triazolyl group revealed a pseudo-η3-allylic interaction between the π-type MOs of the transformed anthracenyl group and the RhIII center; thus, the singly attached chelating ligand is classified as having rare nonadenticity.