F. Richard Keene

Isolation and characterisation of stereoisomers in di- and tri-nuclear complexes

A number of synthetic methodologies have recently been developed for polymetallic supramolecular assemblies, commonly without consideration of the stereochemistry of the component octahedral metal centres. This review discusses stereochemical aspects of ligand-bridged di- and tri-nuclear complexes, with an emphasis on those involving ruthenium(II) octahedral metal centres coordinated to bidentate N-heterocyclic ligands. It examines recent studies devoted to the isolation of individual stereoisomers of such complexes using both stereoselective synthetic procedures through precursors with pre-determined chiralities and/or chromatographic techniques. The characterisation of the stereoisomers is also addressed.

Stereochemistry and polymetallic ligand-bridged molecular assemblies

There have been many recent developments in synthetic methodologies for polymetallic ligand-bridged molecular assemblies, encouraged by the prospect that such materials have potential application to photochemical molecular devices. The assemblies have involved ruthenium (II) metal centers, which are invariably octahedral. However, the synthetic advances have often occurred without consideration of the problem of stereochemical ambiguity in the produets. The present review examines this uncertainty and ways in which it may be addressed. In particular, it assesses approaches to the pre-determination of the stereochemistry of poly-nuclear assemblies incorporating Ru(II) and related centers {e.g. Os(II)} by the use of precursors with an established geometry, and the use of chromatographic techniques in the separation of stereoisomeric mixtures. Some of our own work is elaborated, where we have been able to separate stereoisomers of chiomophore-quencher complexes and of dinuclear and trinuclear ligand-bridged species. Additionally, the review summarizes our preliminary studies of their physical properties as a function of the spatial arrangement of the components.

Metal-ion promotion of the oxidative dehydrogenation of coordinated amines and alcohols

The oxidative dehydrogenations of amines and alcohols are promoted by their coordination to transition metal centers, with ruthenium and osmium being particularly effective. The dehydrogenation reaction is well known in macrocyclic chemistry, and has been reported for a variety of monodentate and bidentate ligands as well. The initial step in the process is the one-electron oxidation of the metal center. However, the mechanism of the subsequent intramolecular redox reaction (in which the ligand is oxidized and the metal reduced) is ambiguous—it may take place either by one-electron steps through a ligand-radical intermediate, or involve higher oxidation states of the metal so that alternative two-electron pathways are possible. This review investigates studies of the mechanistic features of the reaction. The particular efficacy of ruthenium and osmium in promotion of ligand oxidation is related to their ability to attain an oxidation state two units greater than the final state, stabilized by deprotonation, and allowing a low-energy pathway for the even-electron processes required in the dehydrogenations of the amine and alcohol substrates.

Mechanism of Cytotoxicity and Cellular Uptake of Lipophilic Inert Dinuclear Polypyridylruthenium(II) Complexes

The accumulation, uptake mechanism, cytotoxicity, cellular localisation of—and mode of cell death induced by—dinuclear ruthenium(II) complexes ΔΔ/ΛΛ‐[{Ru(phen)2}2{μ‐bbn}]4+ (Rubbn), where phen is 1,10‐phenanthroline, bbn is bis[4(4′‐methyl‐2,2′‐bipyridyl)]‐1,n‐alkane (n=2, 5, 7, 10, 12 or 16), and the corresponding mononuclear complexes containing the bbn ligands, were studied in L1210 murine leukaemia cells. Cytotoxicity increased with linker chain length, and the ΔΔ‐Rubb16 complex displayed the highest cytotoxicity of the series, with an IC50 value of 5 μM, similar to that of carboplatin in the L1210 murine leukaemia cell line. Confocal microscopy and flow cytometry studies indicated that the complexes accumulate in the mitochondria of L1210 cells, with the magnitude of cellular uptake and accumulation increasing with linking chain length in the bbn bridge of the metal complex. ΔΔ‐Rubb16 entered the L1210 cells by passive diffusion (with a minor contribution from protein‐mediated active transport), inducing cell death via apoptosis. Additionally, metal‐complex uptake in leukaemia cells was approximately 16‐times that observed in healthy B cells highlighting that the bbn series of complexes may have potential as selective anticancer drugs.

Reduction of carbon dioxide by tris(2,2′-bipyridine)cobalt(I)

Abstract Preliminary stoichiometric and kinetic results bearing on the mechanism of the reduction of HCO3− to CO by tris(2,2′-bipyridine)cobalt(I) in aqueous media are reported. The results indicate that CO (not formate) is the dominant carbon product and that it is scavenged by Co(bpy)3+ to give insoluble [Co(bpy)(CO)2]2. At pH ∼ 9, bicarbonate reduction occurs in competition with H2O reduction. Both processes are inhibited by bpy and promoted by H+, suggesting the common intermediate Co(bpy)2(H2O)H2+. The bicarbonate reaction itself branches to give H2 and CO in ∼ 3:1 ratio.

4,5-Di(2-pyridyl)-1,2,3-triazolate: the elusive member of a family of bridging ligands that facilitate strong metal–metal interactions

The new click-adduct 4,5-di(2-pyridyl)-1,2,3-triazole acts as a doubly-chelating anionic bridging ligand that forms dinuclear ruthenium(II) complexes which exhibit strong metal-metal interactions.

In vitro susceptibility and cellular uptake for a new class of antimicrobial agents: dinuclear ruthenium(II) complexes

OBJECTIVES To determine the in vitro susceptibility and cellular uptake for a series of dinuclear ruthenium(II) complexes [{Ru(phen)(2)}(2){μ-bb(n)}](4+) (Rubb(n)), and the mononuclear complexes [Ru(Me(4)phen)(3)](2+) and [Ru(phen)(2)(bb(7))](2+) against Staphylococcus aureus, methicillin-resistant S. aureus, Escherichia coli and Pseudomonas aeruginosa. METHODS The in vitro susceptibility was determined by MIC and MBC assays, and time-kill curve experiments, while the cellular uptake was evaluated by monitoring the fluorescence of the complexes remaining in the supernatant of the cultures after incubation for various periods of time, flow cytometry and confocal microscopy. RESULTS Rubb(12) and Rubb(16) are highly active, with MIC and MBC values of 1-2 mg/L (0.5-1 μM) for the two Gram-positive strains and 2-4 mg/L for E. coli and 16-32 mg/L for P. aeruginosa. Rubb(16) showed equal or better activity (on a molar basis) to gentamicin and ampicillin for all strains apart from P. aeruginosa. The relative MBC to MIC values indicated that Rubb(12) and Rubb(16) are bactericidal, and from the time-kill curve experiments, the ruthenium complexes can kill the bacteria within 2-6 h. The cellular uptake studies demonstrated that the observed antimicrobial activity is correlated with the level of uptake of the ruthenium complexes. Confocal microscopy confirmed the cellular uptake of Rubb(16), and tentatively suggested that the ruthenium complex is localized in the bacteria. CONCLUSIONS The inert dinuclear ruthenium(II) complexes Rubb(12) and Rubb(16) have potential as new antimicrobial agents. The structure of the dinuclear ruthenium complexes can be readily further modified in order to increase their selectivity for bacteria over human cells.

Dinuclear ruthenium(II) antimicrobial agents that selectively target polysomes in vivo

Wide-field fluorescence microscopy at high magnification was used to study the intracellular binding site of Rubb16 in Escherichia coli. Upon incubation of E. coli cells at the minimum inhibitory concentration, Rubb16 localised at ribosomes with no significant DNA binding observed. Furthermore, Rubb16 condensed the ribosomes when they existed as polysomes. It is postulated that the condensation of polysomes would halt protein production, and thereby inhibit bacterial growth. The results of this study indicate that the family of inert dinuclear ruthenium complexes Rubbn selectively target RNA over DNA in vivo. Selective RNA targeting could be advantageous for the development of therapeutic agents, and because of differences in ribosome structure between bacteria and eukaryotic cells, the Rubbn complexes could be selectively toxic to bacteria. In support of this hypothesis, the toxicity of Rubb16 was found to be significantly less to liver and kidney cell lines than against a range of bacteria.

Selective mitochondrial accumulation of cytotoxic dinuclear polypyridyl ruthenium(II) complexes

The lipophilic ligand-bridged dinuclear cation Rubb₁₆ is significantly cytotoxic and preferentially accumulates in the mitochondria of the L1210 murine leukemia cancer cell line.

Mechanism of mediation of the electrochemical oxidation of K4Fe(CN)6 at poly-[tris(3-{ω-[4-(2,2′-bipyridyl)] alkyl}-thiophene)iron(II)]-film modified electrodes in aqueous solutions

Abstract The kinetics of the electrochemical oxidation of K4Fe(CN)6 at poly-[tris(3-{ω-[4-(2,2′-bipyridyl)]alkyl}thiophene)iron(II)]-film modified electrodes have been investigated in aqueous solutions, using cyclic voltammetry and rotating disk electrode voltammetry. The retro-electrocatalytic reaction of the substrate at the polymer-coated electrodes is dependent on the alkyl chain length between the thiophene and 2,2′-bipyridine moieties and on the concentration of the substrate. The electrodes coated with the films possessing short alkyl chains exhibit more reversible voltammetric behavior and better catalytic activity to the oxidation of [Fe(CN)6]4− species in aqueous solutions compared with those possessing long alkyl chains. Kinetic parameters, calculated on the basis of modified Levich equations, indicate that under most circumstances the mediated reactions are controlled by the chemical step.