Inhibition of Thioredoxin Reductase by Triosmium Carbonyl Clusters.

Tumor cells are characterized by increased reactive oxygen species production in parallel with an enhanced antioxidant system to avoid oxidative damage. The inhibition of antioxidant systems is an effective way to kill cancer cells, and the thioredoxin system or, more specifically, the cytosolic selenocysteine-containing enzyme thioredoxin reductase (TrxR) has become an interesting target for cancer therapy. We show here that the known cytotoxic and apoptosis-inducing osmium carbonyl cluster Os3(CO)10(NCCH3)2 (1) is a nonsubstrate inhibitor of mammalian TrxR, with an IC50 of 5.3 ± 0.9 µM. It inhibits TrxR selectively over the closely related glutathione reductase (GR) and in the presence of excess reduced glutathione (GSH). This inhibition has also been demonstrated in cell lysates, suggesting that TrxR inhibition is a potential apoptotic pathway for 1.

Structural Mimics of the [Fe]-Hydrogenase: A Complete Set for Group VIII Metals.

A set of structural mimics of the [Fe]-hydrogenase active site comprising all the group VIII metals, viz., [M(2-NHC(O)C5H4N)(CO)2(2-S-C5H4N)], has been synthesized. They exist as a mixture of isomers in solution, and the relative stability of the isomers depends on the nature of the metal and the substituent at the 6-position of the pyridine ligand.

Embedding a Ruthenium-Based Structural Mimic of the [Fe]-Hydrogenase Cofactor into Papain.

We describe the synthesis of the ruthenacyclic carbamoyl complexes [Ru(2-NHC(O)C5H3NMe)(CO)2( o,o-Me2-C6H3S)(L)] (L = H2O or MeCN), which have a labile water or acetonitrile ligand at their sixth coordination sites. Steric bulk around the ruthenium center is essential in preventing isomerization and dimerization, and embedding within papain can be achieved via coordination of its sole free cysteine residue. The observed chemistry parallels that of the natural [Fe]-hydrogenase.

Vibrational spectroscopy of metal carbonyls for bio-imaging and -sensing.

Transition metal carbonyls exhibit strong CO absorptions in the 2200-1800 cm(-1) region, which is free of interference from other functional groups. This feature has led to their applications in bio-imaging and -sensing, in particular through mid-IR, Raman and more recently, surface-enhanced Raman spectroscopy (SERS). Their use in mid-IR quantitative sensing based on vibrational intensities, and chemical sensing based on frequency shifts and vibrational lifetimes, is reviewed. Their development for Raman sensing following the breakthrough in SERS highlights the potential of coupling metal carbonyls to plasmonic nanostructures as novel optical materials for SERS-based bio-imaging and -sensing.

A rapid and label-free SERS detection method for biomarkers in clinical biofluids.

A metal carbonyl-functionalized nanostructured substrate can be used in a rapid and simple assay for the detection of A1AT, a potential biomarker for bladder cancer, in clinical urine samples. The assay involves monitoring changes in the carbonyl stretching vibrations of the metal carbonyl via surface-enhanced Raman spectroscopy (SERS). These vibrations lie in the absorption spectral window of 1800-2200 cm(-1), which is free of any spectral interference from biomolecules.

A transition metal carbonyl probe for use in a highly specific and sensitive SERS-based assay for glucose.

A triosmium carbonyl cluster-boronic acid conjugate is used as a secondary carbohydrate probe in a SERS-based assay. The assay does not require conjugation of the metal carbonyl probe to a SERS-active species, and it utilizes the CO stretching vibrations of the metal carbonyl, which lies in a silent region of the SERS spectrum (1800-2200 cm(-1)), for quantification. High selectivity for glucose over fructose and galactose is obtained, and a human urine sample doped with glucose is detected accurately.

Biological and cytoselective anticancer properties of copper(II)-polypyridyl complexes modulated by auxiliary methylated glycine ligand.

A series of ternary copper(II)-1,10-phenanthroline complexes with glycine and methylated glycine derivatives, [Cu(phen)(aa)(H(2)O)]NO(3)·xH(2)O 1-4 (amino acid (aa): glycine (gly), 1; DL: -alanine (DL: -ala), 2; 2,2-dimethylglycine (C-dmg), 3; sarcosine (sar), 4), were synthesized and characterized by FTIR, elemental analysis, electrospray ionization-mass spectra (ESI-MS), UV-visible spectroscopy and molar conductivity measurement. The determined X-ray crystallographic structures of 2 and 3 show each to consist of distorted square pyramidal [Cu(phen)(aa)(H(2)O)](+) cation, a nitrate counter anion, and with or without lattice water, similar to previously reported structure of [Cu(phen)(gly)(H(2)O)]NO(3)·1½H(2)O. It is found that 1-4 exist as 1:1 electrolytes in aqueous solution, and the cationic copper(II) complexes are at least stable up to 24 h. Positive-ion ESI-MS spectra show existence of only undissociated [Cu(phen)(aa)](+) species. Electron paramagnetic resonance, gel electrophoresis, fluorescence quenching, and restriction enzyme inhibition assay were used to study the binding interaction, binding affinity and selectivity of these complexes for various types of B-form DNA duplexes and G-quadruplex. All complexes can bind selectively to DNA by intercalation and electrostatic forces, and inhibit topoisomerase I. The effect of the methyl substituents of the coordinated amino acid in the above complexes on these biological properties are presented and discussed. The IC(50) values (24 h) of 1-4 for nasopharyngeal cancer cell line HK1 are in the range 2.2-5.2 µM while the corresponding values for normal cell line NP69 are greater than 13.0 µM. All complexes, at 5 µM, induced 41-60 % apoptotic cell death in HK1 cells but no significant cell death in NP69 cells.

Metal carbonyl-gold nanoparticle conjugates for live-cell SERS imaging.

Conjugates of organometallic osmium carbonyl clusters and gold nanoparticles show a strong carbonyl signal in surface-enhanced Raman spectroscopy. The ease of bio-functionalization and the high stability and good dispersibility in aqueous solution make these conjugates excellent candidates for biomedical applications, as demonstrated by live-cell imaging with the carbonyl signals of OM-NP(PEG)-L conjugates.

Ultrafast vibrational relaxation dynamics of carbonyl stretching modes in Os3(CO)12.

The vibrational relaxation dynamics of the four infrared active carbonyl (CO) stretching normal modes of Os(3)(CO)(12) at 2068 cm(-1), 2034 cm(-1), 2014 cm(-1), and 2002 cm(-1) were measured using broad-band frequency resolved pump-probe spectroscopy. Transient absorption spectra of these modes were collected, and the fundamental, overtone, and combination bands were assigned. The frequency resolved pump-probe traces measured at the fundamental frequencies for the four stretching normal modes exhibited marked differences: the two axial modes at frequencies of 2068 cm(-1) and 2034 cm(-1) yielded similar bi-exponential decay traces, while the two equatorial modes at 2014 cm(-1) and 2002 cm(-1) showed a rising component, in addition to a bi-exponential decay. Due to the independence of the axial and equatorial stretching modes, it is shown that the axial-equatorial combination anharmonicity constants are near zero. This results in the appearance of the pump-probe signals of these combination bands at the same frequencies as the fundamental transitions, thus leading to interference and the resultant anomalous rising features. If unaccounted for, these interferences may lead to erroneous conclusions about the dynamics of these vibrational stretches. To avoid such pitfalls, it is therefore imperative to resolve such ambiguities. A corrected dynamical picture of the equatorial modes can be obtained by varying the center frequency of the pump pulse. The four modes have a slow vibrational excited population decay time of between 400 to 600 ps. We observe no obvious direct vibrational energy transfer between the axial and equatorial CO stretching modes.

Group VIII Metal Carbonyl Cluster-Boronic Acid Conjugates: Cytotoxicity and Mode of Action Studies.

A set of metal carbonyl cluster-boronic acid conjugates of the group VIII metals (Fe, Ru, and Os) were synthesized and their antiproliferative effects measured against two breast cancer cell lines (MCF-7 and MDA-MB-231) and a noncancerous breast epithelial (MCF-10A) cell line. The cytotoxicity followed the order Ru > Os > Fe for the MDA-MB-231 cells, although the latter two exhibited similar cytotoxicity against MCF-7 and MCF-10A cells. The osmium species {Os3(CO)10(µ-H)[µ-SC6H4-p-B(OH)2]} (2) could be chemically oxidized to its hydroxy analogue [Os3(CO)10(µ-H)(µ-SC6H4 -p-OH)] (2-OH), which showed comparable cytotoxicity. Mode of action studies pointed to an apoptotic pathway for cell death.

Osmium carbonyl clusters containing labile ligands hyperstabilize microtubules.

A study into the possible molecular targets of the osmium carbonyl cluster Os(3)(CO)(10)(NCCH(3))(2) (2) in the ER- breast carcinoma (MDA-MB-231) cell line was carried out. Infrared and (1)H NMR analyses of cells treated with 2 showed the formation of carboxylato- and thiolato-bridged clusters from the interaction with intracellular carboxylic acid and sulfhydryl residues. The cytotoxicity of 2 was reduced in the presence of fetal bovine serum, and measurement with Ellman's reagent as well as fluorescence confocal microscopy with tetramethylrhodamine-5-maleimide staining all demonstrated binding to intracellular sulfhydryl groups leading up to cell disruption. Tubulin-FITC antibody staining of treated cells showed disruption of the microtubules, and a tubulin polmerization assay showed that 2 induced hyperstabilization of the microtubules.

A comparative study on atomically precise Au nanoclusters as catalysts for the aldehyde-alkyne-amine (A3) coupling reaction: ligand effects on the nature of the catalysis and efficiency.

Atomically precise Au13 nanoclusters stabilized by stibines catalyze the aldehyde-alkyne-amine coupling reaction more efficiently than those stabilized by thiols or phosphines. The nature of the catalytic activity is also different, and may be attributed to the weaker coordinating ability of the stibine ligands.

Stibine-protected Au13 nanoclusters: syntheses, properties and facile conversion to GSH-protected Au25 nanocluster.

Monostibine-protected ionic Au13 nanoclusters, namely, [Au13(L)8(Cl)4][Cl] (L= SbPh3, 2a·Cl; Sb(p-tolyl)3, 2b·Cl) were prepared by the direct reduction of Au(L)Cl with NaBH4 in dichloromethane. Anion exchange with 2a·Cl afforded [Au13(SbPh3)8(Cl)4][X] (X = PF6, 2a·PF6; BPh4, 2a·BPh4). All these have been characterized by multinuclear NMR, ESI-MS and UV-Vis spectroscopy. Crystallographic analysis of 2a·BPh4 reveals that the cation possesses C 2v symmetry and the tridecagold core adopts a closed icosahedron configuration. The weaker coordinating ability of the stibine ligands leads to the ready reaction of 2b·Cl with PPh3 or glutathione (GSH) to form the smaller phosphine-protected cluster [Au11(PPh3)8Cl2][Cl] or larger thiolate-protected cluster Au25(SG)18, respectively. In the latter reaction, the addition of a small amount (0.5 to 3.5 equivalents) of a suitable oxidant such as K3(Fe(CN)6 accelerates the conversion rate significantly.

Organometallic-Constructed Tip-Based Dual Chemical Sensing by Tip-Enhanced Raman Spectroscopy for Diabetes Detection.

Tip-enhanced Raman spectroscopy (TERS) is capable of probing specific molecular information with high sensitivity, but dual chemical sensing remains a challenge. Another major hindrance to TERS chemical detection in biosamples such as blood is the interference from the strong absorptions of biomolecules. Herein, we report the preparation of an organometallic-conjugated TERS tip. We demonstrate that organometallic chemistry can be perfectly coupled with TERS for dual-molecule sensing. The unique Raman signals generated by the organometallic compound circumvent signal interference from the biomolecules in blood, allowing the rapid analysis of two important molecules (glucose and thiol) in ultralow volume (50 nL) samples. This enabled a correlation between the thiol and glucose levels in the blood of nondiabetic and diabetic patients to be drawn.

Osmocenyl-tamoxifen derivatives target the thioredoxin system leading to a redox imbalance in Jurkat cells.

The synthesis and the biological effects of two ferrocifen analogs in the osmium series, namely the monophenolic complex 1, the tamoxifen-like complex 2 and their oxidized quinone methide (QM) derivatives, 1-QM and 2-QM, are reported. Inhibition of purified thioredoxin reductase (TrxR) is observed with 1 and 2 only after their enzymatic oxidation by the hydrogen peroxide/horseradish peroxidase (H2O2/HRP) system with IC50 of 2.4 and 1.2µM respectively. However, this inhibition is larger than that obtained with the corresponding quinone methides (IC50=5.4µM for 1-QM and 3.6µM for 2-QM). The UV-Vis spectra of 1 or 2 incubated in the presence of H2O2/HRP show that the species generated is not a quinone methide, but probably the corresponding cation. In Jurkat cells, 2 shows high toxicity (IC50=7.4µM), while 1 is less effective (IC50=42µM). Interestingly, a significant inhibition of TrxR activity is observed in cells incubated with 2 (about 70% inhibition with 15µM) while the inhibition induced by 1 is much weaker (about 30% inhibition with 50µM). This strong inhibition of TrxR by 2 leads to accumulation of thioredoxin and peroxiredoxin 3 in oxidized form and to a decrease of the mitochondrial membrane potential (MMP). These results show that cytotoxicity of the osmocifens depends on their oxidation within the cell and that inhibition of thioredoxin reductase by oxidized species is a key factor in rationalizing the cytotoxicity of these complexes on Jurkat cells.

High nuclearity carbonyl clusters as near-IR contrast agents for photoacoustic in vivo imaging.

High nuclearity carbonyl clusters of ruthenium and osmium are found to exhibit good photoacoustic (PA) activity in the near-IR (NIR) region. Their potential as PA contrast agents for full body imaging has been demonstrated for the first time with mice; intravenous administration of the osmium carbonyl cluster Na2[Os10(µ6-C)(CO)24] afforded up to a four-fold enhancement of the PA signal in various tissues. The cluster exhibits low toxicity, high stability and superior PA stability compared to the clinically approved NIR dye, indocyanine green.

Preparation and characterization of Cr(CO)(4)dpp (chromium tetracarbonyl 2,3-bis(2'-pyridyl)pyrazine) adsorbed on silver nanoparticles.

A transition metal carbonyl species, Cr(CO)(4)dpp, has been successfully attached to bare silver nanoparticles prepared by laser ablation of a metal foil in ethanol. Transmission electron microscopy (TEM) images have shown that at least a portion of the silver nanoparticles have been capped by the chromium species, and ligand shells corresponding to Cr(CO)(4)dpp multilayer adsorption onto the silver nanoparticles of 30-50 nm diameter have been observed. The detection of the strongest Raman-active nu(CO) band of Cr(CO)(4)dpp at 2004 cm(-1) revealed that the species has been adsorbed without decomposition. The time-of-flight secondary ion mass spectrometry (TOF-SIMS) signals recorded of the chromium-capped silver nanoparticles were also consistent with the nondecomposition adsorption process. Density functional calculations have been used to reproduce the Raman spectrum using Ag(7)(+) as a model surface. A large binding energy of about 122 kJ/mol has also been computed between silver and nitrogen atoms thus lending support to Cr(CO)(4)dpp being chemisorbed onto the silver surface.

C-S Bond Cleavage and C-C Coupling in Cyclopentadienylchromium Complexes To Give the First Dithiooxamide-Bridged and Doubly Dithiocarbamate-Bridged Double Cubanes: [Cp6 Cr8 S8 {(C(S)NEt2 )2 }] and [Cp6 Cr8 S8 (S2 CNEt2 )2 ].

Thermolysis of the dithiocarbamate complex 1 led to the formation of the thiocarbenoid complex 2 and two double cubanes: 3, which has an intercubane Cr-Cr bond and a dithiooxamide ligand in the µ-η2 ,η4 bonding mode, and 4, which contains two dithiocarbamate ligands in the µ-η1 ,η2 bonding mode.

[Cp*IrCl2]2 catalyzed formation of 2,2'-biindoles from 2-ethynylanilines.

[Cp*IrCl2]2 catalyzes the cyclization of 2-ethynylanilines to 2,2'-biindoles via intramolecular hydroamination. A reaction pathway has been proposed on the basis of deuterium labeling experiments and computational studies.