Crystallographic evidence for the stereoselective substitution of equatorial pyridyl ligands in ruthenium(III) complexes.

Mononuclear Ru complexes catalyze dioxygen formation via water splitting; therefore, a detailed investigation into their water-oxidation process is necessary. In this study, we synthesized a series of Ru(III) complexes containing a dianionic tridentate ligand with three pyridine groups (one coordinated to Ru while the other two are "free") and investigated their substitution reactions in a water/acetonitrile mixture. Among the monodentate pyridyl ligands, the one at the equatorial position was crystallographically proven to be selectively substituted. Therefore, our results experimentally demonstrate the proposed coordination geometry for an intermediate during water oxidation over Ru complexes.

Isolation and structural comparison of RuII-dnp complexes [dnp = 2,6-bis-(1,8-naphthyridin-2-yl)pyridine] with axially or equatorially coordinating NCS ligands.

The mol-ecular and crystal structures of two ruthenium(II) complexes, viz. cis-aqua-[2,6-bis-(1,8-naphthyridin-2-yl)pyridine-κ3 N,N',N''](thio-cyanato-κN)(tri-phen-yl-phosphine-κP)ruthenium(II) hexa-fluorido-phosphate-acetone-water (1/0.5/1), [Ru(NCS)(C21H13N5)(C18H15P)(H2O)]PF6·0.5C3H6O·H2O (I) and trans-[2,6-bis-(1,8-naphthyridin-2-yl)pyridine-κ3'N,N',N'']bis-(pyridine-κN)(thiocyanato-κN)ruthenium(II) thio-cyanate, [Ru(NCS)(C21H13N5)(C5H5N)2]NCS (II), with an N-coordinating thio-cyanato group and a tridentate polypyridyl supporting ligand, are reported. The RuII atom in each of the cationic complexes adopts a distorted octa-hedral coordination sphere, defined by an N atom of the thio-cyanato ligand, three N atoms from the tridentate polypyridyl ligand, and an O and P atom in (I) or two pyridine-N atoms in (II) derived from monodentate ligands. The thio-cyanato ligand in (I) coordinates in an axial manner to the {Ru-dnp} unit [dnp = 2,6-bis-(1,8-naphthyridin-2-yl)pyridine], whereas it coordinates in an equatorial manner in (II). In the crystal structure of compound (I), intra-molecular C-H⋯O, C-H⋯N and O-H⋯N hydrogen bonds as well as π-π contacts are present, in addition to inter-molecular C-H⋯F, C-H⋯O and O-H⋯O hydrogen bonds. In the crystal structure of compound (II), intra-molecular C-H⋯N hydrogen bonds are observed along with inter-molecular C-H⋯N and C-H⋯S hydrogen bonds as well as a π-π inter-action.

Hydroquinone/quinone electro- and photochemical interconversion in isolable polypyridylruthenium(II) complexes.

Quinone derivatives and their metal complexes are well-known molecules that participate in electron-transfer reactions relevant to diverse fields. However, the fundamental knowledge on the unique reactivity of redox-active quinone complexes is limited by the difficulty in their isolation. Herein, the synthesis of isolable mononuclear polypyridylruthenium(ii) complexes containing both hydroquinone and quinone units is described. Three types of monodentate ligands are conveniently used to control the electronic states of the complexes. Both reduced (hydroquinone) and oxidised (quinone) forms are successfully isolated and characterised by spectroscopic and crystallographic analysis, allowing direct comparisons of their properties. The redox-rich and visible light-responsive nature of the ruthenium complexes enables to investigate the quinone/hydroquinone interconversion induced by electron transfer, photoirradiation and photoswitching based on ligand substitution reactions. These results demonstrate the occurrence of synergistic effects between metal complexes and redox-active organic compounds.

Effects of Chemically-Modified Polypyridyl Ligands on the Structural and Redox Properties of Tricarbonylmanganese(I) Complexes.

Carbonyl complexes with manganese(I) as the central metal are very attractive catalysts. The introduction of redox-active ligands, such as quinones and methyl viologen analogs into these catalysts, would be expected to lead to superior catalyst performances, since they can function as excellent electron carriers. In this study, we synthesized four tricarbonylmanganese(I) complexes containing typical bidentate polypyridyl ligands, including 1,10-phenanthroline (phen) and 2,2'-bipyridine (bpy) frameworks bound to redox-active ortho-quinone/catechol or methyl viologen-like units. The molecular structures of the resulting complexes were determined by X-ray crystallography to clarify their steric features. As expected from the infrared (IR) data, three CO ligands for each complex were coordinated in the facial configuration around the central manganese(I) atom. Additionally, the structural parameters were found to differ significantly between the quinone/catechol units. Electrochemical analysis revealed some differences between them and their reference complexes, namely [MnBr(CO)3(phen)] and [MnBr(CO)3(bpy)]. Notably, interconversions induced by two-electron/two-proton transfers between the quinone and catechol units were observed in the phenanthroline-based complexes. This work indicated that the structural and redox properties in tricarbonylmanganese(I) complexes were significantly affected by chemically modified polypyridyl ligands. A better understanding of structures and redox behaviors of the present compounds would facilitate the design of new manganese complexes with enhanced properties.

Synthesis and crystal structures of manganese(I) carbonyl complexes bearing ester-substituted α-di-imine ligands.

The crystal structures of two manganese(I) complexes with ester-substituted bi-pyridine or bi-quinoline supporting ligands are reported, namely, fac-bromido-tricarbon-yl(diethyl 2,2'-bi-pyridine-4,4'-di-carboxyl-ate-κ2 N,N')mangan-ese(I), [MnBr(C16H16N2O4)(CO)3], I, and fac-bromido-tricarbon-yl(diethyl 2,2'-bi-quinoline-4,4'-di-carboxyl-ate-κ2 N,N')manganese(I), [MnBr(C24H20N2O4)(CO)3], II. In both complexes, the manganese(I) atom adopts a distorted octa-hedral coordination sphere defined by three carbonyl C atoms, a Br- anion and two N atoms from the chelating α-di-imine ligand. Both complexes show fac configurations of the carbonyl ligands. In I, the complex mol-ecules are linked by C-H⋯Br hydrogen bonds and aromatic π-π contacts. In II, intra-molecular C-H⋯O hydrogen bonds are present as well as inter-molecular C-H⋯O and C-H⋯Br hydrogen bonds and π-π inter-actions.

Selective synthesis and crystal structures of manganese(I) complexes with a bi- or tridentate terpyridine ligand.

The crystal structures of two manganese(I) complexes with a different coordination mode of the supporting ligand are reported: fac-bromido-tricarbon-yl(4'-phenyl-2,2':6',2''-terpyridine-κ2 N,N')manganese(I), [MnBr(C21H15N3)(CO)3], I, and cis-bromido-dicarbon-yl(4'-phenyl-2,2':6',2''-terpyridine-κ3 N,N',N'')manganese(I), [MnBr(C21H15N3)(CO)2], II. In both complexes, the manganese(I) atom is coordinated by terminal carbonyl ligands, a bromide ion, and a 4'-phenyl-2,2':6',2''-terpyridine ligand within a distorted octa-hedral environment. In I, the metal ion is facially coordinated by three carbonyl ligands and the terpyridine ligand binds in a bidentate fashion. The non-coordinating nitro-gen atom in the terpyridine ligand is positioned on the side opposite to the bromido ligand. In II, the metal ion is coordinated by two carbonyl ligands in a cis configuration and the terpyridine ligand binds in a tridentate fashion; notably, one carbonyl and the trans bromido ligand are mutually disordered over two positions. In I, the complex mol-ecules are linked by C-H⋯Br hydrogen bonds. In II, aromatic π-π contacts are present, as well as pairs of C-H⋯Br and C-H⋯O hydrogen bonds.

Coordination Chemistry of Ru(II) Complexes of an Asymmetric Bipyridine Analogue: Synergistic Effects of Supporting Ligand and Coordination Geometry on Reactivities.

The reactivities of transition metal coordination compounds are often controlled by the environment around the coordination sphere. For ruthenium(II) complexes, differences in polypyridyl supporting ligands affect some types of reactivity despite identical coordination geometries. To evaluate the synergistic effects of (i) the supporting ligands, and (ii) the coordination geometry, a series of dicarbonyl-ruthenium(II) complexes that contain both asymmetric and symmetric bidentate polypyridyl ligands were synthesized. Molecular structures of the complexes were determined by X-ray crystallography to distinguish their steric configuration. Structural, computational, and electrochemical analysis revealed some differences between the isomers. Photo- and thermal reactions indicated that the reactivities of the complexes were significantly affected by both their structures and the ligands involved.

Crystal structure of a dinuclear ruthenium(II) complex with a bent CO22- bridge.

The mol-ecular and crystal structures of a CO22--bridged dinuclear ruthenium complex is reported, namely, µ-carbonito-κ2C:O-bis-[bis(2,2'-bi-pyridine-κ2N,N')carbon-ylruthenium(II)] bis-(hexa-fluorido-phosphate)-aceto-nitrile-diethyl ether (1/1/0.5), [Ru2(CO)2(C10H8N2)4(µ:κ2-C:O-CO2)](PF6)2·CH3CN·0.5C4H10O. The complex cation in the title compound consists of two {Ru(CO)(bpy)2}2+ units (bpy = 2,2'-bi-pyridine) singly bridged by a µ:κ2-C:O carbonite anion, resulting in an unsymmetrical dinuclear structure. Some of the inter-atomic C⋯O distances involving the carbonyl ligands are shorter than the sum of the van der Waals radii. There are intra-molecular C-H⋯O and aromatic π-π contacts in the cationic complex. In the crystal, the cations are linked by pairs of C-H⋯F hydrogen bonds in addition to weak C-H⋯F inter-actions between the solvent mol-ecules and PF6- counter-anions. The equatorial F atoms of one of the PF6- anions are disordered over two sets of sites with an occupancy ratio of 0.908 (7):0.092 (7) while the central O atom of the diethyl ether solvent mol-ecule is disordered over an inversion centre.

Neuroprotective effect of nobiletin on cerebral ischemia-reperfusion injury in transient middle cerebral artery-occluded rats.

Nobiletin, a citrus polymethoxylated flavone, is reported to possess various pharmacological activities such as anticancer, anti-inflammation, and antioxidant effects. Recently, nobiletin was shown to provide therapeutic benefit for the treatment of Alzheimer׳s disease by activating cAMP-response element-binding protein (CREB). In the present study, we investigated whether nobiletin could protect the brain against ischemia-reperfusion (I/R) injury and improve functional outcome in cerebral I/R model rats, since CREB activation is known to protect neuronal cells in cerebral ischemia. Nobiletin was injected twice at 0 and 1h after the start of reperfusion in transient middle cerebral artery occlusion (t-MCAO) rats. Cerebral I/R induced prominent brain damage in the ischemic hemisphere of t-MCAO rat brains; however, nobiletin treatment significantly reduced the infarct volume and suppressed the brain edema. Immunohistochemical and TUNEL staining indicated that nobiletin treatment significantly suppressed neutrophil invasion into the ischemic region and significantly decreased apoptotic brain cell death in ischemic hemisphere, suggesting that the anti-inflammatory effect and anti-apoptotic effect should be regarded as the neuroprotective mechanism of nobiletin. Moreover, nobiletin treatment ameliorated motor functional deficits in the ischemic rats compared with those deficits of the vehicle-treated group. These results indicate that nobiletin is a potential neuroprotectant for the treatment of cerebral I/R injury.

cis-Bis(2,2'-bipyridine-κ(2) N,N')carbonyl-chloridoruthenium(II) hexa-fluorido-phosphate.

In the title compound, [RuCl(C10H8N2)2(CO)]PF6, the Ru(II) atom is coordinated in a distorted octa-hedral geometry by four N atoms of the bipyridine ligands, a carbonyl C atom and a chloride ion. The carbonyl and chloride ligands in the cation adopt a mutually cis arrangement and these are disordered over two sets of sites with site occupancies of 0.721 (6) and 0.279 (6). The Ru-N bond length [2.117 (2) Å] trans to the carbonyl ligand is slightly longer than the average of the other Ru-N bond lengths (2.08 Å), which can be explained by the expected trans influence of the carbonyl group. In the crystal, weak C-H⋯F inter-actions are observed between the complex cation and the PF6(-) anion, leading to the formation of a three-dimensional supramolecular structure. The crystal studied was an inversion twin with twin fractions of 0.78 (4) and 0.22 (4).

Nanoparticles accumulate in ischemic core and penumbra region even when cerebral perfusion is reduced.

The use of a liposomal drug delivery system is a promising strategy for avoiding side effects and enhancing drug efficiency by changing the distribution of the intact drug. We have previously shown that liposomal agents quickly accumulated in an ischemia-reperfusion region and ameliorated cerebral ischemia-reperfusion injury when they were injected after reperfusion in transient middle cerebral artery occlusion (t-MCAO) rats. In the present study, we hypothesized that liposomes also act effectively as a drug carrier in the ischemic state, since the integrity of the blood brain barrier is disrupted at an early stage after an ischemic event. To test this hypothesis, the cerebral distribution of fluorescence-labeled liposomes was observed in permanent MCAO (p-MCAO) rats. The liposomes accumulated in the ischemic core and the penumbra region when injected at 1 or 2h after occlusion. The accumulation in the ischemic core region was clearly greater than that in the penumbra region, despite the cerebral blood perfusion of the core region being substantially reduced. This result suggests that drug delivery to an ischemic region using liposomes is possible even when cerebral blood circulation has not recovered. Because liposomal drug delivery systems have the potential to effectively employ a number of agents that have failed in clinical trials, they may offer an effective strategy for achieving neuroprotection in stroke patients.

Treatment of cerebral ischemia-reperfusion injury with PEGylated liposomes encapsulating FK506.

FK506 (Tacrolimus) has the potential to decrease cerebral ischemia-reperfusion injury. However, the clinical trial of FK506 as a neuroprotectant failed due to adverse side effects. This present study aimed to conduct the selective delivery of FK506 to damaged regions, while at the same time reducing the dosage of FK506, by using a liposomal drug delivery system. First, the cytoprotective effect of polyethylene glycol-modified liposomes encapsulating FK506 (FK506-liposomes) on neuron-like pheochromocytoma PC12 cells was examined. FK506-liposomes protected these cells from H2O2-induced toxicity in a dose-dependent manner. Next, we investigated the usefulness of FK506-liposomes in transient middle cerebral artery occlusion (t-MCAO) rats. FK506-liposomes accumulated in the brain parenchyma by passing through the disrupted blood-brain barrier at an early stage after reperfusion had been initiated. Histological analysis showed that FK506-liposomes strongly suppressed neutrophil invasion and apoptotic cell death, events that lead to a poor stroke outcome. Corresponding to these results, a single injection of FK506-liposomes at a low dosage significantly reduced cerebral cell death and ameliorated motor function deficits in t-MCAO rats. These results suggest that liposomalization of FK506 could reduce the administration dose by enhancing the therapeutic efficacy; hence, FK506-liposomes should be a promising neuroprotectant after cerebral stroke.

A single injection of liposomal asialo-erythropoietin improves motor function deficit caused by cerebral ischemia/reperfusion.

Modification of the liposomal surface with a targeting molecule is a promising approach for the targeted delivery of therapeutics. Asialo-erythropoietin (AEPO) is a potent tool for targeting an ischemic region by binding to the EPO receptors on neuronal cells. Additionally, it shows a strong cytoprotective effect against programed cell death. Hence, AEPO-modified liposomes appear likely to have both a neuronal-targeting character and a neuroprotective effect on cerebral ischemic injury. In this study, we assessed the targeting ability of AEPO-modified PEGylated liposomes (AEPO-liposomes) to ischemic region and their improvement effect on neurological deficits induced by ischemia/reperfusion (I/R) in transient middle cerebral artery occlusion (t-MCAO) rats. Immunohistological analysis showed that the AEPO-liposomes given immediately after reperfusion extravasated into the ischemic region and attached strongly to neuronal cells. Also, neuronal nuclei (NeuN) staining was clearly visible only in the AEPO-liposome-treated group, suggesting that AEPO-liposomes protected neuronal cells from ischemia/reperfusion-induced damage. Moreover, a single administration of low-dose AEPO-liposomes significantly improved the neurological deficit compared to vehicle and free-AEPO treatment at 7 days after injection. In conclusion, AEPO-liposomes have clear potential as a neuroprotectant after stroke and as a DDS device targeting ischemic regions.

Amelioration of cerebral ischemia-reperfusion injury based on liposomal drug delivery system with asialo-erythropoietin.

Cerebral ischemia-reperfusion (I/R) injury induces secondary cerebral damage. As drugs for treating this type of injury have shown poor efficacy and adverse side effects in clinical trials, a novel therapeutic strategy has been long awaited. In this study, we focused on the disruption of the blood-brain barrier after stroke, and applied a liposomal drug delivery system (DDS) designed to enhance the pharmacological effect of the neuroprotectant and to avoid side effects. PEGylated liposomes were injected at varying time after the start of reperfusion in transient middle cerebral artery occlusion (t-MCAO) model rats. The results showed PEGylated liposomes accumulated in the ischemic hemisphere at an early stage after reperfusion and were retained in the lesion for at least 24h after injection. We also investigated the effectiveness of asialo-erythropoietin (AEPO)-modified PEGylated liposomes (AEPO-liposomes) in treating the cerebral I/R injury. AEPO-liposome treatment significantly reduced TTC-defined cerebral legion following cerebral I/R injury, and ameliorated motor function compared with vehicle and AEPO treatment. In conclusion, these results indicate that AEPO-liposomes are a promising liposomal formulation for protecting the brain from I/R injury, and that this liposomal DDS has potential as a novel strategy for the treatment of cerebral I/R injury.

Aqua-[2-(2-pyrid-yl)-1,8-naphthyridine-κN,N](2,2':6',2''-terpyridine-κN,N',N'')ruthenium(II) bis-(hexa-fluorido-phosphate) acetone sesquisolvate.

The asymmetric unit of the title compound, [Ru(C(13)H(9)N(3))(C(15)H(11)N(3))(H(2)O)](PF(6))(2)·1.5C(3)H(6)O, consists of two crystallographically independent Ru(II) complexes. Each complex is approximately octa-hedral with the Ru(II) atom bound by an N,N'-coordinated 2-(2-pyrid-yl)-1,8-naphthyridine (pynp) ligand, a meridional 2,2':6',2''-terpyridine (tpy) ligand and one aqua ligand. The tpy ligand is coordinated in a planar tridentate fashion with the central N atom closest to the Ru(II) atom. The aqua ligand is trans to the pyridine N atom of pynp. The long Ru-O distances [2.150 (5) and 2.138 (5) Å] are typical for aqua ligands in polypyridyl ruthenium complexes. In the crystal, both intra-molecular O-H⋯N and inter-molecular O-H⋯O hydrogen bonds are observed.

PET imaging of nobiletin based on a practical total synthesis.

A practical synthesis of nobiletin, a polymethoxylated citrus flavone, was accomplished by utilizing our novel flavone synthesis. Synthetic nobiletin was labelled by selective demethylation and rapid incorporation of (11)C atom. Positron emission tomography images successfully visualized the brain distribution, which may provide therapeutic benefits in the treatment of Alzheimer's disease.

(2,2'-Bipyridine-κN,N')chlorido[4'-(2,5-dimethoxy-phen-yl)-2,2':6',2''-terpyridine-κN,N',N'']ruthenium(II) hexa-fluorido-phosphate acetonitrile monosolvate.

In the title compound, [RuCl(C(10)H(8)N(2))(C(23)H(19)N(3)O(2))]PF(6)·CH(3)CN, the ligand environment about the Ru(II) atom is distorted octa-hedral, with the substituted terpyridyl ligand coordinated in a meridional fashion, the bipyridyl ligand coordinated in a cis fashion and the Cl atom trans to one of the bipyridyl N atoms. The Ru-N distances are in the range 2.036 (2)-2.084 (2) Šwith the exception of the central Ru-N bond from the terpyridyl ligand, which is shorter [1.9503 (19) Å], as expected. The pendant dimethoxy-phenyl substituent is not coplanar with the terpyridyl unit; the dihedral angle between the central pyridyl ring and the benzene ring is 46.72 (11)°. The anion is disordered equally over two positions around an F-P-F bond axis.

cis,trans-Dicarbonyl-dichlorido[2-(2-pyrid-yl)-1,8-naphthyridine-κN,N]ruthenium(II).

The asymmetric unit of the title compound, [RuCl(2)(C(13)H(9)N(3))(CO)(2)], consists of four crystallographically independent Ru(II) complexes. Each Ru(II) atom is in a distorted octa-hedral environment coordinated by two carbonyl ligands, two Cl atoms and a chelating 2-(2-pyrid-yl)-1,8-naphthyridine (pynp) ligand. The carbonyl ligands are cis to each other, while the Cl atoms are trans. Relatively short inter-atomic distances (2.60-2.67 Å) between the uncoordinated N atom of pynp and the C atom of the carbonyl imply a donor-acceptor inter-action between the pynp and carbonyl ligands.