Catalytic asymmetric synthesis of spirocyclic azlactones by a double Michael-addition approach.

Spirocyclic azlactones are shown to be useful precursors of cyclic quaternary amino acids, such as the constrained cyclohexane analogues of phenylalanine. These compounds are of interest as building blocks for the synthesis of artificial peptide analogues with controlled folds in the peptide backbone. They were prepared in the present study by a step- and atom-economic catalytic asymmetric tandem approach, requiring two steps starting from N-benzoyl glycine and divinylketones.

A critical evaluation of whole cell patch clamp studies on electroporation using the voltage sensitive dye ANNINE-6.

The patch clamp technique in the whole cell configuration is potentially a powerful tool to investigate electroporation (electric-field-induced membrane permeabilization). Membrane polarization beyond certain threshold voltages leads to a steep conductance increase either indicating field-induced pore formation or being due to patch clamp artifacts (seal resistance breakdown). Protoplasts derived from tobacco culture cell lines (Bright Yellow-2, BY-2; Virginia bright Italian-0, VBI-0) were stained with the voltage-sensitive dye ANNINE-6.

(η(6)-p-Cymene)(1,3-dimesityl-2,3-dihydro-1H-imidazol-2-yl-idene)bis-(pentafluorobenzoato-κO)ruthenium(II) dichloro-methane disolvate.

The title compound, [Ru(C7F5O2)2(C10H14)(C21H24N2)]·2CH2Cl2, is formed as an orange crystalline powder by the reaction of RuCl2(p-cymene)(IMes) and AgOCOC6F5 in anhydrous tetra-hydro-furan (IMes = 1,3-dimesityl-2,3-di-hydro-1H-imidazol-2-yl-idene). The asymetric unit consists of two independent [Ru(C6F5COO)2(η(6)-p-cymene)(IMes)] com-plexes and four dichloro-methane solvent mol-ecules. In each complex molecule, the Ru atom presents a pseudo-octa-hedral environment with the p-cymene ligand occupying three facial coordination sites, while the remaining coordination positions are occupied by the O atoms of the penta-fluoro-benzoate ligands and by the imidazolyl-idene ligand.

Sensitivity enhanced nanothermal sensors for photoacoustic temperature mapping.

Photoacoustic imaging can be used to guide and validate the therapeutic outcome of nanoparticle-mediated photothermal therapy through its ability to visualize the delivery of nanoparticle contrast agents, image the temperature distribution inside living tissue, and confirm tissue coagulation. In this image-guided process, temperature mapping plays a critical role for thermal dosage control. Therefore, developing a sensitive and accurate photoacoustic technique to quantitatively measure the temperature distribution during thermal therapy is essential.

Quantitative photoacoustic imaging of nanoparticles in cells and tissues.

Quantitative visualization of nanoparticles in cells and tissues, while preserving the spatial information, is very challenging. A photoacoustic imaging technique to depict the presence and quantity of nanoparticles is presented. This technique is based on the dependence of the photoacoustic signal on both the nanoparticle quantity and the laser fluence.

Synchronizing steric and electronic effects in {Ru(II)(NNNN,P)} complexes: the catalytic dehydrative alkylation of anilines by using alcohols as a case study.

A series of new hexacoordinated {Ru(II)(NNNN,P)} complexes was prepared from [RuCl(2)(R(3)P)(3)]. Their structure was determined by X-ray crystallography. The catalytic potential of this new class of complexes was tested in the alkylation of aniline with benzyl alcohol.

Reaction of 1-nitroso-2-naphthols with α-functionalized ketones and related compounds: the unexpected formation of decarbonylated 2-substituted naphtho[1,2-d][1,3]oxazoles.

Reactions between 1-nitroso-2-naphthols and α-functionalized ketones such as α-bromo-, α-chloro-, α-mesyloxy-, α-tosyloxy-, and α-hydroxy ketones under basic conditions delivered 2-substituted naphtho[1,2-d][1,3]oxazoles in a single synthetic operation. The product formation was accompanied by the unexpected loss of the C═O group from the α-functionalized ketones. With aryl bromides, allyl bromides, α-bromo diketones, α-bromo cyanides, α-bromoesters, and α-bromo ketoesters as substrates the formation of naphtho[1,2-d][1,3]oxazoles was also observed.

Intranasal delivery of insulin via the olfactory nerve pathway.

Objectives: Intranasal delivery has been shown to target peptide therapeutics to the central nervous system (CNS) of animal models and induce specific neurological responses. In an investigation into the pathways by which intranasal administration delivers insulin to the CNS, this study has focused on the direct delivery of insulin from the olfactory mucosa to the olfactory bulbs via the olfactory nerve pathway.

Methods: Nasal and olfactory tissues of mice were imaged with fluorescent and electron microscopy 30 min following intranasal administration.

Intranasal treatment of central nervous system dysfunction in humans.

One of the most challenging problems facing modern medicine is how to deliver a given drug to a specific target at the exclusion of other regions. For example, a variety of compounds have beneficial effects within the central nervous system (CNS), but unwanted side effects in the periphery. For such compounds, traditional oral or intravenous drug delivery fails to provide benefit without cost.

Use of portable sleep monitors to diagnose sleep apnea during predeployment assessment.

Introduction: Portable sleep monitors (PMs) may be more expeditious and convenient than in-laboratory sleep studies in diagnosing obstructive sleep apnea (OSA). We report for the first time the use of PMs in a military population to demonstrate feasibility in predeployment assessments.

Methods: A nested, descriptive study was undertaken at 7 military medical facilities as part of a larger clinical trial.

Bispalladacycle-catalyzed Michael addition of in situ formed azlactones to enones.

The development and further evolution of the first catalytic asymmetric conjugate additions of azlactones as activated amino acid derivatives to enones is described. Whereas the first-generation approach started from isolated azlactones, in the second-generation approach the azlactones could be generated in situ starting from racemic N-benzoylated amino acids. The third evolution stage could make use of racemic unprotected α-amino acids to directly form highly enantioenriched and diastereomerically pure masked quaternary amino acid products bearing an additional tertiary stereocenter.

A dicationic ruthenium alkylidene complex for continuous biphasic metathesis using monolith-supported ionic liquids.

A dicationic ruthenium-alkylidene complex [Ru(dmf)(3)(IMesH(2))(=CH-2-(2-PrO)-C(6)H(4))][(BF(4))(2)] (1; IMesH(2) =1,3-dimesitylimidazolin-2-ylidene) has been prepared and used in continuous metathesis reactions by exploiting supported ionic-liquid phase (SILP) technology. For these purposes, ring-opening metathesis polymerization (ROMP)-derived monoliths were prepared from norborn-2-ene, tris(norborn-5-ene-2-ylmethyloxy)methylsilane, and [RuCl(2)(PCy(3))(2)(CHPh)] (Cy=cyclohexyl) in the presence of 2-propanol and toluene and surface grafted with norborn-5-en-2-ylmethyl-N,N,N-trimethylammonium tetrafluoroborate ([NBE-CH(2)-NMe(3)][BF(4)]). Subsequent immobilization of the ionic liquid (IL), 1-butyl-2,3-dimethylimidazolium tetrafluoroborate ([BDMIM][BF(4)]), containing ionic catalyst 1 created the SILP catalyst.

Solution and solid-state dynamics of metal-coordinated white phosphorus.

The dynamic behavior in solution of eight mono-hapto tetraphosphorus transition metal-complexes, trans-[Ru(dppm)(2)(H)(η(1)-P(4))]BF(4) ([1]BF(4)), trans-[Ru(dppe)(2)(H)(η(1)-P(4))]BF(4) ([2]BF(4)), [CpRu(PPh(3))(2)(η(1)-P(4))]PF(6) ([3]PF(6)), [CpOs(PPh(3))(2)(η(1)-P(4))]PF(6) ([4]PF(6)), [Cp*Ru(PPh(3))(2)(η(1)-P(4))]PF(6) ([5]PF(6)), [Cp*Ru(dppe)(η(1)-P(4))]PF(6) ([6]PF(6)), [Cp*Fe(dppe)(η(1)-P(4))]PF(6) ([7]PF(6)), [(triphos)Re(CO)(2)(η(1)-P(4))]OTf ([8]OTf), and of three bimetallic Ru(μ,η(1:2)-P(4))Pt species [{Ru(dppm)(2)(H)}(μ,η(1:2)-P(4)){Pt(PPh(3))(2)}]BF(4) ([1-Pt]BF(4)), [{Ru(dppe)(2)(H)}(μ,η(1:2)-P(4)){Pt(PPh(3))(2)}]BF(4) ([2-Pt]BF(4)), [{CpRu(PPh(3))(2))}(μ,η(1:2)-P(4)){Pt(PPh(3))(2)}]BF(4) ([3-Pt]BF(4)), [dppm=bis(diphenylphosphanyl)methane; dppe=1,2-bis(diphenylphosphanyl)ethane; triphos=1,1,1-tris(diphenylphosphanylmethyl)ethane; Cp=η(5)-C(5)H(5); Cp*=η(5)-C(5)Me(5) ] was studied by variable-temperature (VT) NMR and (31)P{(1)H} exchange spectroscopy (EXSY). For most of the mononuclear species, NMR spectroscopy allowed to ascertain that the metal-coordinated P(4) molecule experiences a dynamic process consisting, apart from the free rotation about the M-P(4) axis, in a tumbling movement of the P(4) cage while remaining chemically coordinated to the central metal. EXSY and VT (31)P NMR experiments showed that also the binuclear complex cations [1-Pt](+)-[3-Pt](+) are subjected to molecular motions featured by the shift of each metal from one P to an adjacent one of the P(4) moiety.

Gold catalysis: non-spirocyclic intermediates in the conversion of furanynes by the formal insertion of an alkyne into an aryl-alkyl C-C single bond.

It takes al-kynes: The formation of furyl-substituted heterocycles from furanynes with donor groups on the furan-alkyne tether and mechanistic control experiments indicate the involvement of open-chained carbenium ions in the overall insertion of an alkyne into a C-C bond, rather than the usual spirocyclic intermediates.

Intranasal delivery of deferoxamine reduces spatial memory loss in APP/PS1 mice.

Intranasal administration, which bypasses the blood-brain barrier and minimizes systemic exposure, is a non-invasive alternative for targeted drug delivery to the brain. While identification of metal dysregulation in Alzheimer's brain has led to the development of therapeutic metal-binding agents, targeting to the brain has remained an issue. The purpose of this study was to both determine concentrations of deferoxamine (DFO), a high-affinity iron chelator, reaching the brains of mice after intranasal administration and to determine its efficacy in a mouse model of spatial memory loss.

Intranasal deferoxamine improves performance in radial arm water maze, stabilizes HIF-1α, and phosphorylates GSK3β in P301L tau transgenic mice.

Deferoxamine (DFO), a metal chelator, has been previously reported to slow the loss of spatial memory in a mouse model of amyloid accumulation when delivered intranasally (IN). In this study, we determined whether IN DFO also has beneficial effects in the P301L mouse, which accumulates hyperphosphorylated tau. Mice were intranasally treated three times per week with either 10% DFO (2.

Aspects of plant plasmalemma charging induced by external electric field pulses.

The charging of the plasmalemma is a necessary condition for permeabilization of the plasma membrane (electroporation) in response to external electric field exposure. Common theories explain this permeabilization by formation of pores in the lipid bilayer. Using pulsed laser fluorescence microscopy, we measured the charging process of the membrane during the application of an external electric field with a temporal resolution of 5 ns.

Lysosomal enzyme can bypass the blood-brain barrier and reach the CNS following intranasal administration.

Here we provide the first evidence that therapeutic levels of a lysosomal enzyme can bypass the blood-brain barrier following intranasal administration. α-L-iduronidase (IDUA) activity was detected throughout the brains of IDUA-deficient mice following a single intranasal treatment with concentrated Aldurazyme® (laronidase) and was also detected after intranasal treatment with an adeno-associated virus (AAV) vector expressing human IDUA. These results suggest that intranasal routes of delivery may be efficacious in the treatment of lysosomal storage disorders.

Imprinting control region (ICR) of the Peg3 domain.

The imprinting and transcription of the 500 kb genomic region surrounding the mouse Peg3 is predicted to be regulated by the Peg3-differentially methylated region (DMR). In the current study, this prediction was tested using a mutant mouse line lacking this potential imprinting control region (ICR). At the organismal level, paternal and maternal transmission of this knockout (KO) allele caused either reduced or increased growth rates in the mouse, respectively.

Intranasal delivery of siRNA to the olfactory bulbs of mice via the olfactory nerve pathway.

Adopting RNAi technology for targeted manipulation of gene expression in the central nervous system (CNS) will require delivery of RNAi constructs to the CNS followed by cellular transfection and induction of the RNAi machinery. Significant strides have been made in enhancing RNAi transfection and tailoring knockdown toward specific gene targets, however, delivery of the RNAi constructs to the CNS remains a significant challenge. One possible solution for targeting siRNA to the CNS is intranasal administration, which noninvasively delivers a variety of compounds to the CNS.

Intranasal delivery of growth differentiation factor 5 to the central nervous system.

Context: Growth differentiation factor 5 (GDF5), in addition to its role in bone and joint development, protects dopaminergic (DA) neurons from degeneration, and is a potential therapeutic agent for Parkinson's disease. Its large size and insolubility at physiologic pH are obstacles for drug administration to the central nervous system (CNS) in humans.

Objective: In this study, formulations to deliver GDF5 to the brain using intranasal (IN) administration were developed.

Paramagnetic palladacycles with Pd(III) centers are highly active catalysts for asymmetric aza-Claisen rearrangements.

A combination of spectroscopic and electrochemical methods--XANES, EXAFS, X-ray, (1)H NMR, EPR, Mössbauer, and cyclic voltammetry--demonstrate that the most efficient Pd catalysts for the asymmetric rearrangement of allylic trifluoroacetimidates unexpectedly possess in the activated oxidized form a Pd(III) center bound to a ferrocene core which remains unchanged (Fe(II)) during the oxidative activation. These are the first recognized Pd(III) complexes acting as enantioselective catalysts.

Designer ionic liquid crystals based on congruently shaped guanidinium sulfonates.

Ionic liquid crystals are mesogenic compounds that consist of cations and anions, usually rod-like cations and spherical anions. Herein we report a new method for the synthesis of ionic liquid crystals by using cations and anions of the same molecular shape with oppositely charged head groups. Thus, 4-alkoxyphenylpentamethylguanidinium 4-alkoxyphenylsulfonate ion pairs have been synthesised.

Comparison of central versus peripheral delivery of pregabalin in neuropathic pain states.

Background: Although pregabalin therapy is beneficial for neuropathic pain (NeP) by targeting the CaVα2δ-1 subunit, its site of action is uncertain. Direct targeting of the central nervous system may be beneficial for the avoidance of systemic side effects.

Results: We used intranasal, intrathecal, and near-nerve chamber forms of delivery of varying concentrations of pregabalin or saline delivered over 14 days in rat models of experimental diabetic peripheral neuropathy and spinal nerve ligation.