Rhodium and iridium complexes of flexible scorpionate ligands based on azaindole were synthesised in good yields. The complexes were characterised in solution and in the solid state. Structural characterisation revealed a B-H-metal interaction, which is retained in solution. Given the greater flexibility of the ligand and potential cooperative effect of boron, the complexes were tested for their activity in the transfer hydrogenation of ketones.

Novel ‘tweezer-type’ complexes that exploit the interactions between p-electron-rich pyrenyl groups and p-electron deficient diimide units have been designed and synthesised. The component molecules leading to complex formation were accessed readily from commercially available starting materials through short and efficient syntheses. Analysis of the resulting complexes, using the visible charge- transfer band, revealed association constants that increased sequentially from 130 to 11,000 M 1 as increasing numbers of p–p-stacking interactions were introduced into the systems. Computational modelling was used to analyse the structures of these complexes, revealing low-energy chain-folded conformations for both components, which readily allow close, multiple p–p-stacking and hydrogen bonding to be achieved. In this paper, we give details of our initial studies of these complexes and outline how their behaviour could provide a basis for designing self-healing polymer blends for use in adaptive coating systems.

Novel phosphoramidates of acyclovir have been prepared and evaluated in vitro against acyclovir-sensitive and -resistant herpes simplex virus (HSV) types 1 and 2 and varicella-zoster virus (VZV). Unlike the parent nucleoside these novel phosphate prodrugs retain antiviral potency versus the ACV-resistant virus strain, suggesting an efficient bypass of the viral thymidine kinase.

For most viruses, there is a need for antimicrobials that target unique viral molecular properties. Acyclovir (ACV) is one such drug. It is activated into a human herpesvirus (HHV) DNA polymerase inhibitor exclusively by HHV kinases and, thus, does not suppress other viruses. Here, we show that ACV suppresses HIV-1 in HHV-coinfected human tissues, but not in HHV-free tissue or cell cultures. However, addition of HHV-6-infected cells renders these cultures sensitive to anti-HIV ACV activity. We hypothesized that such HIV suppression requires ACV phosphorylation by HHV kinases. Indeed, an ACV monophosphorylated prodrug bypasses the HHV requirement for HIV suppression. Furthermore, phosphorylated ACV directly inhibits HIV-1 reverse transcriptase (RT), terminating DNA chain elongation, and can trap RT at the termination site. These data suggest that ACV anti-HIV-1 activity may contribute to the response of HIV/HHV-coinfected patients to ACV treatment and could guide strategies for the development of new HIV-1 RT inhibitors.

Background and purpose: The epithelial sodium channel (ENaC) is a key regulator of airway mucosal hydration and mucus clearance. Negative regulation of airway ENaC function is predicted to be of clinical benefit in the cystic fibrosis lung. The aim of this study was to develop a small animal model to enable the direct assessment of airway ENaC function in vivo. Experimental approach: Tracheal potential difference (TPD) was utilized as a measure of airway epithelial ion transport in the guinea-pig. ENaC activity in the trachea was established with a dose-response assessment to a panel of well-characterized direct and indirect pharmacological modulators of ENaC function, delivered by intra-tracheal (i.t.) instillation. Key results: The TPD in anaesthetized guinea-pigs was attenuated by the direct ENaC blockers: amiloride, benzamil and CF552 with ED 50 values of 16, 14 and 0.2 μg kg -1 (i.t.), respectively. 5-(N-Ethyl-N-isopropyl) amiloride, a structurally related compound but devoid of activity on ENaC, was without effect on the TPD. Intra-tracheal dosing of the Kunitz-type serine protease inhibitors aprotinin and placental bikunin, which have previously been demonstrated to inhibit proteolytic activation of ENaC, likewise potently attenuated TPD in guinea-pigs, whereas α 1-antitrypsin and soya bean trypsin inhibitor were without effect. Conclusions and implications: The pharmacological sensitivity of the TPD to amiloride analogues and also to serine protease inhibitors are both consistent with that of ENaC activity in the guinea-pig trachea. The guinea-pig TPD therefore represents a suitable in vivo model of human airway epithelial ion transport. © 2008 Macmillan Publishers Limited All rights reserved.

Potassium (K+) channels can regulate ionic conduction through their pore by a mechanism, involving the selectivity filter, known as C-type inactivation. This process is rapid in the hERG K+ channel and is fundamental to its physiological role. Although mutations within hERG are known to remove this process, a structural basis for the inactivation mechanism has yet to be characterized. Using MD simulations based on homology modeling, we observe that the carbonyl of the filter aromatic, Phe627, forming the S0 K+ binding site, swiftly rotates away from the conduction axis in the wild-type channel. In contrast, in well-characterized non-inactivating mutant channels, this conformational change occurs less frequently. In the non-inactivating channels, interactions with a water molecule located behind the selectivity filter are critical to the enhanced stability of the conducting state. We observe comparable conformational changes in the acid sensitive TASK-1 channel and propose a common mechanism in these channels for regulating efflux of K+ ions through the selectivity filter.

It is suggested here that liquisolid technique has the potential to be optimized for the reduction of drug dissolution rate and thereby production of sustained release systems. In the present study, propranolol hydrochloride was dispersed in polysorbate 80 as the liquid vehicle. Then a binary mixture of carrier-coating materials (Eudragit RL or RS as the carrier and silica as the coating material) was added to the liquid medication under continuous mixing in a mortar. The final mixture was compressed using the manual tableting machine. The effect of drug concentration, loading factor, thermal treating and aging on release profile of propranolol hydrochloride from liquisolid compacts were investigated at two pH values (1.2 and 6.8). The release rate of propranolol HCl from liquisolid compacts was compared to the release of propranolol HCl from conventional tablets. X-ray crystallography and DSC were used to investigate the formation of any complex between drug and excipients or any crystallinity changes during the manufacturing process. Propranolol HCl tablets prepared by liquisolid technique showed greater retardation properties in comparison with conventional matrix tablets. This investigation provided evidence that polysorbate 80 (Tween 80) has important role in sustaining the release of drug from liquisolid matrices, and a reduction of Tg of the polymer can be the reason for the release prolongation of liquisolid tablets. The results also showed that wet granulation had remarkable impact on release rate of propranolol HCl from liquisolid compacts, reducing the release rate of drug from liquisolid compacts. The results showed that aging (liquisolid tablets were kept at 25 °C/75% relative humidity for 6 months) had no effect on hardness and dissolution profile of drug. The kinetics studies revealed that most of the liquisolid formulations followed the zero-order release pattern. X-ray crystallography and DSC ruled out any changes in crystallinity or complex formation during the manufacturing process of liquisolid formulations. © 2008 Elsevier B.V. All rights reserved.

Gliclazide (GL) is a second-generation sulphonylurea, widely used for the treatment of non-insulin dependent diabetes mellitus. The low water-solubility of GL leads to a low dissolution rate and variable bioavailability. The aim of this study was to enhance the dissolution rate of GL by the preparation of micron-sized particles using a solvent change method. The in situ micronization process was carried out using solvent change method in the presence of HPMC or Brij 35 (0.05 or 0.1 g) as stabilizing agents. GL (0.5 or 1 g) was dissolved in acetone and the stabilizing agent in water (as non-solvent). The non-solvent was poured rapidly into the drug solution under stirring at 26,000 rpm by an ultra-homogenizer, and the resultant was freeze-dried. The crystalline shape of GL changed from rod-shape to diamond- or cube-shape. The FTIR and DSC results showed no interaction between the drug and the stabilizers. Presence of sharp peaks in the XRD diffractograms of microcrystals with 10 times smaller height than untreated crystals indicates that a crystalline habit modification has occurred in the microcrystals without any polymorphic changes. The particle size was reduced about 50 times and the dissolution efficiency of GL at 15 min (DE15%) was increased about 4 times. © 2008 Elsevier B.V. All rights reserved.

PURPOSE. Comparative drug release kinetics from nanoparticles was carried out using conventional and our novel models with the aim of finding a general model applicable to multi mechanistic release. Theoretical justification for the two best general models was also provided for the first time. METHODS. Ten conventional models and three models developed in our laboratory were applied to release data of 32 drugs from 106 nanoparticle formulations collected from literature. The accuracy of the models was assessed employing mean percent error (E) of each data set, overall mean percent error (OE) and number of Es less than 10 percent. RESULTS. Among the models the novel reciprocal powered time (RPT), Weibull (W) and log-probability (LP) ones produced OE values of 6.47, 6.39 and 6.77, respectively. The OEs of other models were higher than 10%. Also the number of errors less than 10% for the models was 84.9, 80.2 and 78.3 percents of total number of data sets. CONCLUSIONS. Considering the accuracy criteria the reciprocal powered time model could be suggested as a general model for analysis of multi mechanistic drug release from nanoparticles. Also W and LP models were the closest to the suggested model RPT.

Various methods are available to formulate water soluble drugs into sustained release dosage forms by retarding the dissolution rate. One of the methods used to control drug release and thereby prolong therapeutic activity is to use hydrophilic and lipophilic polymers. In this study, the effects of various polymers such as hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC) and sodium carboxymethylcellulose (CMC) and surfactants (sodium lauryl sulphate, cetyltrimethylammonium bromide and Arlacel 60) on the release rate of captopril were investigated. The results showed that an increase in the amount of HPMC K15M resulted in reduction of the release rate of captopril from these matrices. When HPMC was partly replaced by NaCMC (the ratio of HPMC/NaCMC was 5:1), the release rate of the drug significantly decreased. However, there was no significant difference in release rate of captopril from matrices produced with ratios of 5:1 and 2:1 of HPMC/NaCMC. The presence of lactose in matrices containing HPMC and NaCMC increased the release rate of captopril. It was interesting to note that although partial replacement of HPMC by EC reduced the release rate of the drug (ratio of HPMC/EC 2:1), the release rate was increased when the ratio of HPMC/EC was reduced to 1:1. The effects of various surfactants on the release rate of captopril from HPMC/EC (1:1) matrices were also investigated. The results showed that the surfactants did not significantly change the release rate of the drug. Release data were examined kinetically and the ideal kinetic models were estimated for the drug release. The kinetic analysis of drug release data from various formulations showed that incorporation of surfactants in HPMC/EC matrices did not produce a zero-order release pattern.

The purpose of this research was to obtain directly compressible agglomerates of naproxen containing disintegrant by spherical crystallization technique. Acetone-water containing hydroxypropyl celloluse (HPC) and disintegrant was used as the crystallization system. In this study croscarmellose sodium (Ac-Di-Sol) was employed as disintegrant. The agglomerates were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRPD), and scanning electron microscopy and were evaluated for flow, packing and tableting properties and drug release. The growth of particle size and the spherical form of the agglomerates resulted in formation of products with good flow and packing properties. The improved compaction properties of the agglomerated crystals were due to their fragmentation occurred during compression. DSC and XRPD studies showed that naproxen particles, crystallized in the presence of HPC and Ac-Di-Sol did not undergo structural modifications. The dissolution rate of naproxen from tablets made of naproxen-(Ac-Di-Sol) agglomerates was enhanced significantly because of including the disintegrant in to the particles. This was attributed to an increase in the surface area of the practically water insoluble drug is exposed to the dissolution medium. In conclusion the spherical crystallization technique developed in this study is suitable for obtaining agglomerates of drug with disintegrant. © American Association of Pharmaceutical Scientists 2007.

A polysaccharide mucilage derived from the seeds of fenugreek, Trigonella foenum-graceum L (family Fabaceae) was investigated for use in matrix formulations containing propranolol hydrochloride. Methocel® hypomellose K4M was used as a standard controlled release polymer for comparison purposes. In this study the effect of lactose on the release behaviour of propranolol hydrochloride from matrices formulated to contain the fenugreek mucilage also was investigated. An increase in concentration of the mucilage in matrices resulted in a reduction in the release rate of propranolol hydrochloride comparable to that observed with hypomellose matrices. The rate of release of propranolol hydrochloride from fenugreek mucilage matrices was mainly controlled by the drug:mucilage ratio. However, the mechanism of release from matrices containing drug:mucilage ratios of 1:1, 1:1.25, 1:1.5, and 1:2 remained the same. The kinetics of release, utilising the release exponent n, showed that the values of n were between 0.46-0.57 indicating that the release from fenugreek mucilage matrices was predominantly by diffusion. The presence of lactose in matrices containing mucilage increased the release rate of propranolol hydrochloride. This is due to a reduction in tortuoisity and increased pore size of channels caused by lactose through which propranolol diffuses and therefore diffusion of water into the tablet is facilitated. Copyright © Informa Healthcare USA, Inc.

The purpose of the present research was to obtain directly compactible agglomerates of naproxen containing disintegrant by a novel crystallo-co-agglomeration (CCA) technique. Acetone-water containing hydroxypropylcellulose (HPC) was used as the crystallization medium. Acetone acted as a good solvent for naproxen as well as a bridging liquid for agglomeration of crystallized drug with disintegrant and aqueous phase as non-solvent. The agglomerates were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRPD) and scanning electron microscopy. The agglomerates were compressed at different compression pressures and dissolution studies were carried out for the tablets produced at lowest compression force. The growth of particle size and the spherical form of the agglomerates resulted in formation of products with good flow and packing properties. The improved compaction properties of the agglomerated crystals were due to the fragmentation which occurred during compression. DSC and XRPD studies showed that naproxen particles, crystallized in the presence of HPC and disintegrant did not undergo structural modifications. The dissolution rate of naproxen from the agglomerates could be controlled by the amount of included disintegrant, being enhanced as the latter was increased. Moreover, the results showed that when the disintegrants were included both intragranularly and extragranularly during agglomeration of naproxen particles, tablets containing these agglomerates dissolved at a faster rate than the tablets containing crystallized naproxen with the same amount of disintegrant incorporated only extragranularly by physical mixing. In conclusion, the properties of agglomerated crystals, such as flowability, compactibility and dissolution rate were improved profoundly using the developed technique resulting in successful direct tableting without need to additional process of physical blending of agglomerates and disintegrants. © 2007 Elsevier B.V. All rights reserved.

The solubility of paracetamol in water-ethanol-propylene glycol binary and ternary mixtures at 25 and 30°C was determined using flask shake method. The generated data extended the solubility database for further computational investigations and also was used to assess the prediction capability of the Jouyban-Acree model. A new version of the model was proposed for modeling the solubility data in water-cosolvent mixtures with the cosolvent concentration of <50% which is required in pharmaceutical formulations. The accuracy of the predicted solubilities was evaluated by the mean percentage deviation (MPD) between the predicted and experimental solubilities. The overall MPD of the Jouyban-Acree model and the log-linear model of Yalkowsky for the entire composition range of the cosolvents were 11.0±8.7 and 55.4±17.8%, respectively; the corresponding values for the predicted solubilities in mixtures having a cosolvent concentration of <50% were 12.0±9.1 and 22.0±11.0%. © 2008 Pharmaceutical Society of Japan.

Oral osmotic devices including an elementary osmotic pump (EOP) are efficient systems for the delivery of drugs with high/moderately water-solublility. In this study we designed a new type of EOP for the efficient delivery of poorly water-soluble and practically insoluble drugs. In this system, called swellable elementary osmotic pump (SEOP), drug is released from the delivery orifice in the form of a very fine dispersion of drug in gel which is ready for dissolution and absorption. Factors affecting the release of drug from the SEOP containing a poorly water-soluble drug, nifedipine, were explored extensively. To this end, effect of swelling and wetting agents, orifice size, concentration of osmotic agent, and hydrophobic plasticizer were investigated. Interestingly, in the absence or low concentration of a hydrophobic plasticizer (caster oil), the osmotic devices did not retain their integrity in dissolution media. Caster oil in concentration of > 1% was necessary for tablets to retain their integrity during dissolution process. A zero-order release kinetics for nifedipine was achieved following the effective optimization of the concentrations of swelling agent, osmotic agent, wetting agent, and also size of orifice and membrane thickness in SEOP. The zero-order release lasted for 10 hr at pH 6.8 dissolution medium. The designed SEOP is suggested as an efficient controlled delivery system for oral delivery of a poorly water soluble drug such as nifedipine. Copyright © Informa Healthcare USA, Inc.

A new type of elementary osmotic pump (EOP) tablet for efficient delivery of poorly water-soluble/practically insoluble drugs has been designed. Drug release from the system, called swellable elementary osmotic pump (SEOP), is through a delivery orifice in the form of a very fine dispersion ready for dissolution and absorption. SEOP tablets were prepared by compressing the mixture of micronized drug and excipients into convex tablets. Factors affecting the release of drug from the SEOP tablets containing a poorly water-soluble drug, indomethacin, have been explored. The release behaviour of indomethacin from different formulations of this dosage form was studied at pH 6.8 for a period of 24 h. The formulations were compared based on four comparative parameters, namely, D24h (total release after 24 h), tL (lag time), RSQzero (R square of zero order equation) and D%zero (percentage deviation from zero order kinetics). The drug release profile from osmotic devices showed that the type of polymer in the core formulation can markedly affect the drug release. The results showed that concentration of wetting agent in the core formulation was a very important parameter in D24h and release pattern of indomethacin from SEOP system. Increasing the amount of wetting agent to an optimum level (60 mg) significantly increased D24h and improved zero order release pattern of indomethacin. Increasing concentration of caster oil (hydrophobic) in the semipermeable membrane of the device or hydrophilic plasticizer (glycerin) in coating formulation markedly increased tL and decreased D24h. The results also demonstrated that aperture size is a critical parameter and should be optimized for each SEOP system. Optimum aperture diameter for the formulations studied here was determined to be 650 μm for zero order release pattern. tL and D%zero were dramatically decreased whereas D24h and RSQzero increased with increasing the aperture size to optimum level. This study also revealed that optimization of semipermeable membrane thickness is very important for approaching zero order kinetics. © 2007 Elsevier B.V. All rights reserved.

The kinetic energy of benzene and water molecules photodesorbed from astrophysically relevant ices on a sapphire substrate under irradiation by a UV laser tuned to the S-1 <- S-0 pi -> pi* transition of benzene has been measured using time-of-flight mass spectrometry. Three distinct photodesorption mechanisms have been identified - a direct adsorbate-mediated desorption of benzene, an indirect adsorbate-mediated desorption of water, and a substrate-mediated desorption of both benzene and water. The translational temperature of each desorbing population was well in excess of the ambient temperature of the ice matrix. (C) 2008 American Vacuum Society.

Reflection absorption infrared spectroscopy (RAIRS) and temperature programed desorption (TPD) have been used to probe the adsorption and desorption of ethanol on highly ordered pyrolytic graphite (HOPG) at 98 K. RAIR spectra for ethanol show that it forms physisorbed multilayers on the surface at 98 K. Annealing multilayer ethanol ices (exposures > 50 L) beyond 120 K gives rise to a change in morphology before crystallization within the ice occurs. TPD shows that ethanol adsorbs and desorbs molecularly on the HOPG surface and shows four different species in desorption. At low coverage, desorption of monolayer ethanol is observed and is described by first-order kinetics. With increasing coverage, a second TPD peak is observed at a lower temperature, which is assigned to an ethanol bilayer. When the coverage is further increased, a second multilayer, less strongly bound to the underlying ethanol ice film, is observed. This peak dominates the TPD spectra with increasing coverage and is characterized by fractional-order kinetics and a desorption energy of 56.3 +/- 1.7 kJ mol(-1). At exposures exceeding 50 L, formation of crystalline ethanol is also observed as a high temperature shoulder on the TPD spectrum at 160 K. (c) 2008 American Institute of Physics.

Despite considerable attention in the literature being given to the desorption behaviour of smaller volatiles, the thermal properties of complex organics, such as ethanol (C2H5OH), which are predicted to be formed within interstellar ices, have yet to be characterized. With this in mind, reflection absorption infrared spectroscopy (RAIRS) and temperature programmed desorption (TPD) have been used to probe the adsorption and desorption of C2H5OH deposited on top of water (H2O) films of various thicknesses grown on highly oriented pyrolytic graphite (HOPG) at 98 K. Unlike many other molecules detected within interstellar ices, C2H5OH has a comparable sublimation temperature to H2O and therefore gives rise to a complicated desorption pro. le. RAIRS and TPD show that C2H5OH is incorporated into the underlying ASW film during heating, due to a morphology change in both the C2H5OH and H2O ices. Desorption peaks assigned to C2H5OH co-desorption with amorphous, crystalline (CI) and hexagonal H2O-ice phases, in addition to C2H5OH multilayer desorption are observed in the TPD. When C2H5OH is deposited beneath ASW films, or is co-deposited as a mixture with H2O, complete co-desorption is observed, providing further evidence of thermally induced mixing between the ices. C2H5OH is also shown to modify the desorption of H2O at the ASW-CI phase transition. This behaviour has not been previously reported for more commonly studied volatiles found within astrophysical ices. These results are consistent with astronomical observations, which suggest that gas-phase C2H5OH is localized in hotter regions of the ISM, such as hot cores.

The formation of CO2 in the gas phase and on a polyaromatic hydrocarbon surface (coronene) via three possible pathways is investigated with density functional theory. Calculations show that the coronene surface catalyses the formation of CO2 on model grain surfaces. The addition of O-3 to CO is activated by 2530 K in the gas phase. This barrier is lowered by 253 K for the Eley-Rideal mechanism and 952 K for the hot-atom mechanism on the surface of coronene. Alternative pathways for the formation of CO2 are the addition of O-3 to the HCO radical, followed by dissociation of the HCO2 intermediate. The O + HCO addition is barrierless in the gas phase and on the surface and is more than sufficiently exothermic to subsequently cleave the H-C bond. The third mechanism, OH + CO addition followed by H removal from the energized HOCO intermediate, has a gas-phase exit barrier that is 1160 K lower than the entrance barrier. On the coronene surface, however, both barriers are almost equal. Because the HOCO intermediate can also be stabilized by energy dissipation to the surface, it is anticipated that for the surface reaction the adsorbed HOCO could be a long-lived intermediate. In this case, the stabilized HOCO intermediate could react, in a barrierless manner, with a hydrogen atom to form H-2 + CO2, HCO2H, or H2O + CO.

The sequential addition of H atoms to CO adsorbed on a siliceous edingtonite surface is studied with an embedded cluster approach, using density functional theory for the quantum mechanical (QM) cluster and a molecular force field for the molecular mechanical (MM) cluster. With this setup, calculated QM/MM adsorption energies are in agreement with previous calculations employing periodic boundary conditions. The catalytic effect of the siliceous edingtonite (100) surface on CO hydrogenation is assessed because of its relevance to astrochemistry. While adsorption of CO on a silanol group on the hydroxylated surface did not reduce the activation energy for the reaction with a H atom, a negatively charged defect on the surface is found to reduce the gas phase barriers for the hydrogenation of both CO and H2C = O. The embedded cluster approach is shown to be a useful and flexible tool for studying reactions on (semi-)ionic surfaces and specific defects thereon. The methodology presented here could easily be applied to study reactions on silica surfaces that are of relevance to other scientific areas, such as biotoxicity of silica dust and geochemistry.

Two common astrochemical surface reactions, hydrogenation and oxidation of unsaturated compounds, increase the molecular complexity in the interstellar medium. The catalytic effect of a negatively charged silica surface site on addition reactions to adsorbed unsaturated organic molecules is investigated computationally. Adsorbates bind relatively strongly to the silanolate group (SiO-) with a pronounced weakening of their multiple bonds, which results in a significant reduction in the activation barrier of the H atom addition to COads, H2C = O-ads, H2C = CH2,ads and HC CHads with respect to the corresponding gas phase barriers. More strikingly, the sizable gas phase barrier (21 kJ/mol) for the O-3 + CO reaction is almost entirely removed. This strong catalytic effect allows for effective CO2 formation in dark molecular clouds where other routes are inefficient. Furthermore, negatively charged siliceous dust particles could also play an important role in the hydrogenation of CO and hydrocarbons in the interstellar medium.

We present experimental measurements of photodesorption from ices of astrophysical relevance. Layers of benzene and water ice were irradiated with a laser tuned to an electronic transition in the benzene molecule. The translational energy of desorbed molecules was measured by time-of-flight (ToF) mass spectrometry. Three distinct photodesorption processes were identified: a direct adsorbate-mediated desorption producing benzene molecules with a translational temperature of around 1200 K, an indirect adsorbate-mediated desorption resulting in water molecules with a translational temperature of around 450 K, and a substrate-mediated desorption of both benzene and water producing molecules with translational temperatures of around 530 and 450 K, respectively. The translational temperature of each population of desorbed molecules is well above the temperature of the ice matrix. The implications for gas-phase chemistry in the interstellar medium are discussed.

Getting down to business: Reduction of the LaIII tricyclopentadienide complex [LaCp′′3] (Cp′′=η5-1,3-(SiMe3)2C5H3) by K and [18]crown-6 or [2,2,2]cryptand produced thermally stable mononuclear crystalline lanthanate(II) salts. The La +2 oxidation state in these complexes was confirmed both in solution (EPR) and the solid state (EPR, SQUID, X-ray diffraction) and was supported by a computational study.

The reaction of UI3 and KCpRR' (CpRR' = pentamethylcyclopentadienyl, trimethylsilylcyclopentadienyl or tetramethylcyclopentadienyl) in diethyl ether results in the two-electron reduction of the solvent to form trimetallic, mixed valence uranium oxo species.

The stoichiometric reaction of 1 equiv of CO with [(U(eta-C8H6{SiiPr3-1,4}2)(eta-Cp*)] affords the linear diuranium ynediolate complex [(U(eta-C8H6{SiiPr3-1,4}2)(eta-Cp*)]2(mu-eta1:eta1-C2O2) which does not react with further CO to give the deltate derivative [(U(eta-C8H6{SiiPr3-1,4}2)(eta-Cp*)]2(mu-eta1:eta2-C3O3). Spectroscopic and computational studies suggest a plausible mechanism for the formation of the deltate complex, in which a "zig-zag" diuranium ynediolate species is the key intermediate.

The reaction of the pentalene salt C8H4{(SiPr3)-Pr-i-1,4}(2)[K](2) with [SmCp*(mu-I)(THF)(2)](2) yields not the expected Sm(II) pentalene-bridged dimer but the Sm(III) sandwich complexes [Sm(eta(8)-C8H4{(SiPr3)-Pr-i-1,4}(2))(eta(5)-Cp*)] (1) and [Sm(eta(8)-C8H4{(SiPr3)-Pr-i-1,4}(2))(eta(5)-C8H5{(SiPr3)-Pr-i-1,4}(2))] (2) and the mixed-valence cluster [Cp*Sm-6(6)(OMe)(8)O][K(THF)(6)] (3) via solvent activation of THF. The samarium(III) sandwich compound 2 incorporates an eta(8)-pentalene ligand and an eta(5)-hydropentalenyl ligand. X-ray crystallography shows the Sm(II)/Sm(III) mixed-valence cluster compound 3 to contain a centrosymmetric hexanuclear array of Cp*Sm units, bridged by face-centered mu(3)-methoxy groups, with a central oxo unit.

From an historical perspective, much of the chemistry associated with the s-block elements has centred on the synthesis and structural characterization of an eclectic selection of compounds, with less effort directed towards developing their chemistry with regards to synthetically useful applications. Whilst obvious exceptions to this general statement exist, and the fundamental academic studies are invaluable in their own right, it is only in recent years that a renewed interest in the application of metal-ligand compounds of these elements has been evident. This short review is focussed on progress made in the molecular1 chemistry of the s-block metals, as presented in the literature in the period 2006-2007. Each section is divided into two parts: (i) advances in the synthesis of new complexes and ligand design, leading to a better understanding of the chemistry of these elements is initially presented; (ii) the latter part of each section concentrates on the application of these compounds in a number of synthetically important areas. Clearly with such a broad topic as this, not all of the literature can be covered, and it is important to state that this review does not include the vast literature concerning the organic transformation chemistry of organolithium and related reagents. Where possible, however, the author has selected examples that he feels will be of interest to the readers of Current Organic Chemistry

Deposition of fluorene-1-carboxylic acid molecules on Cu(110) surface has been investigated by LEED and STM. By saturating the surface with one monolayer, a (4 x 4) pg ordered structure is formed judged from the LEED pattern. STM image shows that the ordered structure is formed in small locally areas. STM results indicate that the molecular aromatic plane of FC-1 is parallel to the substrate. First-principle calculations determined the favorable adsorption site. The adsorption structure presents a chiral property. Two FC-1 molecules, in one unit cell, have their carboxylic groups bonded in identical geometry and equivalent orientation, but with opposite chirality.

The oxidative stability of blends of poly(methyl methacrylate) (PMMA) with four types of rubber, poly(ethylene-stat-propylene-stat-5-methylene-2-norbornene) (EPDM), poly(ethylene-stat-vinyl acetate) (EVA), dicarboxy terminated poly(acrylonitrile-stat-butadiene) (NBR) and poly(1,3-butadiene-stat-styrene) (SBR), has been investigated as models for rubber-toughened PMMA. Chemiluminescence was used to monitor the oxidation of the rubber in the blends, revealing an unexpected accelerating effect of PMMA on the oxidation of all the rubbers investigated. The effect varies according to the type of rubber and the temperature. The thermo-oxidative stability of PMMA has also been found to decrease in the presence of the rubber as proved by thermogravimetry, confirming mutually antagonistic effects of PMMA and rubber in the blend oxidation. On the basis of results from all techniques, including identification of oxidation products by FTIR spectroscopy, a possible mechanism is suggested, involving the formation of mobile radicals in PMMA induced by rubber oxidation. These radicals are suggested to play a crucial role in enhancing rubber phase oxidation.

DNA sequence information underpins genetic research, enabling discoveries of important biological or medical benefit. Sequencing projects have traditionally used long (400800 base pair) reads, but the existence of reference sequences for the human and many other genomes makes it possible to develop new, fast approaches to re-sequencing, whereby shorter reads are compared to a reference to identify intraspecies genetic variation. Here we report an approach that generates several billion bases of accurate nucleotide sequence per experiment at low cost. Single molecules of DNA are attached to a flat surface, amplified in situ and used as templates for synthetic sequencing with fluorescent reversible terminator deoxyribonucleotides. Images of the surface are analysed to generate high-quality sequence.We demonstrate application of this approach to human genome sequencing on flow-sorted X chromosomes and then scale the approach to determine the genome sequence of a male Yoruba from Ibadan, Nigeria. We build an accurate consensus sequence from.303 average depth of paired 35-base reads. We characterize four million single-nucleotide polymorphisms and four hundred thousand structural variants, many of which were previously unknown. Our approach is effective for accurate, rapid and economical whole-genome re-sequencing and many other biomedical applications.

The alkylation reaction of 2-mercapto-1-methylimidazole 1a with iodoethane and chlorobutane produced S-alkylmethimazole halides 2a and 2b which were subjected to anion metathesis with two different metal salts (MA) to afford methimazole-based room-temperature ionic liquids 3a, 3b, and 3c in 82%, 85%, and 87% yields, respectively. S-Alkylation giving 2a and 2b suggests that methimazole reacts through the thione tautomer.

The kinetic shift that exists between two competing unimolecular fragmentation processes has been used to establish whether or not gas-phase Mn2+ exhibits preferential solvation when forming mixed clusters with water and methanol. Supported by molecular orbital calculations, these first results for a metal dication demonstrate that Mn2+ prefers to be solvated by methanol in the primary solvation shell.

The ordered adsorption structures of tetracene on Ag(110) have been studied by low energy electron diffraction (LEED), scanning tunneling microscopy (STM) and density functional theory (DFT) calculations. At a low coverage, as calibrated with LEED, both p(4 x 4) and c(8 x 4) ordered structures are simultaneously formed on an Ag(110) surface at room temperature. STM images suggest the molecular plane is parallel to the Ag surface with its long molecular axis aligned along the [001] azimuth. DFT optimization reveals a separation of 0.3 nm between the molecular plane and substrate surface while the center of the tetracene molecule is on the long bridge site. Increasing coverage slightly, a structure is formed while the adsorbed molecules maintain the flat-lying geometry with adjacent molecules alternating their height relative to the surface.

The reaction of UI3 and KCpRR' (CpRR' = pentamethylcyclopentadienyl, trimethylsilylcyclopentadienyl or tetramethylcyclopentadienyl) in diethyl ether results in the two-electron reduction of the solvent to form trimetallic, mixed valence uranium oxo species.

Compound of formula (I) and salts thereof are provided: wherein X, Y, Z, R1, R2 and R3 are as defined in the specification. Processes for preparation, pharmaceutical compositions, and uses thereof as a medicament, for example in the treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function, such as schizophrenia or cognition impairment, are also disclosed.

Reaction of the alkylzinc bromide Zn(C{SiMe3}2{SiMe2hpp})Br (hppH = 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine) with an excess of sodium hydride gives good yields of an unusual zinc hydride cluster, in which five zinc atoms are linked by (-H) bridges

Phospha(III)guanidines, R2PC{NR}{NHR}, have been used to synthesize multimetallic compounds containing combinations of aluminum with platinum or copper, in which the main-group metal is N,N-bound by an amidinate moiety, thereby generating a metal-functionalized phosphine that bonds to the transition metal through phosphorus.

The reaction of [Ru(CHCH2)Cl(CS)(PPh3)2] with Na[HB(mt)3] (mt = methimazolyl) provides the ruthenaboratrane [Ru(CS)(PPh3){B(mt)3}]. The reaction of [Ru(CO)(PPh3){B(mt)3}] with CO to provide [Ru(CO)2{B(mt)3}] is reversible, while the phosphine-free ruthenaboratranes [Ru(CO)(CNR){B(mt)3}] (R = tBu, C6H3Me2-2,6, C6H2Me3-2,4,6) form irreversibly upon addition of isonitriles (CNR) to [Ru(CO)(PPh3){B(mt)3}]. The crystal structures of the ruthenaboratranes [Ru(CS)(PPh3){B(mt)3}], [Ru(CO)(CNtBu)({B(mt)3}], and [Ru(CO)(CNC6H2Me3-2,4,6){B(mt)3}] are reported.

A combined theoretical and experimental study of electronic transitions in the complex [Zn(pyridine)4]2+ provides the first example of a state-resolved electronic spectrum to be recorded for a dication complex in the gas phase.

Di-interstitial defects appear to play a key role in the microscopic understanding of radiation-induced damage in graphite. Their formation has been invoked as both one of the main causes of dimensional change and as an energy releasing step in annealing cryogenic radiation-induced damage. In the present work, first principles calculations are employed to examine several models for these defects. Two of the structures possess nearly equal energy, yet take very different forms. The results suggest that di-interstitial defects cannot play the principal role in radiation damage that has been assigned to them. The possibility that one of the structures may exhibit ferromagnetism is also investigated.

Compounds of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, are disclosed: wherein R<1 >is C1-6alkyl, haloC1-6alkyl, C2-6alkenyl, amino, monoC1-4alkylamino or diC1-4alkylamino; R<2 >and R<3>, which may be the same or different, are hydrogen, halogen, C1-6alkyl, haloC1-6alkyl, C1-4alkoxy, haloC1-4alkoxy, cyano, amino, monoC1-4alkylamino or diC1-4alkylamino; each R<4>, which may be the same or different, is C1-6alkyl, halogen, C1-6alkyl, haloC1-6alkyl, C1-4alkoxy, haloC1-4alkoxy, cyano, nitro, amino, monoC1-4alkylamino or diC1-4alkylamino; p is 0, 1 or 2; n is 1 or 2; R<5 >and R<6>, which may be the same or different, are hydrogen, halogen, C1-6alkyl, haloC1-6alkyl, C1-4alkoxy, haloC1-4alkoxy, cyano, amino, monoC1-4alkylamino or diC1-4alkylamino; and Het is thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, pyrrolyl, quinolyl, thiazolyl or furyl, each of which may be substituted by one or more groups independently selected from the list consisting of C1-6alkyl, C1-6alkoxy, acetyl, halogen, haloC1-6alkyl, cyano, nitro, amino, monoC1-4alkylamino and diC1-4alkylamino. Methods of preparation of the compounds, and uses thereof in medicine, for example treatment of schizophrenia, are also disclosed.

Two novel lithium compounds containing either the phosphorus-chalcogenide anions [Ph2PS] or [Cy2PS2] were isolated as decomposition products in the attempted formation of phospha(V)guanidinate anions. Lithium diphenylthiophosphinite was structurally characterized as the dimeric TMEDA adduct [Li(Ph2PS)(TMEDA)]2 (1), in which a rare example of the 1-S bonding mode was observed for the anion. The dicyclohexyldithiophosphinate anion was incorporated into an aggregated structure with molecular formula [Li5(Cy2PS2)4(OH)]2 (2). DFT calculations were performed on the isolated [R2PS]- and [R2PS2]- anions (R = Ph, Cy), indicating delocalization of electron density into the P-S bonds for each model, in agreement with bond-lengths taken from crystallographic data

Treatment of MI3 ( M = Sc, Y, Tm, and U) with three equivalents of KP3C2Bu2t in refluxing toluene led to the corresponding monomeric, formally eight coordinate, complexes [M(eta(5)-P3C2Bu2t)(2)(eta(2)-P3C2Bu2t)] in moderate yields. In the solid state the complexes, which are all iso-structural, display an interesting assembly of ligands comprising of one eta(2)-(bent) and two eta(5)-ligated triphospholyl rings. NMR studies indicate that the complexes are fluxional in solution.

The stoichiometric reaction of 1 equiv of CO with [(U(η-C8H6{SiiPr3-1,4}2)(η-Cp*)] affords the linear diuranium ynediolate complex [(U(η-C8H6{SiiPr3-1,4}2)(η-Cp*)]2(μ-η1:η1-C2O2) which does not react with further CO to give the deltate derivative [(U(η-C8H6{SiiPr3-1,4}2)(η-Cp*)]2(μ-η1:η2-C3O3). Spectroscopic and computational studies suggest a plausible mechanism for the formation of the deltate complex, in which a “zig-zag” diuranium ynediolate species is the key intermediate.

The beta alpha-repeat class of proteins, represented by the (beta alpha)(8) barrel and the alpha/beta/alpha sandwich, are among the most common structural platforms in biology. Previous studies on the folding mechanisms of these motifs have revealed or suggested that the initial event involves the submillisecond formation of a kinetically trapped species that must at least partially unfold before productive folding to the respective native conformation can occur. To test the generality of these observations, CheY, a bacterial response regulator, was subjected to an extensive analysis of its folding reactions. Although earlier studies had proposed the formation of an off-pathway intermediate, the data available were not sufficient to rule out an alternative on-pathway mechanism. A global analysis of single- and double-jump kinetic data, combined with equilibrium unfolding data, was used to show that CheY folds and unfolds through two parallel channels defined by the state of isomerization of a prolyl peptide bond in the active site. Each channel involves a stable, highly structured folding intermediate whose kinetic properties are better described as the properties of an off-pathway species. Both intermediates subsequently flow through the unfolded state ensemble and adopt the native cis-prolyl isomer prior to forming the native state. Initial collapse to off-pathway folding intermediates is a common feature of the folding mechanisms of beta alpha-repeat proteins, perhaps reflecting the favored partitioning to locally determined substructures that cannot directly access the native conformation. Productive folding requires the dissipation of these prematurely folded substructures as a prelude to forming the larger-scale transition state that leads to the native conformation. Results from Go-modeling studies in the accompanying paper elaborate on the topological frustration in the folding free-energy landscape of CheY.

Photoelectron spectroscopy and scanning tunneling microscopy have been used to investigate how the oxidation state of Ce in CeO2-x(111) ultrathin films is influenced by the presence of Pd nanoparticles. Pd induces an increase in the concentration of Ce3+ cations, which is interpreted as charge transfer from Pd to CeO2-x(111) on the basis of DFT+U calculations. Charge transfer from Pd to Ce4+ is found to be energetically favorable even for individual Pd adatoms. These results have implications for our understanding of the redox behavior of ceria-based model catalyst systems.

Compound of formula (I) and salts thereof are provided: wherein A, R1, R, R2 are as defined in the specification. Processes for preparation, pharmaceutical compositions, and uses thereof as a medicament, for example in the treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function, such as schizophrenia or cognition impairment, are also disclosed.

The (-)-(11R,2'S)-enantiomer of the antimalarial drug mefloquine has been found to be a reasonably potent and moderately selective adenosine A(2A) receptor antagonist. Further investigation of this compound has led to the discovery of a series of keto-aryl thieno[3,2-d]pyrimidine derivatives, which are potent and selective antagonists of the adenosine A(2A) receptor. These derivatives show selectivity against the A(1) receptor. Furthermore, some of these compounds have been shown to have in vivo activity in a commonly used model, suggesting the potential for the treatment of Parkinson's disease

The organometallic chemistry of the silicon-substituted tris(trimethylsilyl)methide ('trisyl') anion, [C(SiMe3)3]–, has been enhanced through the incorporation of additional donor substituents (L) able to chelate to the metal centre. To date, such species of general formula [C(SiMe3)n(SiMe2L)3-n]–, have been restricted to those in which a four- or five-membered metallacycle are formed, illustrated for L = NMe2 (A) and 2-pyridyl (B), respectively. We anticipated that upon chelation to a metal, the guanidyl-substituted derivative, HC(SiMe3)2(SiMe2hpp) (hppH = 1,3,4,6,7,8,-hexahydro-2H-pyrimido[1,2-a]pyrimidine) would enhance the bulk of these already sterically demanding ligands through formation of a six-membered metallacycle (C), and strong donation from the imine nitrogen would stabilize otherwise highly reactive organometallics. In this presentation we report some early results of the chemistry of this new addition to the family of substituted trisyl-ligands, focusing on their structural chemistry as determined by X-ray crystallography.

We report results of applying a commercial implementation of the dissolution dynamic nuclear polarization (DNP) methodology developed by K. G. Golman et al. to a range of molecular species in the mass range of 100400 Da. The molecules are typical of those that might be encountered in natural product chemistry or pharmaceutical analysis. Using an experimental protocol previously reported, in combination with the ERETIC method for generating a reference signal for estimation of concentra- tions, we determine the signal enhancement and high-field, liquid-state T1 values for many of the carbon atoms in the six species studied. The results presented in this work suggest that the measured varia- tion in nuclear magnetic resonance enhancements within a given molecule, arising from the dissolu- tion DNP method, is accounted for principally by relaxation of 13C atoms towards thermal polariza- tion values in the liquid state. We conclude that dissolution DNP will be able to be employed for a wide range of chemical species, provided that the total time taken for dissolution and transfer of so- lutions is comparable to, or shorter than, the high-field, liquid-state T1 values in the species being studied.

Compound of formula (I) and salts thereof are provided: Wherein R1, R2, R4 and R5 are as defined in the specification. Processes for preparation, pharmaceutical compositions, and uses thereof as a medicament, for example in the treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function, such as schizophrenia or cognition impairment, are also disclosed.

Continuing efforts to establish a more general "user-friendly" protocol for the palladium-catalysed arylation of amines (Buchwald-Hartwig reaction) are described herein. Significant advances have been made through the use of the versatile (SIPr)Pd(methallyl)Cl complex in conjunction with the reliable base lithium hexamethyldisilazide (LHMDS).

Inter-spin distances between 1 nm and 4.5 nm are measured by continuous wave (CW) and pulsed electron paramagnetic resonance (EPR) methods for a series of nitroxide-spin-labelled peptides. The upper distance limit for measuring dipolar coupling by the broad- ening of the CW spectrum and the lower distance limit for the present optimally-adjusted double electron electron resonance (DEER) set-up are determined and found to be both around 1.61.9 nm. The methods for determining distances and corresponding distributions from CW spectral line broadening are reviewed and further developed. Also, the work shows that a correction factor is required for the analysis of inter-spin distances below approximately 2 nm for DEER measurements and this is calculated using the density matrix formalism.

5-HT1 receptor antagonists have been discovered with good selectivity over the 5-HT transporter. This is the first report of highly potent, selective ligands for the 5-HT1A/B/D receptors with low intrinsic activity, which represent a useful set of molecules for further understanding the roles of the 5-HT1 receptor subtypes and providing new approaches,for the treatment of depression.

The new bis(pentalene) complex Cr-2(eta(5):eta(5)-C8H4 (1,4-Si1Pr3))(2) has been synthesized and characterized; it is found to exhibit paramagnetism at room temperature, and solid-state magnetic studies show that the dimer is best modeled as containing a pair of antiferromagnetically interacting S = 1/2 centers with the separation between the singlet ground state and triplet excited state being 2.23 kJ mol(-1). Structural data show a Cr-Cr distance of 2.2514(15) angstrom, consistent with a strong metal-metal interaction. The bonding has been further investigated by density functional, hybrid, and CASPT2 methods. The metal-metal interaction is best described by a double bond with each metal having an 18-electron count. Theory predicts the singlet and triplet states to lie close in energy but puts the triplet state at a slightly lower energy than the singlet. The energy difference predicted by CASPT2 is closest to the experimental value.

The reaction of the new platinaboratrane salt [PtH(PTol3){B(mt)3}]Cl(Pt--&gt;B)8 (mt = methimazolyl, Tol = C6H4Me-4) with 2 equivalents of PR3 (R = Me, Et) affords, via hydride migration to boron and ligand substitution, the salts [Pt(PR3)2{kappa 2-S,S'-HB(mt)3}]Cl, which slowly undergo B-H reactivation, to afford, ultimately, the platinaboratrane salts [PtH(PR3){B(mt)3}]Cl(Pt--&gt;B)8.

Partial deprotonation of the bicyclic guanidine 1,4,6-triazabicyclo[3.3.0]oct-4-ene (Htbo) is achieved using nBuLi. Isolation of the resulting lithium salts has resulted in the structural characterization of the mixed anion complex {[Li(tbo)( VIII)(tboH)]2} 1a (where VIII-H = 1-(2-aminoethyl)-2-imidazolidinethione) and the partially deprotonated salt Li6(tbo)6(Htbo)3, 1b. The neutral guanidine Htbo reacts cleanly with AlMe3 and ZnMe2 to afford the organometallic complexes [Al(tbo)Me2]2 [ 2]2, and Zn3(tbo)4Me2 ( 3). Structural characterization of these compounds enables comparison between the {5:5}-bicyclic system, [tbo]-, and the previously reported {6:6}-bicyclic system, [hpp]- (where hppH = 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine). Results indicate that delocalization within the [tbo]- anion is restricted to the CN2 amidinate component, with retention of electron density in the non-bonding nitrogen lone-pair. These conclusions are supported by a DFT analysis of the neutral guanidines, Htbo and hppH.

The low-valent complexes of uranium (i.e. those containing U(III) centres) are characterised as reactive, highly reducing species that can effect novel, and potentially useful, transformations of small molecules. In this chapter we review one particular class of these compounds - those supported by cyclooctatetraene and pentalene ligands - whose reduction chemistry has recently demonstrated novel and unexpected results, including the cyclooligomerisation of CO. The syntheses and structures of these compounds are presented, and their reactivity towards a variety of small molecules is examined and reviewed. The reactivity towards carbon monoxide is discussed in reference to the historical development of obtaining oxocarbons from CO.

Protein engineering techniques have emerged as powerful tools for characterizing transition states (TSs) for protein folding. Recently, the Si analysis, in which double-histidine mutations create the possibility of reversible crosslinking in the native state, has been proposed as an additional approach to the well-established F analysis. We present here a combination of these two procedures for defining the structure of the TS of ubiquitin, a small a/ protein that has been used extensively as a model system for both experimental and computational studies of the protein-folding process. We performed a series of molecular dynamics simulations in which F and S values were used as ensemble-averaged structural restraints to determine an ensemble of structures representing the TS of ubiquitin. Although the available values for ubiquitin did not, by themselves, generate well-defined TS ensembles, the inclusion of the restricted set of zero or unity values, but not fractional ones, provided useful complementary information to the F analysis. Our results show that the TS of ubiquitin is formed by a relatively narrow ensemble of structures exhibiting an overall native-like topology in which the N-terminal and C-terminal regions are in close proximity.

The outcomes and the mechanistic pathways of the palladium-catalyzed Heck-type cascade oligocyclizations of various 2-bromoalkenediynes were explored with respect to the lengths of the tethers between the multiple bonds and the nature of the substituent at the acetylenic terminus. Just like substrates containing two three-atom tethers, 2-bromotridec-1-ene-6,13-diynes 10a,b with one three- and one four-atom tether undergo two consecutive intramolecular 5- and 6-exo-dig carbopalladations with subsequent 6 pi-electrocyclization and beta-hydride elimination to form tricycles 35a,b with a central benzene ring in 67 and 61 % yield, respectively, independent of the fact that 10a contains an electron donor and lob an electron acceptor at the acetylene terminus. However, when 2-bromotetradec-1-ene-7,13-diynes 22, 29 on one side and 16, 27, 31 on the other are subjected to Heck reaction conditions, tricycles with a central benzene ring are formed only, when the substituent at the acetylene terminus is not a methoxycarbonyl group as in 22, 29. Thus, the bisannelated benzene derivatives 36 and 37 are formed from 22 and 29 in 79 and 18 % yield, respectively, whereas 16, 27 and 31 with their methoxycarbonyl substituents at the acetylenic end yield tetracyclic systems 38, 39 and 40, consisting of a central five-membered and two annelated six-membered as well as an additional annelated three-membered ring, predominantly (54, 19 and 18 % yield, respectively). The cascade reaction leading to the latter products must involve a 5-exo-trig carbopalladation rather than 6 pi-electrocyclization as the third step. Apparently, the nature and the substitution pattern of the tether in the substrates 16, 22, 31 linking the vinyl bromide moiety with the internal acetylene affect the yield of the tetracyclic product

The platinaboratrane [Pt(PPh3){B(mt)3}](PtB)10 (mt = methimazolyl) is prone to oxidative addition reactions with a range of substrates (Cl2, Br2, I2, HCl, CH3I) without disrupting the platinum-boron dative bond, as illustrated by the first structurally characterized platinaboratranes [PtH(PPh3){B(mt)3}]Cl(PtB)8 and [PtI2{B(mt)3}](PtB)8.

Compounds of formula (I), and salts and solvates thereof are provided. Processes for preparation, pharmaceutical compositions, and uses thereof as a medicament, for example in the treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function, such as schizophrenia or cognition impairment, are also disclosed.

A compound of formula (I) and salts thereof are provided: wherein A is defined in the specification. Processes for preparation, pharmaceutical compositions, and uses thereof as a medicament, for example in the treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function, such as schizophrenia or cognition impairment, are also disclosed.

An efficient new methodology for the arylation of aldehydes is disclosed which uses dirhodium(II) catalysts and N-heterocyclic carbene (NHC) ligands. Complexes of Rh-2(OAc)(4) with one and two NHCs attached on the axial positions were successfully isolated, fully characterized, and used as catalysts in the reaction. The saturated monocomplex ((NHC 5)Rh-2(OAc)(4)) 31 was shown to be the most active catalyst and was particularly efficient in the arylation of alkyl aldehydes. DFT calculations support participation of complexes with one axial NHC in the reaction as the catalysts active species and indicate that hydrogen bonds involving dirhodium unit, reactants, and solvent (alcohol) play an important role on the reaction mechanism.

Protonation of the {6,6}- and {5,5}-bicyclic guanidines 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2a]pyrimidine (hppH) and 1,4,6-triazabicyclo[3.3.0]oct-4-ene (Htbo), respectively, to afford the hydrochloride salts [hppH2][Cl] (1a) and [HtboH][Cl] (2) was achieved using [NEt3H][Cl]. Anion exchange involving 1a and NaBPh4 generated the borate salt [hppH2][BPh4] (1c). Crystal structure analysis of 1a and the analogous hydrobromide salt [hppH2][Br] (1b) showed two NHX hydrogen-bonds between the cation and the anion, and association of the [hppH2][X] ion-pairs into dimeric units. In salt 1c the [hppH2]+ cation was shown to be located within a cavity defined by phenyl substituents from the [BPh4] anion, with no hydrogen bonding present. Reducing the size of the heterocyclic rings from {6,6}- to {5,5}- in the [HtboH]+ salt promotes formation of extended structures due to a wider angle between the projected hydrogen-bonds to the halide anion. Results from analysis of the bond parameters within the guanidinium cations are used to explain the distribution of -electron density throughout the bicyclic framework

The dimers [trans-[(neopentyl)Pd(mu-Cl)(I(t)lBu)](2), 2, and (cis-[(neopentyl)Pd(mu-Cl)(IPr)](2), 3 ((IBu)-Bu-t = 1,3-bis-tert-butylimidazol-2-ylidene, IPr = 1,3-bis-2,6-diidopropylimidazol-2-ylidene), have been synthesized from [Pd(neopentyl)(Cl)(1,5-COD)], and their reactivity toward a variety of nucleophiles has been evaluated. In particular, this study revealed that 2 can be readily cleaved by primary and secondary amines, affording stable transamination products, which are surprisingly resistant to deprotonation. Dimer 3 was subsequently used as a catalyst in a series of Buchwald-Hartwig amination reactions of aryl chlorides.