Conformational studies of mixed-ligand copper(II) chelates. Crystal and molecular structure of (N,N-dimethyl-N′-ethyl-1,2-diaminoethane-(1-phenyl-1,3,-butanedionato)copper(II) perchlorate

The IR and ligand field spectra and the structure of the mixed-ligand compound [N,N-dimethyl-N′-ethyl-1,2-diaminoethane(1-phenyl-1,3-butanedionato)(perchlorato)copper(II)]), [Cu(dmeen)bzac(OClO3)], are reported. The structure was determined by single crystal X-ray diffraction analysis (triclinic, space group ). The structure is square pyramidal with the apical position occupied by one oxygen of the tetrahedral perchlorato group (distance from copper 2.452(5) Å). The plane of the phenyl ring is tilted forming an angle of 16.72(14)° with the plane of the β-dionato moiety. The nitrogenous base adopts the gauche conformation with torsional angle of 108.72(14)°. The ethyl group is cis oriented relative to the phenyl group, occupying the equatorial position with the vector of the carbon-nitrogen bond forming an angle of 143.9(3)° with the CuNN plane. The interactions of the adjacent axial hydrogen with an oxygen of the perchlorato group result in hydrogen bond formation. The IR spectra reveal that in the solid state the Br− or Cl− displace easily the ClO4− group. The shifts in the ligand field spectra indicate that polar solvents participate in donor-acceptor interactions with the metal centre along an axis perpendicular to the CuN2O2 plane.

Influence of hydrogen bonding in the structure of mixed-ligand copper(II) chelates. Spectra and structure of [aquo((2,2'-dipyridylamine)-(3-chloro-2,4-pentanedionato)copper(II)] nitrate

The IR, the ligand field spectra and the crystal structure of the mixed-ligand compound [(aquo)2,2P1 , a = 8.718(5), b = 9.407(5), c = 13.484 (7) Å, = 94.17(4)°, = 105.12(5)°, = 119.75(5)°, Z = 2, R = 0.0332, R W = 0.0869).

Copper(II) complexes of benzene-1,2-dioxyacetic acid (bdoaH2): X-ray crystal structure of [Cu2(bdoa)(phen)4]bdoa·13H2O (phen = 1,10-phenanthroline)

Copper(II) acetate reacts with benzene-1,2-dioxyacetic acid (bdoaH2) in aqueous media to give [Cu(bdoa)(H2O)2] (1). Complex 1 reacts with the N-donor ligands pyridine (py), ammonia and 1,10-phenanthroline (phen) to give [Cu(bdoa)(NH3)2]·H2O (2), [Cu(bdoa)(py)2]·H2O (3) and [Cu2(bdoa)(phen)4]bdoa·13H2O (4), respectively. The X-ray crystal structure of the dicopper(II,II) complex 4 shows each copper atom at the centre of a distorted trigonal bipyramid comprising four nitrogen atoms from two chelating phen ligands and a single oxygen atom from one of the carboxylate moieties of the bridging bdoa2− ligand. The cyclic voltammogram of 4 shows a single reversible wave for the Cu2+/Cu+ couple at E = + 115 mV (vs Ag/AgCl). Spectroscopic and magnetic data for the complexes are given.

Metal cluster expansion by addition of low-valent group 4B reagents: crystal and molecular structure of [Os3SnH2(CO)10{CH(SiMe3)2}2]; a compound with hydrogen bridging osmium and tin

Cluster expansion of [Os3H2(CO)10] with [SnR2][R = CH(SiMe3)2] take place in high yield to give [Os3SnH2(CO)10R2], the first closed triosmium–main-group metal cluster to be structurally characterized; a novel feature is the presence of a hydrogen atom bridging the tin atom and one of the osmium atoms.

Molecular modelling studies of binding of DACD derivatives into G-Quadruplex DNA: comparison of force field and quantum polarized ligand docking methods

The DNA G-qadruplexes are one of the targets being actively explored for anti-cancer therapy by inhibiting them through small molecules. This computational study was conducted to predict the binding strengths and orientations of a set of novel dimethyl-amino-ethyl-acridine (DACA) analogues that are designed and synthesized in our laboratory, but did not diffract in Synchrotron light.Thecrystal structure of DNA G-Quadruplex(TGGGGT)4(PDB: 1O0K) was used as target for their binding properties in our studies.We used both the force field (FF) and QM/MM derived atomic charge schemes simultaneously for comparing the predictions of drug binding modes and their energetics. This study evaluates the comparative performance of fixed point charge based Glide XP docking and the quantum polarized ligand docking schemes. These results will provide insights on the effects of including or ignoring the drug-receptor interfacial polarization events in molecular docking simulations, which in turn, will aid the rational selection of computational methods at different levels of theory in future drug design programs. Plenty of molecular modelling tools and methods currently exist for modelling drug-receptor or protein-protein, or DNA-protein interactionssat different levels of complexities.Yet, the capasity of such tools to describevarious physico-chemical propertiesmore accuratelyis the next step ahead in currentresearch.Especially, the usage of most accurate methods in quantum mechanics(QM) is severely restricted by theirtedious nature. Though the usage of massively parallel super computing environments resulted in a tremendous improvement in molecular mechanics (MM) calculations like molecular dynamics,they are still capable of dealing with only a couple of tens to hundreds of atoms for QM methods. One such efficient strategy that utilizes thepowers of both MM and QM are the QM/MM hybrid methods. Lately, attempts have been directed towards the goal of deploying several different QM methods for betterment of force field based simulations, but with practical restrictions in place. One of such methods utilizes the inclusion of charge polarization events at the drug-receptor interface, that is not explicitly present in the MM FF.

Synthesis and evaluation of lipophilic BTBP ligands for An/Ln separation in nuclear waste treatment: the effect of alkyl substitution on extraction properties and implications for ligand design

Four new 6,6′-bis(1,2,4-triazin-3-yl)-2,2′-bipyridine (BTBP) ligands, which contain either additional alkyl groups on the pyridine rings or seven-membered aliphatic rings attached to the triazine rings, have been synthesized, and the effects of the additional alkyl substitution in the 4- and 4′-positions of the pyridine rings on their extraction properties with LnIII and AnIII cations in simulated nuclear waste solutions have been studied. The speciation of ligand 13 with some trivalent lanthanide nitrates was elucidated by 1H NMR spectroscopic titrations and ESI-MS. Although 13 formed both 1:1 and 1:2 complexes with LaIII and YIII, only 1:2 complexes were observed with EuIII and CeIII. Quite unexpectedly, both alkyl-substituted ligands 12 and 13 showed lower solubilities in certain diluents than the unsubstituted ligand CyMe4-BTBP. Compared to CyMe4-BTBP, alkyl-substitution was found to decrease the rates of metal-ion extraction of the ligands in both 1-octanol and cyclohexanone. A highly efficient (DAm > 10) and selective (SFAm/Eu > 90) extraction was observed for 12 and 13 in cyclohexanone and for 13 in 1-octanol in the presence of a phase-transfer agent. The implications of these results for the design of improved extractants for radioactive waste treatment are discussed.

The SV2A ligand levetiracetam inhibits presynaptic Ca2+ channels via an intracellular pathway

Levetiracetam (LEV) is a prominent antiepileptic drug (AED) which binds to neuronal synaptic vesicle glycoprotein 2A (SV2A) protein and has reported effects on ion channels, but retains a poorly-defined mechanism of action. Here, we investigate inhibition of voltage-dependent Ca2+ (CaV) channels as a potential mechanism by which LEV imparts effects on neuronal activity. We used electrophysiological methods to investigate the effects of LEV on cholinergic synaptic transmission and CaV channel activity in superior cervical ganglion neurons (SCGNs). In parallel, we investigated effects of the LEV ‘inactive’ R-enantiomer, UCB L060. Thus, LEV, but not UCB L060 (each 100 μM), inhibited synaptic transmission between SCGNs in long-term culture in a time-dependent manner, significantly reducing excitatory postsynaptic potentials (EPSP) following ≥30 min application. In isolated SCGNs, LEV pretreatment (≥1 h), but not acute (5 min) application, significantly inhibited whole-cell IBa amplitude. In current clamp recordings, LEV reduced the amplitude of the afterhyperpolarizing potential (AHP) in a Ca2+-dependent manner, but also increased action potential (AP) latency in a Ca2+-independent manner, suggesting further mechanisms associated with reduced excitability. Intracellular LEV application (4-5 min) caused a rapid inhibition of IBa amplitude to an extent comparable to that seen following extracellular LEV pretreatment ( ≥ 1 h). Neither pretreatment nor intracellular application of UCB L060 produced any inhibitory effects on IBa amplitude. These results identify a stereospecific intracellular pathway by which LEV inhibits presynaptic CaV channels; resultant reductions in neuronal excitability are proposed to contribute to the anticonvulsant effects of LEV.

FunFOLDQA: a quality assessment tool for protein-ligand binding site residue predictions

The estimation of prediction quality is important because without quality measures, it is difficult to determine the usefulness of a prediction. Currently, methods for ligand binding site residue predictions are assessed in the function prediction category of the biennial Critical Assessment of Techniques for Protein Structure Prediction (CASP) experiment, utilizing the Matthews Correlation Coefficient (MCC) and Binding-site Distance Test (BDT) metrics. However, the assessment of ligand binding site predictions using such metrics requires the availability of solved structures with bound ligands. Thus, we have developed a ligand binding site quality assessment tool, FunFOLDQA, which utilizes protein feature analysis to predict ligand binding site quality prior to the experimental solution of the protein structures and their ligand interactions. The FunFOLDQA feature scores were combined using: simple linear combinations, multiple linear regression and a neural network. The neural network produced significantly better results for correlations to both the MCC and BDT scores, according to Kendall’s τ, Spearman’s ρ and Pearson’s r correlation coefficients, when tested on both the CASP8 and CASP9 datasets. The neural network also produced the largest Area Under the Curve score (AUC) when Receiver Operator Characteristic (ROC) analysis was undertaken for the CASP8 dataset. Furthermore, the FunFOLDQA algorithm incorporating the neural network, is shown to add value to FunFOLD, when both methods are employed in combination. This results in a statistically significant improvement over all of the best server methods, the FunFOLD method (6.43%), and one of the top manual groups (FN293) tested on the CASP8 dataset. The FunFOLDQA method was also found to be competitive with the top server methods when tested on the CASP9 dataset. To the best of our knowledge, FunFOLDQA is the first attempt to develop a method that can be used to assess ligand binding site prediction quality, in the absence of experimental data.

Bridging a yawning chasm: EEG investigations into the debate concerning the role of the human mirror neuron system in contagious yawning

Ongoing debate in the literature concerns whether there is a link between contagious yawning and the human mirror neuron system (hMNS). One way of examining this issue is with the use of the electroencephalogram (EEG) to measure changes in mu activation during the observation of yawns. Mu oscillations are seen in the alpha bandwidth of the EEG (8–12 Hz) over sensorimotor areas. Previous work has shown that mu suppression is a useful index of hMNS activation and is sensitive to individual differences in empathy. In two experiments, we presented participants with videos of either people yawning or control stimuli. We found greater mu suppression for yawns than for controls over right motor and premotor areas, particularly for those scoring higher on traits of empathy. In a third experiment, auditory recordings of yawns were compared against electronically scrambled versions of the same yawns. We observed greater mu suppression for yawns than for the controls over right lateral premotor areas. Again, these findings were driven by those scoring highly on empathy. The results from these experiments support the notion that the hMNS is involved in contagious yawning, emphasise the link between contagious yawning and empathy, and stress the importance of good control stimuli.

Corticotropin-releasing factor binding protein dimerizes after association with ligand.

We have suggested recently that the fall in plasma CRF-binding protein (BP) during the last few weeks of pregnancy is a direct effect of association with its ligand because of the rapid decrease in plasma BP concentration seen in normal males reaching a nadir some 15 min after a bolus injection of synthetic CRF. In the present study, we have investigated the physicochemical properties of both natural and recombinant BP by gel filtration under physiological conditions and have shown that association of human CRF to this BP results in an increase in molecular weight consistent with the formation of a dimer form of the BP ligand complex. The dimer is more stable when the interaction occurs in the presence of serum or if a peptide with a higher affinity for the BP is substituted as ligand. Experimental evidence would also suggest that the dimer BP has a higher affinity for ligand than the monomeric form. We suggest that this dimerization occurs in vivo when CRF is released into the bloodstream and provides the trigger that causes the uptake of the complex at specific receptor sites.

Complexation of lanthanides, actinides and transition metal cations with a 6-(1,2,4-triazin-3-yl)-2,2′:6′,2′′-terpyridine ligand: implications for actinide(III)/lanthanide(III) partitioning

The quadridentate N-heterocyclic ligand 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1,2,4-benzotriazin- 3-yl)-2,2′ : 6′,2′′-terpyridine (CyMe4-hemi-BTBP) has been synthesized and its interactions with Am(III),U(VI), Ln(III) and some transition metal cations have been evaluated by X-ray crystallographic analysis, Am(III)/Eu(III) solvent extraction experiments, UVabsorption spectrophotometry, NMR studies and ESI-MS. Structures of 1 : 1 complexes with Eu(III), Ce(III) and the linear uranyl (UO2 2+) ion were obtained by X-ray crystallographic analysis, and they showed similar coordination behavior to related BTBP complexes. In methanol, the stability constants of the Ln(III) complexes are slightly lower than those of the analogous quadridentate bis-triazine BTBP ligands, while the stability constant for the Yb(III)complex is higher. 1H NMR titrations and ESI-MS with lanthanide nitrates showed that the ligand forms only 1 : 1 complexes with Eu(III), Ce(III) and Yb(III), while both 1 : 1 and 1 : 2 complexes were formed with La(III) and Y(III) in acetonitrile. A mixture of isomeric chiral 2 : 2 helical complexes was formed with Cu(I), with a slight preference (1.4 : 1) for a single directional isomer. In contrast, a 1 : 1 complex was observed with the larger Ag(I) ion. The ligand was unable to extract Am(III) or Eu(III) from nitric acid solutions into 1-octanol, except in the presence of a synergist at low acidity. The results show that the presence of two outer 1,2,4-triazine rings is required for the efficient extraction and separation of An(III)from Ln(III) by quadridentate N-donor ligands.

Influence of diluent alkyl substitution on the extraction of Am(III) and Eu(III) by a 6,6'-bis(1,2,4-triazinyl)-2,2'-bipyridine ligand dissolved in alkylated cyclohexanone diluents

Several alkylated cyclohexanones were investigated as potential diluents for the selective extraction of Am(III) and Eu(III) from nitric acid solutions by the CyMe4-BTBP ligand. No significant extraction of either of the metal ions was observed for these diluents themselves. In the extractions from 1 M HNO3, 3-methylcyclohexanone and 4-methylcyclohexanone gave comparable results to cyclohexanone whereas in the extractions from 4 M HNO3, 2-methylcyclohexanone, 3-methylcyclohexanone and 4-methylcyclohexanone all gave superior results. For the monomethylated diluents, DAm and SFAm/Eu decreased in the order of alkyl substitution 2 > 4 ~ 3. However, alkyl substitution of cyclohexanone significantly slows down the extraction kinetics compared to cyclohexanone, and the position of alkyl substitution was found to play an important role in the solvents properties. 3-Methylcyclohexanone was identified as the most promising of the diluents.

Bridging the Faraoni and Selli oceanic anoxic events: late Hauterivian to early Aptian dysaerobic to anaerobic phases in the Tethys.

A detailed geochemical analysis was performed on the upper part of the Maiolica Formation in the Breggia (southern Switzerland) and Capriolo sections (northern Italy). The analysed sediments consist of well-bedded, partly siliceous, pelagic carbonate, which lodges numerous thin, dark and organic-rich layers. Stable-isotope, phosphorus, organic-carbon and a suite of redox-sensitive trace-element contents (RSTE: Mo, U, Co, V and As) were measured. The RSTE pattern and Corg:Ptot ratios indicate that most organic-rich layers were deposited under dysaerobic rather than anaerobic conditions and that latter conditions were likely restricted to short intervals in the latest Hauterivian, the early Barremian and the pre-Selli early Aptian. Correlations are both possible with organic-rich intervals in central Italy (the Gorgo a Cerbara section) and the Boreal Lower Saxony Basin, as well as with the facies and drowning pattern in the Helvetic segment of the northern Tethyan carbonate platform. Our data and correlations suggest that the latest Hauterivian witnessed the progressive installation of dysaerobic conditions in the Tethys, which went along with the onset in sediment condensation, phosphogenesis and platform drowning on the northern Tethyan margin, and which culminated in the Faraoni anoxic episode. This episode is followed by further episodes of dysaerobic conditions in the Tethys and the Lower Saxony Basin, which became more frequent and progressively stronger in the late early Barremian. Platform drowning persisted and did not halt before the latest early Barremian. The late Barremian witnessed diminishing frequencies and intensities in dysaerobic conditions, which went along with the progressive installation of the Urgonian carbonate platform. Near the Barremian-Aptian boundary, the increasing density in dysaerobic episodes in the Tethyan and Lower Saxony Basins is paralleled by a change towards heterozoan carbonate production on the northern Tethyan shelf. The following return to more oxygenated conditions is correlated with the second phase of Urgonian platform growth and the period immediately preceding and corresponding to the Selli anoxic episode is characterised by renewed platform drowning and the change to heterozoan carbonate production. Changes towards more humid climate conditions were the likely cause for the repetitive installation of dys- to anaerobic conditions in the Tethyan and Boreal basins and the accompanying changes in the evolution of the carbonate platform towards heterozoan carbonate-producing ecosystems and platform drowning.

From BTBPs to BTPhens: the effect of ligand pre-organization on the extraction properties of quadridentate bis-triazine ligands

The synthesis, lanthanide complexation and solvent extraction of An(III) and Ln(III) radiotracers from nitric acid solutions by a pre-organized, phenanthroline-derived bis-triazine ligand CyMe4-BTPhen are described. It was found that the ligand separated Am(III) and Cm(III) from the lanthanides with remarkably high efficiency, high selectivity, and faster extraction kinetics compared to its 2,2’-bipyridine counterpart CyMe4-BTBP. The origins of the ligands extraction properties were established by a combination of solvent extraction experiments, X-ray crystallography, kinetics and surface tension measurements and lanthanide NMR spectroscopy.