Small molecule recognition of c-Src via the Imatinib-binding conformation

The cancer drug, Imatinib, is a selective Abl kinase inhibitor that does not inhibit the closely related kinase c-Src. This one drug and its ability to selectively inhibit Abl over c-Src has been a guiding principle in virtually all kinase drug discovery efforts in the last 15 years. A prominent hypothesis explaining the selectivity of Imatinib is that Abl has an intrinsic ability to adopt an inactive conformation (termed DFG-out), whereas c-Src appears to pay a high intrinsic energetic penalty for adopting this conformation, effectively excluding Imatinib from its ATP pocket. This explanation of the difference in binding affinity of Imatinib for Abl versus c-Src makes the striking prediction that it would not be possible to design an inhibitor that binds to the DFG-out conformation of c-Src with high affinity. We report the discovery of a series of such inhibitors. We use structure-activity relationships and X-ray crystallography to confirm our findings. These studies suggest that small molecules are capable of inducing the generally unfavorable DFG-out conformation in c-Src. Structural comparison between c-Src in complex with these inhibitors allows us to speculate on the differential selectivity of Imatinib for c-Src and Abl.     

Electronic perturbation in a molecular nanowire of [IrCl5(NO)]- units

The nitrosyl in [IrCl5(NO)]- is probably the most electrophilic known to date. This fact is reflected by its extremely high IR frequency in the solid state, electrochemical behavior, and remarkable reactivity in solution. PPh4[IrCl5(NO)] forms a crystal in which the [IrCl5(NO)]- anions are in a curious wire-like linear arrangement, in which the distance between the N--O moiety of one anion and the trans chloride of the upper one nearby is only 2.8 A. For the same complex [IrCl5(NO)]- but with a different counterion, Na[IrCl5(NO)], the anions are stacked one over the other in a side-by-side arrangement. In this case the electronic distribution can be depicted as the closed-shell electronic structure Ir III-NO+, as expected for any d(6) third-row transition metal complex. However, in PPh4[IrCl5(NO)] an unprecedented electronic perturbation takes place, probably due to NO*-Cl- acceptor-donor interactions among a large number of [IrCl5(NO)]- units, favoring a different electronic distribution, namely the open-shell electronic structure Ir IV-NO*. This conclusion is based on XANES experimental evidence, which demonstrates that the formal oxidation state for iridium in PPh4[IrCl5(NO)] is +4, as compared with +3 in K[IrCl5(NO)]. In agreement, solid-state DFT calculations show that the ground state for [IrCl5(NO)]- in the PPh4+ salt comprises an open-shell singlet with an electronic structure which encompasses half of the spin density mainly localized on a metal-centered orbital, and the other half on an NO-based orbital. The electronic perturbation could be seen as an electron promotion from a metal-chloride to a metal-NO orbital, due to the small HOMO-LUMO gap in PPh4[IrCl5(NO)]. This is probably induced by electrostatic interactions acting as a result of the closeness and wire-like spatial arrangement of the Ir metal centers, imposed by lattice forces due to pi-pi stacking interactions among the phenyl rings in PPh4+. Experimental and theoretical data indicate that in PPh4[IrCl5(NO)] the Ir-N-O moiety is partially bent and tilted.     

Development of a new sample pre-treatment procedure based on pressurized liquid extraction for the determination of metals in edible seaweed

A new, simple, fast and automated method based on acetic acid-pressurized liquid extraction (PLE) has been developed for the simultaneous extraction of major and trace elements (As, Ca, Cd, Co, Cr, K, Mg, Mn, Na, Pb, Sr and Zn) from edible seaweeds. The target elements have been simultaneously determined by inductively coupled plasma-optical emission spectrometry (ICP-OES). The influence of several extraction parameters (e.g. acetic acid concentration, extraction temperature, extraction time, pressure, number of cycles, particle size and diatomaceous earth (DE) mass/sample mass ratio) on the efficiency of metal leaching has been evaluated. The results showed that metal extraction efficiency depends on the mass ratio of the dispersing agent mass and the sample. The optimized procedure consisted of the following conditions: acetic acid (0.75 M) as an extracting solution, 5 min of extraction time, one extraction cycle at room temperature at a pressure of 10.3 MPa and addition of a dispersing agent (at a ratio of 5:1 over the sample mass). The leaching procedure was completed after 7 min (5 min extraction time plus 1 min purge time plus 1 min end relief time). Limits of detection and quantification and repeatability of the over all procedure have been assessed. Method validation was performed analysing two seaweed reference materials (NIES-03 Chlorella Kessleri and NIES-09 Sargasso). The developed extraction method has been applied to red (Dulse and Nori), green (Sea Lettuce) and brown (Kombu, Wakame and Sea Spaghetti) edible seaweeds.     

Rayleigh-Taylor instabilities in reaction-diffusion systems inside Hele-Shaw cell modified by the action of temperature

The influence of temperature in the buoyancy driven Rayleigh-Taylor instability of reaction-diffusion fronts is investigated experimentally in Hele-Shaw cells. The acid autocatalysis of chlorite-tetrathionate reaction coupled to molecular diffusion yields exothermic planar reaction-diffusion fronts separating two miscible reactant and product solutions. The resulting chemical front moves downwards invading the fresh reactants, leaving the products of the reaction behind it. The density of the product solution is higher than the reactant solution; hence, the traveling front is buoyantly unstable and develops density fingers in time (Rayleigh-Taylor instability) when the products are above the reactants. The kinetic constant of a chemical reaction varies due to thermal effects. This may stabilize the exothermic descending front when temperature is increased, so that the mixing zone decreases, modifying the fingering patterns, until it almost disappears. The authors study the influence of the temperature variation on the instability pattern figure observed in the chlorite-tetrathionate reaction for long times, corresponding to the nonlinear regime.     

Determination of major and trace elements in human scalp hair by pressurized-liquid extraction with acetic acid and inductively coupled plasma–optical-emission spectrometry

An analytical method has been developed for determination of major (Ca, K, Mg, and Na) and trace elements (As, Cd, Co, Li, Ni, and Sr) in human scalp hair. The proposed method includes a novel, simple, rapid, highly efficient, and automated metal-leaching procedure, by pressurized-liquid extraction (PLE), combined with a rapid simultaneous detection system—inductively coupled plasma–optical-emission spectrometry (ICP–OES). PLE is one of the most promising recently introduced sample-preparation techniques, with the advantages of reducing solvent consumption and enabling automated sample handling. The operating conditions for PLE, including concentration of the extraction solvent, extraction temperature, static time, number of extraction steps, pressure, mean particle size, diatomaceous earth (DE) mass/sample mass ratio, and flush volume were studied using an experimental design (Plackett–Burman design, PBD). The optimum conditions were use of 0.75 mol L⁻¹ acetic acid as extracting solution and powdered hair samples thoroughly mixed with DE, as a dispersing agent, at a DE mass/sample mass ratio of 4. Extraction was performed at room temperature and an extraction pressure of 140 atm for 5 min in one extraction step. The flush volume was fixed at 60%. The PLE-assisted multi-element leaching proposed is complete after 7 min (5 min static time plus 1 min purge time plus 1 min end relief time). Under the optimised conditions the figures of merit, for example limits of detection and quantification, repeatability of the over-all procedure, and accuracy, were evaluated. Analysis of GBW-07601 (human hair) certified reference material revealed accuracy was good for the target elements. The optimised method was finally applied to several human scalp-hair samples.     

Electrochemical behavior of copper complexes with substituted polypyridinic ligands: an experimental and theoretical study

Experimental redox potentials of the couples [Cu(R-L ( n ))(CH 3CN)] (2+,+), where L (1) is bis-(pyridine-2-ylmethyl)-benzylamine, L (2) is (pyridine-2-ylethyl)(pyridine-2-ylmethyl)-benzylamine, and R is H, Me, or CF 3, were determined in dichloromethane solution. The compounds exhibited one simple quasi-reversible wave over the measured potential range of -500 to +1200 mV, and the E 1/2 values varied from +200 to +850 mV versus SCE. These experimental values were correlated with redox potentials calculated using density functional theory. The optimized geometries and the predicted redox potentials were obtained using the BP86 functional and a combination of the basis sets LACV3P** (for Cu) and cc-pVTZ(-f) (for light atoms). A distortion analysis of all of the optimized geometries for both oxidation states was performed using the generalized interconversion coordinate phi. A linear relation was obtained between this parameter and the redox potentials. However, the [Cu(CF 3-L (1))(CH 3CN)] (+) complex showed the largest deviation, which was explained by the more-rigid structure of the ligand.     

Determination of organic anions in atmospheric aerosol samples by capillary electrophoresis after reversed pre-electrophoresis

This work presents the determination of low-molecular-mass (LMM) organic acids by CE after extraction with MeOH and preconcentration by evaporation. The interference arising from the simultaneous concentration of fast mobile anions (chloride, nitrate, and sulfate) at levels 200 times higher than those of LMM organic acids was reduced by the application of reversed pre-electrophoresis (RPE) as clean-up technique. This methodology allows for an effective elimination of high levels of fast mobile anions from the capillary before the separation has taken place, although analytes are also partially eliminated according to their electrophoretic velocities. In order to achieve an accurate quantification of organic anions, the use of a mathematical correction based on the linear relation between the analyte's effective volume removed during RPE and its mobility is proposed. Methods based on the use of one and two internal standards are discussed and evaluated. The proposed method is applied to the determination of organic acids in atmospheric particulate matter samples.     

Polyethyleneglycol-pepsin interaction and its relationship with protein partitioning in aqueous two-phase systems

The interaction between the acidic protein, pepsin, and the non-charged polyethyleneglycol polymer was studied by dynamic light scattering, fluorescence spectroscopy and measurements of the protein thermal stability at neutral pH. Polyethyleneglycol of average molecular mass 1450 showed a higher interaction capacity with the protein than polyethyleneglycol of average molecular mass 8000. Polyethyleneglycol of average molecular mass 1450 showed a molecular mechanism where the interpolymer interaction led to the complex formation. This fact can be explained taking into account that the extended form on this polymer molecule favours the interaction with the protein, which is highly dependent of the polymer total concentration. Polyethyleneglycol of average molecular mass 8000 showed a cooperative interaction between the polymer and protein molecules which was independent of the PEG concentration.     

Some L~γ Inequalities for the Polar Derivative of a Polynomial

In this paper,we consider an operator D_α which maps a polynomial P(z)in to D_αP(z):=np(z) +(α-z)P'(z),where α∈■ and obtain some L~γ inequalities for lucanary polynomials having zeros in |z|≤k≤1.Our results yields several generalizations and refinements of many known results and also provide an alternative proof of a result due to Dewan et al.[7],which is independent of Laguerre's theorem.     

Determination of Carbendazim by Adsorptive Stripping Differential Pulse Voltammetry Employing Glassy Carbon Paste Electrode Modified with Graphene and Amberlite XAD 2 Resin

Graphene nanosheets (GNS) and amberlite XAD‐2 (XAD2) modified glassy carbon paste electrode (GNS‐XAD2‐GCPE) were fabricated for voltammetric determination of Carbendazim (MBC). GNS was synthesized by Hummer’s method and characterized by SEM, EDAX, and XRD techniques. After optimizing the analytical conditions in 0.4 M citrate buffer (pH 4.0), the peak current was found to be linear in the range of 8.36×10^?9 to 4.13×10^?6 M (r=0.9986) with detection limit of 3.14×10^?9 M (S/N=3) by AdSDPV. The method was validated for the determination of MBC in soil, fruit, blood serum, urine, waste and ground water samples with satisfactory recoveries.