New 2,3-disubstituted-5-hydroxyquinoxaline ligands and their coordination chemistry with cyclometallated iridium(III): syntheses, structures and tunable electronic properties

A new series of para-substituted 2,3-diphenyl-5-hydroxyquinoxaline ligands (LH(n)) were synthesised and characterised. These ligands were prepared in high yield via a two-step synthetic method. Four novel heteroleptic iridium(III) complexes were correspondingly prepared in high yield giving [Ir(ppy)(2)(L(n))]. Two X-ray crystallographic studies were undertaken on LH(3) and [Ir(ppy)(2)(L(2))] with each confirming the proposed formulations, with the complex showing the O,N-coordination mode of the quinoxalinato ligand. Density functional theoretical calculations were performed, firstly to compare the coordinated quinoxalinato system with the related quinolinato analogue, and secondly to probe the influence of the variation in para-substitution on the ancillary ligand. The calculations suggest that for either the quinoline or quinoxaline systems ligand-centred character appears to dominate the HOMO and LUMOs. Experimental electrochemical and spectroscopic characterisation showed that the subtle variations in absorption and emission wavelengths are probably due to ligand-dominated transitions that are influenced by the electronic nature of the para-substituted phenyl units in coordinated L(n).     

An experimental approach probing the conformational transitions and energy landscape of antibodies: a glimmer of hope for reviving lost therapeutic candidates using ionic liquid

Understanding protein folding in different environmental conditions is fundamentally important for predicting protein structures and developing innovative antibody formulations. While the thermodynamics and kinetics of folding and unfolding have been extensively studied by computational methods, experimental methods for determining antibody conformational transition pathways are lacking. Motivated to fill this gap, we prepared a series of unique formulations containing a high concentration of a chimeric immunoglobin G4 (IgG4) antibody with different excipients in the presence and absence of the ionic liquid (IL) choline dihydrogen phosphate. We determined the effects of different excipients and IL on protein thermal and structural stability by performing variable temperature circular dichroism and bio-layer interferometry analyses. To further rationalise the observations of conformational changes with temperature, we carried out molecular dynamics simulations on a single antibody binding fragment from IgG4 in the different formulations, at low and high temperatures. We developed a methodology to study the conformational transitions and associated thermodynamics of biomolecules, and we showed IL-induced conformational transitions. We showed that the increased propensity for conformational change was driven by preferential binding of the dihydrogen phosphate anion to the antibody fragment. Finally, we found that a formulation containing IL with sugar, amino acids and surfactant is a promising candidate for stabilising proteins against conformational destabilisation and aggregation. We hope that ultimately, we can help in the quest to understand the molecular basis of the stability of antibodies and protein misfolding phenomena and offer new candidate formulations with the potential to revive lost therapeutic candidates.

Probing the energy landscape and thermodynamics of biomolecules for drug design.     

A spectroscopic and computational exploration of the cybotactic region of gas-expanded liquids: methanol and acetone

Local compositions in supercritical and near-critial fluids may differ substantially from bulk compositions, and such differences have important effects on spectroscopic observations, phase equilibria, and chemical kinetics. Here, we compare such determinations around a solute probe dissolved in CO2-expanded methanol and acetone at 25 degrees C from solvatochromic experiments with molecular dynamics simulations. UV/vis and steady-state fluorescence measurements of the dye Coumarin 153 in the expanded liquid phase indicate preferential solvation in both the S0 and S1 states by the organic species. Simple dielectric continuum models are used to estimate local compositions from the spectroscopic data and are compared to molecular dynamics simulations of a single C153 molecule dissolved in the liquid phase at bubble point conditions. The simulations provide information about the local solvent structure around C153. They suggest the presence of large solvent clustering near the electron-withdrawing side of the probe. Preferential solvation exists in both the S0 and S1 states, but a large disagreement between simulation and experiment exists in the S1 state. Potential reasons for this disparity are discussed.     

Protein aggregation containing beta-amyloid,alpha-synuclein and hyperphosphorylated tau in cultured cells of hippocampus,substantia nigra and locus coeruleus after rotenone exposure

Background  

Protein aggregates containing alpha-synuclein, beta-amyloid and hyperphosphorylated tau are commonly found during neurodegenerative processes which is often accompanied by the impairment of mitochondrial complex I respiratory chain and dysfunction of cellular systems of protein degradation. In view of this, we aimed to develop an in vitro model to study protein aggregation associated to neurodegenerative diseases using cultured cells from hippocampus, locus coeruleus and substantia nigra of newborn Lewis rats exposed to 0.5, 1, 10 and 25 nM of rotenone, which is an agricultural pesticide, for 48 hours.     

Thermoluminescence of pure and doped ThO2

Thermoluminescence (TL) measurements in the temperature range 295–675 K indicate the existence of at least five trapping centres for single crystals of nominally pure “reduced” ThO₂ and three trapping centres for “oxidized” ThO₂. Deliberate doping with Ca²⁺, Y³⁺ and Ta⁵⁺ impurities decreases TL emission. For reduced ThO₂, accidentally incorporated rare-earth impurities, Pr³⁺, Tb³⁺, Er³⁺ act as the electron-hole recombination sites. In oxidized crystals the impurity Fe³⁺ is thought to be involved in the recombination process. In the temperature range 80–295 K an additional eight trapping centres exist for both oxidized and reduced ThO₂. For the reduced crystals the emission is probably associated with Fe in the +2 state, and in the +3 state for oxidized crystals. The differences in the TL glow curve intensities are partially explained by differences in the temperature dependence of the luminescence efficiency of the different recombination centres.     

A formal synthesis of aflatoxin B2: a Dötz benzannulation approach

A Dötz benzannulation reaction has been utilized in the synthesis of the furo[2,3-b]furan core of aflatoxin B2.