Intramolecular Pd(II)-catalyzed cyclization of propargylamides: straightforward synthesis of 5-oxazolecarbaldehydes

Direct synthesis of 2-substituted 5-oxazolecarbaldehydes was performed by intramolecular reaction of propargylamides through treatment with a catalytic amount of Pd(II) salts in the presence of a stoichiometric amount of reoxidant agent. The heterocyclization process was well-tolerated by a wide range of aryl, heteroaryl, and alkyl propargylamides. This protocol constitutes a valuable synthetic pathway to 5-oxazolecarbaldehydes, alternative to the formylation on oxazole rings, often unsatisfactory in term of regioselectivity and yields.     

Fluidic and air-stable supported lipid bilayer and cell-mimicking microarrays

As drug delivery, therapy, and medical imaging are becoming increasingly cell-specific, there is a critical need for high fidelity and high-throughput screening methods for cell surface interactions. Cell membrane-mimicking surfaces, i.e., supported lipid bilayers (SLBs), are currently not sufficiently robust to meet this need. Here we describe a method of forming fluidic and air-stable SLBs through tethered and dispersed cholesterol groups incorporated into the bottom leaflet. Achieving air stability allows us to easily fabricate SLB microarrays from direct robotic spotting of vesicle solutions. We demonstrate their application as cell membrane-mimicking microarrays by reconstituting peripheral as well as integral membrane components that can be recognized by their respective targets. These demonstrations establish the viability of the fluidic and air-stable SLB platform for generating content microarrays in high throughput studies, e.g., the screening of drugs and nanomedicine targeting cell surface receptors.     

Comparative study of water dissociation on Rh(111) and Ni(111) studied with first principles calculations

The dissociation and formation of water on the Rh(111) and Ni(111) surfaces have been studied using density functional theory with generalized gradient approximation and ultrasoft pseudopotentials. Calculations have been performed on 2x2 surface unit cells, corresponding to coverages of 0.25 ML, with spot checks on 3x3 surface unit cells (0.11 ML). On both surfaces, the authors find that water adsorbs flat on top of a surface atom, with binding energies of 0.35 and 0.25 eV, respectively, on Rh(111) and Ni(111), and is free to rotate in the surface plane. Barriers of 0.92 and 0.89 eV have to be overcome to dissociate the molecule into OH and H on the Rh(111) and Ni(111) surfaces, respectively. Further barriers of 1.03 and 0.97 eV need to be overcome to dissociate OH into O and H. The barriers for the formation of the OH molecule from isolated adsorbed O and H are found to be 1.1 and 1.3 eV, and the barriers for the formation of the water molecule from isolated adsorbed OH and H are 0.82 and 1.05 eV on the two surfaces. These barriers are found to vary very little as coverage is changed from 0.25 to 0.11 ML. The authors have also studied the dissociation of OH in the presence of coadsorbed H or O. The presence of a coadsorbed H atom only weakly affects the energy barriers, but the effect of O is significant, changing the dissociation barrier from 1.03 to 1.37 and 1.15 eV at 0.25 or 0.11 ML coverage on the Rh(111) surface. Finally, the authors have studied the dissociation of water in the presence of one O atom on Rh(111), at 0.11 ML coverage, and the authors find a barrier of 0.56 eV to dissociate the molecule into OH+OH.     

Insights into the Ligand Binding to Bromodomain-Containing Protein 9 (BRD9): A Guide to the Selection of Potential Binders by Computational Methods

The estimation of the binding of a set of molecules against BRD9 protein was carried out through an in silico molecular dynamics-driven exhaustive analysis to guide the identification of potential novel ligands. Starting from eight crystal structures of this protein co-complexed with known binders and one apo form, we conducted an exhaustive molecular docking/molecular dynamics (MD) investigation. To balance accuracy and an affordable calculation time, the systems were simulated for 100 ns in explicit solvent. Moreover, one complex was simulated for 1 µs to assess the influence of simulation time on the results. A set of MD-derived parameters was computed and compared with molecular docking-derived and experimental data. MM-GBSA and the per-residue interaction energy emerged as the main indicators for the good interaction between the specific binder and the protein counterpart. To assess the performance of the proposed analysis workflow, we tested six molecules featuring different binding affinities for BRD9, obtaining promising outcomes. Further insights were reported to highlight the influence of the starting structure on the molecular dynamics simulations evolution. The data confirmed that a ranking of BRD9 binders using key parameters arising from molecular dynamics is advisable to discard poor ligands before moving on with the synthesis and the biological tests.     

A valuable heterocyclic ring transformation: from isoxazolin-5(2H)-ones to quinolines

A new synthesis of quinoline derivatives was achieved by catalytic hydrogenation of 3,4-disubstituted 2-(2-formylphenyl)-isoxazolin-5(2H)-ones. In the same way, 2,3-disubstituted [1,8]naphthyridine was obtained.     

Biological chemistry of organotin compounds: Interactions and dealkylation by dithiols

In this paper, we review our past and current efforts toward the elucidation of the biological chemistry of organotin compounds. In particular, we cover two prominent aspects of organotin compounds: their reactivity toward biological dithiols, and their degradation (or metabolization) mechanism using a combination of experimental and computational techniques.     

Interactions of alkyltin salts with biological dithiols: dealkylation and induction of a regular beta-turn structure in peptides

Organotin compounds specifically target vicinal dithiols, thereby inhibiting the function of essential enzymes. Here, we present the NMR binding studies of trimethyltin (TMT) and dimethyltin (DMT) chlorides with a linear peptide (ILGCWCYLR) derived from the membrane protein stannin (SNN). We show that this peptide is able to dealkylate TMT and bind DMT, adopting a stable type-I beta-turn conformation. Both the NMR data and the calculated structures indicate that the two cysteines coordinate the tin atom in a distorted tetrahedral geometry. The molecular geometries and tin coordination state were confirmed using density functional theory (DFT). In addition, NMR spectral parameters back calculated from the DFT minimized structure compared well with experimental data. These results in conjunction with studies on peptide variants (i.e., C4S, C6S, and Y7F) demonstrate unequivocally the key role of biological dithiols in both the dealkylation and binding of organotin compounds. This peptide serves as a model system for alkyltin-protein interactions and gives new insights into the biological fate of alkyltin compounds.     

Health benefits of pistachios consumption

The health benefits of nuts, mainly in relation to the improvement of dysmetabolic conditions such as obesity, type 2 diabetes mellitus and the related cardiovascular diseases, have been widely demonstrated. Compared to other nuts, pistachios have a lower fat and caloric content, and contain the highest levels of unsaturated fatty acids, potassium, γ-tocopherol, phytosterols and xanthophyll carotenoids, all substances that are well known for their antioxidant and anti-inflammatory actions. This variety of nutrients contributes to the growing body of evidence that the consumption of pistachios improves health, leading to a greater potential of healthy antioxidant and anti-inflammatory activity, glycemic control, and endothelial function. The present review examines the nutrients and phytochemicals present in pistachios as well as the potential health benefits of including pistachios in a diet.     

Trastuzumab quantification in serum: a new,rapid, robust ELISA assay based on a mimetic peptide that specifically recognizes trastuzumab

Trastuzumab, a humanized monoclonal antibody directed against the epidermal growth factor receptor 2 (HER2), is a milestone in the treatment of HER2-overexpressing breast cancer patients. An enzyme-linked immunosorbent assay (ELISA) for trastuzumab has been developed for routine use in the laboratory to support clinical and pharmacokinetic studies to optimize therapy. The method relies on an antigen peptide linked to a 96-well plate via the streptavidin/biotin system. The peptide sequence mimics the extracellular portion of the HER2 receptor that is recognized by trastuzumab. The calibration range of the assay is 10 to 360 ng/mL per well, corresponding to a trastuzumab serum concentration from 5 to 180 μg/mL with a lower limit of quantification of 10 μg/mL. Validation results demonstrate that trastuzumab can be accurately and precisely quantified in human serum using this assay. The procedure was also tested in sera obtained from breast cancer patients to evaluate trastuzumab serum levels, confirming the applicability of method that could be a valid assay to use in daily laboratory practice.     

PHRONESIS: A One-Shot Approach for Sequential Assignment of Protein Resonances by Ultrafast MAS Solid-State NMR Spectroscopy

Solid-state NMR (ssNMR) spectroscopy has emerged as the method of choice to analyze the structural dynamics of fibrillar, membrane-bound, and crystalline proteins that are recalcitrant to other structural techniques. Recently, ¹H detection under fast magic angle spinning and multiple acquisition ssNMR techniques have propelled the structural analysis of complex biomacromolecules. However, data acquisition and resonance-specific assignments remain a bottleneck for this technique. Here, we present a comprehensive multi-acquisition experiment (PHRONESIS) that simultaneously generates up to ten 3D ¹H-detected ssNMR spectra. PHRONESIS utilizes broadband transfer and selective pulses to drive multiple independent polarization pathways. High selectivity excitation and de-excitation of specific resonances were achieved by high-fidelity selective pulses that were designed using a combination of an evolutionary algorithm and artificial intelligence. We demonstrated the power of this approach with microcrystalline U-¹³C,¹⁵N GB1 protein, reaching 100 % of the resonance assignments using one data set of ten 3D experiments. The strategy outlined in this work opens up new avenues for implementing novel ¹H-detected multi-acquisition ssNMR experiments to speed up and expand the application to larger biomolecular systems.