New pyrazolo[3,4-b]pyridones as selective A(1) adenosine receptor antagonists: synthesis, biological evaluation and molecular modelling studies

A series of ethyl 4-amino-1-(2-chloro-2-phenylethyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylates () has been synthesized as potential A(1) adenosine receptor (A(1) AR) ligands. Binding affinities of the new compounds were determined for adenosine A(1), A(2A) and A(3) receptors. Compounds and showed good affinity (K(i)= 299 nM and 517 nM, respectively) and selectivity towards A(1) AR, whereas showed good affinity for A(2A) AR (K(i)= 290 nM), higher than towards A(1) AR (K(i)= 1000 nM). The only arylamino derivative of the series displayed high affinity (K(i)= 4.6 nM) and selectivity for A(3) AR. Molecular modelling and 3D-QSAR (CoMFA) studies carried out on the most active compounds gave further support to the pharmacological results.     

Insulator to metal transition in fluid deuterium

We have investigated the insulator to metal transition in fluid deuterium using first principles simulations. Both density functional and quantum Monte Carlo calculations indicate that the electronic energy gap of the liquid vanishes at about ninefold compression and 3000 K. At these conditions the computed conductivity values are characteristic of a poor metal. These findings are consistent with those of recent shock wave experiments but the computed conductivity is larger than the measured value. From our ab initio results we conclude that the transition is driven by molecular dissociation rather than disorder and that both temperature and pressure play a key role in determining structural changes in the fluid.     

Expanding the Use of Dynamic Electrostatic Repulsion Reversed-Phase Chromatography: An Effective Elution Mode for Peptides Control and Analysis

Bioactive peptides are increasingly used in clinical practice. Reversed-phase chromatography using formic or trifluoroacetic acid in the mobile phase is the most widely used technique for their analytical control. However, sometimes it does not prove sufficient to solve challenging chromatographic problems. In the search for alternative elution modes, the dynamic electrostatic repulsion reversed-phase was evaluated to separate eight probe peptides characterised by different molecular weights and isoelectric points. This technique, which involves TBAHSO₄ in the mobile phase, provided the lowest asymmetry and peak width at half height values and the highest in peak capacity (about 200 for a gradient of 30 min) and resolution concerning the classic reversed-phase. All analyses were performed using cutting-edge columns developed for peptide separation, and the comparison of the chromatograms obtained shows how the dynamic electrostatic repulsion reversed-phase is an attractive alternative to the classic reversed-phase.     

Optimization and validation of a new approach based on CE-HRMS for the screening analysis of novel psychoactive substances (cathinones,phenethylamines, and tryptamines) in urine

The continuous introduction in the market of new psychoactive drugs (NPS) represents a well-known international emergency. Indeed, the European Monitoring Centre for Drugs and Drug Addiction and the United Nations Office on Drugs and Crime are paying great attention to the spread of NPS. In addition to the traditional analytical approaches based on GC-MS and HPLC-MS, also CE coupled with MS has proved to be a precious tool for the toxicological screening of biosamples. On these grounds, the aim of the present work was to test the application of CE-HRMS as a new screening tool for the rapid detection of these novel drugs in urine. Separations were performed in an uncoated fused-silica capillary with id of 75 μm with a total length of 100 cm, by applying a constant voltage of 15 kV. The QTOF-MS was implemented with an electrospray ion source operating in positive ionization full scan mode in the range of 100–1000 m/z. Under these conditions, different NPS has been tested, including eight cathinones, five phenethylamine, and seven tryptamines. The method was validated after optimization of the following analytical parameters: BGE composition and pH, separation voltage, sheath liquid composition, and flow rate and ESI source settings. The applicability of the method was successfully tested by analyzing a series of real urine samples obtained from drug users.     

“Click” on Tubes: a Versatile Approach towards Multimodal Functionalization of SWCNTs

Organic functionalization of carbon nanotube sidewalls is a tool of primary importance in material science and nanotechnology, equally from a fundamental and an applicative point of view. 1 , 2 Here, an efficient and versatile approach for the organic/organometallic functionalization of single‐walled carbon nanotubes (SWCNTs) capable of imparting multimodality to these fundamental nanostructures, is described. Our strategy takes advantage of well‐established Cu‐mediated acetylene‐azide coupling (CuAAC) reactions applied to phenylazido‐functionalized SWCNTs for their convenient homo‐/heterodecoration with a number of organic/organometallic frameworks, or mixtures thereof, bearing terminal acetylene pendant arms. Phenylazido‐decorated SWCNTs were prepared by chemoselective arylation of the CNT sidewalls with diazonium salts under mild conditions, and subsequently used for the copper‐mediated cycloaddition protocol in the presence of terminal acetylenes. The latter reaction was performed in one step by using either single acetylene derivatives or equimolar mixtures of terminal alkynes bearing either similar functional groups (masked with orthogonally cleavable protecting groups) or easily distinguishable functionalities (on the basis of complementary analytical/spectroscopic techniques). All materials and intermediates were characterized with respect to their most relevant aspects/properties by TEM microscopy, thermogravimetric analysis coupled with MS analysis of volatiles (TG‐MS), elemental analysis, cyclic voltammetry (CV), Raman and UV/Vis spectroscopy. The functional loading and related chemical grafting of both primary amino‐ and ferrocene‐decorated SWCNTs were spectroscopically (UV/Vis, Kaiser test) and electrochemically (CV) determined, respectively.     

An intramolecular G-quadruplex structure is required for binding of telomeric repeat-containing RNA to the telomeric protein TRF2

Telomeric repeat-containing RNA (TERRA) is important for telomere regulation, but the structural basis for how TERRA localizes to chromosome ends is unknown. Here we report on studies exploring whether the TERRA G-quadruplex structure is critical for binding to telomeres. We demonstrate that the telomeric protein TRF2 binds TERRA via interactions that necessitate the formation of a G-quadruplex structure rather than the TERRA sequence per se. We also show that TRF2 simultaneously binds TERRA and telomeric duplex or G-quadruplex DNA. These observations suggest that the TERRA G-quadruplex is a key feature of telomere organization.     

Optical properties of silicon clusters in the presence of water: a first principles theoretical analysis

We investigate the impact of water on the optical absorption of prototypical silicon clusters. Our clusters contain 5 silicon atoms, tetrahedrally coordinated and passivated with either hydrogen or oxygen. We approach this complex problem by assessing the contributions of three factors: chemical reactivity, thermal equilibration, and dielectric screening. We find that the silanone (Si=O) functional group is not chemically stable in the presence of water and exclude this as a source of significant red shift in absorption in aqueous environments. We perform first principles molecular dynamics simulations of the solvation of a chemically stable, oxygenated silicon cluster with explicit water molecules at 300 K. We find a systematic 0.7 eV red shift in the absorption gap of this cluster, which we attribute to thermally induced fluctuations in the molecular structure. Surprisingly, we find no observable screening impact of the solvent, in contrast with consistent blue shifts observed for similarly sized organic molecules in polar solvents. The predicted red shift is expected to be significantly smaller for larger Si quantum dots produced experimentally, guaranteeing that their vacuum optical properties are preserved even in aqueous environments.     

Challenges in the electrochemical (bio)sensing of nonelectroactive food and environmental contaminants

Electrochemical detection of nonelectroactive contaminants can be successfully faced via the use of indirect detection strategies. These strategies can provide sensitive and selective responses often coupled with portable and user-friendly analytical tools. Indirect detection strategies are usually based on the change in the signal of an electroactive probe, induced by the presence of the target molecule at a modified electrode. This critical review aims at addressing the developments in indirect electrosensing strategies for nonelectroactive contaminants in food and environmental analysis in the last few years. Emphasis is given to the strategy design, the electrode modifiers used and the feasibility of technological transfer.     

X-ray absorption near-edge structure (XANES) spectroscopy identifies differential sulfur speciation in corneal tissue

The chemical composition of tissues can influence their form and function. As a prime example, the lattice-like arrangement of collagen fibrils required for corneal transparency is controlled, in part, by sulfated proteoglycans, which, via core proteins, bind to the collagen at specific locations along the fibril axis. However, to date, no studies have been able to directly identify and characterize sulfur (S) in the cornea as a function of tissue location. In this study, X-ray absorption near-edge structure spectroscopy and micro-beam X-ray fluorescence (μ-XRF) chemical contrast imaging were employed to probe the nature of the mature (bovine) cornea as a function of position from the anterior sub-epithelial region into the deep stroma. Data indicate an inhomogeneity in the composition of S species in the first ≈50 μm of stromal depth. In μ-XRF chemical contrast imaging, S did not co-localize with phosphorous (P) in the deep stroma where sulfates are prominent. Rather, P is present only as isolated micrometric spots, presumably identifiable as keratocytes. This study lends novel insights into the elemental physiology of mature cornea, especially in relation to its S distribution; future studies could be applied to human tissues. Moreover, it defines an analytical protocol for the interrogation of S species in biological tissues with micrometric resolution.

meso-(2-Pyridyl)-boron(III)-subporphyrin: Perimeter Iridium(III) Coordination

Peripherally metalated porphyrinoids are promising functional π-systems displaying characteristic optical, electronic, and catalytic properties. In this work, 5-(2-pyridyl)- and 5,10,15-tri(2-pyridyl)-B^III-subporphyrins were prepared and used to produce cyclometalated subporphyrins by reactions with [Cp*IrCl₂]₂, which proceeded through an efficient C−H activation to give the corresponding mono- and tri-Ir^III complexes, respectively. While the mono-Ir^III complex was obtained as a diastereomeric mixture, a C₃-symmetric tri-Ir^III complex with the three Cp*-units all at the concave side was predominantly obtained in a high yield of 90 %, which displays weak NIR phosphorescence even at room temperature in degassed CH₂Cl₂, differently from the mono-Ir^III complexes.