Pathophysiological Role and Medicinal Chemistry of A2A Adenosine Receptor Antagonists in Alzheimer’s Disease

The A_2A adenosine receptor is a protein belonging to a family of four GPCR adenosine receptors. It is involved in the regulation of several pathophysiological conditions in both the central nervous system and periphery. In the brain, its localization at pre- and postsynaptic level in striatum, cortex, hippocampus and its effects on glutamate release, microglia and astrocyte activation account for a crucial role in neurodegenerative diseases, including Alzheimer’s disease (AD). This ailment is considered the main form of dementia and is expected to exponentially increase in coming years. The pathological tracts of AD include amyloid peptide-β extracellular accumulation and tau hyperphosphorylation, causing neuronal cell death, cognitive deficit, and memory loss. Interestingly, in vitro and in vivo studies have demonstrated that A_2A adenosine receptor antagonists may counteract each of these clinical signs, representing an important new strategy to fight a disease for which unfortunately only symptomatic drugs are available. This review offers a brief overview of the biological effects mediated by A_2A adenosine receptors in AD animal and human studies and reports the state of the art of A_2A adenosine receptor antagonists currently in clinical trials. As an original approach, it focuses on the crucial role of pharmacokinetics and ability to pass the blood–brain barrier in the discovery of new agents for treating CNS disorders. Considering that A_2A receptor antagonist istradefylline is already commercially available for Parkinson’s disease treatment, if the proof of concept of these ligands in AD is confirmed and reinforced, it will be easier to offer a new hope for AD patients.     

Hybrid Platforms of Silicon Nanowires and Carbon Nanotubes in an Ionic Liquid Bucky Gel

Silicon nanowires (NWs) are appealing building blocks for low-cost novel concept devices with improved performances. In this research paper, we realized a hybrid platform combining an array of vertically oriented Si NWs with different types of bucky gels, obtained from carbon nanotubes (CNT) dispersed into an ionic liquid (IL) matrix. Three types of CNT bucky gels were obtained from imidazolium-based ionic liquids (BMIM-I, BIMI-BF₄, and BMIM-Tf₂N) and semiconductive CNTs, whose structural and optical responses to the hybrid platforms were analyzed and compared. We investigated the electrical response of the IL-CNT/NW hybrid junctions in dark and under illumination for each platform and its correlation to the ionic liquid characteristics and charge mobility. The reported results confirm the attractiveness of such IL-CNT/NW hybrid platforms as novel light-responsive materials for photovoltaic applications. In particular, our best performing cell reported a short-circuit current density of 5.6 mA/cm² and an open-circuit voltage of 0.53 V.     

Optically Transparent Gold Nanoparticles for DSSC Counter-Electrode: An Electrochemical Characterization

A gold nanoparticles transparent electrode was realized by chemical reduction. This work aims to compare the transparent gold nanoparticles electrode with a more commonly utilized gold-film-coated electrode in order to investigate its potential use as counter-electrode (CE) in dye-sensitized solar cells (DSSCs). A series of DSSC devices, utilizing I⁻/I³⁻ and Co(III)/(II) polypyridine redox mediators [Co(dtb)3]³⁺/²⁺; dtb = 4,4′ditert-butyl-2,2′-bipyridine)], were evaluated. The investigation focused firstly on the structural characterization of the deposited gold layers and then on the electrochemical study. The novelty of the work is the realization of a gold nanoparticles CE that reached 80% of average visible transmittance. We finally examined the performance of the transparent gold nanoparticles CE in DSSC devices. A maximum power conversion efficiency (PCE) of 4.56% was obtained with a commercial I⁻/I³⁻-based electrolyte, while a maximum 3.1% of PCE was obtained with the homemade Co-based electrolyte.     

Comparative two-dimensional mapping of prion protein isoforms in human cerebrospinal fluid and central nervous system

The cellular prion protein (PrP(C)) is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein abundant in neurons. Although its precise function is unknown, PrP(C) represents the substrate for the generation of a conformational pathogenic isoform (PrP(Sc)) in human and animal transmissible spongiform encephalopathies, or prion diseases. By applying novel solubilization cocktails, we analyzed normal human brain and cerebrospinal fluid (CSF) PrP(C) by immunoblot of two-dimensional (2-D) gel electrophoresis preparations, using specific antibodies. Here, we show that PrP(C) from brain and CSF is composed of several charge isomers of differently glycosylated isoforms of the full-length PrP(C) and two N-terminally truncated fragments of 20 and 18 kDa. In the CSF, substantial amounts of the highly glycosylated PrP(C) isoforms and of the unglycosylated 18 kDa fragment are detected. Our study, for the first time, provides a detailed 2-D map of human PrP(C) both in brain and CSF, and establishes an innovative and sensitive method that might help in detecting the CSF pathological PrP(Sc) isoform in vivo. It also shows the incredible microheterogeneity of such isoforms (ca. 60 spots!), as revealed in 2-D mapping, as opposed to 3-4 main zones by mono-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE).     

Capillary electrophoresis investigation of a partially unfolded conformation of beta(2)-microglobulin

Dialysis-related amyloidosis is a disease in which partial unfolding of beta(2)-microglobulin plays a key pathogenetic role in the formation of the amyloid fibrils. We have recently demonstrated that a partially unfolded conformer of beta(2)-microglobulin is involved in fibrillogenesis and that this species is significantly populated under physiological conditions. In this work capillary electrophoresis has been used to measure the equilibrium between the native protein and this conformer in samples known to have a higher or lower amyloidogenic potential, namely full-length beta(2)-microglobulin, two truncated species and a mutant, created by replacing histidine in position 31 with thyrosine. In addition, for all protein species folding stability experiments have been carried out by monitoring the secondary structure by circular dichroism at increasing concentrations of guanidinium chloride. The values of free energy of unfolding in the absence of denaturant, obtained by elaboration of these experiments, were found to be inversely correlated to the area percent of the partially unfolded conformer, as measured by capillary electrophoresis. Affinity capillary electrophoresis experiments have been also carried out under nondenaturing conditions to assess the affinity of copper and suramin to either the native form or the conformational intermediate of full-length beta(2)-microglobulin.     

Efficient and general synthesis of 5-(alkoxycarbonyl)methylene-3-oxazolines by palladium-catalyzed oxidative carbonylation of prop-2-ynylamides

A variety of prop-2-ynylamides have been carbonylated under oxidative conditions to give oxazolines, oxazolines with chelating groups, and bisoxazolines bearing an (alkoxycarbonyl)methylene chain at the 5 position in good yields. The cyclization-alkoxycarbonylation process was carried out in alcoholic media at 50-70 degrees C and under 24 bar pressure of 3:1 carbon monoxide/air in the presence of catalytic amounts of 10% Pd/C or PdI2 in conjunction with KI. Cyclization occurred by anti attack of an oxygen function on the palladium-coordinated triple bond, followed by stereospecific alkoxycarbonylation, strictly resulting in E-stereochemistry. The structures of representative oxazolines and bisoxazolines have been determined by X-ray diffraction analysis.     

Preparation and reactivity of mixed-ligand ruthenium(II) hydride complexes with phosphites and polypyridyls

Chloro complexes [RuCl(N-N)P3]BPh4 (1-3) [N-N = 2,2'-bipyridine, bpy; 1,10-phenanthroline, phen; 5,5'-dimethyl-2,2'-bipyridine, 5,5'-Me2bpy; P = P(OEt)3, PPh(OEt)2 and PPh2OEt] were prepared by allowing the [RuCl4(N-N)].H2O compounds to react with an excess of phosphite in ethanol. The bis(bipyridine) [RuCl(bpy)2[P(OEt)3]]BPh4 (7) complex was also prepared by reacting RuCl2(bpy)2.2H2O with phosphite and ethanol. Treatment of the chloro complexes 1-3 and 7 with NaBH4 yielded the hydride [RuH(N-N)P3]BPh4 (4-6) and [RuH(bpy)2P]BPh4 (8) derivatives, which were characterized spectroscopically and by the X-ray crystal structure determination of [RuH(bpy)[P(OEt)3]3]BPh4 (4a). Protonation reaction of the new hydrides with Br?nsted acid was studied and led to dicationic [Ru(eta2-H2)(N-N)P3]2+ (9, 10) and [Ru(eta(2-H2)(bpy)2P]2+ (11) dihydrogen derivatives. The presence of the eta2-H2 ligand was indicated by a short T(1 min) value and by the measurements of the J(HD) in the [Ru](eta2-HD) isotopomers. From T(1 min) and J(HD) values the H-H distances of the dihydrogen complexes were also calculated. A series of ruthenium complexes, [RuL(N-N)P3](BPh4)2 and [RuL(bpy)2P](BPh4)2 (P = P(OEt)3; L = H2O, CO, 4-CH3C6H4NC, CH3CN, 4-CH3C6H4CN, PPh(OEt)2], was prepared by substituting the labile eta2-H2 ligand in the 9, 10, 11 derivatives. The reactions of the new hydrides 4-6 and 8 with both mono- and bis(aryldiazonium) cations were studied and led to aryldiazene [Ru(C6H5N=NH)(N-N)P3](BPh4)2 (19, 21), [[Ru(N-N)P3]2(mu-4,4'-NH=NC6H4-C6H4N=NH)](BPh4)4 (20), and [Ru(C6H5N=NH)(bpy)2P](BPh4)2 (22) derivatives. Also the heteroallenes CO2 and CS2 reacted with [RuH(bpy)2P]BPh4, yielding the formato [Ru[eta1-OC(H)=O](bpy)2P]BPh4 and dithioformato [Ru[eta1-SC(H)=S](bpy)2P]BPh4 derivatives.     

Determining pirimiphos-methyl in durum wheat samples using an acetylcholinesterase inhibition assay

An electrochemical assay used for detecting acetylcholinesterase (AChE) inhibitors has been optimised to detect pirimiphos-methyl in durum wheat. Pirimiphos-methyl is a phosphothionate insecticide and so it needs to be transformed into the corresponding oxo form to act as an effective AChE inhibitor. The inhibition assay was based on the electrochemical detection of the product of AChE, choline, via choline oxidase biosensors obtained with Prussian-Blue modified screen printed electrodes. The procedure for the oxidation of pirimiphos methyl via N-bromosuccinimide (NBS) and AChE inhibition was optimised for reagent concentrations and inhibition time in a buffer solution. A calibration of the pirimiphos-methyl (25–1,000 ng/ml) was obtained in the buffer. The intra-electrode CV ranged between 1.6 and 15.0, whereas the inter-electrode CV ranged between 4.6 and 16.0. The detection limit (LOD) was 38 ng/ml, and the I_50% was 360 ng/ml. The assay conditions were then re-optimised to work with durum wheat extracts, and the calibrations were obtained under different experimental conditions, such as sample pretreatment (milled or whole grains) and extract concentration. The calibrations were slightly affected by the sample matrix, resulting in an increased LOD (65–133 ng/ml) and I_50% (640–1,650 ng/ml). The LOD found for the sample, determined under optimal conditions, was 3 mg/kg. Spiked samples were prepared at the EU regulated level (5 mg/kg) and analysed with the optimised protocol, resulting in an average recovery of 70.3%.     

Reactions of benzotriazoles with diethyl ethoxymethylenemalonate; ethylation and michael addition. Comparison with other esters and N-heterocycles

Benzotriazole and its 5-methyl-and 5-nitro derivatives react with diethyl ethoxymethylenemalonate by ethylation at each of the ring N-atoms and through Michael addition, to give the isomeric esters ethyl (E/Z) 3-[5(6)-R-benzotriazol-1-yl]propenoates. Benzotriazole and its 5-nitro derivative react similarly with ethyl acetoacetate but N-ethyl derivatives are obtained in lower yields. Other 1,2,3-triazoles derivatives and indole were ineffective in this reaction while benzimidazole produced similar results but accompanied with a small amount of a benzimidazoline addition product, whose structure has been determined by crystallo-graphic analysis.     

Colour fading in textiles: A model study on the decomposition of natural dyes

This paper describes an analytical procedure based on GC-MS to identify in textiles the most common flavonoid yellow dyes used in Europe since ancient times, extracted from weld, young fustic, dyer's broom, sawwort and the berries of some species of Rhamnus. Later on, old fustic and quercitron bark were introduced as sources of yellow colours.The method is based on the solvent extraction of flavonoids from raw plant materials (weld, dyer's broom and old fustic), aged and not aged alum-mordanted wool dyed specimens; subsequently, flavonoids are derivatised with N,O-bis(trimethylsilyl)trifluoroacetamide and analysed by GC-MS. The method easily allows the identification of a dyestuff by the detection of the molecular markers apigenin, luteolin, genistein, morin, maclurin, together with 4-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 2,4,6- trihydroxybenzoic acid, which survive in aged textiles. Two photo-oxidative degradation pathways for colour fading, one involving the mordant metallic ion and the other the light as a catalyst, are suggested.