Therapeutic Potential of Highly Selective A3 Adenosine Receptor Ligands in the Central and Peripheral Nervous System

Ligands of the G_i protein-coupled adenosine A₃ receptor (A₃R) are receiving increasing interest as attractive therapeutic tools for the treatment of a number of pathological conditions of the central and peripheral nervous systems (CNS and PNS, respectively). Their safe pharmacological profiles emerging from clinical trials on different pathologies (e.g., rheumatoid arthritis, psoriasis and fatty liver diseases) confer a realistic translational potential to these compounds, thus encouraging the investigation of highly selective agonists and antagonists of A₃R. The present review summarizes information on the effect of latest-generation A₃R ligands, not yet available in commerce, obtained by using different in vitro and in vivo models of various PNS- or CNS-related disorders. This review places particular focus on brain ischemia insults and colitis, where the prototypical A₃R agonist, Cl-IB-MECA, and antagonist, MRS1523, have been used in research studies as reference compounds to explore the effects of latest-generation ligands on this receptor. The advantages and weaknesses of these compounds in terms of therapeutic potential are discussed.     

Polyphenols from Dichrostachys cinerea Fruits Anti-Inflammatory,Analgesic, and Antioxidant Capacity in Freund’s Adjuvant-Induced Arthritic Rat Model

Dichrostachys cinerea (L.) Wigth & Arn. (DC) is widely used in traditional medicine against several inflammatory diseases, especially rheumatoid arthritis, because of its antioxidant and anti-inflammatory effects. This study aimed to characterize the polyphenol-rich DC fruit extracts and investigate the analgesic, anti-inflammatory, and antioxidant effects in a rat inflammation model induced by complete Freund’s adjuvant (CFA). Water and ethanolic extracts were characterized using liquid chromatography coupled with mass spectrometry (LC-MS), Fourier-transform infrared (FTIR) spectroscopy, and gas chromatography coupled with mass spectrometry (GC-MS). The polyphenol-rich extracts were administered in three different concentrations for 30 days. Pain threshold, thermal hyperalgesia, edema, and serum biomarkers specific to inflammatory processes or oxidative stress were evaluated. Both extracts were rich in polyphenolic compounds, mainly flavan-3-ols, proanthocyanidins, and flavone glycosides, which had important in vitro antioxidant capacity. DC fruit extracts administration had the maximum antinociceptive and anti-inflammatory effects after one day since the CFA injection and showed promising results for long-term use as well. The measurement of pro-inflammatory cytokines, cortisol, and oxidative stress parameters showed that DC extracts significantly reduced these parameters, being dose and extract-type dependent. These results showed potential anti-inflammatory, analgesic, and antioxidative properties and revealed the necessity of using a standardized polyphenolic DC extract to avoid result variability.     

Stabilization of foams with inorganic colloidal particles

Wet foams are used in many important technologies either as end or intermediate products. However, the thermodynamic instability of wet foams leads to undesired bubble coarsening over time. Foam stability can be drastically improved by using particles instead of surfactants as foam stabilizers, since particles tend to adsorb irreversibly at the air-water interface. Recently, we presented a novel method for the preparation of high-volume particle-stabilized foams which show neither bubble growth nor drainage over more than 4 days. The method is based on the in-situ hydrophobization of initially hydrophilic particles to enable their adsorption on the surface of air bubbles. In-situ hydrophobization is accomplished through the adsorption of short-chain amphiphiles on the particle surface. In this work, we illustrate how this novel method can be applied to particles with various surface chemistries. For that purpose, the functional group of the amphiphilic molecule was tailored according to the surface chemistry of the particles to be used as foam stabilizers. Short-chain carboxylic acids, alkyl gallates, and alkylamines were shown to be appropriate amphiphiles to in-situ hydrophobize the surface of different inorganic particles. Ultrastable wet foams of various chemical compositions were prepared using these amphiphiles. The simplicity and versatility of this approach is expected to aid the formulation of stable wet foams for a variety of applications in materials manufacturing, food, cosmetics, and oil recovery, among others.     

The CK2 alpha/CK2 beta interface of human protein kinase CK2 harbors a binding pocket for small molecules

The Ser/Thr kinase CK2 (previously called casein kinase 2) is composed of two catalytic chains (CK2 alpha) attached to a dimer of noncatalytic subunits (CK2 beta). CK2 is involved in suppression of apoptosis, cell survival, and tumorigenesis. To investigate these activities and possibly affect them, selective CK2 inhibitors are required. An often-used CK2 inhibitor is 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB). In a complex structure with human CK2 alpha, DRB binds to the canonical ATP cleft, but additionally it occupies an allosteric site that can be alternatively filled by glycerol. Inhibition kinetic studies corroborate the dual binding mode of the inhibitor. Structural comparisons reveal a surprising conformational plasticity of human CK2 alpha around both DRB binding sites. After local rearrangement, the allosteric site serves as a CK2 beta interface. This opens the potential to construct molecules interfering with the CK2 alpha/CK2 beta interaction.     

CrCl2-promoted stereospecific and stereoselective alkyl- and silylcyclopropanation of alpha,beta-unsaturated amides

An efficient chromium-promoted alkyl- or silylcyclopropanation of alpha,beta-unsaturated amides is described. These reactions can be carried out on (E)- or (Z)-alpha,beta-enamides in which the C-C double bond is di-, or trisubstituted. This process takes place with total stereospecificity and the new stereogenic center is generated with high or total stereoselectivity. Some synthetic applications of the obtained silylcyclopropyl amides are also reported. Two mechanisms based on the generation of carbenoid or carbene complexes have been proposed to explain this cyclopropanation reaction.     

Microwave-assisted three-component synthesis of 7-aryl-2-alkylthio-4,7-dihydro-1,2,4-triazolo[1,5-a]-pyrimidine-6-carboxamides and their selective reduction

Multicomponent reactions (MCRs) and microwave-assisted organic synthesis (MAOS) have been used as key methods for the synthesis of fused dihydropyrimidine derivatives. The three-component condensation of 3-amino-5-alkylthio-1,2,4-triazoles with aromatic aldehydes and acetoacetamides under microwave irradiation was developed as a rapid and efficient solution-phase method for the high-yielding preparation of 7-aryl-2-alkylthio-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine-6-carboxamide libraries. In addition, the selective reduction of the formed dihydrotriazolopyrimidines to trans-trans-2-alkylthio-7-aryl-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidine-6-carboxamides was established. The described synthetic protocols provide rapid access to novel and diversely substituted dihydroazolopyrimidine libraries.     

Heat capacity of methacetin in a temperature range of 6 to 300 K

Heat capacity of methacetin (N-(4-methoxyphenyl)-acetamide) has been measured in the temperature range 5.8–300 K. No anomalies in the C _p(T) dependence were observed. Thermodynamic functions were calculated. At 298.15 K, the values of entropy and enthalpy are equal to 243.1 J K⁻¹ mol⁻¹ and 36360 J mol⁻¹, respectively. The heat capacity of methacetin in the temperature range 6–10 K is well fitted by Debye equation C _p = AT ³. The thermodynamic data obtained for methacetin are compared with those for the monoclinic and orthorhombic polymorphs of paracetamol.     

Excited-state absorption properties of platinum(II) terpyridyl acetylides

A comprehensive photophysical study is presented which compares the ground- and excited-state properties of four platinum(II) terpyridyl acetylide compounds of the general formula [Pt(tBu3tpy)(CCR)]+, where tBu3tpy is 4,4',4' '-tri-tert-butyl-2,2':6',2' '-terpyridine and R is an alkyl or aryl group. [Ru(tBu3tpy)3]2+ and the pivotal synthetic precursor [Pt(tBu3tpy)Cl]+ were also investigated in the current work. The latter two complexes possess short excited-state lifetimes and were investigated using ultrafast spectrometry while the other four compounds were evaluated using conventional nanosecond transient-absorption spectroscopy. The original intention of this study was to comprehend the nature of the impressive excited-state absorptions that emanate from this class of transition-metal chromophores. Transient-absorbance-difference spectra across the series contain the same salient features, which are modulated only slightly in wavelength and markedly in intensity as a function of the appended acetylide ligand. More intense absorption transients are observed in the arylacetylide structures relative to those bearing an alkylacetylide, consistent with transitions coupled to the pi system of the ancillary ligand. Reductive spectroelectrochemical measurements successfully generated the electronic spectrum of the tBu3tpy radical anion in all six complexes at room temperature. These measurements confirm that electronic absorptions associated with the tBu3tpy radical anion simply do not account for the intense optical transitions observed in the excited state of the Pt(II) chromophores. Transient-trapping experiments using the spectroscopically silent reductive quencher DABCO clearly demonstrate the loss of most transient-absorption features in the acetylide complexes throughout the UV, visible, and near-IR regions following bimolecular excited-state electron transfer, suggesting that these features are strongly tied to the photogenerated hole which is delocalized across the Pt center and the ancillary acetylide ligand.     

Copper‐Catalyzed Intermolecular Asymmetric Propargylic Dearomatization of Indoles

The first copper‐catalyzed intermolecular dearomatization of indoles by an asymmetric propargylic substitution reaction was developed. This method provides a highly efficient synthesis of versatile furoindoline and pyrroloindoline derivatives containing a quaternary carbon stereogenic center and a terminal alkyne moiety with up to 86 % yield and 98 % ee.