Structural flexibility of favipiravir and its structural analogues in solutions: experimental and computational insight.

Combined UV-vis and quantum chemical studies of the structural flexibility and tautomerism of 6-R-3-hydroxy-2-pyrazine carboxamides in solutions revealed that their keto-enol transformations are accompanied by the deprotonation of enol tautomers and the formation of the corresponding anionic species. Both the solvent and the 6-R substituent strongly influence the relative abundance of the above forms in solutions. Anions are not formed in 1,2-dichloroethane (DCE), but the probability of deprotonation in neutral water and N,N-dimethylformamide (DMF) increases in the order R = H < F < NO2. Only enol tautomers of all solutes are found in DCE. DMF stabilizes keto forms only moderately and assists much strongly in the deprotonation of all three compounds. Water tends to stabilize both keto tautomers and deprotonated anions: the keto form dominates in the case of R = H (antiviral drug T-1105), the anions are found exclusively for R = NO2, and the aqueous solution of another antiviral drug, favipiravir (R = F), contains both the keto tautomer and the anionic form. The results of quantum chemical free energy calculations are in agreement with the experimental observations.

Carbon Dioxide Electroreduction and Formic Acid Oxidation by Formal Nickel(I) Complexes of Di-isopropylphenyl Bis-iminoacenaphthene.

Processing CO2 into value-added chemicals and fuels stands as one of the most crucial tasks in addressing the global challenge of the greenhouse effect. In this study, we focused on the complex (dpp-bian)NiBr2 (where dpp-bian is di-isopropylphenyl bis-iminoacenaphthene) as a precatalyst for the electrochemical reduction of CO2 into CH4 as the sole product. Cyclic voltammetry results indicate that the realization of a catalytically effective pattern requires the three-electron reduction of (dpp-bian)NiBr2. The chemically reduced complexes [K(THF)6]+[(dpp-bian)Ni(COD)]- and [K(THF)6]+[(dpp-bian)2Ni]- were synthesized and structurally characterized. Analyzing the data from the electron paramagnetic resonance study of the complexes in solutions, along with quantum-chemical calculations, reveals that the spin density is predominantly localized at their metal centers. The superposition of trajectory maps of the electron density gradient vector field ∇ ρ r ${\nabla \rho \left({\bf r}\right)}$ and the electrostatic force density field F e s r ${{{\bf F}}_{{\rm e}{\rm s}}\left({\bf r}\right)}$ per electron, as well as the atomic charges, discloses that, within the first coordination sphere, the interatomic charge transfer occurs from the metal atom to the ligand atoms and that the complex anions can thus be formally described by the general formulae (dpp-bian)2-Ni+(COD) and (dpp-bian)2 -Ni+. It was also shown that the reduced nickel complexes can be oxidized by formic acid; resulting from this reaction, the two-electron and two-proton addition product dpp-bian-2H is formed.

Linkage of the Dinuclear Gold(I) Complex Luminescence and Origin of Endocyclic Amino Group of Cyclic P2N2-Bridging Ligands.

Gold(I) complexes of LAu2Cl2 composition based on P2N2 ligands, namely 1,5-diaza-3,7-diphosphacyclooctanes, containing ethylpyridyl substituents at the phosphorus atoms and sp2- or sp3-hybridized endocyclic nitrogen atoms were synthesized. The SCXRD analysis indicated the strong impact of the geometry of the nitrogen atom on the structure and conformational flexibility of the complexes. The N-aryl substituted ligand with the planar endocyclic nitrogen atom provides higher flexibility of the complex and an ability to bind the solvent molecules in the "host-guest" mode, whereas that kind of behavior is forbidden for the complex with an N-alkyl substituted ligand with a pyramidal nitrogen atom. The substituents at nitrogen atoms also control the origin of the emission, which is phosphorescence for the N-aryl substituted complex and fluorescence for the N-alkylaryl substituted complex. The phosphorescent gold(I) complex displays high cytotoxicity without selectivity toward the m-HeLa and normal cells, but the core-shell nanoparticles formed on the base of the complex demonstrate reduced cytotoxicity. The luminescence of the NPs allows tracking the complexes in the cell samples.

Identification of Key TRIM Genes Involved in Response to Pseudomonas aeruginosa or Chlamydia spp. Infections in Human Cell Lines and in Mouse Organs.

Bacterial infections represent an unsolved problem today since bacteria can evade antibiotics and suppress the host's immune response. A family of TRIM proteins is known to play a role in antiviral defense. However, the data on the involvement of the corresponding genes in the antibacterial response are limited. Here, we used RT-qPCR to profile the transcript levels of TRIM genes, as well as interferons and inflammatory genes, in human cell lines (in vitro) and in mice (in vivo) after bacterial infections caused by Pseudomonas aeruginosa and Chlamydia spp. As a result, the genes were identified that are involved in the overall immune response and associated primarily with inflammation in human cells and in mouse organs when infected with both pathogens (TRIM7, 8, 14, 16, 17, 18, 19, 20, 21, 47, 68). TRIMs specific to the infection (TRIM59 for P. aeruginosa, TRIM67 for Chlamydia spp.) were revealed. Our findings can serve as a basis for further, more detailed studies on the mechanisms of the immune response to P. aeruginosa and Chlamydia spp. Studying the interaction between bacterial pathogens and the immune system contributes to the search for new ways to successfully fight bacterial infections.

A Model of iPSC-Derived Macrophages with TNFAIP3 Overexpression Reveals the Peculiarities of TNFAIP3 Protein Expression and Function in Human Macrophages.

Macrophages play a crucial role in the development and control of inflammation. Understanding the mechanisms balancing macrophage inflammatory activity is important to develop new strategies for treating inflammation-related diseases. TNF-α-induced protein 3 (TNFAIP3, A20) is a negative regulator of intracellular inflammatory cascades; its deficiency induces hyper-inflammatory reactions. Whether A20 overexpression can dampen macrophage inflammatory response remains unclear. Here, we generated human-induced pluripotent stem cells with tetracycline-inducible A20 expression and differentiated them into macrophages (A20-iMacs). A20-iMacs displayed morphology, phenotype, and phagocytic activity typical of macrophages, and they displayed upregulated A20 expression in response to doxycycline. A20 overexpression dampened the A20-iMac response to TNF-α, as shown by a decreased expression of IL1B and IL6 mRNA. A dynamic analysis of A20 expression following the generation of A20-iMacs and control iMacs showed that the expression declined in iMacs and that iMacs expressed a lower molecular weight form of the A20 protein (~70 kDa) compared with less differentiated cells (~90 kDa). A low-level expression of A20 and the predominance of a low-molecular-weight A20 form were also characteristic of monocyte-derived macrophages. The study for the first time developed a model for generating macrophages with an inducible expression of a target gene and identified the peculiarities of A20 expression in macrophages that likely underlie macrophage preparedness for inflammatory reactivity. It also suggested the possibility of mitigating inflammatory macrophage responses via A20 overexpression.

Chemical and Electrochemical Reductions of Monoiminoacenaphthenes.

Redox properties of monoiminoacenaphthenes (MIANs) were studied using various electrochemical techniques. The potential values obtained were used for calculating the electrochemical gap value and corresponding frontier orbital difference energy. The first-peak-potential reduction of the MIANs was performed. As a result of controlled potential electrolysis, two-electron one-proton addition products were obtained. Additionally, the MIANs were exposed to one-electron chemical reduction by sodium and NaBH4. Structures of three new sodium complexes, three products of electrochemical reduction, and one product of the reduction by NaBH4 were studied using single-crystal X-ray diffraction. The MIANs reduced electrochemically by NaBH4 represent salts, in which the protonated MIAN skeleton acts as an anion and Bu4N+ or Na+ as a cation. In the case of sodium complexes, the anion radicals of MIANs are coordinated with sodium cations into tetranuclear complexes. The photophysical and electrochemical properties of all reduced MIAN products, as well as neutral forms, were studied both experimentally and quantum-chemically.

Cobalt(II) coordination to an N4-acenaphthene-based ligand and its sodium complex.

A new bifunctional N4-ligand was obtained via the condensation reaction of acenaphthenequinone and 2-picolylamine. A peculiarity of this synthesis is the formation of a new intramolecular C-C bond during the reaction. The structure and redox properties of the ligand were studied. The anion-radical form of the ligand was prepared via the chemical reduction of the latter with metallic sodium as well as in situ via its electrochemical reduction in a solution. The sodium salt prepared was structurally characterized using single-crystal X-ray diffraction (XRD). New cobalt complexes with the ligand in neutral and anion-radical forms were synthesized and further studied. As a result, three new homo- and heteroleptic cobalt(II) complexes were obtained, in which the cobalt atom demonstrates different modes of coordination with the ligand. Cobalt(II) complex CoL2 with two monoanionic ligands was prepared by the electrochemical reduction of a related L2CoBr2 complex or by treating cobalt(II) bromide with the sodium salt. XRD was used to study the structures of all cobalt complexes prepared. Magnetic and electron paramagnetic resonance studies were performed: CoII ion states with S = 3/2 and S = 1/2 were found for the complexes. A quantum-chemical study confirmed that the spin density is mainly located at the cobalt center.

Overexpression of Parkin in the Neuronal Progenitor Cells from a Patient with Parkinson's Disease Shifts the Transcriptome Towards the Normal State.

Parkinson's disease (PD) is a neurodegenerative pathology caused by the progressive loss of dopaminergic neurons in the substantia nigra. Juvenile PD is known to be strongly associated with mutations in the PARK2 gene encoding E3 ubiquitin ligase Parkin. Despite numerous studies, molecular mechanisms that trigger PD remain largely unknown. Here, we compared the transcriptome of the neural progenitor (NP) cell line, derived from a PD patient with PARK2 mutation resulting in Parkin loss, with the transcriptome of the same NPs but expressing transgenic Parkin. We found that Parkin overexpression led to the substantial recovery of the transcriptome of NPs to a normal state indicating that alterations of transcription in PD-derived NPs were mainly caused by PARK2 mutations. Among genes significantly dysregulated in PD-derived NPs, 106 genes unambiguously restored their expression after reestablishing of the Parkin level. Based on the selected gene sets, we revealed the enriched Gene Ontology (GO) pathways including signaling, neurotransmitter transport and metabolism, response to stimulus, and apoptosis. Strikingly, dopamine receptor D4 that was previously associated with PD appears to be involved in the maximal number of GO-enriched pathways and therefore may be considered as a potential trigger of PD progression. Our findings may help in the screening for promising targets for PD treatment.

Synthesis, Structure, and Electrochemical Properties of 2,3,4,5-Tetraphenyl-1-Monophosphaferrocene Derivatives.

Heteroleptic 2,3,4,5-tetraphenyl-1-monophosphaferrocene [FeCp(η5-PC4Ph4)] was obtained at a 62% yield through the reaction of lithium 2,3,4,5-tetraphenyl-1-monophosphacyclopentadienide Li(PC4Ph4) (1) with [FeCp(η6-C6H5CH3)][PF6]. The structure of 1-monophosphaferrocene 2 and its W(CO)5-complex 3 were confirmed by multinuclear NMR and single-crystal X-ray diffraction study and further supported by DFT calculations. Cyclic voltammetry demonstrated that [FeCp(η5-PC4Ph4)] 2 has a quasi-reversible oxidation wave. The comparison of the properties of phosphaferrocene 2 with those of W(CO)5-complex 3 shows the possibility of changing the coordination type during oxidation.

Glial Cultures Differentiated from iPSCs of Patients with PARK2-Associated Parkinson's Disease Demonstrate a Pro-Inflammatory Shift and Reduced Response to TNFα Stimulation.

Parkinson's disease (PD) is the second most common neurodegenerative diseases characterized by progressive loss of midbrain dopaminergic neurons in the substantia nigra. Mutations in the PARK2 gene are a frequent cause of familial forms of PD. Sustained chronic neuroinflammation in the central nervous system makes a significant contribution to neurodegeneration events. In response to inflammatory factors produced by activated microglia, astrocytes change their transcriptional programs and secretion profiles, thus acting as immunocompetent cells. Here, we investigated iPSC-derived glial cell cultures obtained from healthy donors (HD) and from PD patients with PARK2 mutations in resting state and upon stimulation by TNFα. The non-stimulated glia of PD patients demonstrated higher IL1B and IL6 expression levels and increased IL6 protein synthesis, while BDNF and GDNF expression was down-regulated when compared to that of the glial cells of HDs. In the presence of TNFα, all of the glial cultures displayed a multiplied expression of genes encoding inflammatory cytokines: TNFA, IL1B, and IL6, as well as IL6 protein synthesis, although PD glia responded to TNFα stimulation less strongly than HD glia. Our results demonstrated a pro-inflammatory shift, a suppression of the neuroprotective gene program, and some depletion of reactivity to TNFα in PARK2-deficient glia compared to glial cells of HDs.

Green Emissive Copper(I) Coordination Polymer Supported by the Diethylpyridylphosphine Ligand as a Luminescent Sensor for Overheating Processes.

Tertiary diethylpyridylphosphine was synthesized by the reaction of pyridylphosphine with bromoethane in a suberbasic medium. The reaction of phosphine with the copper(I) iodide led to the formation of a copper(I) coordination polymer, which, according to the X-ray diffraction data, has an intermediate structure with a copper-halide core between the octahedral and stairstep geometries of the Cu4I4 clusters. The obtained coordination polymer exhibits a green emission in the solid state, which is caused by the 3(M+X)LCT transitions. The heating up of the copper(I) coordination polymer to 138.5 °C results in its monomerization and the formation of a new solid-state phase. The new phase exhibits a red emission, with the emission band maximum at 725 nm. According to the experimental data and quantum chemical computations, it was concluded that depolymerization probably leads to a complex that is formed with the octahedral structure of the copper-halide core. The resulting solid-state phase can be backward-converted to the polymer phase via recrystallization from the acetone or DMF. Therefore, the obtained coordination polymer can be considered a sensor or detector for the overheating of processes that should be maintained at temperatures below 138 °C (e.g., engines, boiling liquids, solar heat systems, etc.).

Emission and Luminescent Vapochromism Control of Octahedral Cu4 I4 Complexes by Conformationally Restricted P,N Ligands.

A conformationally restricted P,N-ligand capable of the design of polynuclear copper(I) complexes was synthesized via the reaction of primary pyridylphosphine, paraformaldehyde, and benzhydrylamine. The reaction of the ligand with copper(I) iodide leads to the tetranuclear copper(I) complex with the octahedral type of copper-iodide core. Different orientation of coordination bonds of the ligands relative to the P,N2 -heterocyclic fragments and to the Cu4 I4 cores leads to the existence of two types of conformers of the complex with "compact" or "stretched" geometry of the Cu4 I4 cluster. This lability of the complex allowed for obtaining two crystalline phases displaying green or red luminescence. The TDDFT computations along with XRD structural analysis gave a strong interpretation of the green emission belonging to the "compact" form of the complex and belonging of the red emission to the "stretched" form. Moreover, both crystalline phases demonstrate the strong vapochromic responses of luminescence on the vapors of wide range of solvents.

Thermodynamics of trans/gauche conformational equilibria and vibrational spectra of 1,2-dihaloethanes in various media.

The recently developed efficient protocols to implicit [Grimme et al., J. Phys. Chem. A 125, 4039-4054 (2021)] and explicit quantum mechanical modeling of non-rigid molecules in solution [Katsyuba et al., J. Phys. Chem. B 124, 6664-6670 (2020)] are used to describe conformational equilibria of 1,2-dichloroethane and 1,2-dibromoethane in various media. Two approaches for evaluation of trans/gauche free energy differences, ΔGt-g, are compared: (a) direct ΔGt-g computation in implicit solution; (b) the use, together with experimental intensities, of infrared absorption coefficients and Raman scattering cross sections computed for each explicitly modeled solution. The same cluster model of a solute surrounded by the first solvation shell of solvent molecules was used to simulate both Raman and IR spectra. The good agreement between the two approaches indicates the reliability of both methods. The importance of using correct absorption coefficients and Raman scattering factors for each medium is discussed. The ΔGt-g estimates from both implicit and explicit solvation simulations were combined with experimentally measured enthalpy differences ΔHt-g available in the literature to obtain condensed-state ΔSt-g estimates.

Conductive Mediators in Oxidation Based on Ferrocene Functionalized Phosphonium Ionic Liquids.

Herein, the synthesis of ferrocene-containing salts is presented. Acylation of ferrocene (Fc) according to the Friedel-Crafts method led to ω-bromoacyl ferrocenes. The ω-bromoacyl ferrocenes were subsequently introduced to quaternization reaction with tri-tert-butyl phosphine, which resulted in phosphonium salts. Obtained phosphonium salts were characterized by physical methods. The electrochemical properties of phosphonium salts were studied by cyclic voltammetry (CV). It was found that the replacement of n-butyl fragments at the phosphorus atom by tert-butyl leads to a more anodic potential shift. In contrast to isolobal structures Fc-C(O)(CH2)nP+(n-Bu)3X- and Fc-(CH2)n+1P+(n-Bu)3X-, the CV curves of Fc-C(O)(CH2)nP+(t-Bu)3X- and Fc-(CH2)n+1P+(t-Bu)3X- did not show a large discrepancy between forward and reverse currents. The transformation of the C=O groups to CH2 fragments had a significant effect on the electrochemical properties of ferrocene salts, the oxidation potential of which is close to that of pure ferrocene.

The Phosphinate Group in the Formation of 2D Coordination Polymer with Sm(III) Nodes: X-ray Structural, Electrochemical and Mössbauer Study.

A coordination polymer has been synthesized using ferrocene-based ligand-bearing phosphinic groups of 1,1'-ferrocene-diyl-bis(H-phosphinic acid)), and samarium (III). The coordination polymer's structure was studied by both single-crystal and powder XRD, TG, IR, and Raman analyses. For the first time, the Mössbauer effect studies were performed on ferrocenyl phosphinate and the polymer based on it. Additionally, the obtained polymer was studied by the method of cyclic and differential pulse voltammetry. It is shown that it has the most positive potential known among ferrocenyl phosphinate-based coordination polymers and metal-organic frameworks. Using the values of the oxidation potential, the polymer was oxidized and the ESR method verified the oxidized Fe(III) form in the solid state. Additionally, the effect of the size of the phosphorus atom substituent of the phosphinate group on the dimension of the resulting coordination compounds is shown.

iPSC-Derived Macrophages: The Differentiation Protocol Affects Cell Immune Characteristics and Differentiation Trajectories.

The generation of human macrophages from induced pluripotent stem cells (iMacs) is a rapidly developing approach used to create disease models, screen drugs, study macrophage-pathogen interactions and develop macrophage-based cell therapy. To generate iMacs, different types of protocols have been suggested, all thought to result in the generation of similar iMac populations. However, direct comparison of iMacs generated using different protocols has not been performed. We have compared the productivity, the differentiation trajectories and the characteristics of iMacs generated using two widely used protocols: one based on the formation of embryoid bodies and the induction of myeloid differentiation by only two cytokines, interleukin-3 and macrophage colony-stimulating factor, and the other utilizing multiple exogenous factors for iMac generation. We report inter-protocol differences in the following: (i) protocol productivity; (ii) dynamic changes in the expression of genes related to inflammation and lipid homeostasis following iMac differentiation and (iii) the transcriptomic profiles of terminally differentiated iMacs, including the expression of genes involved in inflammatory response, antigen presentation and lipid homeostasis. The results document the dependence of fine iMac characteristics on the type of differentiation protocol, which is important for further development of the field, including the development of iMac-based cell therapy.

Comparison of crystal structure and DFT calculations of triferrocenyl trithiophosphite's conformance.

A triferrocenyl trithiophosphite was studied by X-ray single-crystal diffraction. Triferrocenyl trithiophosphite has nine axes of internal rotation: three P-S bonds, three C-S bonds and three Fe-cyclopentadienyl axes. Rotation around the P-S bonds results in a totally asymmetric structure with three ferrocenylthio groups exhibiting different orientations towards the phosphorus lone electron pair (LEP). A comparison of DFT calculations and X-ray diffraction data is presented, herein we show which conformations are preferred for a given ligand.

Ferrocene-based P-chiral amidophosphinate: stereoselective synthesis and X-ray structural study.

Racemic and enantiopure ferrocene-based P-chiral amidophosphinates have been simply and stereoselectively synthesized by ortho-lithiation of rac- or (R)-Ugi's amine and further reaction with amidochlorophenylphosphinate Cl-P(O)(Ph)NEt2. This is the first example of an asymmetric reaction of ortho-lithiated Ugi's amine with tetracoordinated phosphorus(V) chlorides. The structures of rac- and (R)-Ugi's amine ferrocenyl(phenyl)phosphinic acid N,N-diethylamide have been extensively studied experimentally (NMR, X-ray analysis, electrochemistry). The CV first peak refers to the oxidation of the amine fragment, which is clearly seen when (R)-Ugi's amine ferrocenyl(phenyl)phosphinic acid N,N-diethylamide reacts with anhydrous acid. The addition of two equivalents of CF3COOH leads to the protonation of nitrogen atoms, and a classical reversible wave of oxidation of Fe(II) to Fe(III) is observed.

Synthesis and electrochemical properties of 3,4,5-tris(chlorophenyl)-1,2-diphosphaferrocenes.

A novel representative of sodium 3,4,5-triaryl-1,2-diphosphacyclopentadienide containing a chloro substituent in the meta-position of the aryl groups was obtained with a high yield based on the reaction of tributyl(1,2,3-triarylcyclopropenyl)phosphonium bromide and sodium polyphosphides. Further reaction of sodium 3,4,5-tris(3-chlorophenyl)-1,2-diphosphacyclopentadienide with [FeCp(η6-C6H5CH3)][PF6] complex gives a new 3,4,5-tris(3-chlorophenyl)-1,2-diphosphaferrocene. The electrochemical properties of 3,4,5-tris(3-chlorophenyl)-1,2-diphosphaferrocene were studied and compared to 3,4,5-tris(4-chlorophenyl)-1,2-diphosphaferrocene. It was found that the position of the chlorine atom on the aryl fragment has an influence on the reduction potential of 1,2-diphosphaferrocenes, while the oxidation potentials do not change.

Deep-Blue Emissive Copper(I) Complexes Based on P-Thiophenylethyl-Substituted Cyclic Bisphosphines Displaying Photoinduced Structural Transformations of the Excited States.

A synthetic method for a primary 2-(thiophen-2'-yl)ethylphosphine was developed. The reaction of thiophenylethylphosphine with paraformaldehyde and primary arylamines leads to the formation of cyclic bisphosphines, namely, 1,5-di(aryl)-3,7-bis(thiophenylethyl)-1,5-diaza-3,7-diphosphacyclooctane (aryl = phenyl, p-tolyl). The obtained bisphosphines form cationic bis-P,P-chelate complexes with copper(I) tetrafluoroborate, which were structurally characterized by NMR spectroscopy, mass spectrometry, and elemental and XRD analyses. Surprisingly, the copper(I) complexes display a multiband emission in the solid state with maxima at 355-360, 425-430, and 480-490 nm and nanosecond lifetimes (1.2-1.4 ns) upon a 335 nm excitation. The excitation of the complexes at 360 nm at room temperature results in a deep-blue emission at 425-430 nm and a tail at 460-490 nm. A temperature decrease leads to an increased intensity of the emission band at 480 nm, while the luminescence lifetimes insignificantly increased up to 14 ns. Quantum chemical calculations explain the observed unusual luminescent behavior by the existence of "undistorted" and "flattened" singlet excited states of copper(I) complexes at room temperature and at 77 K, respectively.