Free NH Groups Research Articles

WLB-87848, a Selective σ1 Receptor Agonist, with an Unusually Positioned NH Group as Positive Ionizable Moiety and Showing Neuroprotective Activity.

The synthesis and pharmacological activity of a new series of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as sigma-1 receptor (σ1R) ligands are reported. A hit from a high-throughput screening program was evolved into a highly potent and selective σ1R agonist (14qR) that contains a free NH group as positive ionizable moiety, not fulfilling the usual pharmacophoric features of the σ1R. The compound shows good physicochemical and ADMET characteristics, displays an agonist profile in the binding immunoglobulin protein/σ1R association assay, induces neuron viability in an in vitro model of β-amyloid peptide intoxication, and presents positive results against recognition memory impairment induced by hippocampal injection of Aβ peptide in rats after oral treatment, altogether making 14qR (WLB-87848) an interesting candidate for neuroprotection.

Serum Fructosamine as a Marker for Glycemic Control in Patients with Diabetic Nephropathy

Diabetes mellitus (DM) is a metabolic disease of chronic insulin deficiency or resistance. The progression of DM is associated with long-term damage to macro- and micro-vascular body systems and causes serious health complications. Up to 40% of DM patients develop chronic kidney disease (CKD), mainly as a consequence of diabetic nephropathy (DN). Hence, strict glycemic control is recommended to slow down CKD progression. Hyperglycemia causes complications in diabetic patients through the glycation of various proteins. The interaction of glucose with the free NH2 groups of proteins results in the formation of the early glycation product fructosamine (FA). FA has a short half-life (1 to 2 weeks) and hence it has the potential of an early marker for glycemic control. Although long used in the clinical practice, the FA diagnostic and prognostic significance remains questionable. In this study, we tested the FA potential to serve as a glycemic marker in DM patients with DN. We found that DM patients have significantly higher serum FA levels than non-diabetics. Further, the serum FA level in diabetics correlates positively with the blood glucose concentration. Finally, the mean serum FA level was higher in DM patients with DN, compared to those without DN. These results establish FA as a promising marker for glycemic control in DN patients.

Regioselective synthesis of 3,4-diarylpyrimido[1,2-b]indazole derivatives enabled by iron-catalyzed ring-opening of styrene oxides.

The first synthesis of 3,4-diarylpyrimido[1,2-b]indazole derivatives from 3-aminoindazoles has been realized. The FeCl3-catalyzed intermolecular epoxide ring-opening reaction altered the order of annulation, with the free primary NH2 groups in 3-aminoindazoles preferentially reacting with styrene oxides instead of aromatic aldehydes. This protocol is further highlighted by its broad substrate compatibility, high chemo- and regioselectivities, and the late-stage modifications of bioactive molecules. Without aromatic aldehydes, the synthesis of 3-aryl-4-acylpyrimido[1,2-b]indazole derivatives can also be accomplished using alternative reaction conditions.

Preparation of 2,5‐Disubstituted Tetrazoles using a Copper‐Catalysed Regioselective Direct Coupling of Tetrazoles with Free NH Groups and Boronic Acid Derivatives

AbstractThe development of a mild and efficient protocol that allows the direct C−N coupling of N−H free tetrazole and low toxic boronic acid was presented. A careful optimization of the reaction conditions revealed that reaction proceeded smoothly in presence of a 10 mol % copper complex catalytic system without the need of any additives. Thus, the results presented herein represents a reliable and efficient protocol for the synthesis of regioselective 2,5‐disubstituted tetrazoles.

Mixtures of Heterocycles and Iodine as the Catalysts for the Formation of Organic Carbonates from Epoxides and CO2

Combinations of a series of nitrogen-containing heterocycles with iodine were tested as the catalysts for the synthesis of cyclic carbonates from epoxides and CO2. It is shown that the systems containing aliphatic substituents are more efficient, the presence of a free NH group has a beneficial effect on the conversion, and the systems with two or more nitrogen atoms are more active.

Acetoxy Group-Directed Regioselective C2 Alkenylation of Indoles via Pd-Ag Bimetallic Catalysis.

Regioselective C-H functionalizations of indoles reported to date with directing groups at C3 mainly rely on functional groups that are linked to the indole via C-C bonds. However, groups that are linked to the indole core by C-X linkages are also attractive due to the possibility of further modifications of the C-X bond. Herein, we report a 3-acetoxy directing group for the regioselective C2 alkenylation of indoles via a C-H activation-based, cross-dehydrogenative, oxidative Heck-type reaction. The reaction is catalyzed by Pd(II) and Ag(I) with stoichiometric Cu(II) as the oxidant and provides the 2-alkenylated indoles in yields of 52-84%. The reaction conditions are compatible with several functional groups at different positions as well as different N-protecting groups or free NH groups on the indole core. With respect to the alkene coupling partners, the reactions are successful with acrylates, vinyl sulfates, and phosphates. Specifically designed experiments, as well as density functional theory (DFT) computational studies, reveal that a heterodinuclear [Pd(μ-OAc)3Ag] bimetallic species is the actual catalyst responsible for the C-H alkenylation. A mechanistic path involving this catalytic species was also found to be favorable over other possible pathways for explaining the observed regioselectivity through DFT studies.

All natural mussel-inspired bioadhesives from soy proteins and plant derived polyphenols with marked water-resistance and favourable antibacterial profile for wound treatment applications

HypothesisImplementation of tissue adhesives from natural sources endowed with good mechanical properties and underwater resistance still represents a challenging research goal. Inspired by the extraordinary wet adhesion properties of mussel byssus proteins resulting from interaction of catechol and amino residues, hydrogels from soy protein isolate (SPI) and selected polyphenols i.e. caffeic acid (CA), chlorogenic acid (CGA) and gallic acid (GA) under mild aerial oxidative conditions were prepared. ExperimentsThe hydrogels were subjected to chemical assays, ATR FT-IR and EPR spectroscopy, rheological and morphological SEM analysis. Mechanical tests were carried out on hydrogels prepared by inclusion of agarose. Biological tests included evaluation of the antibacterial and wound healing activity, and hemocompatibility. FindingsThe decrease of free NH2 and SH groups of SPI, the EPR features, the good cohesive strength and excellent underwater resistance (15 days for SPI/GA) under conditions relevant to their use as surgical glues indicated an efficient interaction of the polyphenols with the protein in the hydrogels. The polyphenols greatly also improved the mechanical properties of the SPI/ agarose/polyphenols hydrogels. These latter proved biocompatible, hemocompatible, not harmful to skin, displayed durable adhesiveness and good water-vapour permeability. Excellent antibacterial properties and in some cases (SPI/CGA) a favourable wound healing activity on dermal fibroblasts was obtained.

Synthesis of a novel next-generation positively charged polymer and its in-situ grafting into thin film composite membranes to enhance the performance for desalination

High efficiency of the polyamide membranes can be achieved by rationally tailoring the active layer, which empowers the membrane with better anti-fouling characteristics, high flux, and separation efficiencies. Herein, a next-generation anti-fouling positively charged copolymer of diallyldimethylammonium chloride (DADMAC) and N1, N1-diallyldodecane-1,12-diammonium chloride (DADAC) was synthesized and thoroughly characterized by TGA, FTIR, proton (1H) and the carbon (13C) NMR. The synthesized poly(DADMAC-co-DADAC), after conversion to poly(DADMAC-co-DADA) having free NH2 group, was in-Situ grafted while forming the active layer due to its rationally designed anchoring points of NH2 group. The in-Situ grafting resulted in a cross-linked polyamide active layer containing positively charged brushes of poly (DADMAC-co-DADA) at regular intervals. The AFM analysis has shown that the polyamide layer's surface roughness increased with the poly-(DADMAC-co-DADA) grafting concentration, which positively impacts the membranes' flux. When exposed to the water, the grafted poly-(DADMAC-co-DADA) expanded and spread a positively quaternary ammonium network on the membrane surface, effectively repelling the cations. The introduced membrane has shown high performance compared to the pristine polyamide membrane. The functionalized membranes have displayed a 3.5 times flux for 2000 ppm of NaCl while maintaining a good rejection at 93.1%. The anti-fouling behavior of the membranes was evaluated against the model positively charged CTAB (cetyltrimethylammonium bromide) foulants (2000 ppm). Poly- (DADMAC-co-DADA) grafted membranes have shown a high anti-fouling tendency. After 600 min (10 h) of continuous operation, the flux declined less than 15%, whereas the pristine polyamide membrane lost 99%. The poly-(DADMAC-co-DADA) grafted membranes recovered more than 93% of their maximum flux. Thus, the in-Situ grafting of positively charged polymer is a possible opportunity to develop the next generation of high-performance polyamide membranes.

Assessing the In Vitro Digestion of Lactoferrin-Curcumin Nanoparticles Using the Realistic Gastric Model.

Nanosized delivery systems have been the subject of research and discussion in the scientific community due to their unique properties and functionality. However, studies reporting the behaviour of nanodelivery systems under dynamic in vitro digestion conditions are still very scarce. To address this gap, this study aims to assess the dynamic in vitro gastric digestion of lactoferrin/curcumin nanoparticles in the realistic gastric model (RGM). For this purpose, the INFOGEST standard semi-dynamic digestion protocol was used. The nanosystems were characterized in terms of hydrodynamic size, size distribution, polydispersity index (PdI), and zeta potential using dynamic light scattering (DLS), before and during the digestion process. Confocal laser scanning microscopy (CLSM) was also used to examine particle aggregation. In addition, the release of curcumin was evaluated spectroscopically and the intrinsic fluorescence of lactoferrin was measured throughout the digestion process. The protein hydrolysis was also determined by UV-VIS-SWNIR spectroscopy to estimate, in real-time, the presence of free NH2 groups during gastric digestion. It was possible to observe that lactoferrin/curcumin nanoparticles were destabilized during the dynamic digestion process. It was also possible to conclude that low sample volumes can pose a major challenge in the application of dynamic in vitro digestion models.

Elementary molecular processes that govern the chemical stimulation of a polyurethane-based shape memory polymer

After programming, polyurethanes like ESTANE ETE 75DT3 (SMP-E) show chemically triggered one-way shape memory effect (1WE). When small molecules enter the polymer, weakening the hydrogen bonds between the SMP-E macromolecules and reducing TSWITCH below the environmental temperature. Herein, we investigate how three alcohols—methanol, ethanol and 1-propanol—perform in chemically actuating the 1WE in SMP-E. Weight gain studies show that a smaller size molecule more rapidly saturates SMP-E. The results from mechanical spectroscopy show that TSWITCH decreases with increasing alcohol molecular concentrations, independent of their chemical nature. In line with these findings, all three alcohols show the same amount of shape recovery, which is the fastest when using the smallest methanol molecule for chemical actuation. Infrared spectroscopy helps to identify the mechanism responsible for the decrease in TSWITCH during chemical exposure. Small alcohol molecules interrupt hydrogen bonds between macromolecular chains attaching to C=O groups and creating free NH groups.

Unique Metal–Ligand Interplay in Directing Discrete and Polymeric Derivatives of Isomeric Azole-Carboxylate. Varying Electronic Form, C–C Coupling, and Receptor Feature

This article dealt with the ruthenium and osmium derivatives of isomeric 1H-indazole-3-carboxylic acid/2H-indazole-3-carboxylic acid (H2L1) and 1H-benzimidazole-2-carboxylic acid (H2L2) along with the π-acidic bpy (bpy = 2,2'-bipyridine) and pap (pap = 2-phenylazopyridine) co-ligands. It thus extended structurally authenticated monomeric ([(bpy)2RuII(HL1-)]ClO4 [1]ClO4, (pap)2RuII(L12-) 2, (bpy)2OsII(L12-) 3, (pap)2OsII(L12-) 4, (bpy)2RuII(L22-) 5, (bpy)2OsII(L22-) 8, and (pap)2OsII(L22-) 9) and dimeric ([(bpy)2RuII(μ-L22-)RuII(bpy)2](ClO4)2 [6](ClO4)2) complexes. It also described modified L2'2- (L2'2- = 2,2'-bisbenzimidazolate)-bridged [(pap)2RuII(μ-L2'2-)RuII(pap)2](ClO4)2 [7](ClO4)2, where L2'2- was developed selectively with the {Ru(pap)2} metal fragment via in situ intermolecular C-C coupling of the two units of decarboxylated benzimidazolate. Moreover, chemical oxidation (OsII to OsIII) of (bpy)2OsII(L12-) 3 (E0 = 0.11 V versus SCE) and (bpy)2OsII(L22-) 8 (E0 = 0.12 V versus SCE) by AgClO4 yielded unprecedented OsIII-AgI derived polymeric {[(bpy)2OsIII-L12--AgI(CH3CN)](ClO4)2}n {[10](ClO4)2}n and dimeric [(bpy)2OsIII-L22--AgI(CH3CN)](ClO4)2 [11](ClO4)2 complexes as a function of trans and cis orientations of the active N2 donor with special reference to the carboxylate O2 of L2-, respectively. Microscopic (FE-SEM, TEM-EDX, and AFM) and DLS experiments suggested a homogeneously dispersed hollow spherical shaped morphology of {[10](ClO4)2}n with an average particle size of 200-400 nm as well as its non-dissociative feature in the aprotic medium. Experimental (structure, spectroscopy, and electrochemistry) and theoretical (DFT/TD-DFT) explorations revealed a redox non-innocent feature of L2- in the present coordination situations and the selective anion sensing (X = F-, CN-, and OAc-) event of [1]ClO4 involving a free NH group at the backface of HL1-, which proceeded via the NH···X hydrogen bonding interaction.

Feasibility of using a realistic food bolus for semi-dynamic in vitro gastric digestion of hard cheese with pH-stat monitoring of protein hydrolysis

Oral processing of solid foods leads to boluses made of a human saliva and particles distributed in the size range ∼ 0 to 5 mm. However, studies on the release of nutrients from realistic solid food boluses during digestion are scarce because such mechanisms are difficult to investigate in vivo, and in vitro experiments generally recommend to extensively mince solid foods during the oral stage. Similarly, it has previously been shown that the peptic hydrolysis of protein solutions during in vitro gastric digestion can be monitored by acid titration in both static and dynamic pH conditions, but such approach has never been evaluated in the presence of particles of several millimetres in size. The first objective of the study was therefore to test the feasibility of using a realistic food bolus for gastric digestion studies with a pH-stat monitoring of proteolysis, using Emmental cheese as a solid food and with consideration of gastric acidifying kinetics. Degree of hydrolysis (DH) of proteins was monitored from two series of experiments performed in the presence and absence of pepsin. Other DH measurements, estimated from an independent approach based on the amount of free NH2 groups (OPA method) contained by peptides released in the supernatant (UV absorbance) validated the pH-stat results. A second objective of this work was to test the possible influence of human saliva on gastric proteolysis (in comparison with a water-based bolus). Results showed that saliva slightly delayed initiation of proteolysis, which could be explained by the slightly higher initial pH of the saliva-based bolus, but had no statistical effects on pepsin activity. We conclude that acid titration with a pH-stat system can be a valuable approach to monitor the gastric in vitro proteolysis of realistic solid food boluses in dynamic pH conditions.

Construction of a biocompatible alginate-based hydrogel cross-linked by Diels–Alder chemistry for controlled drug release

With the use of the Diels-Alder (DA) reaction, we were able to effectively develop and describe a hydrogel based on alginate that is chemically cross-linked. First, an alginic acid hydrazide intermediate (Alg-Hd) was synthesized; next, the furan-modified alginate (AlgF) was synthesized as the diene part by reacting furoyl chloride with the free NH2 groups of the Alg-Hd. Maleimide-functionalized alginate (Alg-MA) was made by letting 3-maleimidopropionic acid react with the NH2 groups of Alg-Hd through carbodiimide coupling, which is considered the dienophil part. The final hydrogel network was cross-linked from the two different alginate derivatives that perform well together. Elements analysis and 1H NMR spectroscopy were used to figure out that the degree of functionalization (DF) for the Alg-F derivative was between 23 and 53% and that for the Alg-MA derivative was between 21 and 55%. The microstructure, crystallinity, swelling capacity, and rheological behavior of the hydrogel in its as-designed form were examined. The pH sensitivity, biocompatibility, and other properties of hydrogel seemed good for medical uses, especially as a way to deliver drugs like gliclazide.

The Rational Design of Reducing Organophotoredox Catalysts Unlocks Proton-Coupled Electron-Transfer and Atom Transfer Radical Polymerization Mechanisms

Photocatalysis has become a prominent tool in the arsenal of organic chemists to develop and (re)imagine transformations. However, only a handful of versatile organic photocatalysts (PCs) are available, hampering the discovery of new reactivities. Here, we report the design and complete physicochemical characterization of 9-aryl dihydroacridines (9ADA) and 12-aryl dihydrobenzoacridines (12ADBA) as strong reducing organic PCs. Punctual structural variations modulate their molecular orbital distributions and unlock locally or charge-transfer (CT) excited states. The PCs presenting a locally excited state showed better performances in photoredox defunctionalization processes (yields up to 92%), whereas the PCs featuring a CT excited state produced promising results in atom transfer radical polymerization under visible light (up to 1.21 Đ, and 98% I*). Unlike all the PC classes reported so far, 9ADA and 12ADBA feature a free NH group that enables a catalytic multisite proton-coupled electron transfer (MS-PCET) mechanism. This manifold allows the reduction of redox-inert substrates including aryl, alkyl halides, azides, phosphate and ammonium salts (Ered up to -2.83 vs SCE) under single-photon excitation. We anticipate that these new PCs will open new mechanistic manifolds in the field of photocatalysis by allowing access to previously inaccessible radical intermediates under one-photon excitation.

Columnar liquid-crystalline J-aggregates based on N-core-substituted naphthalene diimides

Two approaches have been developed to prepare liquid-crystalline J-aggregates based on naphthalene diimides.

Amino-Alkylphosphonate-Grafted TiO2: How the Alkyl Chain Length Impacts the Surface Properties and the Adsorption Efficiency for Pd.

Amino-alkylphosphonic acid-grafted TiO2 materials are of increasing interest in a variety of applications such as metal sorption, heterogeneous catalysis, CO2 capture, and enzyme immobilization. To date, systematic insights into the synthesis-properties-performance correlation are missing for such materials, albeit giving important know-how towards their applicability and limitations. In this work, the impact of the chain length and modification conditions (concentration and temperature) of amino-alkylphosphonic acid-grafted TiO2 on the surface properties and adsorption performance of palladium is studied. Via grafting with aminomethyl-, 3-aminopropyl-, and 6-aminohexylphosphonic acid, combined with the spectroscopic techniques (DRIFT, 31P NMR, XPS) and zeta potential measurements, differences in surface properties between the C1, C3, and C6 chains are revealed. The modification degree decreases with increasing chain length under the same synthesis conditions, indicative of folded grafted groups that sterically shield an increasing area of binding sites with increasing chain length. Next, all techniques confirm the different surface interactions of a C1 chain compared to a C3 or C6 chain. This is in line with palladium adsorption experiments, where only for a C1 chain, the adsorption efficiency is affected by the precursor concentration used for modification. The absence of a straightforward correlation between the number of free NH2 groups and the adsorption capacity for the different chain lengths indicates that other chain-length-specific surface interactions are controlling the adsorption performance. The increasing pH stability in the order of C1 < C3 < C6 can possibly be associated to a higher fraction of inaccessible hydrophilic sites due to the presence of folded structures. Lastly, the comparison of adsorption performance and pH stability with 3-aminopropyl(triethoxysilane)-grafted TiO2 reveals the applicability of both grafting methods depending on the envisaged pH during sorption.

Post-Translational Modifications Evoked by Reactive Carbonyl Species in Ultraviolet-A-Exposed Skin: Implication in Fibroblast Senescence and Skin Photoaging.

Photoaging is an accelerated form of aging resulting from skin exposure to ultraviolet (UV) radiation. UV-A radiation deeply penetrates the dermis and triggers the generation of reactive oxygen species (ROS) which promotes damage to DNA, lipids and proteins. Lipid peroxidation results from the oxidative attack of polyunsaturated fatty acids which generate a huge amount of lipid peroxidation products, among them reactive carbonyl species (RCS) such as α, β-unsaturated hydroxyalkenals (e.g., 4-hydroxynonenal), acrolein or malondialdehyde. These highly reactive agents form adducts on free NH2 groups and thiol residues on amino acids in proteins and can also modify DNA and phospholipids. The accumulation of RCS-adducts leads to carbonyl stress characterized by progressive cellular and tissular dysfunction, inflammation and toxicity. RCS-adducts are formed in the dermis of skin exposed to UV-A radiation. Several RCS targets have been identified in the dermis, such as collagen and elastin in the extracellular matrix, whose modification could contribute to actinic elastosis lesions. RCS-adducts may play a role in fibroblast senescence via the modification of histones, and the sirtuin SIRT1, leading to an accumulation of acetylated proteins. The cytoskeleton protein vimentin is modified by RCS, which could impair fibroblast motility. A better identification of protein modification and carbonyl stress in the dermis may help to develop new treatment approaches for preventing photoaging.

Halogen–Hydrogen Bonding for the Synthesis of Efficient Polymeric Carbon‐Nitride Photocatalysts

Carbon nitride (CN) materials demonstrate great promise as photocatalysts for various reactions. However, synthesizing a CN with high dispersibility in water, large specific surface area, ordered morphology, and high catalytic activity remains a challenge. Melem (2,5,8‐triamino‐tri‐s‐triazine) has emerged as a monomer for the synthesis of CN materials owing to its high thermal stability, which favors controlled condensation over sublimation and decomposition at high temperatures. Herein, the synthesis of porous CN materials is shown with high dispersibility in water and excellent photocatalytic activity for the hydrogen evolution reaction (HER). To this end, various supramolecular assemblies are designed which are composed of melem combined with different hydrohalogenic acids as precursors of CNs. The results show that the HX (HX (aq), where X = Cl, Br, I) type directs the morphology, optical, and electronic properties of the resulting CN materials, particularly their surface area and photophysical properties. Moreover, the presence of HX results in a CN with a larger amount of free NH2 groups, which allow good dispersibility in water and act as linking groups to a photodeposited Pt cocatalyst. The elucidation of the optimum acid concentration and type leads to the synthesis of a CN with high and stable photocatalytic HER activity.

Iron-Catalyzed Cross-Electrophile Coupling of Inert C–O Bonds with Alkyl Bromides

Iron-Catalyzed Cross-Electrophile Coupling of Inert C–O Bonds with Alkyl Bromides

Immobilization of Gelatin on Fibers for Tissue Engineering Applications: A Comparative Study of Three Aliphatic Polyesters.

Immobilization of cell adhesive proteins on the scaffold surface has become a widely reported method that can improve the interaction between scaffold and cells. In this study, three nanofibrous scaffolds obtained by electrospinning of poly(caprolactone) (PCL), poly(L-lactide-co-caprolactone) (PLCL) 70:30, or poly(L-lactide) (PLLA) were subjected to chemical immobilization of gelatin based on aminolysis and glutaraldehyde cross-linking, as well as physisorption of gelatin. Two sets of aminolysis conditions were applied to evaluate the impact of amine group content. Based on the results of the colorimetric bicinchoninic acid (BCA) assay, it was shown that the concentration of gelatin on the surface is higher for the chemical modification and increases with the concentration of free NH2 groups. XPS (X-ray photoelectron spectroscopy) analysis confirmed this outcome. On the basis of XPS results, the thickness of the gelatin layer was estimated to be less than 10 nm. Initially, hydrophobic scaffolds are completely wettable after coating with gelatin, and the time of waterdrop absorption was correlated with the surface concentration of gelatin. In the case of all physically and mildly chemically modified samples, the decrease in stress and strain at break was relatively low, contrary to strongly aminolyzed PLCL and PLLA samples. Incubation testing performed on the PCL samples showed that a chemically immobilized gelatin layer is more stable than a physisorbed one; however, even after 90 days, more than 60% of the initial gelatin concentration was still present on the surface of physically modified samples. Mouse fibroblast L929 cell culture on modified samples indicates a positive effect of both physical and chemical modification on cell morphology. In the case of PCL and PLCL, the best morphology, characterized by stretched filopodia, was observed after stronger chemical modification, while for PLLA, there was no significant difference between modified samples. Results of metabolic activity indicate the better effect of chemical immobilization than of physisorption of gelatin.