Urea Receptor Research Articles

Recognition of Amino Acid Salts by Temperature-Dependent Allosteric Binding with Stereodynamic Urea Receptors.

Positive homotropic artificial allosteric systems are important for the regulation of cooperativity, selectivity and nonlinear amplification. Stereodynamic homotropic allosteric receptors can transmit and amplify induced chirality by the first ligand binding to axial chirality between two chromophores. We herein report stereodynamic allosteric urea receptors consisting of a rotational shaft as the axial chirality unit, terphenyl units as structural transmission sites and four urea units as binding sites. NMR titration experiments revealed that the receptor can bind two carboxylate guests in a positive homotropic allosteric manner attributed to the inactivation by intramolecular hydrogen-bonding between urea units within the receptor. In addition, the VT-CD spectra observed upon binding of the urea receptor with l- or D-amino acid salts in MeCN showed interesting temperature-dependent Cotton effects, based on the differences of the receptor shaft unit and the guest structure. The successful discrimination of hydrocarbon-based side chains of amino acid salts indicated that the input of chiral and steric information for the guest was amplified as outputs of the Cotton effect and the temperature-dependence of VT-CD spectra through cooperativity of positive allosteric binding.

Focal Congenital Hyperinsulinism (CHI) Due To Paternally Inherited Variant in ABCC8 Gene: Importance of Genetic Testing & PET Imaging in Stratification & Management of Diazoxide Unresponsive CHI

Congenital Hyperinsulinism (CHI) may be transient or permanent and inherited either in autosomal recessive or dominant forms. Variants in ABCC8 and KCNJ11 genes coding for Sulphonyl Urea Receptor (SUR1) and potassium channel subunit (Kir6.2) respectively, account for 82% cases of diazoxide-unresponsive patients and 45% of all cases of CHI. The histology of CHI is classified into focal and diffuse. Approximately half of all cases can be classified as diffuse, 40 % as focal, and 10% of cases are considered atypical. We report a 1 month old male with recurrent hypoglycemia detected with focal congenital hyperinsulinism secondary to a paternally inherited heterozygous ABCC8 gene mutation. Focal disease results due to inheritance of a monoallelic recessive paternal ABCC8 or KCNJ11 variant together with somatic Loss of Heterozygosity (LOH) of the maternal allele at 11p15 within a pancreatic progenitor cell. Infants & children with focal disease may be cured by resection of their hyperplastic lesion and the risk for postoperative diabetes is significantly lower as compared to that following pancreatectomy for diffuse CHI. The report describes molecular mechanisms underlying CHI & emphasises the need of genetic testing and diagnostic functional imaging modalities in diazoxide unresponsive CHI to guide management and improve clinical outcomes.

Targeting Host Sulphonyl Urea Receptor 2 Can Reduce Severity of Helicobacter pylori Associated Gastritis.

While most Helicobacter pylori-infected individuals remain asymptomatic throughout their lifetime, in a significant proportion, the resulting severe chronic gastritis drives the development of gastric cancer. In this study, we examine a new therapeutic target, a host potassium channel regulatory subunit, SUR2 (encoded by ABCC9), with potential to protect against H pylori-associated diseases. SUR2 gene (ABCC9) expression in human gastric biopsies was analyzed by quantitative polymerase chain reactions. Helicobacter-infected mice were administered the SUR2-channel agonists, pinacidil and nicorandil, then gastric tissues analyzed by histology, immunohistochemistry and quantitative polymerase chain reaction, and splenic tissues by enzyme-linked immunosorbent assays. Invitro studies were performed on human and mouse macrophages, human gastric epithelial cells and mouse splenocytes. ABCC9 expression in human and mouse stomachs is downregulated with H pylori infection. Treatment of Helicobacter-infected mice with SUR2 channel modulators, pinacidil or nicorandil, significantly reduced gastritis severity. In gastric epithelial cells, nicorandil-induced opening of the SUR2 channel increased intracellular K+ and prevented H pylori-mediated Ca2+ influx and downstream pro-inflammatory signaling. SUR2 is a novel host factor that regulates Helicobacter pathogenesis. Pharmacological targeting of SUR2 provides a potential approach for reducing the severity of H pylori-associated gastritis, without eradicating infection.

Terminal substituent-induced differential aggregation and sensing properties: A case study of neutral benzimidazole-based urea receptors

Two neutral benzimidazole-based urea receptors (R1 and R2) with modulation in the terminal substituent have been reported and a comparative study regarding their aggregation as well as sensing potential was performed.

Binding and Transport Properties of a Benzo[b]thiophene‐Based Mono‐(thio)urea Library

AbstractUsing the chemical versatility of the benzo[b]thiophene motif, an extensive library of 24 (thio)urea receptors, with different binding properties and lipophilicities, was prepared and included α,α‐, α,β‐, β,β‐, β,γ‐, α,γ‐, and γ,γ‐benzo[b]thiophene positional isomers, as well as β‐ or γ‐benzo[b]thiophene‐based molecules decorated with aliphatic chains or aryl moieties with different fluorination degrees. 1H NMR titrations, X‐ray crystallographic studies, and DFT calculations were used to study the chloride binding affinities between receptors and substrates. Experimental efflux studies suggested that the anion transmembrane transport activity is dependent on the receptors′ lipophilicity and hydrogen bonding ability. Moreover, LUV based assays indicated that anion efflux occurs mainly through an uniport mechanism. Further MD simulations showed that anion transport is highly dependent on the orientation and interactions of the receptors at the water/lipid interface.

Therapeutic Efficacy of Ficus Glomerata Leaves in Alloxan Monohydrate Induced Type-1 Diabetes in Albino Rats

Present study was aimed to evaluate the anti-diabetic efficacy of Ficus glomerata in Alloxan monohydrate induced albino rats. Oral administration of fresh Ficus glomerataleaves (2 - 4 g/day) for 60 days shows significant blood glucose lowering effect in experimental alloxan induced diabetic rats. These diabetic rats blood glucose level became normal when fed with Ficus glomerata leaves. It is amply revealed that fresh Ficus glomerata indica leaves possessed anti-diabetic properties. The results suggest that statistically significant anti-diabetic potential in alloxan monohydrate induced diabetic rats. The Ficus glomerata leaves to be almost similar effect like insulin treatment in alloxan monohydrate administered animal model. From the present investigation it appeared that Ficus glomerata leaves might have some ingredients to increase the output of insulin by binding to the receptors of the Beta cells of the Langerhans located in the pancreas. Once they bind to the Sulphonyl urea receptors, the K+ -ATP channels are probably closed and therefore the membrane is depolarized and insulin production is stimulated.

Design and Electrochemical Investigation of Ureido-Sulfonamidic Receptors for Phosphates

Anions play an important role in biological systems. At the same time, many of them are the major environmental pollutants and substances endangering living organisms [1]. For these purposes the anion recognition, elimination and sensing would find application in many branches including application in medicine or environmental chemistry. Suitable examples of anion pollutants are phosphates, which could cause eutrophication of water and they are also known for their limited removal from body fluids, which could lead to serious health problems. Therefore, the aim of our research group is the design and preparation of anionic receptors with suitable binding sites to bind these anions.In the first step of our synthesis a series of substituted nosylamidic intermediates (fig. a, b) was prepared. These substances are suitable precursors for the synthesis of novel receptors bearing ureido functions (fig. c). The sulfonamidic motif itself is known as a neutral donor of hydrogen bond. Hence for better understanding of the behaviour of the final urea receptors, the properties of intermediate molecules were studied by various physicochemical techniques including spectroscopic and electrochemical methods.Spectroscopic methods were used to evaluate the binding ability of this motif and to determine its acid-basic properties. Electrochemical methods (represented by polarography and cyclic voltammetry with mercury dropping or hanging electrodes in dimethylformamide with Bu4N PF6 as electrolyte) were chosen because the nitro groups in our intermediate molecules are not only important substituents enabling continuation in synthesis, but also electrochemical "probes" reflecting the properties of the parent molecule. Their reduction in aprotic media is generally known after the first one-electron reversible reduction step where a stable radical anion is formed, a three-electron irreversible process follows resulting in the corresponding hydroxylamine [2]. However, the reduction pattern of the series (b) is totally different: After the first irreversible step (theoretically involving 4/5 of electron) a one-electron reversible reduction takes place followed by a multielectron process. This behaviour can be explained by using autoprotonation mechanism [3] where the acidic hydrogen of the sulfonamidic group is involved.Then our attention focused on final receptors (fig c). It was shown, that sulfonamidic moiety can be utilized as an electron-withdrawing group useful to enhance the anion complexation properties of urea-based receptors. On the other hand, it brings an inherent predisposition for deprotonation in the presence of more basic anions. In order to shift the deprotonation/complexation equilibrium in favour of the complexation, the receptors were derivatized by electron-donating groups like –OCH3 at sulfonamidic moiety. The binding for this receptor was evaluated in a competitive solvent (DMSO) by using NMR titration experiments. The experimental results show a considerable selectivity of our receptor to phosphates compared to another biologically important anions such as Cl-, NO3 - and HSO4 - [4].Based on these results, the prepared receptors appear to be suitable motifs for binding phosphate anions. In order to take advantage of their binding capabilities, these molecules need to be attached to the surface of a suitable molecular carrier. The formation of these functional materials (in our case especially dendrimers) is also associated with the need to design and optimize methods to describe anion binding ability, as well as the possibility to recycle the prepared materials. This was the reason for which it seems to be interesting to consider the presence of an electrochemical “probe” also in the final molecular receptors. The redox transformation of such a probe should fundamentally affect the complexing abilities of the receptor and allow targeted degradation of the complex. Acknowledgements: The work was supported by the grant number 18-12150S and 20-07833S.

Epidermal growth factor alleviates the negative impact of urea on frozen-thawed bovine sperm, but the subsequent developmental competence is compromised

Upon insemination, sperm cells are exposed to components of the female reproductive tract (FRT) fluids, such as urea and epidermal growth factor (EGF). It has been shown that both urea and EGF use EGF receptor signaling and produce reactive oxygen species (ROS) that are required at certain levels for sperm capacitation and acrosome reaction. We therefore hypothesized that during bovine sperm capacitation, a high level of urea and EGF could interfere with sperm function through overproduction of ROS. High-level urea (40 mg/dl urea is equal to 18.8 mg/dl of blood urea nitrogen) significantly increased ROS production and TUNEL-positive sperm (sperm DNA fragmentation, sDF) percentage, but decreased HOS test score, progressive motility, acrosome reaction and capacitation. The EGF reversed the negative effects of urea on all sperm parameters, with the exception of ROS production and DNA fragmentation, which were higher in urea-EGF-incubated sperm than in control-sperm. The developmental competence of oocytes inseminated with urea-EGF-incubated sperm was significantly reduced compared to the control. A close association of ROS production or sDF with 0-pronuclear and sperm non-capacitation rates was found in the network analysis. In conclusion, EGF enhanced urea-reduced sperm motility; however, it failed to reduce urea-increased sperm ROS or sDF levels and to enhance subsequent oocyte competence. The data suggests that any study to improve sperm quality should be followed by a follow-up assessment of the fertilization outcome.

Therapeutic Efficacy of Ficus Glomerata leaves in Alloxan Monohydrate Induced Type-1 Diabetes in Albino Rats

Present study was aimed to evaluate the anti-diabetic efficacy of Ficus glomerata in Alloxan monohydrate induced in the albino rats. Oral administration of fresh Ficus glomerata leaves (2-4 g/day) for 60 days shows significant blood which is glucose lowering effect in experimental alloxan induced diabetic rats. These diabetic rats blood glucose level becamenormal when fed with Ficus glomerata leaves. It is amply revealed that fresh Ficus glomerata indica leaves possessed anti-diabetic properties. The results suggest that statistically significant anti-diabetic potential in alloxan monohydrate induced diabetic rats. The Ficus glomerata leaves to be almost similar effect like insulin treat ment in alloxan monohydrate administered animal model. From the present investigation it appeared that Ficus glomerata leaves might have some ingredients to increase the output of insulin by binding to the receptors of the Beta cells of the Langerhans loca ted in the pancreas. Once they bind to the Sulphonyl urea receptors, the channels are probably closed and therefore the membrane is depolarized and insulin production is stimulated.

Deploying hydrogen bond donor/acceptor on arylethynyl scaffold II: Urea based tripodal ionophores for polymeric membrane nitrate selective electrodes

Along the line for developing ionophores by deploying hydrogen bond donor/acceptor on arylethynyl acaffold, two tripodal urea receptors were used as ionophores for the first time to fabricate polymeric membrane nitrate-selective electrodes. Replacing the hydrogens with fluorine atoms in the arylethynyl core facilitates the selectivity for nitrate over halides, originating from the additional anion–π interactions electron between nitrate and deficient fluorinated core. By optimizing membrane composition such as plasticizers and lipophilic additives, the proposed ISEs showed Nernstian response to nitrate with superior selectivity to both lipophilic ions and halides. Although the formation constants of anions-ionophore complex in membrane phase did not correlate well with the selectivity pattern of the ISEs, these data were consistent with that in solvent such as binary DMSO/CHCl3. The proposed ISEs could work in wide pH range solutions with short response time, good reversibility and reproducibility, which led to the success of determination of nitrate in real mineral water, tap water, as well as river water samples.

Therapeutic Potential of Aegle marmelos (Linn.) Leaves in Alloxan Monohydrate Induced Type-1 Diabetes in Experimental Rats

Present study was aimed to evaluate the anti-diabetic activity of Aegle marmelos in Alloxan monohydrate induced albino rats. Oral administration of fresh Aegle marmelos leaves (2 - 4 g/day) for 28 days shows significant blood glucose lowering effect in experimental alloxan induced diabetic rats. These diabetic rats blood glucose level became normal when fed with Aegle marmelos leaves. It is amply revealed that Aegle marmelos leaves possessed anti-diabetic and beta cells restoration properties. The results suggest that statistically significant anti-diabetic potential in alloxan monohydrate induced diabetic rats. The Aegle marmelos leaves to be almost similar effect like insulin treatment in alloxan monohydrate administered experimental animal model. From the present study it appeared that Aegle marmelos might have some key ingredients to increase the output of insulin by binding to the receptors of the Beta cells of the Langerhans located in the pancreas. Once they bind to the Sulphonyl urea receptors, the K+ -ATP channels are probably closed and therefore the membrane is depolarized and insulin production is stimulated. During the course of study, Aegle marmelos leaves fed experimental animals were normal blood glucose levels compared to insulin treated animals.

Design and synthesis of novel 1-phenyl-3-(5-(pyrimidin-4-ylthio)-1,3,4-thiadiazol- 2-yl)urea derivatives with potent anti-CML activity throughout PI3K/AKT signaling pathway.

In this investigation, a series of 1-phenyl-3-(5-(pyrimidin-4-ylthio)-1,3,4- thiadiazol-2-yl)urea receptor tyrosine kinase inhibitors were synthesized by a simple and efficient structure-based design. Structure-activity relationship (SAR) analysis of these compounds based on cellular assays led to the discovery of a number of compounds that showed potent activity against human chronic myeloid leukemia (CML) cell line K562, but very weak or no cellular toxicity through monitoring the growth kinetics of K562 cell during a period of 72 h using the real-time live-cell imaging. Among these compounds, 1-(5-((6-((3-morpholinopropyl) amino)pyrimidin-4-yl)thio)-1,3,4-thiadiazol-2-yl)-3-(4-(trifluoromethyl)phenyl)urea (7) exhibited the least cellular toxicity and better biological activity in cellular assays (K562, IC50: 0.038 μM). Compound 7 also displayed very good induced-apoptosis effect for human CML cell line K562 and exerted its effect via a significantly reduced protein phosphorylation of PI3K/Akt signal pathway by Human phospho-kinase array analysis. In vitro results indicate that 1-phenyl-3-(5-(pyrimidin-4-ylthio)-1,3,4- thiadiazol-2-yl)urea derivatives are lead molecules for further development as treatment of chronic myeloid leukemia and cancer.

Fixation of atmospheric CO2 and recognition of anions/hydrated anions: Differential binding mode in protonated vs. neutral tripodal urea/thiourea receptors

Tris-(2-aminoethyl) amine (Tren) based tripodal thiourea (L1 and L2) and urea (L3) receptors are reported. L1 efficiently fix atmospheric CO2 as CO32– in presence of the hydroxide ion. Both L1 and L2 encapsulate SO42− anion by forming 2:1 host–guest capsular assemblies through hydrogen-bond activated proton transfer. Both L1 and L2 show strong anion binding in their neutral form through strong non-covalent interactions. On contrary, tris-urea ligand L3 recognizes SiF62− and Br− trapped cyclic/acyclic anion-water network assemblies outside the protonated receptor cavities in presence of corresponding inorganic acids HF and HBr respectively.

Ice-like Cyclic Water Hexamer Trapped within a Halide Encapsulated Hexameric Neutral Receptor Core: First Crystallographic Evidence of a Water Cluster Confined within a Receptor-Anion Capsular Assembly

Over the past few decades, the tren [tris(2-aminoethyl)amine] skeleton has materialized as one of the supreme anion binding building blocks demonstrating a strong interplay among topology, complementarity, cooperativity, and coordination. However, anion recognition by modest tren-based unsubstituted aromatic urea has been underexplored, mainly due to the deficiency of π-acidic or electron-withdrawing aryl terminals. This report establishes an infrequent hexameric neutral receptor-anion-water molecular self-assembly, where a conformationally flexible C3v-symmetric halide (F–/Cl–) encapsulated electron-rich naphthyl group containing N-bridged tripodal urea receptor effectively entraps a chair-shaped ice-like neutral cyclic water hexamer within the hexameric cavity of a neutral receptor-halide host–guest assembly.

Halo-methylphenyl substituted neutral tripodal receptors for cation-assisted encapsulation of anionic guests of varied dimensionality

Two neutral tris([(halo-methylphenyl)amino]ethyl)-urea receptors with asymmetric electronic aryl-functionalization have been developed for encapsulation of anionic guests of variable size.

99mTc-labeled glimepiride as a tracer for targeting pancreatic β-cells mass: preparation and preclinical evaluation

Complexation of glimepiride with 99mTc, factors affecting yield and suitability of the 99mTc-glimepiride as a tracer for pancreatic β-cells mass were investigated. The radiocomplex showed maximum RCP of 98.2% and remained more than 90% stable up to 8 h in saline and serum. the complex structure and its binding to target sulphonyl urea receptor were assessed in silico. The 99mTc-glimepiride showed saturated in vitro binding with islet cells with a maximum uptake of 73%. Biodistribution and imaging studies suggested the feasibility of the tracer as a good candidate for specifically targeting β-cells mass in humans.

Urea and thiourea based anion receptors in solution and on polymer supports

Herein we report the development of a new series of surface bound anion sensors exploiting the urea or thiourea motif capable of binding anions through hydrogen bonding interactions. The use of high resolution magic angle spinning 1H NMR allows the direct comparison of the anion binding properties of these receptors in solution versus those tethered to polymer resins. Some intramolecular hydrogen bonding and solvent effects were observed at the solution:surface interface however in general the anion binding properties of the polymer bound urea and thiourea receptors were maintained.

Crystal structures of the 2:2 complex of 1,1'-(1,2-phenyl-ene)bis-(3-m-tolyl-urea) and tetra-butyl-ammonium chloride or bromide.

The title compounds, tetra-butyl-ammonium chloride-1,1'-(1,2-phenyl-ene)bis-(3-m-tolyl-urea) (1/1), C16H36N+·Cl-·C22H22N4O2 or [(n-Bu4N+·Cl-)(C22H22N4O2)] (I) and tetra-butyl-ammonium bromide-1,1'-(1,2-phenyl-ene)bis-(3-m-tolyl-urea) (1/1), C16H36N+·Br-·C22H22N4O2 or [(n-Bu4N+·Br-)(C22H22N4O2)] (II), both comprise a tetra-butyl-ammonium cation, a halide anion and an ortho-phenyl-ene bis-urea mol-ecule. Each halide ion shows four N-H⋯X (X = Cl or Br) inter-actions with two urea receptor sites of different bis-urea moieties. A crystallographic inversion centre leads to the formation of a 2:2 arrangement of two halide anions and two bis-urea mol-ecules. In the crystals, the dihedral angle between the two urea groups of the bis-urea mol-ecule in (I) [defined by the four N atoms, 165.4 (2)°] is slightly smaller than that in (II) [167.4 (2)°], which is probably due to the smaller ionic radius of chloride compared to bromide.

Anion binding consistency by influence of aromatic meta-disubstitution of a simple urea receptor: regular entrapment of hydrated halide and oxyanion clusters

Consistent recognition of asymmetric divalent sulphate, hydrated chloride and acetate along with fluoride induced bicarbonate within self-assembly of bis-urea receptor is observed.

Hydrogen-Bonded Homoleptic Fluoride-Diarylurea Complexes: Structure, Reactivity, and Coordinating Power.

Hydrogen bonding with fluoride is a key interaction encountered when analyzing the mode of action of 5'-fluoro-5'-deoxyadenosine synthase, the only known enzyme capable of catalyzing the formation of a C-F bond from F-. Further understanding of the effect of hydrogen bonding on the structure and reactivity of complexed fluoride is therefore important for catalysis and numerous other applications, such as anion supramolecular chemistry. Herein we disclose a detailed study examining the structure of 18 novel urea-fluoride complexes in the solid state, by X-ray and neutron diffraction, and in solution phase and explore the reactivity of these complexes as a fluoride source in SN2 chemistry. Experimental data show that the structure, coordination strength, and reactivity of the urea-fluoride complexes are tunable by modifying substituents on the urea receptor. Hammett analysis of aryl groups on the urea indicates that fluoride binding is dependent on σp and σm parameters with stronger binding being observed for electron-deficient urea ligands. For the first time, defined urea-fluoride complexes are used as fluoride-binding reagents for the nucleophilic substitution of a model alkyl bromide. The reaction is slower in comparison with known alcohol-fluoride complexes, but SN2 is largely favored over E2, at a ratio surpassing all hydrogen-bonded complexes documented in the literature for the model alkyl bromide employed. Increased second-order rate constants at higher dilution support the hypothesis that the reactive species is a 1:1 urea-fluoride complex of type [UF]- (U = urea) resulting from partial dissociation of the parent compound [U2F]-. The dissociation processes can be quantified through a combination of UV and NMR assays, including DOSY and HOESY analyses that illuminate the complexation state and H-bonding in solution.