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Reversible protein phosphorylation on serine, threonine, and tyrosine residues is essential for fast, specific, and accurate signal transduction in cells. Up to now, the identification and quantification of phosphorylated amino acids, peptides, and proteins continue to be one of the significant challenges in contemporary bioanalytical research. In this paper, a series of surface grafted monoliths in the capillary format targeting phosphorylated serine has been prepared by first synthesizing a monolithic core substrate material based on trimethylolpropane trimethacrylate, onto which a thin surface-imprinted layer was established by oriented photografting of a variety of mono- and bis- imidazolium host monomers at subzero temperature, using six different continuous or pulsed UV light sources. The imprinted monolith capillaries were evaluated in a capillary liquid chromatographic system connected to a mass spectrometer in order to test the specific retention of phosphorylated peptides. Site-specific recognition selectivity and specificity for phosphorylated serine was demonstrated when separating amino acids and peptides, proving that the optimized materials could be used as novel trapping media in affinity-based phosphoproteomic analysis.

Ionic liquids (ILs) are ionic compounds with low melting points that can be designed to be used in an extensive set of commercial and industrial applications. However, the design of ILs is limited by the quantity and quality of the available data in the literature; therefore, the estimation of physicochemical properties of ILs by computational methods is a promising way of solving this problem, since it provides approximations of the real values, resulting in savings in both time and money. We studied two data sets of 281 and 134 liquids based on the molecule imidazole that were analyzed with QSPR techniques. This paper presents a software architecture that uses clustering techniques to improve the robustness of estimation models of the melting point of ILs. These results indicate an error of 6.25% in the previously unmodeled data set and an error of 4.43% in the second data set. We have an improvement with the second data set of 1.81% over the last results previously found.

An efficient large-scale synthesis of acid 1, a penultimate precursor to the HCV NS5A inhibitor BMS-986097, along with the final API step are described. Three routes were devised for the synthesis of 1 at the various stages of the program. The third generation route, the one that proved scalable and is the main subject of this paper, features a one-step Michael addition of t-butyl 2-((diphenylmethylene)amino)acetate (24) to (E)-benzyl 4-(1-hydroxycyclopropyl)but-2-enoate (28) followed by cyclization and chiral separation to form 27c, the core skeleton of cap piece 1. The epimerization and chiral resolution of 27c followed by further synthetic manipulations involving the carbamate formation, lactone reduction and cyclization, afforded cyclopropyl pyran 1. A detailed study of diphenylmethane deprotection via acid hydrolysis as well as a key lactone to tetrahydropyran conversion, in order to avoid a side reaction that afforded an alternative cyclization product, are discussed. This synthesis was applied to the preparation of more than 100 g of the final API BMS-986097 for toxicology studies.

This paper describes the design and synthesis of a conjugate (Q7R) comprising the synthetic host cucurbit[7]uril (Q7) linked to the fluorescent dye tetramethylrhodamine (TMR), and the characterization of its optical and guest-binding properties as well as its cellular uptake. Q7R was synthesized in two steps from monofunctionalized azidobutyl-Q7 and NHS-activated TMR. The fluorescence of Q7R is quenched upon guest binding, and this observable was used to determine equilibrium dissociation constant (K d ) values. Unexpectedly, the K d values for guests binding to Q7R and to unmodified Q7 were essentially identical. Therefore, Q7R can directly report binding to Q7 without an energetic penalty due to the conjugated fluorophore. This result demonstrates a potentially general strategy for the design of single-component host-indicator conjugates that respond sensitively to analytes without perturbing the binding properties of the host. The unique properties of Q7R enabled measurement of K d values across 3 orders of magnitude and at concentrations as low as 0.7 nM. This result is particularly relevant given the unmatched range of guests and binding affinities demonstrated for Q7. Confocal fluorescence microscopy of live and fixed HT22 neurons revealed the cellular uptake of Q7R and its punctate localization in the cytoplasm. Q7R did not alter cell growth at concentrations up to 2.2 μM over 4 days. These experiments demonstrate the feasibility of Q7R as a direct sensor for guest binding and as a cell-permeable compound for imaging applications.

The work in this paper describes the optimization of the 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine chemical series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (21a). The cocrystal structure of compound 21a bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chemical class and the role of the cyclobutylamine moiety. Compound 21a demonstrated high enzymatic potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compound 21a also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma.

During the manufacturing of pharmaceutical compounds, solvent mixtures are commonly used, where the addition of a cosolvent allows for the tuning of the intermolecular interactions present in the system. Here we demonstrate how a similar effect can be accomplished using a room temperature ionic liquid. The pharmaceutical compound acetaminophen is studied in 21 common ionic liquids composed of a 1-n-alkyl-3-methylimidazolium cation with 1 of 7 anions. Using the acetate anion, we predict a large enhancement in solubility of acetaminophen relative to water. We show how this is caused by a synergistic effect of favorable interactions between the ionic liquid and the phenyl, hydroxyl and amide groups of acetaminophen, demonstrating how the ionic liquid cation and anion may be chosen to preferentially solvate different functional groups of complex pharmaceutical compounds. Additionally, while the use of charge scaling in ionic liquid force fields has previously been found to have a minute effect on ionic liquid structural properties, we find it appreciably affects the computed solvation free energy of acetaminophen, which in turn affects the predicted solubility.

The effect of glucosamine analogues (glucosamine and acetylglucosamine) and free ammonium on the formation of 4-methylimidazole (4-MeI) was investigated in the caramel model reaction systems. Methylglyoxal (MGO) was detected after derivatization by high-performance liquid chromatography with a diode array detector (HPLC-DAD). 4-MeI in the Maillard reaction was tested using a high-performance cation exchange chromatography coupled with APCI-MS (HPCEC-MS). The levels of pyrazines tested by gas chromatography (GC) coupled with MS were applied to mark the condensation reaction between dicarbonyls and free ammonium. Results showed that the formation of 4-MeI and its precursor MGO was inhibited in glucosamine analogue model reaction systems. Besides, the results from pyrazines and brown intensity in glucosamine analogues model reaction systems indicated that glucosamine analogues mainly underwent the reaction of intra-intermolecular polymerization into melanoidins rather than the degradation reaction into MGO. Using glucosamine analogues to produce the caramel color with a low level of 4-MeI was applicable.

In this paper, palladium-catalyzed oxidative cycloaromatization of 2-phenylimidazo[1,2-a]pyridine (PIP) with internal alkyne is studied. From this reaction, two classes of fused N-heterocycle, naphtho[1',2':4,5]imidazo[1,2-a]pyridine (NIP) and imidazo[5,1,2-cd]indolizine (IID), were formed through dehydrogenative coupling featured with cleavage of the C-H bonds located on different moiety of the PIP substrates. Moreover, when 5-methyl-2-phenylimidazo [1,2-a]pyridine or 2-mesitylimidazo[1,2-a]pyridine was used, either NIP or IID could be obtained as an exclusive product with good efficiency. Intriguingly, Pd(II) showed different action mode in promoting this reaction compared with Rh(III) and led to the formation of NIP with reversed regio-selectivity for the reaction of asymmetrical alkyne.

This paper describes the molecular recognition of the tripeptide Tyr-Leu-Ala by the synthetic receptor cucurbit[8]uril (Q8) in aqueous buffer with nanomolar affinity and exceptional specificity. This combination of characteristics, which also applies to antibodies, is desirable for applications in biochemistry and biotechnology but has eluded supramolecular chemists for decades. Building on prior knowledge that Q8 binds to peptides with N-terminal aromatic residues, a library screen of 105 peptides was designed to test the effects of residues adjacent to N-terminal Trp, Phe, or Tyr. The screen used tetramethylbenzobis(imidazolium) (MBBI) as a fluorescent indicator and resulted in the unexpected discovery that MBBI can serve not only as a turn-off sensor via the simultaneous inclusion of a Trp residue but also as a turn-on sensor via the competitive displacement of MBBI upon binding of Phe- or Tyr-terminated peptides. The unusual fluorescence response of the Tyr series prompted further investigation by (1)H NMR spectroscopy, electrospray ionization mass spectrometry, and isothermal titration calorimetry. From these studies, a novel binding motif was discovered in which only 1 equiv of peptide binds to Q8, and the side chains of both the N-terminal Tyr residue and its immediate neighbor bind within the Q8 cavity. For the peptide Tyr-Leu-Ala, the equilibrium dissociation constant value is 7.2 nM, whereas that of its sequence isomer Tyr-Ala-Leu is 34 μM. The high stability, recyclability, and low cost of Q8 combined with the straightforward incorporation of Tyr-Leu-Ala into recombinant proteins should make this system attractive for the development of biological applications.

This paper reports the effects of synthesis time, temperature, and reactant ratio on ZIF-71 particle size and the effect of particle size on membrane performance. Temperature has the greatest effect on particle size, as the synthesis temperature varies from -20 °C to 35 °C. The synthesized ZIF-71 has particle diameters ranging from 150 nm to 1 µm. ZIF-71 particle size is critical in ZIF-71/PDMS composite membrane performance for ethanol and 1-butanol removal from water through pervaporation. The membranes that are made with micrometer-sized ZIF-71 particles exhibit higher alcohol/water selectivity than those with smaller particles. Both alcohol and water permeability increase when larger-sized ZIF-71 particles are incorporated, because the pathways through the membranes are less tortuous. [ABSTRACT FROM AUTHOR]

We demonstrate a controllable doping technique of few-layer black phosphorus (BP) via surface charge transfer using an ionic liquid mixture of EMIM(C6H11N2+):TFSI(C2F6NO4S2-) [EMIM:TFSI, 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl) imide]. A wide range of hole carrier densities, from 1011 cm-2 (nondegenerate) to 1013 cm-2 (degenerate), can be obtained by controlling the weight percentage of the ionic liquid mixture. The doping method we proposed in this paper can be applied to make a multifunctional homogeneous lateral p-n junction device. By doping a fraction of the BP sample and by applying a gate voltage to the other fraction of the BP, we obtain homogeneous lateral p+-p, p+-n, p+-n+ junction diodes in a single BP channel. The homogeneous lateral BP p+-p and p+-n junctions display ideal rectifying behavior and a much stronger photoresponse due to the built-in potential. Furthermore, at high positive gate voltages, the interband tunneling enables the homogeneous lateral p+-n+ junction transistors to provide both a negative differential resistance (NDR) and a negative transconductance (NTC) in the current-voltage characteristics at room temperature. On the basis of our results, it is possible to build novel devices utilizing the large NDR and NTC in BP such as amplifiers, oscillators, and multivalued logic systems. [ABSTRACT FROM AUTHOR]

This paper presents the computational assessment of the electrochemical stability of a series of alkyl methylimidazolium-based ionic liquids for their use as lithium battery electrolytes. The oxidation and reduction potentials of the constituent cation and anion of each ionic liquid with respect to a Li+/Li reference electrode were calculated using density functional theory following the method of thermodynamic cycles, and the electrochemical stability windows (ESW)s of these ionic liquids were obtained. The effect of varying the length of alkyl side chains of the methylimidazolium-based cations on the redox potentials and ESWs was investigated. The results show that the limits of the ESWs of these methylimidazolium-based ionic liquids are defined by the oxidation potential of the anions and the reduction potential of alkyl-methylimidazolium cations. Moreover, ionic liquids with [PF6]- anion have a wider ESW. In addition to characterizing structure-function relationships, the accuracy of the computational approach was assessed through comparisons of the data against experimental measurements of ESWs. The potentials calculated by the thermodynamic cycle method are in good agreement with the experimental data while the HOMO/LUMO method overestimates the redox potentials. This work demonstrates that these approaches can provide guidance in selecting ionic liquid electrolytes when designing high-voltage rechargeable batteries. [ABSTRACT FROM AUTHOR]

Description of the local microscopic structure in ionic liquids (ILs) is a prerequisite to obtain a comprehensive understanding of the influence of the nature of ions on the properties of ILs. The local structure is mainly determined by the spatial arrangement of the nearest neighboring ions. Therefore, the main interaction patterns in ILs, such as cation-anion H-bond-like motifs, cation-cation alkyl tail aggregation, and ring stacking, were considered within the framework of the nearest-neighbor approach with respect to each particular interaction site. We employed classical molecular dynamics (MD) simulations to study in detail the spatial, radial, and orientational relative distribution of ions in a set of imidazolium-based ILs, in which the 1-butyl-3-methylimidazolium (C4mim+) cation is coupled with the acetate (OAc-), chloride (Cl-), tetrafluoroborate (BF4 -), hexafluorophosphate (PF6 -), trifluoromethanesulfonate (TfO-), or bis(trifluoromethanesulfonyl)amide (TFSA-) anion. It was established that several structural properties are strongly anion-specific, while some can be treated as universally applicable to ILs, regardless of the nature of the anion. Namely, strongly basic anions, such as OAc- and Cl-, prefer to be located in the imidazolium ring plane next to the C-H2/4-5 sites. By contrast, the other four bulky and weakly coordinating anions tend to occupy positions above/below the plane. Similarly, the H-bond-like interactions involving the H² site are found to be particularly enhanced in comparison with the ones at H4-5 in the case of asymmetric and/or more basic anions (C4mimOAc, C4mimCl, C4mimTfO, and C4mimTFSA), in accordance with recent spectroscopic and theoretical findings. Other IL-specific details related to the multiple H-bond-like binding and cation stacking issues are also discussed in this paper. The secondary H-bonding of anions with the alkyl hydrogen atoms of cations as well as the cation-cation alkyl chain aggregation turned out to be poorly sensitive to the nature of the anion. [ABSTRACT FROM AUTHOR]

This paper reports the thermodynamicinhibition effect of sevenionic liquids (ILs) on methane hydrate formation. The isochoric multistepheating dissociation pressure search method is applied for experimentallydetermining the phase boundary between hydrate–liquid–vapor(H–L–V) phases and liquid–vapor (L–V)phases in the pressure and temperature ranges of 3.45–13.28MPa and 274.3–287.6 K, respectively. All the studied IL aqueoussolutions are used at a mass fraction of 0.1. A comparison of thethermodynamic inhibitory performance of various ILs is carried outand reveals the predominant role of the type of anion of ILs. Consideringthe difficulty in directly measuring the dissociation enthalpies,the values of ΔHof methane hydrate are alsocalculated using the Clausius–Clapeyron equation. It is foundthat the mean dissociation enthalpies of methane hydrate in the presenceof the seven ILs vary from 59.05 to 60.81 kJ·mol–1, and are very close to that in pure water. [ABSTRACT FROM AUTHOR]

A methacrylate-basedpolyampholyte homopolymer was synthesizedstarting from N-methacryloyl-l-histidine(MHist). This paper reports the inhibitory effects ofpoly-N-methacryloyl-l-histidine (poly-MHist) on the in vitrosilicic acid condensation. Inparticular, the ability of poly-MHistto retard silicicacid condensation in aqueous supersaturated solutions at three pHvalues, 5.5, 7.0, and 8.5, is studied. The direct role of the imidazolering was confirmed by substantial changes in silicic acid stabilizationefficiency based on the following observations: (a) the protonationdegree of the imidazole ring affects stabilization. At a relativelylow pH of 5.5, the imidazole is protonated and the entire polymeracquires a zwitterionic character (−COO–isalso present). Inhibitory activity increases considerably. In contrast,at a high pH of 8.5, the imidazole ring is neutral and the polymerbackbone is anionic due to the presence of −COO–moieties. This results in total inactivity with respect to silicicacid stabilization. (b) The use of a similar, but pH-insensitive derivativepoly(N-acryloyl-l-phenylalanine) (poly-PHE), which contains a phenylalanine instead of histidine,results in total loss of silicic acid stabilization activity. Finally, poly-MHistalso shows effects on colloidal silica particlemorphology. Increasing the poly-MHistconcentration resultsin a reduced size of silica particles. [ABSTRACT FROM AUTHOR]

This paper presents the physicochemical properties of micellar aggregates formed from a series of zwitterionic surfactants of the type 3-(1-alkyl-3-imidazolio)propane-sulfonate (ImS3-n), with n = 10, 12, 14, and 16. The ImS3-n dipolar ionic surfactants represent a versatile class of dipolar ionic compounds, which form normal and reverse micelles. Furthermore, they are able to stabilize nanoparticles in water and in organic media. Aqueous solubility is too low at room temperature to allow characterization of micellar aggregates but increases with addition of salts, allowing determination of aggregation number and cmc. As expected, these parameters depend on the length of the alkyl chain, and cmc values follow Klevens equation. In the presence of NaClO4, all ImS3-n micelles become anionoid by incorporating ClO4- on the micellar interface. A special feature of these surfactants is the ability to form reverse micelles and solubilize copious amounts of saline solutions in chloroform. ¹H NMR and infrared spectroscopic evidence showed that the maximum water to surfactant molar ratio w0 achievable depends on the concentration and type of salt dissolved. Reverse micelles of the ImS3-n surfactants can be used to stabilize metallic nanoparticles, whose size may be tuned by the amount of water dissolved. [ABSTRACT FROM AUTHOR]

A practicaldeoxyfluorination with novel deoxyfluorinating reagentPhenoFluorMix, a mixture of N,N′-1,3-bis(2,6-diisopropylphenyl)chloroimidazoliumchloride and CsF, is presented. PhenoFluorMix overcomes the challengesassociated with hydrolysis of PhenoFluor. PhenoFluorMix does not hydrolyze,is readily available on decagram scale, and is storable in air. Inthis paper, we demonstrate the practicality of the reagent and exhibitthe deoxyfluorination of a variety of phenols and heterocycles. [ABSTRACT FROM AUTHOR]

Inthis paper we prepare three “neat” supported membranes,ZIF-8, ZIF-90, and Matrimid 5218, on porous alumina disks and comparetheir permeation behaviors in the separation of H2/CO2with the corresponding zeolitic imidazolate framework (ZIF)/Matrimidmixed matrix membranes (MMMs). These MMMs consist of ZIF-8 and ZIF-90nanoparticles which are embedded in Matrimid. We found that the embeddingof the nanoparticles modifies the separation performance of the Matrimid5218 membrane for separating H2from CO2. TEMand SEM images of the ZIF-8 and ZIF-90/Matrimid MMMs show that theZIFs are well embedded into the polymer. Thus, the separation behaviorof these MMMs can be described with the Maxwell model. However, betterseparation results could be obtained by binding ZIF-90 particles covalentlywith ethylenediamine to the Matrimid matrix. In comparison to theMMMs that contain nonbound ZIFs, the covalent amine binding betweenthe ZIF-90 particles and the Matrimid matrix leads to slightly lowerpermeabilities but a much higher H2/CO2separationfactor. [ABSTRACT FROM AUTHOR]

In this paper, we present the resultsfrom molecular dynamics simulationsof the equilibrium properties of liquid/liquid interfaces of roomtemperature ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate([bmim][PF6]) and simple alcohols (i.e., methanol, 1-butanol,and 1-hexanol) at room temperature. Polarizable potential models areemployed to describe the interactions among species. Results fromour simulations show stable interfaces between the ionic liquid and n-alcohols, and we found that the interfacial widths decreasefrom methanol to 1-butanol systems and then increase for 1-hexanolinterfaces. Angular distribution analysis reveals that the interfaceinduces a strong orientational order of [bmim] and n-alcohol molecules near the interface, with [bmim] extending itsbutyl group into the alcohol phase, whereas the alcohol has the OHgroup pointing into the ionic liquid region, which is consistent withthe recent sum-frequency-generation experiments. We found the interfaceto have a significant influence on the dynamics of ionic liquids and n-alcohols. The orientational autocorrelation functionsillustrate that [bmim] rotates more freely near the interface thanin the bulk, whereas the rotation of n-alcohol ishindered at the interface. Additionally, the time scale associatedwith the diffusion along the interfacial direction is found to befaster for [bmim] but slowed down for n-alcoholsapproaching the interface. We also calculate the dipole moment of n-alcohols as a function of the distance normal to the interface.We found that, even though methanol and 1-butanol have different dipolemoments in bulk phase, they reach a similar value at the interface. [ABSTRACT FROM AUTHOR]