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Realizing combination drugs at a molecular level via drug-drug cocrystallization opens a new pathway for effective therapeutic hybrids. A "drug-bridge-drug" strategy is developed to cocrystallize two first-line antitubercular drugs isoniazid and pyrazinamide using fumaric acid as the bridge, overcoming the issue of hardly cocrystallizing two different drugs. The first example of ternary cocrystal with combination drugs exhibits optimized formulation capacity and in vitro/vivo synergistic effects, which provides a new insight into antituberculosis combination drugs. [ABSTRACT FROM AUTHOR]

We have investigated the gas-phase production of isoquinoline by performing collisional activation on benzalaminoacetal, the first intermediate in the classic solution-phase Pomeranz--Fritsch synthesis of isoquinoline. We have elucidated the reaction pathways in the gas phase using tandem mass spectrometry. Unlike the corresponding condensed-phase reaction, where catalytic proton exchange between intermediate(s) and solvent (Brønsted--Lowry base) is known to drive the reaction, the gas-phase reaction follows the "mobile proton model" to form the products via a number of intermediates, some the same as in their condensed-phase counterparts. Energy-resolved mass spectrometry, deuterium labeling experiments, and theoretical calculations (B3LYP/6-31G**) identified 27 different reaction routes in the gas phase, forming a complex interlinked reaction network. The experimental measurements and theoretical calculations confirm the proton hopping onto different basic sites of the precursors and intermediates to transform them ultimately into isoquinoline. [ABSTRACT FROM AUTHOR]

Conspectus: Bioorthogonal chemistry has had a major impact on the study of biological processes in vivo. Biomolecules of interest can be tracked by using probes and reporters that do not react with cellular components and do not interfere with metabolic processes in living cells. Much time and effort has been devoted to the screening of potential bioorthogonal reagents experimentally. This Account describes how our groups have performed computational screening of reactivity and mutual orthogonality. Our collaborations with experimentalists have led to the development of new and useful reactions. Dozens of bioorthogonal cycloadditions have been reported in the literature in the past few years, but as interest in tracking multiple targets arises, our computational screening has gained importance for the discovery of new mutually orthogonal bioorthogonal cycloaddition pairs. The reactivities of strained alkenes and alkynes with common 1,3-dipoles such as azides, along with mesoionic sydnones and other novel 1,3-dipoles, have been explored. Studies of "inverse-electron-demand" dienes such as triazines and tetrazines that have been used in bioorthogonal Diels-Alder cycloadditions are described. The color graphics we have developed give a snapshot of whether reactions are fast enough for cellular applications (green), adequately reactive for labeling (yellow), or only useful for synthesis or do not occur at all (red). The colors of each box give an instant view of rates, while bar graphs provide an analysis of the factors that control reactivity. This analysis uses the distortion/interaction or activation strain model of cycloaddition reactivity developed independently by our group and that of F. Matthias Bickelhaupt in The Netherlands. The model analyzes activation barriers in terms of the energy required to distort the reactants to the transition state geometry. This energy, called the distortion energy or activation strain, constitutes the major component of the activation energy. The strong bonding interaction between the termini of the two reactants, which we call the interaction energy, overcomes the distortion energy and leads to the new bonds in the products. This Account describes how we have analyzed and predicted bioorthogonal cycloaddition reactivity using the distortion/interaction model and how our experimental collaborators have employed these insights to create new bioorthogonal cycloadditions. The graphics we use document and predict which combinations of cycloadditions will be useful in bioorthogonal chemistry and which pairs of reactions are mutually orthogonal. For example, the fast reaction of 5-phenyl-1,2,4-triazine and a thiacycloheptyne will not interfere with the other fast reaction of 3,6-diphenyl-1,2,4,5-tetrazine and a cyclopropene. No cross reactions will occur, as these are very slow reactions. [ABSTRACT FROM AUTHOR]

Computational chemistry and biochemistry began with Isaac Newton's classical mechanics in the 17th century and the establishment of quantum mechanics in the 1920s. Enabled by extraordinary advances in computers, in the last half century, this field has become a robust partner with experiment. The challenges facing computational chemists and biochemists, the Holy Grails of the field, are described. These include the development of a highly accurate density functional, ideally one that has universal chemical accuracy, and accurate polarizable force fields, as well as methods to handle efficiently the massive number of computations that must be performed for molecular dynamics and for the computation of flexible systems such as proteins. We estimate when the breakthroughs that will make computation a powerful engine for chemical discovery and design will be achieved. The Holy Grails of this field involve methods to enable the accurate and efficient prediction of structures and properties of complex biological systems and materials. The principal Holy Grail is a routine computational method for the prediction and design of multicomponent, often heterogeneous, functional systems and devices. [ABSTRACT FROM AUTHOR]

A copper-catalyzed protocol for reductive methylation of amines and imine with formic acid as a C1 source and phenylsilane as a reductant is reported for the first time, affording the corresponding methylamines in good to excellent yields under mild conditions. This protocol offers an alternative method for indirect utilization of CO2, as formic acid can be readily obtained from hydrogenation of CO2. [ABSTRACT FROM AUTHOR]

We computationally study the chiral transition process of the α-Ala molecule under confined different sizes of armchair SWBNNTs to explore the confinement effect. We find that the influence of a confinement environment (in armchair SWBNNTs) on the α-Ala molecule would lead to different reaction pathways. Meanwhile, the preferred reaction pathway is also different in various sizes of armchair SWBNNTs, and their energy barriers for the rate-limiting step decrease rapidly with the decreasing of the diameters of the nanotubes. It is obvious that significant decrease of the chiral transition energy barrier occurs compared with the isolated α-Ala molecule chirality conversion mechanism, by ∼15.6 kcal mol-1, highlighting the improvement in the activity the enantiomers of α-Ala molecule. We concluded that the confinement environment has a significant impact at the nanoscale on the enantiomer transformation process of the chiral molecule. [ABSTRACT FROM AUTHOR]

Asphaltenes are a solubility class of crude oils comprising polyaromatic and heterocyclic molecules with different interfacial activities. The previously neglected effects of compositional mixture on dilatational rheology are discussed in the light of diffusional relaxation models. It is demonstrated that the reported deviations from the Lucassen-van den Tempel model for a single-component solution could largely originate from a distribution in adsorption coefficients within the asphaltenes class. This particularly applies to the peculiar gel point rheology previously ascribed to asphaltenes cross-linking at the interface. Furthermore, an extensive bibliographical review shows that asphaltenes dilatational rheology data always verify the main features of diffusional relaxation, including a decrease in modulus at high bulk concentrations and phase shift values always lower than 45°. Using diffusional relaxation concepts, the reanalysis of the most extensive dataset so far confirmed recently published studies, showing that asphaltenes exhibit a unique equation of state (EOS) irrespective of adsorption conditions. This EOS proves to be very similar for bitumen and petroleum asphaltenes. Finally, a numerical application of a binary diffusional model proved efficient to capture both dynamic interfacial tension and dilatational rheology, with the same parameters. It appears that a minority of asphaltenes (less than 10%) have a much stronger interfacial activity than the bulk of them, as previously demonstrated by fractionation. These results open up the need for a reinterpretation of the physical mechanisms of asphaltenes adsorption in terms of classical amphiphilic behavior, with a potential impact on emulsion breaking and enhanced oil recovery strategies. [ABSTRACT FROM AUTHOR]

Hydroxyacetone (CH3C(O)CH2OH) is observed as a stable end product from reactions of the (CH3)2COO Criegee intermediate, acetone oxide, in a flow tube coupled with multiplexed photoionization mass spectrometer detection. In the experiment, the isomers at m/z = 74 are distinguished by their different photoionization spectra and reaction times. Hydroxyacetone is observed as a persistent signal at longer reaction times at a higher photoionization threshold of ca. 9.7 eV than Criegee intermediate and definitively identified by comparison with the known photoionization spectrum. Complementary electronic structure calculations reveal multiple possible reaction pathways for hydroxyacetone formation, including unimolecular isomerization via hydrogen atom transfer and -OH group migration as well as self-reaction of Criegee intermediates. Varying the concentration of Criegee intermediates suggests contributions from both unimolecular and self-reaction pathways to hydroxyacetone. The hydroxyacetone end product can provide an effective, stable marker for the production of transient Criegee intermediates in future studies of alkene ozonolysis. [ABSTRACT FROM AUTHOR]

Construction of facile ratiometric fluorescent probes which possess sensitive and selective sensing ability for bioactive small molecules is highly desirable and challenging. Herein, silver nanoclusters capped with denatured lysozyme (dLys-AgNCs) were synthesized and proved to be dual emissive. The facility of the dLys-AgNCs ratiometric probe was attributed to the finding that the lysozyme acted not only as stabilizing ligand but also as fluorescence signal unit In the presence of Fenton reagents, the emission of dLys-AgNCs at 640 nm was quenched by ●OH, whereas the emission at 450 was enhanced due to ●OH-induced oxidation of tyrosine in the lysozyme. This probe could be used for highly sensitive detection of H2O2. The fluorescence changes of F450/F640 had fantastic linearity to H2O2 concentrations in the range of 0.8--200 μmol/L (R² = 0.9993), with a limit of detection (LOD) as low as 0.2 μmol/L. Additionally, this probe was also applied to H2O2-generated oxidase-based biosensing. As a proof-of-concept, glucose and acetylcholine chloride were detected with benefical LOD values of 0.6 μmol/L and 0.8 μmol/L, respectively. Furthermore, fluorescence confocal imaging demonstrated dLys-AgNCs had a sensitive response to fluctuation of ●OH levels in living cells, which might have promising application in study of ●OH-induced oxidative damage to proteins. [ABSTRACT FROM AUTHOR]

Nature synthesizes many strained natural products that have diverse biological activities. Uncovering these biosynthetic pathways may lead to biomimetic strategies for organic synthesis of such compounds. In this work, we elucidated the concise biosynthetic pathway of herquline A, a highly strained and reduced fungal piperazine alkaloid. The pathway builds on a nonribosomal peptide synthetase derived dityrosine piperazine intermediate. Following enzymatic reduction of the P450-cross-linked dicyclohexadienone, N-methylation of the piperazine serves as a trigger that leads to a cascade of stereoselective and nonenzymatic transformations. Computational analysis of key steps in the pathway rationalizes the observed reactivities. [ABSTRACT FROM AUTHOR]

A three-armed star-shaped single-polymer system comprising tris(4-(3-hexyl-5-(7-(4-hexylthiophen-2-yl)benzoc][1,2,5]thiadiazol-4-yl)thiophen-2-yl)phenyl)amine (TN) as red emissive cores, benzothiadiazole (BT) as green emissive dopants, and polyfluorene (PF) as blue arms was successfully developed, in which the construction of the star-shaped architectures can depress intermolecular interactions and concentration quenching. The thermal, photophysical, electrochemical, electroluminescent, and amplified spontaneous emission (ASE) properties of the synthesized polymers are systematically investigated. The modulation of the doping concentration of TN and BT can guarantee the partial energy transfer in a star-shaped single-polymer system, further achieving saturated white emission. Consequently, a current efficiency of 2.41 cd A-1 and Commission Internationale d'Eclairage (CIE) coordinates of (0.34, 0.35) were recorded for TN-R3G4 with 0.03 mol % red core and 0.04 mol % green dopants. The saturated white emission is likely to result from the fine control of partial energy transfer and suppressed intermolecular interactions due to the construction of such a star-shaped single-polymer system. What is more, TN-R3G4 shows impressive ASE characteristics with relatively low threshold of 63 ± 5 μJ/cm2, which demonstrates the potential as gain media for organic lasing applications. Our results have provided new insights and better understanding into the photophysical and optoelectronic behaviors of the resulting star-shaped single-polymer systems with simultaneous RGB emission. [ABSTRACT FROM AUTHOR]

Four limonoids, cipacinoids A-D (1-4), with spirocyclic skeletons were isolated from Cipadessa cinerascens. It is particularly notable that compounds 1-3 had a 17S-configuration for the first time in the limonoid family. Their structures with absolute configurations were assigned by spectroscopic data, X-ray crystallography, and CD analysis. Compound 1 showed moderate protein tyrosine phosphatase 1B (PTP1B) inhibition. [ABSTRACT FROM AUTHOR]

Novel c-6 position oxidized corn starch (OST) with high carboxyl content (26.3-54.5%) was prepared by a green method, using hydrogen peroxide as the oxidant. The as-obtained OSTs were then used as flame-retardant carbon sources with microencapsulated ammonium polyphosphate (MFAPP) in epoxy resin (EP). Compared to EP, the obtained EP/MFAPP/OST composites exhibit significantly enhanced flame retardancy. The introduction of only 6.25 wt % OSTs and 6.25 wt % MFAPP results in remarkably increased limiting oxygen index and decreased heat release rate, and all composites can reach UL94 V-0 rating. Thermogravimetric analyses and cone calorimetry results suggest both OSTs and MFAPP have good catalytic charring effects, and the increased carboxyl content benefits the char formation of the composites. Because of the formation of compact char on the sample surface during combustion, the transfer of oxygen, heat, and flammable gas products is inhibited; the flame retardancy of EP/MFAPP/OST composites is thus remarkably enhanced. [ABSTRACT FROM AUTHOR]

Thecellular recognition and processing of monofunctional–intercalativeDNA adducts formed by [PtCl(en)(L)](NO3)2(P1-A1; en = ethane-1,2-diamine; L = N-[2-(acridin-9-ylamino)ethyl]-N-methylpropionamidine, acridinium cation), a cytotoxichybrid agent with potent anticancer activity, was studied. Excisionof these adducts and subsequent DNA repair synthesis were monitoredin plasmids modified with platinum using incubations with mammaliancell-free extract. On the basis of the levels of [α-32P]-dCTP incorporation, P1-A1–DNA adducts wererapidly repaired with a rate approximately 8 times faster (t1/2≈ 18 min at 30 °C) than theadducts (cross-links) formed by the drug cisplatin. Cellular responsesto P1-A1and cisplatin were also studied in NCI-H460lung cancer cells using immunocytochemistry in conjunction with confocalfluorescence microscopy. At the same dose, P1-A1, butnot cisplatin, elicited a distinct requirement for DNA double-strandbreak repair and stalled replication fork repair, which caused nuclearfluorescent staining related to high levels of MUS81, a specializedrepair endonuclease, and phosphorylated histone protein γ-H2AX.The results confirm previous observations in yeast-based chemicalgenomics assays. γ-H2AX fluorescence is observed as a largenumber of discrete foci signaling DNA double-strand breaks, pan-nuclearpreapoptotic staining, and unique circularly shaped staining aroundthe nucleoli and nuclear rim. DNA cleavage assays indicate that P1-A1does not act as a typical topoisomerase poison, suggestingthe high level of DNA double-strand breaks in cells is more likelya result of topoisomerase-independent replication fork collapse. Overall,the cellular response to platinum–acridines shares strikingsimilarities with that reported for DNA adduct-forming derivativesof the drug doxorubicin. The results of this study are discussed inlight of the cellular mechanism of action of platinum–acridinesand their ability to overcome resistance to cisplatin. [ABSTRACT FROM AUTHOR]

A novelseries of donor–acceptor star-shaped conjugatedmacroelectrolytes (CMEs), denoted as 4FTs, including anionic carboxylicacid sodium groups (4FNaT), neutral diethanolamine groups (4FNOHT),and cationic ammonium groups (4FNBrT), were designed, synthesized,and explored as an excellent platform to investigate the impact ofvarious polar pendent groups on self-assembly behaviors. The resultingCMEs with donor–acceptor star-shaped architectures exhibiteddistinct light-harvesting properties. The interactions between 4FTsand TrNBr, a star-shaped monodisperse CME grafted with cationic quaternaryammonium side chains, were investigated in H2O and CH3OH using steady-state, time-resolved fluorescence, dynamiclight scattering (DLS), and transmission electron microscopy (TEM).Highly favored energy transfer has been proven by the excellent spectraloverlap between TrNBr fluorescence and 4FTs absorptions which canbe tuned by adjusting the pendent polar groups and solvents. It issuggested that self-assembled structures are formed between TrNBrand 4FNaT, while there is no obvious change for TrNBr/4FNOHT and TrNBr/4FNBrTin both H2O and CH3OH at low concentrations(<10–6M). This result is confirmed by the changeof the TrNBr and 4FTs fluorescence properties and the time-resolvedfluorescence data. The overall results manifest that at low concentrationsthe self-assembly between TrNBr and 4FTs is dominated by the electrostaticinteractions. This study suggests that the functionalization of pendentpolar groups of star-shaped CMEs has proven to be effective to modulatethe self-assembly behaviors in dilute solutions and thus provide astrategy to further manage the optoelectronic properties. [ABSTRACT FROM AUTHOR]

OxidativePovarov reaction of N-benzylanilineswas realized under catalytic radical cation salt induced conditions.The mechanism studies revealed that a radical intermediate was involvedin this catalytic oxidation. This method provides a new way to synthesize2,4-diarylquinoline derivatives. [ABSTRACT FROM AUTHOR]

The Diels-Alder reactions of seven 1,2,4,5-tetrazines with unstrained and strained alkenes and alkynes were studied with quantum mechanical calculations (M06-2X density functional theory) and analyzed with the distortion/interaction model. The higher reactivities of alkenes compared to alkynes in the Diels-Alder reactions with tetrazines arise from the differences in both interaction and distortion energies. Alkenes have HOMO energies higher than those of alkynes and therefore stronger interaction energies in inverse-electron-demand Diels-Alder reactions with tetrazines. We have also found that the energies to distort alkenes into the Diels-Alder transition-state geometries are smaller than for alkynes in these reactions. The strained dienophiles, trans-cyclooctene and cyclooctyne, are much more reactive than unstrained trans-2-butene and 2-butyne, because they are predistorted toward the Diels-Alder transition structures. The reactivities of substituted tetrazines correlate with the electron-withdrawing abilities of the substituents. Electron-withdrawing groups lower the LUMO+1 of tetrazines, resulting in stronger interactions with the HOMO of dienophiles. Moreover, electron-withdrawing substituents destabilize the tetrazines, and this leads to smaller distortion energies in the Diels-Alder transition states. [ABSTRACT FROM AUTHOR]

Fluorination density and regioregularity are known factors that have high impact on the performance of organic solar cells; however, due to the limited available fluorination positions, the influence of backbone fluorination positions (such as ortho, para, and meta) has not been well studied. Here we disclose that the fluorination position on a conjugated polymer backbone may have completely opposite effects on its performance. Specifically, compared to the nonfluorinated control, Devices fabricated with the conjugated polymer based on para-fluorinated dibenzo[c,h][2,6]naphthyridine-5,11-(6H,12H)-dione (DBND) block exhibit improved power conversion efficiencies (PCEs) up to 6.55%, while devices fabricated with the conjugated polymer based on ortho-fluorinated DBND block exhibit much worse PCEs as low as 1.44%, although both polymers have similar HOMO/LUMO levels, bandgaps, and backbone torsion angles. It is found that different fluorination positions result in different dipole moments, intermolecular binding energies, and syn/anti conformer ratios, which eventually lead to the distinct phase-separation behaviors of the corresponding solar cells. [ABSTRACT FROM AUTHOR]

A new strategy to prepare β-acyl allylic methylsulfides and -sulfones through acid promoted direct cross-coupling of methyl ketones with dimethyl sulfoxide (DMSO) is reported. The reaction proceeded through the nucleophilic attack of enamine intermidiates derived from ketones to in situ generated thionium ion species, followed by elimination of methanthiol to give ketoallylic methylsulfides. With the prolonged reaction time, such products could be further reacted with a methyl sulfonyl radical, which might be generated from a methylthiosulfonate species, to afford ketoallylic methylsulfones in high yields. Molecular transformations of the allylic methylsulfides were also demonstrated. [ABSTRACT FROM AUTHOR]

The first experimental examples of Diels-Alder (DA) reactions of diazo compounds as heterodienophiles with dienes have been studied with density functional theory (DFT) using the M06-2X functional. For comparison, the reactivities of diazo esters as dienophiles or 1,3-dipoles with 1,3-dienes in intermolecular model systems have been analyzed by the distortion/interaction model. The 1,3-dipolar cycloaddition is strongly favored for the intermolecular system. The intramolecular example is unique because the tether strongly favors the (4 + 2) cycloaddition. [ABSTRACT FROM AUTHOR]

Se--N dynamic covalent bond is a new dynamic covalent bond which has applications in the fabrication of stimuli responsive and self-healing functional materials. Although recent advances have been achieved in the experimental aspect, little is known about the formation mechanism of Se--N dynamic covalent bond. Here the structures and nature of Se--N dynamic covalent bond between three kinds of pyridine derivatives R-C5H4N, [pyridine (R = H), 4-methylpyridine (R = CH3), 4-dimethylamino-pyridine (R = N(CH3)2)] and phenylselenyl bromine (PhSeBr) have been analyzed using density functional theory. The interactions between Se atom in PhSeBr and N atom in pyridine or pyridine derivatives can be divided into three models: dissociation, nonbonding interaction and covalent bond interaction. Quantum chemical calculations on three series compounds show that these three models can convert mutually, which results in the generation of Se--N dynamic covalent bond. Solvent effects produced in polar solvents such as CH2Cl2 can make the conversion between Se--N covalent bond and Se...N nonbonding interactions easier. The kind of the substituents in pyridine ring can affect the conversion process: the stronger the electron-donating ability of the substituent, the easier the structure transformation. [ABSTRACT FROM AUTHOR]

Various interferences from measurement conditions and substrate inhomogeneity are well-known confounding factors for poor reproducibility, which is a challenge in surface-enhanced Raman scattering (SERS) quantification. To address these issues, novel substrates and versatile internal standards have been designed and the repeatability is improved to some degree. However, these internal standards are either complex or unstable enough to resist harsh environments such as acid and oxidation. Graphene-isolated-Au-nanocrystal (GLAN) has unique properties and been applied for cell multimodal imaging and chemotherapy but not for SERS quantification analysis yet. Herein, we chose GLANs to improve the accuracy of SERS analysis. GIAN integrates the SERS effect and internal standard into a simple nanoparticle and is proved to be an ideal platform for SERS analysis given its superior properties: (l) chemical stability, it remains stable in strong acid and oxidation, even mimic bioenvironment; (2) a simple core--shell structure, with a thin graphitic shell which is not only a protector that avoiding inner Au catalysis unnecessary reaction but also an internal standard to eliminate the interference during the Raman detections; (3) the big-IT structure can absorb target molecule thus achieve an enrichment effect and quench background fluorescence. Laser power, focus, and substrate fluctuations as well as coexist substance interferences were investigated and the accuracy was improved greatly with the introduction of 2D band internal standard in Raman silent region with less background. Moreover, GIAN was applied for crystal violet determination directly on fish muscle and scale, which was rapid and convenient without complex extraction process. All these results indicate GIAN is an optimum choice for SERS analysis in complex systems. [ABSTRACT FROM AUTHOR]

Chemical looping combustion (CLC) is an advanced technology with inherent CO2 capture in which a solid oxygen carrier circulates between an air reactor and a fuel reactor. For coal-fueled CLC, the existence of solid impurities requires the oxygen carrier not only to have good reactivity but also to be contaminant-resistant, low-cost, and readily available. Therefore, the development of cost-effective and well-performing oxygen carriers is very meaningful for the coal-fueled CLC process. Natural red mud, a byproduct from the aluminum industry, was found to function well as an oxygen carrier and has also been found to have in situ coal catalytic gasification behavior. A thorough study on the long-term cyclic performance of red mud with coal char in a fluidized reactor was conducted in this work. For the purpose of comprehensively understanding the functions of inert supports as well as the sodium content in red mud, the effect of various inert oxides (Al2O3, SiO2, TiO2, and CaO) and the addition of sodium was evaluated. It has been proven that inert supports, Al2O3, SiO2, and TiO2, have a positive effect on both the reduction and oxidation reactivity of iron-based oxygen carriers by developing a porous structure in the particle. Al2O3 and SiO2 show the ability to stabilize the reactivity of iron oxide with a gaseous reductant (CO), even under fluidized conditions. Both Al2O3 and TiO2 can assist in maintaining the mechanical strength of the oxygen carrier after many cycles in a fluidized-bed reactor. The addition of sodium (Na) to red mud does not exhibit much effect on the reactivity of OC with CO as the fuel. However, it can significantly enhance the char gasification rate due to its catalytic function. Additionally, interaction between the active iron oxide and inert supports or sodium in the form of red mud at high temperatures leads to the formation of spinel phases. The growth of spinel phases results in the reduction of the oxygen carrying capacity. However, it helps fix sodium as a relatively stable chemical compound (NaAlSiO4 or NaFe0.25Al0.75O2). Both inert supports and sodium in natural red mud play critical roles in the performance of red mud as an oxygen carrier from either physical or chemical aspects. [ABSTRACT FROM AUTHOR]

The cycloadditions of benzene and ten different azabenzenes (pyridine, three diazines, three triazines, and three tetrazines) with the ethylene dienophile have been explored with density functional theory (M06-2X) and analyzed with the distortion/interaction model. Activation barriers correlate closely with both distortion energies and interaction energies over an activation energy range of 45 kcal/mol. The replacement of CH with N increases Diels-Alder reactivity due not only to the more favorable orbital interaction, but also to a decrease in distortion energy. The rates of reactions are greatly influenced by the nature of the bonds being formed: two C--C bonds > one C--C bond, and one C--N bond > two C--N bonds. The activation energy of Diels-Alder reactions correlates very well with reaction energies and with the NICS(0) values of the aromatic dienes. The distortion energy of the Diels-Alder reaction transition states mostly arises from the diene out-of-plane distortion energy. [ABSTRACT FROM AUTHOR]

Knowledge of human exposure to imidacloprid, the most extensively used insecticide, and para-hydroxybenzoic acid esters (parabens), the most extensively used preservative, is insufficient. In this study, 295 urine samples collected from subjects in rural and urban areas in China were analyzed for imidacloprid and four parabens (namely, methyl paraben, ethyl paraben, propyl paraben, and butyl paraben) as well as their major metabolites (namely, 6-chloronicotinic acid (6-ClNA) and para-hydroxybenzoic acid (p-HB)). Imidacloprid was detected in 100% of the urine samples from rural Chinese subjects and 95% of the urine samples from urban Chinese subjects. Concentrations of urinary imidacloprid detected in rural Chinese subjects (geometric mean (GM) = 0.18 ng/mL) were slightly higher than those detected in urban Chinese subjects (GM = 0.15 ng/mL) when the effect of pesticide spraying was excluded. However, concentrations of urinary imidacloprid detected in rural adults increased significantly in the subsequent days of pesticide spraying (GM = 0.62 ng/mL), which could return to the normal levels within 3 days. In contrast, concentrations of urinary parabens detected in rural Chinese subjects (GM = 6.90 ng/mL) were lower than that in urban Chinese subjects (GM = 30.5 ng/mL). In addition, the metabolism characteristics of imidacloprid to 6-ClNA and parabens to p-HB were discussed preliminarily. [ABSTRACT FROM AUTHOR]

Protein channels in biologic systemscan effectively transport ions such as proton (H+), sodium(Na+), and calcium (Ca+) ions. However, noneof such channels is able to conduct electrons. Inspired by the biologicproton channels, we report a novel hierarchical nanostructured hydroushexagonal WO3(h-WO3) whichcan conduct both protons and electrons. This mixed protonic–electronicconductor (MPEC) can be synthesized by a facile single-step hydrothermalreaction at low temperature, which results in a three-dimensionalnanostructure self-assembled from h-WO3nanorods. Such a unique h-WO3containsbiomimetic proton channels where single-file water chains embeddedwithin the electron-conducting matrix, which is critical for fastelectrokinetics. The mixed conductivities, high redox capacitance,and structural robustness afford the h-WO3with unprecedented electrochemical performance, including high capacitance,fast charge/discharge capability, and very long cycling life (>50 000cycles without capacitance decay), thus providing a new platform fora broad range of applications. [ABSTRACT FROM AUTHOR]

Redox-active organic molecules have attracted much attention as alternatives to transition-metal-based electrodes for lithium-ion batteries due to their low cost and large abundance. However, the relatively low cycling stability still prevents some of the most promising molecules to be used as lithium-ion electrodes. Herein, we used 1,4,5,8-naphthalene diimide (NDI) as a model molecule to systematically investigate its intrinsic electrochemical property, including its electrolyte compatibility, maximum capacity, cycling stability, and rate capability in different organic electrolytes. Extensive physicochemical characterization, electrochemical measurement, and density function theory (DFT) calculation together show that the electrode-electrolyte interaction is the key factor determining its specific capacity and cycling stability. With a proper selection of electrolytes, NDI molecule, which was considered to be not stable for lithium storage, can achieve near theoretical capacity (based on two-electron reaction), very high rate capability, and high cycling stability. This study suggests the importance of understanding the fundamental electrode-electrolyte interactions in designing high-performance organic electrodes. [ABSTRACT FROM AUTHOR]

A noninvasive topical ocular therapy for the treatment of neovascular or "wet" age-related macular degeneration would provide a patient administered alternative to the current standard of care, which requires physician administered intravitreal injections. This manuscript describes a novel strategy for the use of in vivo models of choroidal neovascularization (CNV) as the primary means of developing SAR related to efficacy from topical administration. Ultimately, this effort led to the discovery of acrizanib (LHA510), a small-molecule VEGFR-2 inhibitor with potency and efficacy in rodent CNV models, limited systemic exposure after topical ocular administration, multiple formulation options, and an acceptable rabbit ocular PK profile. [ABSTRACT FROM AUTHOR]

Structural complexity is of fundamental interest in materials science because it often results in unique physical properties and functions. Founded on this idea, the field of solid state chemistry has a long history and continues to be highly active, with new compounds discovered daily. By contrast, the area of two-dimensional (2D) materials is young, but its expansion, although rapid, is limited by a severe lack of structural diversity and complexity. Here, we report a novel 2D semiconductor with a hierarchical structure composed of covalently linked Re6Se8 clusters. The material, a 2D structural analogue of the Chevrel phase, is prepared via mechanical exfoliation of the van der Waals solid Re6Se8Cl2. Using scanning tunneling spectroscopy, photoluminescence and ultraviolet photoelectron spectroscopy, and first-principles calculations, we determine the electronic bandgap (1.58 eV), optical bandgap (indirect, 1.48 eV), and exciton binding energy (100 meV) of the material. The latter is consistent with the partially 2D nature of the exciton. Re6Se8Cl2 is the first member of a new family of 2D semiconductors whose structure is built from superatomic building blocks instead of simply atoms; such structures will expand the conceptual design space for 2D materials research. [ABSTRACT FROM AUTHOR]

Earth-abundant metal-based nanostructured materials have been widely studied for potential energy conversion and storage. However, controlled synthesis of functional nanostructures with high electron conductivity, high reaction activity, and structural stability is still a formidable challenge for further practical applications. Herein, for the first time, we develop a facile, efficient, and general method for the oriented synthesis of precise carbon-confined nanostructures by low-pressure vapor superassembly of a thin metal–organic framework (MOF) shell and subsequent controlled pyrolysis. The selected nanostructured metal oxide precursors not only act as metal ion sources but also orient the superassembly of gaseous organic ligands through the coordination reactions under the low-pressure condition, resulting in the formation of a tunable MOF shell on their surfaces. This strategy is further successfully extended to obtain various precise carbon-confined nanostructures with diverse compositions and delicate morphologies. Notably, these as-prepared carbon-confined architectures exhibit outstanding electrochemical performances in water splitting and lithium storage. The remarkable performances are mainly attributed to the synergistic effect from appropriate chemical compositions and stable carbon-confined structures. This synthetic approach and proposed mechanism open new avenues for the development of functional nanostructured materials in many frontier fields. [ABSTRACT FROM AUTHOR]

To enhance the interfacial interaction between rubber and hybrid nanofiller (HS) consisting of halloysite nanotubes and silica, and simultaneously prevent migration and volatilization of rubber additives, commercial vulcanization accelerator N-cyclohexyl-2-benzothiazole sulfenamide (CZ) was chemically grafted onto HS to obtain a functionalized nanofiller (HS-s-CZ). It was found that the grafted CZ molecules within an inorganic host structure have better efficiency to accelerate cross-linking reaction than free CZ molecules. In addition, HS-s-CZ could be evenly dispersed into styrene butadiene rubber (SBR) with further improved filler-rubber interaction compared with that between HS and SBR. Consequently, SBR/HS-s-CZ composites exhibited greater mechanical strength than SBR/HS composites containing equivalent accelerator component, showing 45% increase in tensile strength when the filler content was 40 phr. Potentially, this work offers a new design strategy for the surface modification of nanofiller and preparation of high-efficiency rubber additives, which may represent a new path for preparing high-performance elastomer composites. [ABSTRACT FROM AUTHOR]

To enhance the interfacial interaction between rubber and hybrid nanofiller (HS) consisting of halloysite nanotubes and silica, and simultaneously prevent migration and volatilization of rubber additives, commercial vulcanization accelerator N-cyclohexyl-2-benzothiazole sulfenamide (CZ) was chemically grafted onto HS to obtain a functionalized nanofiller (HS-s-CZ). It was found that the grafted CZ molecules within an inorganic host structure have better efficiency to accelerate cross-linking reaction than free CZ molecules. In addition, HS-s-CZ could be evenly dispersed into styrene butadiene rubber (SBR) with further improved filler-rubber interaction compared with that between HS and SBR. Consequently, SBR/HS-s-CZ composites exhibited greater mechanical strength than SBR/HS composites containing equivalent accelerator component, showing 45% increase in tensile strength when the filler content was 40 phr. Potentially, this work offers a new design strategy for the surface modification of nanofiller and preparation of high-efficiency rubber additives, which may represent a new path for preparing high-performance elastomer composites. [ABSTRACT FROM AUTHOR]

Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation. [ABSTRACT FROM AUTHOR]

We report the atom-economic and environmentally friendly synthesis of Z-β-sulfonyl-a,β-unsaturated carbonyl compounds in water. The mechanism study reveals that the hydrosulfonylation of alkynylcarbonyl compounds with sulfinic acids proceeds via a mechanism that features a sulfinic acid molecule protonating an alkynyl motif to form the ethenium intermediate, which subsequently reacted with a sulfonyl anion to afford the desired products. The ethenium intermediate differentiated electronic and steric demands between the two substituents on the CC triple bond of the alkyne substrates to exhibit high regio- and stereoselectivity from a wide range of Z-β-sulfonyl-a,β-unsaturated carbonyl compounds. [ABSTRACT FROM AUTHOR]

Three new ring B-seco limonoids, ciliatonoids A-C (1-3), were isolated from Toona ciliate and structurally characterized by spectroscopic data, X-ray crystallography, and electronic circular dichroism analysis. Ciliatonoids A and B feature an unprecedented limonoid architecture, while ciliatonoid C belongs to a rare class of limonoids. Biological evaluation showed that compound 3 exhibited modest activities against the tested tumor cell lines. [ABSTRACT FROM AUTHOR]

Reinforcing rubbers and expanding their application galleries are two important issues in material science and engineering. In this work, we demonstrate a bioinspired design of high-performance and macroscopically responsive diene-rubber by engineering sacrificial metal-ligand motifs into a chemically cross-linked architecture network. The metal-ligand bonds are formed through the coordination reaction between the pyridine groups in butadiene-styrene-vinylpyridine rubber (VPR) and metal ions. Under external load, the metal-ligand bonds serve as sacrificial bonds that preferentially rupture prior to the covalent network, which dissipates energy and facilitates rubber chain orientation. Based on the function mechanisms, the modulus, tensile strength, and toughness of the samples are simultaneously improved without sacrificing the extensibility, and these properties can be conveniently tuned by varying the structure parameters of the covalently cross-linked network and metal-ligand bonds. Moreover, the dissociation/re-formation of metal-ligand bonds upon heating/cooling can endow VPR with thermally triggered adaptive recovery for shape memory application. [ABSTRACT FROM AUTHOR]

Inductionof phase II antioxidant enzymes by activation of Nrf2/ARE pathwayhas been recognized as a promising strategy for the regulation ofoxidative stress-related diseases. Herein we report our effort onthe discovery and optimization of Nrf2 activators with 1,2,4-oxadiazolecore. Screening of an in-house collection containing 7500 compoundsby ARE-luciferase reporter assay revealed a moderate Nrf2 activator, 1. Aimed at obtaining more derivatives efficiently, molecularsimilarity search by the combination of 2D fingerprint-based and 3Dshape-based search was applied to virtually screening the Chemdivcollection. Three derivatives with the same core were identified tohave better inductivity of Nrf2 than 1. The best hit 4was selected as starting point for structurally optimization,leading to a much more potent derivative 32. It in vitroupregulated gene and protein level of Nrf2 as well as its downstreammarkers such as NQO1, GCLM, and HO-1. It remarkably suppressed inflammationin the in vivo LPS-challenged mouse model. Our results provide a newchemotype as Nrf2-ARE activators which deserve further optimizationwith the aim to obtain active anti-inflammatory agents through Nrf2-AREpathway. [ABSTRACT FROM AUTHOR]

A new class of bioorthogonal reagents, 1,2,4-triazines, is described. These scaffolds are stable in biological media and capable of robust reactivity with trans-cyclooctene (TCO). The enhanced stability of the triazine scaffold enabled its direct use in recombinant protein production. The triazine-TCO reaction can also be used in tandem with other bioorthogonal cycloaddition reactions. These features fill current voids in the bioorthogonal toolkit. [ABSTRACT FROM AUTHOR]

The cycloadditions of tetrazines with cyclopropenes and other strained alkenes have become among the most valuable bioorthogonal reactions. These reactions lead to bicyclic Diels-Alder adducts that spontaneously lose N2. We report quantum mechanical (QM) and quasiclassical trajectory simulations on a number of these reactions, with special attention to stereoelectronic and dynamic effects on spontaneous N2 loss from these adducts. QM calculations show that the barrier to N2 loss is low, and molecular dynamics calculations show that the intermediate is frequently bypassed dynamically. There is a large preference for N2 loss anti to the cyclopropane moiety rather than syn from adducts formed from reactions with cyclopropenes. This is explained by the interactions of the Walsh orbitals of the cyclopropane group with the breaking C-N bonds in N2 loss. Dynamical effects opposing the QM preferences have also been discovered involving the coupling of vibrations associated with the formation of the new C-C bonds in the cycloaddition step, and those of the breaking C-N bonds during subsequent N2 loss. This dynamic matching leads to pronounced nonstatistical effects on the lifetimes of Diels-Alder intermediates. An unusual oscillatory behavior of the intermediate decay rate has been identified and attributed to specific vibrational coupling. [ABSTRACT FROM AUTHOR]