Analyzing airway inflammation with chemical biology: dissection of acidic mammalian chitinase function with a selective drug-like inhibitor

Acidic mammalian chitinase (AMCase) is produced in the lung during allergic inflammation and asthma, and inhibition of enzymatic activity has been considered as a therapeutic strategy. However, most chitinase inhibitors are nonselective, additionally inhibiting chitotriosidase activity. Here, we describe bisdionin F, a competitive AMCase inhibitor with 20-fold selectivity for AMCase over chitotriosidase, designed by?utilizing the AMCase crystal structure and dicaffeine scaffold. In a murine model of allergic inflammation, bisdionin F-treatment attenuated chitinase activity and alleviated the primary features of allergic inflammation including eosinophilia. However, selective AMCase inhibition by bisdionin F also caused dramatic and unexpected neutrophilia in the lungs. This class of inhibitor will be a powerful tool to dissect the functions of mammalian chitinases in disease and represents a synthetically accessible scaffold to optimize inhibitory properties in terms of airway inflammation.     

Simultaneous and high-throughput quantitation of urinary tetranor PGDM and tetranor PGEM by online SPE-LC-MS/MS as inflammatory biomarkers

Quantitation of urinary tetranor PGDM or tetranor PGEM (tPGDM and tPGEM) in the past was performed separately using off-line SPE LC-MS/MS methods. The manual SPE procedure is generally time-consuming and cost-ineffective. In addition, simultaneous quantitation of tPGDM and tPGEM is favorable yet very challenging because of the similar chemical structures and identical MRM transitions. This work describes the development and validation of a high-throughput online SPE-LC-MS/MS method, allowing simultaneous and high-throughput measurement of tPGDM and tPGEM in human urine. The reportable range of the assay was 0.2-40 ng/ml for tPGDM and 0.5-100 ng/ml for tPGEM. Intra- and inter-assay precision and accuracy determined using quality control samples were all within acceptable ranges (% CV and % Bias < 15%). Tetranor PGDM was stable under all tested conditions while tPGEM was stable at 4 °C and after three F/T cycles but not stable at room temperature for 24 h (recovery below 80%). The assay was applied to measure urinary tPGDM and tPGEM among healthy volunteers, smokers and COPD patients. Significantly higher urinary levels of both tPGDM and tPGEM were observed in COPD patients than those of non-smoking healthy volunteers. These results demonstrated that the high-throughput online SPE-LC-MS/MS assay provides sensitive, reproducible and accurate measurement of urinary tPGDM and tPGEM as biomarkers for assessing inflammatory diseases such as COPD.     

2014的产业和市场展望

正2014年,我们将持续信守"更智能的生活、更安全的联结"的承诺,同时顺应电子行业的四大趋势:节能、互联、安全及健康,严谨执行以推出解决方案为主的长期策略。这与中国五年规划目标强调节能、环保和新信息技术高度吻合。随着重大发展的来临,如智能电网在中国推出,恩智浦始终以提供智能、安全和节能的解决方案为核心,惠及大众生活。恩智浦的智能识别技术走进了千家万户的日常     

Phosphorous-filled nanobrick wall multilayer thin film eliminates polyurethane melt dripping and reduces heat release associated with fire

Unique trilayer (TL) thin films of sodium montmorillonite (MMT), poly(allylamine hydrochloride) (PAH) and poly(sodium phosphate) (PSP) are prepared via layer-by-layer (LbL) assembly. This three-component nanocoating completely shuts down melt dripping and reduces heat release of open-celled flexible polyurethane (PU) foam when exposed to direct flame due to a synergistic interaction between PSP and the thermally shielding clay platelets in the condensed phase. Post burn scanning electron microscopy reveals the nanocoating's swollen morphology is able to maintain foam shape, cellular structure, and porosity. Cone calorimetry reveals that 4 TL coated foams (<3 wt% addition) have a peak heat release rate that is reduced by 54% relative to the uncoated control. Using LbL assembly, this work combines two common flame-retarding mechanisms (thermal shielding clay and intumescing PAH/PSP) in a single coating system and provides a foundational platform for new environmentally-benign flame retardant strategies for various substrates (e.g., foam found in home furnishings).     

Aromatic Nucleophilic Substitution: The Reaction of Sodium 2,2,2-Trifluoroethoxide with Chlorobenzonitriles in HMPA

The preparation¹ of fluorinated compounds continues to be of significant interest to organic chemists due to their diverse and important application as polymers, blood substitutes, pharmaceuticals and pesticides. Considerable attention has been directed to the formation of fluoroalkoxy benzenes with the majority of the synthetic routes involving the reaction of an electrophilic haloalkyl fluoride with a nucleophilic phenol derivative^1,2. In a somewhat related procedure, Mendel³ has prepared ortho-2,2,2-trifluoroethoxy methyl benzoate by reacting ortho-hydroxy methyl benzoate with 2,2,2-trifluoroethyl trifluoromethylsulfonate in a potassium carbonate/acetone mixture.     

A [4 + 4] annulation strategy for the synthesis of eight-membered carbocycles based on intramolecular cycloadditions of conjugated enynes

A [4+4] annulation strategy for the synthesis of eight-membered carbocycles is reported that proceeds via a cascade involving two pericyclic processes. In the first step, the [4+2] cycloaddition of a conjugated enyne with an electron-deficient cyclobutene generates a strained six-membered cyclic allene that isomerizes to the corresponding 1,3-cyclohexadiene. In the second step, this bicyclo[4.2.0]octa-2,4-diene intermediate undergoes thermal or acid-promoted 6-electron electrocyclic ring opening to furnish a 2,4,6-cyclooctatrienone. The latter transformation represents the first example of the promotion of 6-electron electrocyclic ring opening reactions by acid.     

Synthesis of polycyclic benzofused nitrogen heterocycles via a tandem ynamide benzannulation/ring-closing metathesis strategy. Application in a formal total synthesis of (+)-FR900482

A two-stage "tandem strategy" for the synthesis of benzofused nitrogen heterocycles is described that is particularly useful for the construction of systems with a high level of substitution on the benzenoid ring. The first stage in the strategy involves a benzannulation based on the reaction of cyclobutenones with ynamides. This cascade process proceeds via a sequence of four pericyclic reactions and furnishes a multiply substituted aniline derivative which can bear a variety of functionalized substituents at the position ortho to the nitrogen. In the second stage of the tandem strategy, ring-closing metathesis generates the nitrogen heterocyclic ring. This two-step sequence provides efficient access to highly substituted dihydroquinolines, benzazepines, benzazocines, and related benzofused nitrogen heterocyclic systems. The application of this chemistry in a concise formal total synthesis of the anticancer agents (+)-FR900482 and (+)-FR66979 is described.     

Relating structural aspects of bimetallic Pt(3)Cr(1)/C nanoparticles to their electrocatalytic activity, stability, and selectivity in the oxygen reduction reaction

Two methods were used to prepare bimetallic Pt(3)Cr(1)/C nanocatalysts with similar composition but different alloying extent (structure). We investigated how these differences in alloying extent affect the catalytic activity, stability and selectivity in the oxygen reduction reaction (ORR). One method, based on slow thermal decomposition of the Cr precursor at a rate that matches that of chemical reduction of the Pt precursor, allows fine control of the composition of the Pt(3)Cr(1)/C alloy, whereas the second approach, using the ethylene glycol method, results in considerable deviation (>25 %) from the projected composition. Consequently, these two methods lead to variations in the alloying extent that strongly influence the Pt d-band vacancy and the Pt electroactive surface area (Pt ESCA). This relationship was systematically evaluated by transmission electron microscopy, X-ray absorption near edge structure spectroscopy, and electrochemical analysis. The ORR activity depends on two effects that nullify each other, namely, the number of active Pt sites and their activity. The Pt-site activity is more dominant in governing the ORR activity. The selectivity of the nanocatalyst towards the ORR and the competitive methanol oxidation reaction (MOR) depend on these two effects acting in cooperation to give enhanced ORR activity with suppressed MOR. The number of active Pt sites is associated with the Pt ESCA value, while Pt-site activity is associated with the alloying extent and Pt d-band vacancy (electronic) effects. The presence of Cr atoms in Pt(3)Cr(1)/C enhances stability during electrochemical treatment. Overall, the Pt(3)Cr(1)/C catalyst prepared by controlled-composition synthesis was shown to be superior in ORR activity, selectivity and stability owing to its favorable alloying extent, Pt d-band vacancy, and Pt ESCA.     

Nanoscale imaging with resonant coherent X rays: extension of multiple-wavelength anomalous diffraction to nonperiodic structures

The methodology of multiple-wavelength anomalous diffraction, widely used for macromolecular structure determination, is extended to the imaging of nonperiodic nanostructures. We demonstrate the solution of the phase problem by a combination of two resonantly recorded coherent scattering patterns at the carbon K edge (285 eV). Our approach merges iterative phase retrieval and x-ray holography approaches, yielding unique and rapid reconstructions. The element, chemical, and magnetic state specificity of our method further renders it widely applicable to a broad range of nanostructures, providing a spatial resolution that is limited, in principle, by wavelength only.     

CCR1 antagonists

CCR1 (CC Chemokine receptor 1) is a widely studied G protein-coupled receptor target expressed on multiple types of leukocytes. It is implicated in initiating and exacerbating inflammatory conditions and thus is viewed as a good target for autoimmune and inflammatory therapeutic applications. Numerous CCR1 antagonists have been reported. Although some early CCR1 antagonists lacked the species cross reactivity that made in vivo animal model study difficult, efforts have been made to improve the compound potency in rodents. Recent identification of new and improved CCR1 antagonists has resulted in promising, in vivo efficacy in a variety of animal models of disease. While several early compounds have been withdrawn from clinical trials due to lack of efficacy, work continues to evaluate CCR1 antagonists in preclinical and clinical settings.