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1.
Chris H. Hill Agnete H. Viuff Samantha J. Spratley Stéphane Salamone Stig H. Christensen Randy J. Read Nigel W. Moriarty Henrik H. Jensen Janet E. Deane 《Chemical science》2015,6(5):3075-3086
Krabbe disease is a devastating neurodegenerative disorder characterized by rapid demyelination of nerve fibers. This disease is caused by defects in the lysosomal enzyme β-galactocerebrosidase (GALC), which hydrolyzes the terminal galactose from glycosphingolipids. These lipids are essential components of eukaryotic cell membranes: substrates of GALC include galactocerebroside, the primary lipid component of myelin, and psychosine, a cytotoxic metabolite. Mutations of GALC that cause misfolding of the protein may be responsive to pharmacological chaperone therapy (PCT), whereby small molecules are used to stabilize these mutant proteins, thus correcting trafficking defects and increasing residual catabolic activity in cells. Here we describe a new approach for the synthesis of galacto-configured azasugars and the characterization of their interaction with GALC using biophysical, biochemical and crystallographic methods. We identify that the global stabilization of GALC conferred by azasugar derivatives, measured by fluorescence-based thermal shift assays, is directly related to their binding affinity, measured by enzyme inhibition. X-ray crystal structures of these molecules bound in the GALC active site reveal which residues participate in stabilizing interactions, show how potency is achieved and illustrate the penalties of aza/iminosugar ring distortion. The structure–activity relationships described here identify the key physical properties required of pharmacological chaperones for Krabbe disease and highlight the potential of azasugars as stabilizing agents for future enzyme replacement therapies. This work lays the foundation for new drug-based treatments of Krabbe disease. 相似文献
2.
3.
A new heuristic for the vehicle routeing problem which makes use of repeated matching is described. The numerical results are comparable to or better than the best published for most of the 14 benchmark problems commonly used to evaluate VRP heuristics. 相似文献
4.
Elizabeth M. Holt Balawant S. Joshi Dilip H. Gawad S. William Pelletier 《Journal of chemical crystallography》1990,20(3):261-264
The crystal and molecular structure of 1-ethyl-4-methoxy-9H-pyrido[3,4b]indole (crenatine) carbonate C14H14N2O·H2CO3, (MS, m/z 226)M
R
288.3, a-carboline alkaloid, has been determined from X-ray diffraction data. The compound crystallizes in the space group Pbca with cell parameters:a=11.616(4),b=18.450(8),c=12.992(5)Å,V=2784(2)Å3,Z=8,D
calc=1.375 g cm–3, (MoK)=0.71069Å,(Mo K)=0.94 cm–1,F(000)=1216,R/R
w
=8.2/10.3% for 1099 reflections. The ring system of the-carboline nucleus is planar. The title compound shows a two center hydrogen bond between the indole N-H group and the oxygen atom of a carbonate group. The structure does not display hydrogen bonding between-carboline groups but rather a bonding network involving the carbonate group. 相似文献
5.
6.
Brett Ammundsen Gary R. Burns Ali Amran Stig E. Friberg 《Journal of Sol-Gel Science and Technology》1995,4(1):23-29
The effects of thermal treatment on composite materials prepared by the gelation of sols comprising large concentrations of metal oxide precursor salts have been investigated, in order to determine the compositional and thermal requirements for forming spinel magnesium manganates in such systems. The preparative technique has been found to give rise to derived gel materials in which the metal oxide phase, in the form of regular spherical particles, is dispersed throughout a continuous silica matrix. Silica-supported mixed magnesium and manganese spinel oxide phases were obtained for systems comprising at least 30 wt% metal nitrate after heating to temperatures between 700 and 850°C, but not without concomitant formation of Mn2O3 and modification of the silica network by magnesium. 相似文献
7.
Accurate quantitation of the four lipid components in a vesicle formulation has been accomplished by selectively changing the high-performance liquid chromatographic mobile phase composition to arrive at an optimal separation requiring less than 10 min. A systematic approach to selection of the mobile phase conditions has minimized the number of experiments required to achieve the necessary separation. Relative standard deviations between one and four percent are obtained for the four lipid components. Accuracy, as measured by recovery experiments for spiked vesicle formulations, varies between one and two percent of target levels at the nominal lipid concentrations investigated. 相似文献
8.
Jan-Olov Willerström Bertil Carlsson Stig Rundqvist 《Journal of solid state chemistry》1980,31(2):227-232
Hf3As has a monoclinic unit cell of dimensions a = 15.3898(14) Å, b = 5.3795(5) Å, c = 15.330(14) Å, β = 90.291(6)°. A structure proposal based on space group (No. 15) has been refined by the least-squares method using a Rietveld-type fullprofile analysis of Guinier-Hägg X-ray powder film intensity data. The Hf3As structure is an intermediate between the Fe3P and the Ti3P types. The atomic coordination follows rules formulated earlier for representatives of the Fe3PTi3PV3S family of structures. 相似文献
9.
Boyd DR Sharma ND King AW Shepherd SD Allen CC Holt RA Luckarift HR Dalton H 《Organic & biomolecular chemistry》2004,2(4):554-561
Direct and indirect evidence, of unexpected stereoselective reductase-catalysed deoxygenations of sulfoxides, was found. The deoxygenations proceeded simultaneously, with the expected dioxygenase-catalysed asymmetric sulfoxidation of sulfides, during some biotransformations with the aerobic bacterium Pseudomonas putida UV4. Stereoselective reductase-catalysed asymmetric deoxygenation of racemic alkylaryl, dialkyl and phenolic sulfoxides was observed, without evidence of the reverse sulfoxidation reaction, using anaerobic bacterial strains. A purified dimethyl sulfoxide reductase, obtained from the intact cells of the anaerobic bacterium Citrobacter braakii DMSO 11, yielded, from the corresponding racemates, enantiopure alkylaryl sulfoxide and thiosulfinate samples. 相似文献
10.
Stig Veibel 《Fresenius' Journal of Analytical Chemistry》1964,205(1):94-109
Zusammenfassung Der grundsätzliche Unterschied zwischen anorganischer und organischer Analyse wird diskutiert, wobei dargelegt wird, daß die Gruppenreaktionen der funktioneilen Gruppen in der organischen Analyse die Funktionen der Ionenreaktionen der anorganischen Analyse übernommen haben.Als Beispiele werden sowohl chemische Reaktionen als auch instrumentelle Methoden zur Identifikation von Hydroxylverbindungen, Carboxylsäuren, Carbonylverbindungen, Aminen, einschließlich Aminosäuren, N-Oxiden, schwefelhaltige Verbindungen, Alkoxyverbindungen und Kohlenwasserstoffen erwähnt.Es wird betont, daß sich die endgültige Identifikation einer organischen Verbindung nur durch Konbination qualitativer und quantitativer Methoden durchführen läßt.
Summary The fundamental difference between inorganic and organic analysis is discussed, and it is shown how group reactions in organic analysis have assumed the function of ionic reactions in inorganic analysis.Chemical reactions and instrumental methods for the identification of the following compounds are mentioned hydroxy compounds, carboxylic acids, carbonyl compounds, amines, including amino-acids, N-oxides, sulphur containing compounds, alkoxy compounds and hydrocarbons. It is emphasized that a combination of qualitative and quantitative methods is necessary for obtaining a final identification.相似文献