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1.
Dr. Sabin Llona‐Minguez Dr. Matthieu Desroses Artin Ghassemian Dr. Sylvain A. Jacques Dr. Lars Eriksson Rebecka Isacksson Tobias Koolmeister Dr. Pål Stenmark Dr. Martin Scobie Prof. Thomas Helleday 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(20):7394-7398
A two‐step synthesis of structurally diverse pyrrole‐containing bicyclic systems is reported. ortho‐Nitro‐haloarenes coupled with vinylic N‐methyliminodiacetic acid (MIDA) boronates generate ortho‐vinyl‐nitroarenes, which undergo a “metal‐free” nitrene insertion, resulting in a new pyrrole ring. This novel synthetic approach has a wide substrate tolerance and it is applicable in the preparation of more complex “drug‐like” molecules. Interestingly, an ortho‐nitro‐allylarene derivative furnished a cyclic β‐aminophosphonate motif. 相似文献
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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
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P. Seelig A. Dax S. Faber M. Gerlach G. Huber T. Kühl D. Marx P. Merz W. Quint F. Schmitt H. Winter M. Würtz 《Hyperfine Interactions》1998,114(1-4):135-139
The investigation of the 1s HFS provides a good possibility for testing QED effects in a combination of a strong electric
and magnetic field. Here, we report about the laserspectroscopic measurements of the ground state hyperfine splitting in 207Pb81+. To handle this M1-transition in the infrared optical regime with its long lifetime, we developed a new detection technique
using a bunched ion beam. For the observation of fluorescence light, a new mirror system is adapted to the emission characteristics
from an ion beam at relativistic velocities.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
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Johan Håstad 《Random Structures and Algorithms》2006,29(4):466-474
We show that the operations of permuting columns and rows separately and independently mix a square matrix in constant time. © 2006 Wiley Periodicals, Inc. Random Struct. Alg., 2006 相似文献
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In this Note, we present a result concerning the non existence of linear monotone schema with fixed stencil on regular meshes for some linear parabolic equation in two dimensions. The parabolic equations of interest arise from non isotropic diffusion modelling. A corollary is that no linear monotone 9 points-schemes can be designed for the one-dimensional heat equation emerged in the plane with an arbitrary direction of diffusion. Some applications of this result are provided: for the Fokker–Planck–Lorentz model for electrons in the context of plasma physics; all linear monotone scheme for the one-dimensional hyperbolic heat equation treated as a two-dimensional problem are not consistent in the diffusion limit for an arbitrary direction of propagation. We also examine the case of the Landau equation. To cite this article: C. Buet, S. Cordier, C. R. Acad. Sci. Paris, Ser. I 340 (2005). 相似文献
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Trond Stølen Gustavsen 《Compositio Mathematica》2003,138(2):199-231
We relate the equisingular deformation theory of plane curve singularities and sandwiched surface singularities. We show the existence of a smooth map between the two corresponding deformation functors and study the kernel of this map. In particular we show that the map is an isomorphism when a certain invariant is large enough. 相似文献