Azasugar inhibitors as pharmacological chaperones for Krabbe disease

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.     

Enantiodiscrimination of racemic electrophiles by diketopiperazine enolates: asymmetric synthesis of methyl 2-amino-3-aryl-butanoates and 3-methyl-aspartates

Enolates of (S)-N,N′-bis-(p-methoxybenzyl)-3-iso-propylpiperazine-2,5-dione exhibit high levels of enantiodiscrimination in alkylations with (RS)-1-aryl-1-bromoethanes and (RS)-2-bromoesters, affording substituted diketopiperazines containing two new stereogenic centres in high de. Deprotection and hydrolysis of the resultant substituted diketopiperazines provides a route to the asymmetric synthesis of homochiral methyl 2-amino-3-aryl-butanoates and 3-methyl-aspartates in high de and ee.     

Zur quantitativen Eiweissbestimmung im Harn

Ohne Zusammenfassung     

Zur Sch?nbein'sehen Reaction auf Blaus?ure

Ohne Zusammenfassung     

Eine neue Reaction des Phenacetins

Ohne Zusammenfassung     

Quantitative Bestimmungen mittels cyclischer Voltammetrie an der Phasengrenze zweier mischbarer Elektrolytl?sungen

Summary This paper presents some applications of cyclic voltammetry at the interface of two immiscible electrolyte solutions by means of an experimental set-up described in a former publication. When using special sample preparation good results are obtained for the determination of iodide and quinine in pharmaceutical products as well as for the determination of quinine in tonic water and dodecylsulfate in a tooth-salt.

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Herrn Prof. Dr. Günther Tölg zum 60. Geburtstag gewidmet     

Rapid convergence of a Galerkin projection of the KdV equation

In this Note, it is shown that a Fourier Galerkin approximation of the Korteweg–de Vries equation with periodic boundary conditions converges exponentially fast if the initial data can be continued analytically to a strip about the real axis. To cite this article: H. Kalisch, C. R. Acad. Sci. Paris, Ser. I 341 (2005).     

Untersuchungen zur Wechselwirkung von gasf?rmigem molekularem Iod mit Silberoberfl?chen mittels XPS und AES

Summary The adsorption of gaseous molecular iodine on clean silver surfaces proceeds in the first stage by dissociative chemisorption. After the formation of half a monolayer of chemisorbed iodine atoms the formation of silver iodide begins, which forms a very regular overlayer on top of the substrate. Both iodine species can be distinguished due to a difference in chemical shift of the M₄N₄, ₅N₄, ₅-Auger transitions. After completion of this overlayer further iodine uptake is slowed down significantly. Above an overlayer thickness of about 10 nm a further progress of the reaction cannot be followed anymore due to the limited information depth of XPS.