Synthesis of aza-C-disaccharides

Cell surface oligosaccharides control cell adhesion, fertilization, inflammation, the immune response and metastasis. Their biosynthesis implies sequences of reactions catalysed by glycosidases and glycosyltranferases. Inhibitors of these enzymes are therefore potential antiviral, antibacterial, antimetastatic, antidiabetes, antihyperglycemic, antiadhesive or immunostimulatory agents. Carbohydrate mimetics are among the most powerful inhibitors of these enzymes. They are more stable towards endogenous degradative enzymes, they have improved bioavailability and reduced clearances rates, and they have a higher affinity and selectivity for their cognate receptors by taking advantages of interactions that the natural saccharide does not. Besides the polyhydroxylated piperidines, pyrrolidines, indolizidines, pyrrolizidines and nortropanes, important classes of glycomimetics are C-glycosides and aza-C-disaccharides. Aza C-disaccharides are an emergent class of glycomimetics that combine the features of azasugars and C-glycosyl compounds. The first part of this work was devoted to the synthesis of new aza-C(1—>2)-disaccharides. The type of reaction applied to generate the C-C linkage-bond to join the two monosaccharide fragments was an aldol reaction. Reaction of 4,6-O-benzylidene-2-deoxy-α-D-erythro-hexopyranosid-3-ulose and a N-protected pyrrolidine-derived aldehyde generated the corresponding aldol adduct. First assays of aldol coupling gave poor yields. The reaction was improved by realizing the instability of the aldehyde partner, increasing the concentration, decreasing the temperature and by addition of HMPA as stabilizer of the enolate intermediate. From the aldol adduct a first aza-C-disaccharide with a hydroxy group on the methano linker and with D-allose configuration for the pyranose ring was prepared. In order to synthesize branched aza-C-disaccharides without heteroatom on the methano linker, dehydration of the β-hydroxyketone (aldol adduct) was done. Best results for this transformation were obtained using DAST as dehydration agent, in order to avoid secondary reactions. Dehydrated E and Z isomers were thus obtained. Further transformations from these isomers generated two other aza-C(1—>2)-disaccharides with D-allose and D-glucose configuration for the pyranose ring, respectively. In the second part of this work a new and efficient combinatorial methodology has been developed for the design and screening of new inhibitors of α-mannosidases. A family of iminederivatives was formed by mixing amines and aldehydes in a 96-wells microplate. The inhibitory activities against two different mannosidases were measured in situ. On the other hand, isolated imines showed analogous activities to the mixtures prepared in the microplates. The rapid biological screening makes the method a valuable tool. Moreover minutes amounts of products are required. This method can be applied for the discovery of new lead compounds of all classes of enzymes and biopolymers.

    Thèse École polytechnique fédérale de Lausanne EPFL, n° 3394 (2005)
    Section de chimie et génie chimique
    Faculté des sciences de base
    Institut des sciences et ingénierie chimiques
    Jury: Claude Friedli, Anthony O'Sullivan, Stefan Pitsch, Inmaculada Robina

    Public defense: 2005-12-16


    Record created on 2005-10-27, modified on 2016-08-08


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