Michael Dubber

Synthesis of octopus glycosides: core molecules for the construction of glycoclusters and carbohydrate-centered dendrimers

Abstract Allyl α- d -glucopyranoside was perallylated to allyl 2,3,4,6-tetra-O-allyl-α- d -glucopyranoside and this was converted into an array of uniformly functionalized spacer glycosides of an “octopus” type, taking advantage of the rich chemistry of the allyl ether function. Thus, carbohydrate-derived pentaaldehydes, pentaalcohols and pentaamines with different spacer lengths were obtained by ozonolysis, reductive amination, hydroboration or photoaddition of cysteamine hydrochloride, respectively. The new octopus glycosides are useful core molecules for the synthesis of glycoclusters and for the construction of carbohydrate-centered dendrimers.

Cluster Mannosides as Inhibitors of Type 1 Fimbriae-Mediated Adhesion ofEscherichia coli: Pentaerythritol Derivatives as Scaffolds

Pentaerythritol derivatives were used as core molecules for the synthesis of two cluster α-D-mannosides, which were designed as oligomannoside mimetics. The problem of glycosyl orthoester formation, which frequently occurs in oligo-mannosylations, was solved. The clusters were tested for their capacity to block binding of Escherichia coli to yeast mannan in vitro and were found to be more than 200 times more potent in inhibiting mannose-specific adhesion than methyl α-D-mannoside.

Oligomannoside mimetics by glycosylation of ‘octopus glycosides’ and their investigation as inhibitors of type 1 fimbriae-mediated adhesion of Escherichia coli

The glycocalyx of eukaryotic cells is composed of glycoconjugates, which carry highly complex oligosaccharide portions. To elucidate the biological role and function of the glycocalyx in cell-cell communication and cellular adhesion processes, glycomimetics have become targets of glycosciences, which resemble the composition and structural complexity of the glycocalyx constituents. Here, we report about the synthesis of a class of oligosaccharide mimetics of a high-mannose type, which were obtained by mannosylation of spacered mono- and oligosaccharide cores. These carbohydrate-centered cluster mannosides have been targeted as inhibitors of mannose-specific bacterial adhesion, which is mediated by so-called type 1 fimbriae. Their inhibitory potencies were measured by ELISA and compared to methyl mannoside as well as to a series of mannobiosides, and finally to the polysaccharide mannan. The obtained results suggest a new interpretation of the mechanisms of bacterial adhesion according to a macromolecular rather than a multivalency effect.

SYNTHESIS OF A CARBOHYDRATE-CENTERED C-GLYCOSIDE CLUSTER[1]

The carbohydrate moieties of glycoconjugates are involved in numerous recognition events in biological systems both in a physiological as well as a pathological context. In these processes, multivalency of molecular interactions plays an important role because certain sugar epitopes are frequently displayed in a polyvalent manner. With regard to the multiple-copy design of natural oligosaccharides, many means for clustering of carbohydrate ligands have been sought in order to provide synthetic mimetics which are more easily obtained than their natural counterparts, while possibly equally active. 4c During our attempts to inhibit the adhesion of Escherichia coli bacteria to high mannose-type structures, we have employed different pathways for glycocluster synthesis comprising glycosidation, peptide coupling, thiourea bridging, and photoaddition reactions. In order to increase the stability of such compounds in a physiological environment, C-glycosides instead of O-glycosides can be employed in the design of carbohydrate-based antiadhesives. Here we present the synthesis of the first carbohydrate-centered C-glycoside cluster (5) using two spacer-modified carbohydrate derivatives (1 and 4) and peptide coupling in the ligation step. Two possible pathways for the synthesis of peptide bond-ligated glycoclusters can be envisaged. Either an oligocarboxylic acid is employed as the core molecule and coated with an amino-functionalized carbohydrate derivative, or an oligoamine core is peptide-coupled to a carboxylated saccharide epitope. In either of these two pathways, according to observations J. CARBOHYDRATE CHEMISTRY, 20(7&8), 755–760 (2001)

Synthesis of chiral carbohydrate-centered dendrimers

D-Glucose was converted into its per-O-(2-aminoethyl)-functionalized derivative 4, which served as initiator core for the construction of the chiral, monodisperse PAMAM-type carbohydrate-centered hybrid dendrimer 7.