PubMed · 8018306
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P F Luckham, P G Hartley. 1994-04-29. Interactions between biosurfaces.. https://doi.org/10.1016/0001-8686(94)80019-7
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2-Deoxy-2,2-difluoroglycosides are a new class of mechanism-based inhibitors of alpha-glycosidases, which function via the accumulation of a stable difluoroglycosyl-enzyme intermediate. Two members of this new class of inhibitor have been synthesized and kinetic studies performed with their target glycosidases. Thus 2,4,6-trinitrophenyl 2-deoxy-2,2-difluoro-alpha-glucoside is shown to inactivate yeast alpha-glucosidase with a second order rate constant of ki/Ki = 0.25 min-1 mM-1. The equivalent difluoromaltoside inactivates human pancreatic alpha-amylase with ki/Ki = 0.0073 min-1 mM-1. Competitive inhibitors protect the enzyme against inactivation in each case, showing reaction to occur at the active site. A burst of release of one equivalent of trinitrophenolate observed upon inactivation of human pancreatic alpha-amylase proves the required 1:1 stoichiometry. These are the first mechanism-based inhibitors of this class to be described, and the first mechanism-based inhibitors of any sort for the medically important alpha-amylase. In addition to having potential as therapeutics, compounds of this class should prove useful in subsequent structural and mechanistic studies of these enzymes.
The selectins are a family of three adhesion molecules (L-, P-, and E-) that direct the interaction of circulating leukocytes with endothelial cells during the first step in recruitment to tissue sites. Their involvement in inflammatory disease makes the selectins attractive targets for anti-inflammatory therapy. The sialyl Lewis x tetrasaccharide binds weakly to all three selectins and has demonstrated anti-inflammatory activity in vivo. However, the synthetic difficulties inherent to sialylated and fucosylated oligosaccharides motivate the search for alternative antagonists. Here we demonstrate that information gained from the biochemical analysis of a physiological selectin ligand can provide new leads for small molecule design. Previous structural analysis of the oligosaccharide chains on GlyCAM-1, an endothelial-derived ligand for L-selectin, revealed two novel structures: 6'-sulfo sialyl Lewis x and 6-sulfo sialyl Lewis x. The sulfate esters on these structures are thought to be essential for high-affinity binding to L-selectin. By incorporating sulfate esters on the analogous positions of the disaccharide lactose, we generated a simple small molecule (lactose 6',6-disulfate) with greater inhibitory potency for L-selectin than sialyl Lewis x.
The O-antigen polysaccharide of the lipopolysaccharide from the enteroaggregative Escherichia coli O44:H18 has been investigated. Sugar and methylation analysis, 1H- and 13C-NMR spectroscopy revealed that the polysaccharide is composed of pentasaccharide repeating units. The sequence of sugar residues was determined by use of two-dimensional nuclear Overhauser effect spectroscopy and heteronuclear multiple bond correlation experiments. The structure of the repeating unit of the O-antigen from Escherichia coli O44:H18 is as follows. [formula: see text]