Total Synthesis of Tri-, Hexa- and Heptasaccharidic Substructures of the O-Polysaccharide of Providencia rustigianii O34.

A general and efficient strategy for synthesis of tri-, hexa- and heptasaccharidic substructures of the lipopolysaccharide of Providencia rustigianii O34 is described. For the heptasaccharide seven different building blocks were employed. Special features of the structures are an α-linked galactosamine and the two embedded α-fucose units, which are either branched at positions-3 and -4 or further linked at their 2-position. Convergent strategies focused on [4+3], [3+4], and [4+2+1] couplings. Whereas the [4+3] and [3+4] coupling strategies failed the [4+2+1] strategy was successful. As monosaccharidic building blocks trichloroacetimidates and phosphates were employed. Global deprotection of the fully protected structures was achieved by Birch reaction.

Chimeric oligosaccharide conjugate induces opsonic antibodies against Streptococcus pneumoniae serotypes 19A and 19F.

Streptococcus pneumoniae 19A (ST19A) and 19F (ST19F) are among the prevalent serotypes causing pneumococcal disease worldwide even after introduction of a 13-valent pneumococcal conjugate vaccine (PCV13). Synthetic glycoconjugate vaccines have defined chemical structures rather than isolated polysaccharide mixtures utilized in marketed vaccines. Ideally, a minimal number of synthetic antigens would cover as many bacterial serotypes to lower cost of goods and minimize the response to carrier proteins. To demonstrate that a chimeric oligosaccharide antigen can induce a protective immune response against multiple serotypes, we synthesized a chimeric antigen (ST19AF) that is comprised of a repeating unit of ST19A and ST19F capsular polysaccharide each. Synthetic glycan epitopes representing only ST19A, and ST19F were prepared for comparison. Semisynthetic glycoconjugates containing chimeric antigen ST19AF induced high antibody titers able to recognize native CPS from ST19A and ST19F in rabbits. The antibodies were able to kill both strains of pneumococci. Chimeric antigens are an attractive means to induce an immune response against multiple bacterial serotypes.

Synthesis of Two Tetrasaccharide Pentenyl Glycosides Related to the Pectic Rhamnogalacturonan I Polysaccharide.

The synthesis of two protected tetrasaccharide pentenyl glycosides with diarabinan and digalactan branching related to the pectic polysaccharide rhamnogalacturonan I is reported. The strategy relies on the coupling of N-phenyl trifluoroacetimidate disaccharide donors to a common rhamnosyl acceptor. The resulting trisaccharide thioglycosides were finally coupled to an n-pentenyl galactoside acceptor to access the two protected branched tetrasaccharides.

Synthesis of branched and linear 1,4-linked galactan oligosaccharides.

We report the synthesis of linear and branched (1→4)-d-galactans. Four tetrasaccharides and one pentasaccharide were accessed by adopting a procedure of regioselective ring opening of a 4,6-O-naphthylidene protecting group followed by glycosylation using phenyl thioglycoside donors. The binding of the linear pentasaccharide with galectin-3 is also investigated by the determination of a co-crystal structure. The binding of the (1→4)-linked galactan to Gal-3 highlights the oligosaccharides of pectic galactan, which is abundant in the human diet, as putative Gal-3 ligands.

Size, Kinetics, and Free Energy of Clusters Formed by Ultraweak Carbohydrate-Carbohydrate Bonds.

Weak noncovalent intermolecular interactions play a pivotal role in many biological processes such as cell adhesion or immunology, where the overall binding strength is controlled through bond association and dissociation dynamics as well as the cooperative action of many parallel bonds. Among the various molecules participating in weak bonds, carbohydrate-carbohydrate interactions are probably the most ancient ones allowing individual cells to reversibly enter the multicellular state and to tell apart self and nonself cells. Here, we scrutinized the kinetics and thermodynamics of small homomeric Lewis X-Lewis X ensembles formed in the contact zone of a membrane-coated colloidal probe and a solid supported membrane ensuring minimal nonspecific background interactions. We used an atomic force microscope to measure force distance curves at Piconewton resolution, which allowed us to measure the force due to unbinding of the colloidal probe and the planar membrane as a function of contact time. Applying a contact model, we could estimate the free binding energy of the formed adhesion cluster as a function of dwell time and thereby determine the precise size of the contact zone, the number of participating bonds, and the intrinsic rates of association and dissociation in the presence of calcium ions. The unbinding energy per bond was found to be on the order of 1 kBT. Approximately 30 bonds were opened simultaneously at an off-rate of koff = 7 ± 0.2 s(-1).

The anti-arthritic and immune-modulatory effects of NHAG: a novel glucosamine analogue in adjuvant-induced arthritis.

Rheumatoid arthritis (RA) is potentially devastating condition which lacks good treatment options. Pro-inflammatory cytokines interleukin-1beta (IL-1 ß ), tumor necrosis factor-alpha (TNF- α ), and oxidative stress markers such as nitric oxide (NO) and peroxide (PO) are mediators of RA pathogenesis. In the present study N-[2,4,5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-3-yl]acrylamide (NHAG), analogue of glucosamine, was evaluated in adjuvant-induced arthritic model of rats. The disease progression was monitored by analysing arthritis scoring, loss of body weight, paw oedema, and histological changes in joints. RA associated hyperalgesia was evaluated by gait analysis. The serum or plasma levels of NO, PO, glutathione (GSH) superoxide dismutase (SOD) IL-1 ß and TNF- α were analyzed to monitor the state of disease severity. The arthritic control animals exhibited significant increase in arthritic score (P < 0.003) and paw oedema (P < 0.001) with parallel loss in body weight (P < 0.04). The NHAG-treated arthritic animals exhibited refinement in the gait changes associated with arthritis. NHAG also significantly decreased the NO (P < 0.02) and PO (P < 0.03) with concurrent increased in GSH (P < 0.04) and SOD (P < 0.007). Both IL-1 ß (P < 0.001) and TNF- α (P < 0.001), were significantly decreased in NHAG-treated group. Thus NHAG might have a therapeutic potential for arthritis by exerting antioxidative and immunomodulatory effects.

Syntheses of 1,2-annulated and 1-spiroannulated carbohydrate derivatives: recent developments.

A variety of different strategies has been used for the 1,2-annulation and the 1-spiroannulation of further rings to monosaccharides. This short review presents some recent methods to access such structures involving radical chemistry, cycloadditions, Michael reactions and metal-catalyzed transformations.

Anti-arthritic effect of GN1, a novel synthetic analog of glucosamine, in the collagen-induced arthritis model in rats.

OBJECTIVE: Glucosamine is a naturally occurring amino monosaccharide that maintains the elasticity and strength of the cartilage tissues. It has been used to treat osteoarthritis in humans; however, in severe conditions of inflammation and pain, glucosamine alone is not enough, and it is important to improve its biological activity. Our research group has recently taken an interest in the synthetic manipulation of amino sugars to develop some efficient pharmacophores, e.g., ß-D-glucosamine, to combat rheumatoid arthritis, and tested its anti-arthritic effects in the collagen-induced arthritis (CIA) model in rats. METHODS: Arthritis was induced in female Sprague-Dawley rats by multiple intradermal injections of bovine type II collagen and challenged again with the same antigen preparation 7 days later. Arthritis was evaluated by arthritic score, body weight loss, paw volume measurement, and histological changes. RESULTS: The animals in the arthritic control group showed a gradual decrease in their body weight and concurrent increase in the paw volumes compared to the normal control group. In contrast, increased hind paw swelling was significantly suppressed with no further noticeable reduction in body weight in the glucosamine (p < 0.05) and GN1-treated (p < 0.02) arthritic animals. Histopathological evaluation of isolated knee joints by grading system and classification of the stages in arthritic lesion development revealed suppression of the inflammatory changes in the GN1-treated animals. Moreover, both the pro-inflammatory markers C-reactive protein (CRP) and low-density lipoprotein (LDL) levels were found to be significantly decreased in animals treated with GN1 (p < 0.03 for CRP and p < 0.05 for LDL) compared to the arthritic control group. CONCLUSION: These results suggest that GN1 has both anti-arthritic and anti-inflammatory properties. Its effects in the CIA model suggest that it could be useful in the treatment of rheumatoid arthritis.

From furan to molecular stairs: syntheses, structural properties, and theoretical investigations of oligocyclic oligoacetals.

The synthesis of oligocyclic oligoacetals using five-membered rings as repetitive unit is described. Furan was used as the starting material, which is converted by a three-step procedure consisting of twofold cyclopropanation, reduction, and oxidative ring enlargement into a tricyclic bis(enol ether). A repetition of this synthetic procedure leads to the formation of extended oligoacetal systems. Insights into the structures were gained by X-ray crystallographic investigations and revealed helical arrangements of the subunits in the solid-state. DFT (B3LYP) calculations have been carried out to elucidate the transition state of the ring enlargement and the flexibility of the annelated oligocyclic systems. Strain energies and topologies of potential cyclically condensed oligoacetals are predicted.