Pentasaccharide Analogues

The pentasaccharide analogues (12) - (14) of the Brucella A antigen have been prepared as their methyl glycosides. Further analogues with a hydroxyl group instead of the formylamino group in the penultimate unit were also reported. ... 

F. Reck, E. Meinjohanns, J. Tan, A.A. Grey, H. Paulsen, H. Schachter, Synthesis of pentasaccharide analogues of the N-glycan substrates of N-acetylglucosaminyltransferases III, IV and V using tetrasaccharide precursors and recombinant beta-(1 2) -N-acetylglucosaminyl-transferase II, Carbohyclr Res, 1995, 275, 22 1 229. 

The anticoagulant fondaparinux, a synthetic analogue of the terminal fragment of heparin, is synthesized using multiple protection/deprotection steps that result in a route of up to 50 steps. There is, as yet, no enzymatic system that approaches the capability to make such a molecule." As this modified pentasaccharide is a natural product, it should, in theory, be accessible through a series of biotransformations, but we currently lack the biocatalytic tools to achieve more than a few steps and would stiU need to use some protection steps to avoid multiple products. Enzymatic synthesis in vivo depends largely on the levels and selectivities of glycosylating enzymes to achieve multistep reactions, a situation that has been mimicked in vitro for simpler systems." ... 

While all these heparin saccharide derivatives are structurally close to the natural active pentasaccharide, a disadvantage is the complex synffiesis comprising more than 30 steps even for the simplified analogues (Scheme 1) which renders a full development of these compounds less likely. 

Meuleman DG, Hobbelen PM, Van Dinther TG et al. (1991) Antifactor Xa activity and antithrombotic activity in rats of structural analogues of the minimum antithrombin III binding sequence discovery of compounds with a longer duration of action than the natural pentasaccharide. Semin Thromb Hemost 17 (Suppl 1) 112—117 Millet J, Theveniaux J, Brown NL (1994) The venous antithrombotic profile of naroparcil in the rabbit. Thromb Haemost 72(6) 874—879... 

The second family of A-linked oligosaccharides are called the lactosamine family in which the D-mannose residues of the core pentasaccharide are substituted 1 2 by lactosamine, which is a lactose analogue with A-acetyl-D-glucosamine substituted for D-glucopyranose at the reducing-end of lactose. The lactosamine is frequently substituted by A-acetyl-D-neu-raminic acid (for the structure of A-acetyl-D-neuraminic acid, see the monomer residue in colominic acid,0 Sect. 8.2 andO Fig. 7) linked 2 3 or 2 6 [142,143]. The third family has a mixed structure of the high mannose and lactosamine families [144,145,146,147]. 

Petitou M, Duchaussoy P, Jaurand G, et al. Synthesis and pharmacological properties of a close analogue of an antithrombotic pentasaccharide (SR 90107A/ORG 31540). J Med Chem 1997 40 1600-1607. 

Analogues of Pentasaccharides and Compounds with Anomalous Linking. - The myo-inositolphosphoglycan 24 has been made in the course of work on GPI anchor compounds. Its conformation in solution and biological activities were determined. " ... 

The synthesis of the biosynthetic chitobiosyl donor (46) by a mixed chemical/enzymic process involved attachment of 3,4,6-tri-0-acetyl-2-deoxy-2-acetamido-tt-D-glucose to dolichol via a pyrophosphate bridge by chemical means as shown in Scheme 9. The monosaccharide pyrophosphate (45) then served, after deprotection, in an enzymic formation of the disaccharide (46). Derivatives (47) of 2-deo -2-acetamido>a-D-glucose 1-phosphate were prepared as simple analogues of moenomycin, a complex pentasaccharide which inhibits bacterial cell wall transglycosidation. ... 

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