Feasible synthesis and biological properties of six 'non-glycosamino' glycan analogues of the antithrombin III binding heparin pentasaccharide.
In this paper, we report the synthesis of 'non-glycosamino' glycan analogues 5-10 of the antithrombin III binding pentasaccharide 1. Pentasaccharides 5-10 feature a pseudo-alternating EFGH tetrasaccharide sequence, that is, the disaccharide fragments EF and GH have the same substitution pattern. In the synthetic strategy applied for the synthesis of pentasaccharides 5-10, the properly protected EF disaccharide fragments 19 and 20 are obtained from their GH counterparts 17 and 18 by base-catalyzed epimerization. Series I, comprising pentasaccharides 5-7, has an invariable EFGH tetrasaccharide containing 2-O-sulfate 3-O-methyl uronic acid moieties. Series II, on the other hand, contains pentasaccharides 8-10 and has an invariable EFGH tetrasaccharide containing 2,3-di-O-methyl uronic acid moieties. Coupling disaccharides 17 with 25 and 18 with 26 exclusively afforded the alpha-coupled tetrasaccharides 27 and 28, respectively. Glycosylation of acceptor tetrasaccharides 29 and 30 with glucosyl donors 35, 36 and 39 provided, after deprotection and sulfation, the title-compounds 5-10. Biological data obtained with series I and II indicate that the in vivo half-life but not the intrinsic anti-Xa activity depends on the substitution pattern of the D-unit. In addition, the applicability of reversed UV capillary electrophoresis as an analytical tool to determine the purity of these 'non-glycosamino' glycans is demonstrated.
Westerduin
P
P
Department of Medicinal Chemistry, N.V. Organon, Oss, The Netherlands.
van Boeckel
C A
CA
Basten
J E
JE
Broekhoven
M A
MA
Lucas
H
H
Rood
A
A
van der Heijden
H
H
van Amsterdam
R G
RG
van Dinther
T G
TG
Meuleman
D G
DG
D000595:Amino Acid Sequence; D000818:Animals; D000990:Antithrombin III / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D002240:Carbohydrate Sequence; D004586:Electrophoresis; D005944:Glucosamine / Q000378:metabolism; D006493:Heparin / Q000031:analogs & derivatives / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009844:Oligosaccharides / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D009844:Oligosaccharides; D000990:Antithrombin III; D006493:Heparin; D005944:Glucosamine