Chemical derivatization as a strategy to study structure-activity relationships of glycosaminoglycans.
Sulfated glycosaminoglycans (GAGs) are amenable to a number of chemical modifications that modulate their biological activity. N-sulfate groups can be exposed and N-acylated (usually N-acetylated), specific O-sulfate groups can be removed, and free hydroxyl groups (either preexisting in the original GAG or exposed by desulfation) can be sulfated. Heparin/heparan sulfate, chondroitin sulfate, and dermatan sulfate have been variously desulfated or sulfated to afford novel GAGs with protein binding and associated biological properties different from those of the original GAGs. Regiospecific sulfation of N-acetyl heparosan ( E. coli K5 polysaccharide) afforded a number of derivatives, some endowed with antithrombotic activity and others with antimetastatic properties. Most of the activities could be correlated with typical sulfation patterns along each GAG backbone. Glycol splitting of nonsulfated glucuronic residues (including a critical residue in the pentasaccharide sequence of the active site for antithrombin) leads to substantial loss of anticoagulant activity of heparin. Partial removal of sulfate groups at position 2 of iduronic acid residues followed by glycol splitting of all nonsulfated uronic acid residues afforded nonanticoagulant, antiangiogenic heparins.
Casu
Benito
B
G. Ronzoni Institute for Chemical and Biochemical Research, Milan, Italy. casu@ronzoni.it
Naggi
Annamaria
A
Torri
Giangiacomo
G
D020533:Angiogenesis Inhibitors / Q000737:chemistry; D000818:Animals; D000925:Anticoagulants / Q000737:chemistry; D006025:Glycosaminoglycans / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D013329:Structure-Activity Relationship; D013431:Sulfates
D020533:Angiogenesis Inhibitors; D000925:Anticoagulants; D006025:Glycosaminoglycans; D013431:Sulfates; C013786:A73025