Preparation and anticoagulant activity of fully O-sulphonated glycosaminoglycans.
Glycosaminoglycans including dermatan sulphate, hyaluronan, heparan sulphate and heparin were chemically modified by O-sulphonation. By altering the reaction conditions, products having a different degree of O-sulphonation could be obtained. Glycosaminoglycan derivatives were prepared having no free hydroxyl groups, with sulphoester group/disaccharide unit ratios of 4.0 for dermatan sulphate and hyaluronan, and sulphoester and sulphamide group/disaccharide unit ratios of 4.22 and 4.88 for heparan sulphate and heparin, respectively. 1H NMR spectroscopy showed that the fully O-sulphonated hyaluronan derivative had a glucuronate residue with an altered conformation. Since glycosaminiglycans and their derivatives are often used as anticoagulant/antithrombotic agents, their anti-amidolytic activities were determined. The anti-factor IIa activity of fully O-sulphonated dermatan sulphate, hyaluronan and heparan sulphate ranged from 40 to 80 units/mg, while no anti-factor Xa activity of the fully O-sulphonated glycosaminoglycans was detected. These values are lower than those reported for low-molecular-weight heparins and are consistent with the requirement of an antithrombin III pentasaccharide binding site for anti-factor Xa activity. Interestingly, the anti-factor Xa of heparin is lost by chemical O-sulphonation.
Toida
T
T
Faculty of Pharmaceutical Sciences, Chiba University, Inage, Japan.
Maruyama
T
T
Ogita
Y
Y
Suzuki
A
A
Toyoda
H
H
Imanari
T
T
Linhardt
R J
RJ
D000925:Anticoagulants / Q000138:chemical synthesis* / Q000494:pharmacology*; D001769:Blood / Q000187:drug effects / Q000378:metabolism; D004187:Disaccharides / Q000737:chemistry; D015951:Factor Xa / Q000187:drug effects; D006025:Glycosaminoglycans / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008970:Molecular Weight; D011516:Prothrombin / Q000187:drug effects; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D014574:Uronic Acids / Q000737:chemistry
D000925:Anticoagulants; D004187:Disaccharides; D006025:Glycosaminoglycans; D014574:Uronic Acids; D011516:Prothrombin; C025337:Factor IIa; D015951:Factor Xa