ANTICOAGULANT ACTIVITY OF DEXTRAN DERIVATIVES

Carboxymethyl dextran benzylamide sulfonate/sulfates (CMDBS) are synth etic polysaccharides with anticoagulant activity. We synthesized eight different highly substituted CMDBS and one CMDSu. We studied both the ir anticoagulant activity and the catalysis of thrombin (T) inhibition by heparin cofactor II (HCII) and antithrombin (AT) in the presence o f these dextran derivatives relative to heparin and dextran sulfate (D XSu). The anticoagulant activity of CMDBS was due both to direct throm bin inhibition and to catalysis of thrombin inhibition by HCII. The an ticoagulant and catalytic activities of CMDBS were related mainly to t heir molecular weight and sulfate content. The interaction of the dext ran derivatives with thrombin does not involve the active site of the enzyme. A kinetic study showed that all the CMDBS exhibited higher aff inity for thrombin than heparin did but lower affinity than DXSu did, suggesting that the benzylamide and sulfate groups potentiate the inte raction between the dextran derivatives and thrombin. This study shows that the mechanism by which the dextran derivatives inhibit thrombin is original and is related to preferential interaction with thrombin; this both inhibits the clotting activity of the enzyme and increases t he reaction rate of thrombin inhibition by HCII. (C) 1998 John Wiley & Sons, Inc.