Studies of the Influence of N-Substitution in Heparin on Its Anticoagulant Activity

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Abstract
Five partially N-desulfated heparin preparations (N-sulfate: 0.73–0.48 mol, O-sulfate: 1.33–1.29 mol, anticoagulant activity: 134–102 USP units) were prepared by solvolytic N-desulfation of the pyridinium salt of hog mucosal heparin (N-sulfate: 0.83 mol, O-sulfate: 1.42 mol, N-acetyl: 0.12 mol, anticoagulant activity: 165 USP units) in DMSO containing 5% water. The preparations, ranging in degree of N-desulfation from 12 to 31 %, which were obtained by reaction at 20°C for 5–60 min, retained an average of 79% of the original activity. A prepara tion with a degree of N-desulfation of 42%, which was obtained by reaction at 20°C for 120 ruin, retained 62% of the original activity. Five N-acetylated heparin preparations (N-acetyl: 0.17–0.49 mol) were prepared by N acetylation of the partially N-desulfated heparins. Their anticoagulant activities (133–107 USP units) were nearly equal to those of the corresponding starting N-desulfated heparins. N-Succinoylation of a partially N-desulfated heparm (N-sulfate: 0.57 mol, anticoagulant activity: 125 USP units) did not enhance its biological activity, but N-resulfation restored its anticoagulant activity to 94% of that of the original heparin. Partially N-acetylated heparin with 0.24 mol of N-acetyl groups, two whale heparin preparations, and a purified heparan sulfate fraction, all of which had similar N-acetyl contents (0.24–0.27 mol), were assayed for anticoagulant activity, and the correlation between biological activities and chemical properties is discussed.

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