PubMed · 2343242
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P Sie. 1990-04-11. [Heparin cofactor II].. https://pubmed.ncbi.nlm.nih.gov/2343242/
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The syntheses of sodium (sodium 2-acetamido-2-deoxy-4-O-sulfonato-beta-D-galactopyranosyl)-(1-->4)-(sodium 2-O-sulfonato-L-idopyran)uronate, a disaccharide fragment of dermatan sulfate, and of its methyl alpha-L-glycoside derivative are reported for the first time. The use of 4-O-acetyl-3,6-di-O-benzyl-2-deoxy-2-trichloroacetamido-1-O-trichloroacetimidoyl-alpha-D-galactopyranose, readily prepared from a D-gluco precursor, allowed the stereocontrolled and high yielding coupling with the low reactive 4-hydroxyl group of L-iduronic acid ester derivatives. Classical transformation of the disaccharide products into the target molecules was achieved in high yield.
The kinetics of thrombin inhibition by heparin cofactor II (HC II) in the presence of dermatan sulphates, native (DS), or oversulphated (DSS 1 and DSS 2) and a biospecific dextran derivative substituted with carboxymethyl, carboxymethyl-benzylamide and carboxymethyl benzylamide-sulphonate functional groups (CMDBS), has been studied as a function of the sulphated polysaccharide concentration. The initial HC II and thrombin concentrations were set at equimolar levels. Analysis of the experimental data obtained for DS, DSS1 and DSS2 was performed using a previously described model which allows computation of the dissociation constant (KPS,HC) of the polysaccharide-HC II complex and the rate constant of thrombin inhibition by the polysaccharide-HC II complex (k). A KPS.HC of 9.6 x'10(-7) M and a k of 4.5 x 10(9) M-1 min-1 were found for DS, whereas KPS,HC 2.1 x 10(-6) M, k 1.1 x 10(10) M-1 min-1 and KPS,HC 4.3 x 10(-7) M, k 1.4 x 10(10) M-1 min-1 were found for DSS1 and DSS2, respectively. Knowing that DSS1 has a sulphur content per disaccharide of 7.8%, compared with 11.5% for DSS2, these results indicate that the polysaccharide affinity for HC II is increased only in the case of DSS 2, whereas the oversulphation increases the reactivities towards thrombin of both complexes DSS1-HC II and DSS2-HC II. A better conformation of these complexes may favour a faster interaction with the protease. Unlike heparin, DS at concentrations higher than 10(-5) M does not modify the reaction rate of thrombin inhibition, a fact which can be explained by the absence of complex formation between DS and thrombin. The experimental data obtained for CMDBS fit a kinetic model in which the biospecific dextran derivative rapidly forms a complex with thrombin which is more reactive towards HC II than the free protease. The reaction rate remained unchanged for CMDBS concentrations equal to or higher than 10(-5) M, whereas CMDBS was found to interfere strongly with the fibrinogen-thrombin interaction. These data suggest that CMDBS has a strong affinity for the protease and no affinity for HC II. The computed dissociation constant of the CMDBS-thrombin complex (KPS,E) was 2.4 x 10(-7) M and the rate constant of the reaction of this complex with HC II (k) was 1.7 x 10(8) M-1 min-1. These findings indicate that CMDBS exerts its catalytic effect through a unique mechanism of action and may constitute a new class of anticoagulant drugs.
Heparins, dermatan sulfate (DS), and Orgaran are the only glycosaminoglycans that have been used as antithrombotic agents in man. The largest experience concerns unfractionated heparin (UH) and its low-molecular-weight derivatives (LMWHs). It is firmly established that UH is efficient and safe in the prevention and treatment of deep vein thrombosis (DVT). Unfractionated heparin is also used as adjunctive therapy in the treatment of arterial thrombosis. Meta-analyses have shown that LMWHs are slightly more efficient than UH. Because they are more convenient for the nurses and the patient, and because they probably induce less bleeding and less immunogallergic thrombocytopenia, they will progressively replace UH in these indications. Clinical experience with DS is still scarce. Unfractionated DS has a low bioavailability after s.c. or i.m. administration; thus, LMW-DS are presently developed. These compounds have a low prohemorrhagic potential, and it has been proven that they are efficient in the prevention of postoperative DVT. Orgaran is a complex mixture of several glycosaminoglycans, excluding heparin. This compound has been found efficient in the prevention and treatment of DVT. Interestingly, in patients presenting heparin-induced thrombocytopenia, Orgaran may be an alternative treatment because a cross-reactivity with heparin is observed in less than 10% of the subjects.