Synthetic carbohydrate derivatives as low sulfated heparin mimetics

The total synthesis of a new family of heparin mimetics containing an hexadeca- (2), an octadeca- (3), and an eicosasaccharide (4) is described. All three oligosaccharides contain a pentasaccharidic antithrombin binding domain(DEFGH: van Boeckel, C. A. A.; Petitou, M. Angew. Chem., Int. Ed. Engl. 1993, 32, 1671-1690), extended at the nonreducing end by a thrombin binding domain composed of repeated 2,3-di-O-methyl-6-O-sodium sulfonato-alpha-D-glucosyl units, The targets were synthesized using a key dodecasaccharide imidate as glycosyl donor as well as di- and tetrasaccharide imidates, all derived from maltose. Condensation of these imidates with a tetrasaccharide precursor of the EFGH part of the antithrombin binding domain gave fully protected hexadeca-, octadeca-, and eicosasaccharide that were deprotected and sulfated to yield 2, 3, and 4. All three displayed antithrombin-mediated antifactor Xa and antithrombin (factor IIa) activity. The most active compound, the eicosasaccharide, showed activity similar to that of low molecular weight heparin. Significantly, unlike heparin and its derivatives, the present: heparin mimetics do not interact with platelet factor 4, an interaction that can cause severe side effects in heparin-treated patients. Thus, this new family of compounds contains interesting drug candidates for the prevention and treatment of thrombosis.