Synthetic carbohydrate derivatives as low sulfated heparin mimetics

The total synthesis of a new family of heparin mimetics containing an hexad eca- (2), an octadeca- (3), and an eicosasaccharide (4) is described. All t hree oligosaccharides contain a pentasaccharidic antithrombin binding domai n(DEFGH: van Boeckel, C. A. A.; Petitou, M. Angew. Chem., Int. Ed. Engl. 19 93, 32, 1671-1690), extended at the nonreducing end by a thrombin binding d omain composed of repeated 2,3-di-O-methyl-6-O-sodium sulfonato-alpha-D-glu cosyl units, The targets were synthesized using a key dodecasaccharide imid ate as glycosyl donor as well as di- and tetrasaccharide imidates, all deri ved from maltose. Condensation of these imidates with a tetrasaccharide pre cursor of the EFGH part of the antithrombin binding domain gave fully prote cted hexadeca-, octadeca-, and eicosasaccharide that were deprotected and s ulfated to yield 2, 3, and 4. All three displayed antithrombin-mediated ant ifactor Xa and antithrombin (factor IIa) activity. The most active compound , the eicosasaccharide, showed activity similar to that of low molecular we ight heparin. Significantly, unlike heparin and its derivatives, the presen t: 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 preven tion and treatment of thrombosis.