Synthesis and anticoagulant activity of bioisosteric sulfonic-acid analogues of the antithrombin-binding pentasaccharide domain of heparin

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Two pentasaccharide sulfonic acids that were related to the antithrombin-binding domain of heparin were prepared, in which two or three primary sulfate esters were replaced by sodium-sulfonatomethyl moieties. The sulfonic-acid groups were formed on a monosaccharide level and the obtained carbohydrate sulfonic-acid esters were found to be excellent donors and acceptors in the glycosylation reactions. Throughout the synthesis, the hydroxy groups to be methylated were masked in the form of acetates and the hydroxy groups to be sulfated were masked with benzyl groups. The disulfonic-acid analogue was prepared in a [2+3] block synthesis by using a trisaccharide disulfonic acid as an acceptor and a glucuronide disaccharide as a donor. For the synthesis of the pentasaccharide trisulfonic acid, a more-efficient approach, which involved elongation of the trisaccharide acceptor with a non-oxidized precursor of the glucuronic acid followed by post-glycosidation oxidation at the tetrasaccharide level and a subsequent [1+4] coupling reaction, was elaborated. In vitro evaluation of the anticoagulant activity of these new sulfonic-acid derivatives revealed that the disulfonate analogue inhibited the blood-coagulation-proteinase factor Xa with outstanding efficacy; however, the introduction of the third sulfonic-acid moiety resulted in a notable decrease in the anti-Xa activity. The difference in the biological activity of the disulfonic- and trisulfonic-acid counterparts could be explained by the different conformation of their L-iduronic-acid residues. The thin red line: The lower activity of the trisulfonic-acid analogue of the antithrombin-binding domain of heparin revealed that the substitution pattern (or number of sulfonates) affected the inhibitory potency of these derivatives for factor Xa.

Original languageEnglish
Pages (from-to)10643-10652
Number of pages10
JournalChemistry - A European Journal
Issue number34
Publication statusPublished - aug. 20 2012


ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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