title: [New synthesis of the anticoagulant pentasaccharide idraparinux and preparation of its analogues containing sulfonic acid moieties].
abstract: Two novel synthetic pathways were elaborated for the preparation of idraparinux, a heparin-related fully O-sulfated, O-methylated anticoagulant pentasaccharide. Both methods based upon a [2+3] block synthesis utilizing the same trisaccharide acceptor which was coupled to either a uronic acid disaccharide donor or its nonoxidized precursor. Two bioisosteric sulfonic acid analogues of idraparinux were also 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. 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 the reference compound idraparinux and the 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.
authors.affiliation: Debreceni Egyetem, Természettudományi és Technológiai Kar, Szerves Kémiai Tanszék, DE-MTA Szénhidrátkémiai Kutatócsoport, 4032, Debrecen Egyetem tér 1. herczeg.mihaly@science.unideb.hu
authors.forename: Mihály
authors.initials: M
authors.lastname: Herczeg
mesh_terms: D000925:Anticoagulants / Q000138:chemical synthesis*; D004187:Disaccharides / Q000138:chemical synthesis; D065427:Factor Xa Inhibitors; D020723:Glucuronic Acid; D020719:Glucuronides; D009844:Oligosaccharides / Q000138:chemical synthesis*; D013451:Sulfonic Acids; D014312:Trisaccharides / Q000138:chemical synthesis
chemical_list: D000925:Anticoagulants; D004187:Disaccharides; D065427:Factor Xa Inhibitors; D020719:Glucuronides; D009844:Oligosaccharides; D013451:Sulfonic Acids; D014312:Trisaccharides; C479958:idraparinux; D020723:Glucuronic Acid