title: Dendritic polyglycerol sulfates as new heparin analogues and potent inhibitors of the complement system.
abstract: Due to several limitations of heparin, a widely used antithrombotic drug, there is large interest to develop alternatives. The aim of the presented study was to produce fully synthetic highly branched heparin mimetics. For this purpose, a new type of 'treelike' polysulfated polymers based on dendritic polyglycerol was synthesized. An efficient synthetic approach has been chosen to prepare several polyglycerol sulfates with different molecular weights as well as a polyglycerol carboxylate analogue and to evaluate them for their anticoagulant and anticomplementary activities. In contrast to the nonderivatized and the carboxylated polyglycerols, the polyglycerol sulfates prolong the activated partial thromboplastin time (APTT) and thrombin time (TT) and inhibit both the classical (CCA) and alternative complement activation (ACA). Whereas their anticoagulant activity in the APTT and in the TT amounts to 5.7-8.1% and 15.7-33.6%, respectively, of that of unfractionated heparin (UFH), their CCA and ACA inhibitory activity is 13.4-23.9 and 2.7-3.7 times, respectively, higher. In contrast to sulfated polysaccharides, the activities are not clearly dependent on the molecular weight, which might be due to the globular 3D-structure of the dendritic molecules. Due to the coherence between coagulation, complement activation and inflammation in the pathophysiology of numerous diseases, polyglycerol sulfates with both anticoagulant and anticomplementary activities represent promising candidates for the development of potential drugs.
authors.affiliation: Freiburg Materials Research Center, Albert-Ludwigs-University of Freiburg, Stefan-Meier-Strasse 21, 79104 Freiburg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Türk
authors.forename: Rainer
authors.initials: R
authors.lastname: Haag
authors.forename: Susanne
authors.initials: S
authors.lastname: Alban
mesh_terms: D000328:Adult; D000465:Algorithms; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000494:pharmacology*; D003169:Complement Inactivator Proteins / Q000138:chemical synthesis* / Q000494:pharmacology*; D003170:Complement Pathway, Alternative / Q000187:drug effects; D003171:Complement Pathway, Classical / Q000187:drug effects; D005990:Glycerol / Q000737:chemistry* / Q000494:pharmacology*; D006493:Heparin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008970:Molecular Weight; D011108:Polymers / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000925:Anticoagulants; D003169:Complement Inactivator Proteins; D011108:Polymers; C043941:polyglycerol; D006493:Heparin; D005990:Glycerol