Anticoagulant sulfated polysaccharides: Part I. Synthesis and structure-activity relationships of new pullulan sulfates

In order to develop new anticoagulants as potential heparin alternatives, t wo pullulans with different molecular weight (MW) were used as starting pol ymers for the partial synthesis of a structurally new class of sulfated pol ysaccharides. Sulfation of these linear alpha- 1,4-/1,6-glucans was carried out by a method with a SO3-pyridine complex in DMF, which had been optimiz ed for the modification of beta -1,3-glucans. Modifications of this methods resulted in pullulan sulfates with degrees of sulfation (DS) ranging from 0.17 to 1.99 and MW between 15 and 250 kDa. More than 50% of the sulfate gr oups were bound to the secondary C atoms in positions 2, 3 and 4 of the glu cose monomers. The anticoagulant activity of the obtained pullulan sulfates was determined in the coagulation assays prothrombin time (PT), activated partial thromboplastin time (APTT), Heptest((R)) and thrombin time (TT). Th ey represent potent anticoagulants reaching the efficacy of heparin. Their activity not only improves with increasing DS and MW, but also: with increa sing part of sulfate groups in positions 2, 3 and 4. In addition, their act ion profile changes in dependence on their individual structure as reflecte d by the ratio of the TT- to the APTT-activity. The pullulan sulfates speci fically interfere with different stages of the coagulation cascade, and the se interactions have different requirements on the chemical structure. (C) 2002 Elsevier Science Ltd. All fights reserved.