STRUCTURE-ACTIVITY RELATIONSHIP OF ANTITHROMBOTIC POLYSACCHARIDE DERIVATIVES

Heparin has been the drug of choice in clinical pre-surgical and post- surgical prophylaxis of thrombotic events. However, because of its sid e-effects, such as bleeding and other disadvantages (i.e. chemical inh omogeneity and variability of its physiological activities), alternati ves to heparin are an important field of research. A necessary procedu re in the development of new drugs is the evaluation of structure-acti vity relationships. Genuine neutral polysaccharides were chemically mo dified and examined for their anticoagulant activities, The linear bet a-1,3-glucan curdlan, an easily available bacterial polysaccharide, se rved as the basic polymer. It could be established that the anticoagul ant activity was dependent on the degree of sulfation and the molecula r weight. For heparin, the sulfation pattern, i.e, the actual location of the sulfate groups along the heparin chain, was of importance in a ddition to the degree of sulfation. Therefore, we investigated whether there was also a relationship between the substitution pattern of the curdlan sulfates and their anticoagulant activity. For determination of the substitution pattern of the sulfated polysaccharides, a method was developed that is based on synthesis of the partially alkylated al ditol acetates of the polymer and examination of these derivatives usi ng combined gas chromatography-mass spectrometry. In addition to the a nalytical data, the structure-activity relationship of anticoagulative curdlan sulfates is presented.