Heparin And Heparan Sulfate

Heparin was originally isolated from liver in 1916 by Maclean, and its anticoagulant properties were immediately realized. However, structural complexity prevented the unambiguous establishment of the accepted chemical structure of heparin until the late 1960s [116]. Heparin's remarkable pharmacological properties have resulted in a large body of research, including the chemical synthesis of heparin fragments and related analogs [117]. The literature pertaining to the synthesis of heparin, heparan sulfate, and their analogs is vast and has been reviewed [118].

Heparin (VI.1) (Fig. 8) is found in a variety of mammalian tissues and consists of a repeating, linear copolymer of ¡(1,4)-linked uronic acid and glucosamine residues, where the uronic acid moiety consists of 90% iduronic acid and 10% glucuronic acid [119]. The most common copolymer of heparin is the trisulfated disaccharide, where sulfation is solely on glucosamine at the C2, C3, and C6 positions. In a number of structural variants, the 2-amino functionality can be sulfated, acetylated or unsub-stituted, and consequently heparin formations are microheterogeneous [120]. The source of antithrombotic activity, hence the anticoagulant activity of heparin, is the result of specific affinity for the serine protease inhibitor antithrombin III (AT-III). Inhibition of AT-III in turn inactivates serine proteases factor Xa and thrombin (factor IIa), which are downstream members of the coagulation cascade [121]. AT-III is a weak inhibitor of factor Xa and thrombin, which is considerably enhanced upon the binding of heparin [122].

Different molecular weight fragments of heparin display different anticoagulant properties. Specifically, heparin polysaccharides above 5 kDa inhibit thrombin and factor Xa in the presence of AT-III, while lower molecular weight heparin fragments only inhibit factor Xa [123]. Studies on heparin fragments obtained from chemical or enzymatic degradation revealed that approximately one-third of the heparin chains had the ability to bind to AT-III [124]. These experiments suggested that a limited number of heparin fragments possessed the structural features that are the source of its biological activity. Subsequently, a unique pentasaccharide domain was identified as necessary and sufficient for binding and activation of AT-III (Fig. 9) [125]. The sequence contains three monosaccharide units that rarely occur in heparin: a 6-O-sulfate-N-acetyl-a-d-glucosamine (unit D in Fig. 9), a ¡-d-glucuronic acid (unit E), and a 3,6-di-O-sulfate-N-sulfate-a-d-glucosamine moiety (unit F). The D unit can be either N-acetylated (VI.3) or N-sulfated (VI.4) depending on the source of the polysaccharide. The discovery that this pentasaccharide was responsible for the biological activity of the larger polysaccharide chain was a considerable breakthrough,

Scheme 50 The Ogawa synthesis of the keratan sulfate I tetrasaccharide, part 2.
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