SYNTHESES OF HEPARIN - LIKE PENTAMERS CONTAINING OPENED URONIC-ACID MOIETIES

The syntheses of four analogues of pentasaccharide Ia, which corresponds to the minimal AT III binding region of heparin, are presented and the biological activities of these analogues will be discussed. Three of these analogues (i.e. compounds II, III and IV) contain an R-glyceric acid oxymethylene residue (i.e. B in fig.3) instead of α-L-iduronic acid and in the other analogue (i.e. compound V) the β-D-glucuronic acid unit has been replaced by an s-glyceric acid oxymethylene residue (i.e. A in fig3). The R and S-glyceric acid oxymethylene residues represent an "opened" iduronic acid unit and an "opened" glucuronic acid unit, respectively, containing the essential carboxylate function in the appropriate configuration. The crucial step in the syntheses of these "opened" uronic acid pentamer analogues, was the preparation of the required glyceric acid oxymethylene residues 8a, 8b and 8c. Analogues II and III, containing an "opened" iduronic acid moiety, display a significant AT III mediated αXa activity. Compound III contains two extra sulphate groups at unit 2. Removal of the contributing O-sulphate groups at position 3 and 6 of unit 6 of compound II (i.e. compound IV) results in a seven-fold drop in αXa activity. Replacement of the β-D-glucuronic acid unit by an S-glyceric acid oxymethylene residue (i.e. compound V) leads to almost a complete loss of αXa activity, notwithstanding the fact that all the essential and contributing charged groups are present in the molecule. © 1990.