Novel regio- and stereoselective modifications of heparin in alkaline solution. Nuclear magnetic resonance spectroscopic evidence

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Abstract

Nuclear magnetic resonance spectroscopic evidence is presented in characterizing three new structurally modified forms of heparin. One of these, polymer M-I, represents a conversion of about two-thirds of the α-L-iduronic acid 2-sulfate residues (1) into residues of a 2,3-anhydro derivative (3), through the action of sodium hydroxide. The formation of 3 is attributed to a base-catalysed displacement of the sulfate group of 1 by an intramolecular attack of O-3 on C-2. In more concentrated sodium hydroxide solution, heparin is transformed almost quantitatively into polymer M-II, which differs from it in having residues of (non-sulfated) α-L-iduronic acid (4) in place of 1. It is likely that 3 is an intermediate, and that a selective nucleophilic attack of hydroxide ion at C-2 accounts for the ido configuration in 4. The third modification, giving polymer M-III, is induced when a neutral or weakly alkaline solution of M-I is heated at 70 °C or above, which promotes a different stereochemistry in the hydrolysis of the 2,3-oxirane ring of 3. Hence, in contrast to residues of 4 in M-II, most of the uronic acid residues of M-III appear to have the alternate, α-L-galacto, configuration. As shown by a comparison of beef lung and hog mucosal heparin, the rate at which M-I is converted into M-III is facilitated by the higher level of structural heterogeneity in the mucosal heparin. Whereas the formation of M-I, -II, and -III is accompanied by only moderate depolymerization, these novel polymers retain little of the anti-coagulant and anti-XA activities of the unmodified heparin. Keywords: NMR spectroscopy, heparin, desulfation, anhydroaldoside, base-catalysed displacement.

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