PREPARATION AND ANTI-HIV ACTIVITY OF 0-ACYLATED HEPARIN AND DERMATAN SULFATE DERIVATIVES WITH LOW ANTICOAGULANT EFFECT

In order to increase the ratio of anti-HIV activity to anticoagulant a ctivity, glycosaminoglycan derivatives selectively substituted at OH a nd/or COOH groups were prepared. Standard heparin, heparin fragments, br dermatan sulfate were- converted to their tributylammonium or tetra butylammonium salts. Their selective O-acylation to various (controlle d) degrees was carried out in a homogeneous way in N,N-dimethylformami de using carboxylic acid anhydrides and 4-(dimethylamino)pyridine as c atalyst. Esterification of the COOH groups was performed by the additi on of alkyl halide to an N,N-dimethylformamide solution of glycosamino glycan tetrabutylammonium sets. The in vitro anticoagulant activity, t he activity against HIV-1 and HIV-2 cytopathicity, the cytotoxicity, a nd the activity on the induction of giant cell formation were determin ed. O-acylation (O-butyrylation or O-hexanoylation) of the heparin fra gments obtained by periodate depolymerization (compounds 2d and 2e), a nd their esters (compounds 7i and 7j), yielded products with very low anticoagulant effects in vitro, yet potent activity against both HIV-1 and HIV-2 induced cytopathicity, and low, if any, cytotoxicity. As co mpared to other anionic polysaccharides, these acylated derivatives ar e more active as inhibitors of HIV-induced giant-cell formation. Their anti-HIV activity is related to the degree of 0-acylation and is main ly due to the inhibition of virus adsorption to the target cells.