T. Barzu et al., PREPARATION AND ANTI-HIV ACTIVITY OF 0-ACYLATED HEPARIN AND DERMATAN SULFATE DERIVATIVES WITH LOW ANTICOAGULANT EFFECT, Journal of medicinal chemistry, 36(23), 1993, pp. 3546-3555
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.