Preparation and anti-HIV activity of O-acylated heparin and dermatan sulfate derivatives with low anticoagulant effect

Abstract

In order to increase the ratio of anti-HIV activity to anticoagulant activity, glycosaminoglycan derivatives selectively substituted at OH and/or COOH groups were prepared. Standard heparin, heparin fragments, or dermatan sulfate were converted to their tributylammonium or tetrabutylammonium salts. Their selective O-acylation to various (controlled) degrees was carried out in a homogeneous way in N,N-dimethylformamide using carboxylic acid anhydrides and 4-(dimethylamino)pyridine as catalyst. Esterification of the COOH groups was performed by the addition of alkyl halide to an N,N-dimethylformamide solution of glycosaminoglycan tetrabutylammonium salts. The in vitro anticoagulant activity, the activity against HIV-1 and HIV-2 cytopathicity, the cytotoxicity, and the activity on the induction of giant cell formation were determined. O-acylation (O-butyrylation or O-hexanoylation) of the heparin fragments obtained by periodate depolymerization (compounds 2d and 2e), and 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 compared to other anionic polysaccharides, these acylated derivatives are more active as inhibitors of HIV-induced giant-cell formation. Their anti-HIV activity is related to the degree of O-acylation and is mainly due to the inhibition of virus adsorption to the target cells.

Antiviral therapy for human immunodeficiency virus infections

“…Dextran sulfate, upon intravenous administration, produces thrombocytopenia (164). Sulfated polymers are also notorious for their anticoagulant activity, but as has been demonstrated with periodate-treated heparin (19) and O-acylated heparin (63), this problem can be overcome by appropriate chemical modifications.…”

Antiviral Portrait Series: 4. Polysuifates as Inhibitors of HIV and Other Enveloped Viruses

“…Using this procedure, the plasma half-life of heparin in humans has been found to be approximately 35 min (after iv injection of 23 mg heparin) (Dawes et al, 1986). However, the anti-HIV activity and anticoagulant effects of sulfated polymers are not necessary correlated (Baba et al, 1990a;Barzu et al, 1993).…”

“…Shortly after the identification and isolation of the virus responsible for the acquired immune deficiency syndrome (AIDS) (subsequently named the human immunodeficiency virus, HIV), several groups, following a suggestion of De Clercq (1986), demonstrated that heparin and other polysulfates are potent and selective inhibitors of HIV-1 replication in cell culture (Ito et el., 1987(Ito et el., , 1991suya et el., 1988;Mizumoto et ei., 1988;Yoshida et al, 1988;Hirabayashi et el., 1989;Jurkiewicz et el., 1989;Sugawara et al, 1989;Tochikura et al, 1989;Anand et el., 1990a,b;Kaneko et al, 1990;Montefiori et al, 1990;Weiler et al, 1990;Schols et sl., 1990aSchols et sl., , 1991Von Briesen et al, 1990;Aoki et al, 1991;Bagasra et al, 1988Bagasra et al, , 1991Sosa et al, 1991;Handa et al, 1991;Hatanaka et al, 1991;McClure et al, 1991;Moriya et al, 1991Moriya et al, , 1993Otake et al, 1991Otake et al, , 1994Witvrouw et al, 1991Witvrouw et al, , 1992Witvrouw et al, , 1994Mizuno et al, 1992;Uryu et al, 1992;Barzu et al, 1993;Beutler et al, 1993;Damonte et el., 1994). Several polysulfates were also found to be active against a wide variety of enveloped viruses (Baba et el., 1988c;De Clercq, 1990, 1993;Andrei et el., 1991;Schols et al...…”

Preparation and Characterization of O-Acylated Fucosylated Chondroitin Sulfate from Sea Cucumber

“…For example, Petitou et al [12] selectively introduced acyl groups into heparin and its fragments. The measurements of anticoagulant and anti-HIV activities of these compounds indicated that their anti-HIV activities did not differ markedly from that of heparin, although their anticoagulant activities were much lower [13]. O -Acylated low-molecular-weight carrageenans were prepared.…”