Synthesis of Azidothymidine-Bound Curdlan Sulfate with Anti-Human Immunodeficiency Virus Activity in vitro

Abstract

ABSTRACT:Azidothymidine (AZT) was introduced into curdlan by biodegradable ester bond to give AZT-bound curdlan (AZT-curdlan) in order to aim at releasing AZT from the polymer backbone by an enzymatic hydrolysis in living organs. Structure of the AZT-curdlan was analyzed by 13 C NMR and 1 H-13 C COSY-FG 2D-NMR spectroscopy, indicating that AZT was bound to C6 hydroxyl group of curdlan as designed. Subsequently, the AZT-curdlan was sulfated with sulfur trioxide-pyridine complex to give sulfated AZT-curdlans (AZT-curdlan sulfates). AZT-curdlan sulfates, in vitro, exhibited anti-HIV activities in the EC 50 range of 0.20 to 0.60/lgml-1 , corresponding to that (EC50 =0.50!lgml-1 ) of highly active curdlan sulfate. They possessed low cytotoxicities of CC50 more than I 000 !lg ml-1 in vitro, indicating that AZT was not released in vitro. However, an increase in the anti-HIV activity and the cytotoxicity was observed when the AZT-curdlan sulfate solution in 90% buffer at pH 7.4 and 10% dimethyl sulfoxide mixture was kept in a refrigerator for a few weeks. The phenomenon indicates that an anti-HIV active AZT was released slowly from the curdlan sulfate carrier. Furthermore, the AZT-curdlan sulfates exhibited low to moderate anticoagulant activities in vitro.

Synthesis of Azidothymidine-Bound Sulfated Alkyl Oligosaccharides and Their Inhibitory Effects on AIDS Virus Infection in vitro

“…The introduction of 5'-Suc-AZT ester moiety did not enhanced the anti-HIV activity of curdlan sulfate. 24 These findings hinted further that mechanism of the inhibitory effect of sulfated oligosaccharide on HIV infection may be different from that of sulfated polysaccharide.…”

“…24 To a cetyl laminaripentaoside (0.15 g, 0.14mmol) solution in pyridine (5 ml) were added 5'-Suc-AZT (0.25 g, 0.68 mmol) and DMAP (0.10 g). Then, DCC (0.20 g) was added gradually to the above solution for 30 min.…”

“…Moreover, it has been reported that ester bond binding AZT with carrier was stable under a moderate pH condition in vitro, 28 and AZT is not released from the carrier. 24 Therefore, it is assumed that activity detected by the MTT method represents that of the prodrug itself, the activity from free AZT can not be added to the activity detected by the MTT in vitro.…”

Synthesis and characterization of starch piperinic ester and its self‐assembly of nanospheres

“…Water-soluble starch with a medium molecular weight (M n 5 12000, M w /M n 5 1.38) was prepared by hydrolysis of commercial starch in the presence of H 2 SO 4 as catalyst, according to the method reported previously. 25 Molecular weight of the water-soluble starch was determined by means of GPC in pH 5 6.8 phosphate buffer solution at 258C. Other reagents were commercially available and used as received.…”

Ester Derivatives of Nucleoside Inhibitors of Reverse Transcriptase: 2. Molecular Systems for the Combined Therapy with 3′-Azido-3′-Deoxythymidine and 2′,3′-Didehydro-3′-Deoxythymidine

“…scriptase inhibitors together with the protease [12][13][14][15] or integrase [16] inhibitors is employed the most widely. The combinations of nucleoside and nonnucleoside inhibitors of reverse transcriptase [17] with immunoactive substances (peptides and polysaccharides [18,19], the compounds affecting stability of the viral particle (e.g., bicyclames) [20], and the receptor antagonists of the HIV target cells (peptides) [21][22][23] are also used. In the combined therapy, it is also suggested to use the conjugates of two drugs that will be biodegraded by cellular enzymes into the two active principles in the physiological medium.…”