REGIOSELECTIVE SYNTHESES OF SULFATED POLYSACCHARIDES - SPECIFIC ANTI-HIV-1 ACTIVITY OF NOVEL CHITIN SULFATES

A novel and convenient method for the regioselective syntheses of sulf ated analogs of chitin and chitosan is described in relation to studie s on structure-biological activity. Fully protected, soluble derivativ es of chitosan were found to be useful intermediates for the syntheses of a novel class of sulfated polysaccharides, amido-2-deoxy-3-O-sulfo -(1-->4)-beta-D-(3-sulfate, 3S, 4) and ->4)-2-deoxy-2-sulfoamido-3-O-s ulfo-(1-->4)-beta-D -glucopyranan (2,3-disulfate, 23-S, 3). These comp ounds were tested for their activities in (i) inhibiting HIV-1 replica tion in vitro and (ii) inhibiting blood coagulation. The results revea l that the selective sulfation at O-2 and/or O-3 affords potent antire troviral agents showing a much higher inhibitory effect on the infecti on of AIDS virus in vitro than that by the known 6-O-sulfated derivati ve (6-sulfate, 6S). Moreover, the 23-S product completely inhibited th e infection of AIDS virus to T lymphocytes at concentrations as low as 0.28 mu g/mL without significant cytotoxicity. The regioselective int roduction of sulfate group(s) at O-2 and/or O-3 had little effect on g enerating anticoagulant activity, whereas 6-O-sulfated chitin strongly inhibits blood coagulation. These results suggest that the specific i nteraction of these new types of chitin sulfates with gp 120 of the AI DS virus depends significantly on the sites of sulfation rather than o n the total degree of substitution on sugar residues. (C) 1998 Elsevie r Science Ltd. All rights reserved.