SYNTHESIS OF ALPHA-GLUCOSIDASE-I INHIBITORS SHOWING ANTIVIRAL (HIV-1)AND IMMUNOSUPPRESSIVE ACTIVITY

The synthesis of a series of analogues of the monosaccharide alpha-glu cosidase I inhibitor N-decyl-1-deoxynojirimycin (1) is described. With the incorporation of a single oxygen atom particularly at position se ven in the N-decyl side chain, i.e. to give N-7-oxadecyl-dNM (4), the therapeutic ratio (oc-glucosidase I inhibitory activity over toxicity in HepG2 cells) increases considerably. N-7-Oxadecyl-dNM inhibits puri fied porcine liver alpha-glucosidase I with an IC50 value of 0.28 mu M . The position of the oxygen atom in the N-decyl side chain is of impo rtance since N-3-oxadecyl-dNM is less active and, moreover, is toxic t o HepG2 cells at 3 mM. Subsequently, the synthesis of a disaccharide i nhibitor of a-glucosidase I is described. The aminodisaccharide ManNH( 2) alpha 1,2Glc (12) inhibits cr-glucosidase I with an IC50 value of 1 5.7 mu M. Two closely related monosaccharide derivatives of 12 did not inhibit the enzyme at low mu M concentrations (no inhibition at 5 mu M), showing the additional effect of binding of the aglycon fragment o f the molecule to the active site of alpha-glucosidase I. Next, the N- alkyl-dNM derivatives were analysed for antiviral and immunomodulatory activity in-vitro. It is found that the most potent alpha-glucosidase I inhibitor from this study, N-7-oxadecyl-dNM (4) inhibits HIV-1 indu ced syncytia formation and lymphocyte proliferation in-vitro. Finally, compound 4 was also investigated in-vivo. N-7-Oxadecyl-dNM (4) reduce d adjuvant-induced arthritis in rats making this compound a potential candidate for treating autoimmune diseases like rheumatoid arthritis.