Synthesis of α-Glucosidase I Inhibitors Showing Antiviral (HIV-1) and Immunosuppressive Activity

Abstract

The synthesis of a series of analogues of the monosaccharide α-glucosidase I inhibitor N-decyl-1-deoxynojirimycin (1) is described. With the incorporation of a single oxygen atom particularly at position seven in the N-decyl side chain, i.e. to give N-7-oxadecyl-dNM (4), the therapeutic ratio (α-glucosidase I inhibitory activity over toxicity in HepG2 cells) increases considerably. N-7-Oxadecyl-dNM inhibits purified porcine liver α-glucosidase I with an ***IC50 value of 0.28 μM. The position of the oxygen atom in the N-decyl side chain is of importance since N-3-oxadecyl-dNM is less active and, moreover, is toxic to HepG2 cells at 3 μM. Subsequently, the synthesis of a disaccharide inhibitor of α-glucosidase I is described. The aminodisaccharide ManNH₂α1,2Glc*** (12) inhibits α-glucosidase I with an IC50 value of 15ṁ7 μM. Two closely related monosaccharide derivatives of 12 did not inhibit the enzyme at low μM concentrations (no inhibition at 5 μM), showing the additional effect of binding of the aglycon fragment of the molecule to the active site of α-glucosidase I. Next, the N-alkyl-dNM derivatives were analysed for antiviral and immunomodulatory activity in-vitro. It is found that the most potent α-glucosidase I inhibitor from this study, N-7-oxadecyl-dNM (4) inhibits HIV-1 induced syncytia formation and lymphocyte proliferation in-vitro. Finally, compound 4 was also investigated in-vivo. N-7-Oxadecyl-dNM (4) reduced adjuvant-induced arthritis in rats making this compound a potential candidate for treating autoimmune diseases like rheumatoid arthritis.