Synthesis of oxygen‐substituted N‐alkyl 1‐deoxynojirimycin derivatives: Aza sugar α‐glucosidase inhibitors showing antiviral (HIV‐1) and immunosuppressive activity

The synthesis of a series of six less-lipophilic analogues of the α-glucosidase inhibitor N-decyl-1-deoxynojirimycin (N-decyl-dNM, 5) is described. With the incorporation of a single oxygen atom, particularly at position seven in the N-decyl side-chain to give N-(7-oxadecyl)-dNM (8), the therapeutic ratio (α-glucosidase I inhibitory activity over toxicity in HepG2 cells) increases considerably. Compound 8 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 (7) is less active than 8 and, moreover, is toxic to HepG2 cells at 3 mM. Subsequently, the synthesis of eight ester derivatives of N-(7-oxadecyl)-dNM is described. All of these ester analogues are less active α-glucosidase inhibitors than the parent compound 8 in HepG2 cells. The compounds were further analyzed 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 (8) inhibits HIV-1-induced syncytia formation and lymphocyte proliferation in vitro. Finally, compound 8 was investigated in vivo. N-(7-Oxadecyl)-dNM (8) reduced adjuvant-induced arthritis in rats making this compound a potential candidate for treating autoimmune diseases like rheumatoid arthritis.