Synthesis of alpha-glucosidase I inhibitors showing antiviral (HIV-1) and immunosuppressive activity.
The synthesis of a series of analogues of the monosaccharide alpha-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 (alpha-glucosidase I inhibitory activity over toxicity in HepG2 cells) increases considerably. N-7-Oxadecyl-dNM inhibits purified porcine liver alpha-glucosidase I with an IC50 value of 0.28 microM. 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 mM. Subsequently, the synthesis of a disaccharide inhibitor of alpha-glucosidase I is described. The aminodisaccharide ManNH2 alpha 1,2Glc (12) inhibits alpha-glucosidase I with an IC50 value of 15.7 microM. Two closely related monosaccharide derivatives of 12 did not inhibit the enzyme at low microM concentrations (no inhibition at 5 microM), showing the additional effect of binding of the aglycon fragment of 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 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.
van den Broek
L A
LA
Department of Medicinal Chemistry, N.V. Organon, Netherlands.
Kat-Van Den Nieuwenhof
M W
MW
Butters
T D
TD
Van Boeckel
C A
CA
D017485:1-Deoxynojirimycin / Q000138:chemical synthesis* / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000378:metabolism; D001169:Arthritis, Experimental / Q000145:classification; D065089:Glycoside Hydrolase Inhibitors; D006801:Humans; D008297:Male; D009161:Mycobacterium; D051381:Rats; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D065089:Glycoside Hydrolase Inhibitors; D017485:1-Deoxynojirimycin