N-Alkylated Nitrogen-in-the-Ring Sugars: Conformational Basis of Inhibitiopn of Glycosidases and HIV-1 Replication

Article abstract of DOI:10.1021/jm00013a012

The conformations of nitrogen-in-the-ring sugars and their N-alkyl derivatives were studied from 1H NMR analyses, mainly using ³J(H,H) coupling constants and quantitative NOE experiments.No significant difference was seen in the ring conformation of 1-deoxynojirimycin (1), N-methyl-1-deoxynojirimycin (2), and N-butyl-1-deoxynojirimycin (3).Hiowever, it was shown that the C6 OH group in 1 is predominantly equatorial to the piperidine ring, while that in 2 or 3 is predominantly axial, and its N-alkyl group is oriented equatorially.In the furanose analogues 1,4-dideoxy-1,4-imino-D-arabinitol (4) and its N-methyl (5) and N-butyl (6) derivatives, the five-membered ring conformation differed significvantly by the presence or absence of the N-substituted group and the length of the N-alkyl chain.Compound 3 reduced its inhibitory effect on almost all glycosidases, resulting in an extremely specific inhibitor for processing α-glucosidase I since N-alkylation of 1 is known to enhance both the potency and specificity of this enzyme in vitro and in vivo.This preferred (C6 OH axial) conformation in 2 and 3 appears to be responsible for their strong α-glucosidase I activity.Compound 4 is a good inhibitor of intestinal α-glucohydrolases, α-glucosidase II, and Golgi α-mannosidases I and II, but is N-alkyl derivatives 5 and 6 markedly decreased inhibitory potential for all enzymes tested.In the case of 2,5-dideoy-2,5-imino-D-mannitol (DMDP, 7), which is a potent toward β-galactosidase inhibitor, its N-methyl (8) and N-butyl (9) derivatives completely lost potency β-galactosidase as well.N-alkylation of compounds 4 and 7, known well as potent yeast α-glucosidase inhibitors, resulted in a serious loss of inhi bitory activity toward yeast α-glucohydrolases.Activity of these nine sugar analogues against HIV-1 replication was determined, based on the inhibition of virus-induced cytopathogenicity in MT-4 and MOLT-4 cells.Compounds 2 and 3, which are better inhibitors of α-glucosidase I than 1, proved active with EC₅₀ values of 69 and 49 μg/mL in MT-4 cells and 100 and 37 μg/mL in MOLT-4 cells, respectively, while none of the furanose analogues exhibited any inhibitory effects on HIV-1.The change in potency and specifity of bioactivity by N-alkylation of nitrogen-in-the-ring sugars appears to be correlated with their conformational change.