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

Abstract

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). However, 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 significantly 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 alpha-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 alpha-glucosidase I activity. Compound 4 is a good inhibitor of intestinal alpha-glucohydrolases, alpha-glucosidase II, and Golgi alpha-mannosidases I and II, but its N-alkyl derivatives 5 and 6 markedly decreased inhibitory potential for all enzymes tested. In the case of 2,5-dideoxy-2,5-imino-D-mannitol (DMDP, 7), which is a potent beta-galactosidase inhibitor, its N-methyl (8) and N-butyl (9) derivatives completely lost potency toward beta-galactosidase as well. N-Alkylation of compounds 4 and 7, known well as potent yeast alpha-glucosidase inhibitors, resulted in a serious loss of inhibitory activity toward yeast alpha-glucohydrolases. Activity of these nine 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 alpha-glucosidase I than 1, proved active with EC50 values of 69 and 49 micrograms/mL in MT-4 cells and 100 and 37 micrograms/mL in MOLT-4 cells, respectively, while none of the furanose analogues exhibited any inhibitory effects on HIV-1. The change in potency and specificity of bioactivity by N-alkylation of nitrogen-in-the-ring sugars appears to be correlated with their conformational change.

Novel α‐L‐fucosidase inhibitors from the bark of Angylocalyx pynaertii (Leguminosae)

“…and seeds of A. pynaertii [5]. Compounds 3 and 11 were identical with N-methyl-DAB and N-methyl-DMJ, which have been chemically synthesized from DAB and DMJ, respectively [10]. From NMR studies, compounds 5, 7, 8 and 9 were identified as new pyrrolidine alkaloids, 1,4-dideoxy-1,4-iminod-xylitol, 2,5-imino-1,2,5-trideoxy-l-glucitol, 2,5-dideoxy-2,5-imino-d-fucitol, and 2,5-imino-1,2,5-trideoxy-d-altritol, respectively.…”

Effect of Environmental Conditions on the α-Glucosidase Inhibitory Activity of Mulberry Leaves

“…Mulberry leaf components inhibit the activity of a kind of digestive enzyme for sugar absorption, -glucosidase, and promote slow absorption of glucose into the blood vessels. [1][2][3] The most important substance in mulberry leaves, 1-deoxynojirimycin (1-DNJ), is known to be a strong intestinal -glucosidase inhibitor. Mulberry leaves contain 1-DNJ, 4) so that mulberry leaf products have been commercialized as health foods.…”

Survey of Anti-HIV and Anti-HCV Compounds from Natural Sources

“…Inhibitors of -glucosidase might reduce the progression of diabetes by decreasing carbohydrate digestion and absorption. In addition, -glucosidase inhibition is a promising strategy for the development of novel anti-HIV agents because the glycosylation of viral envelope glycoproteins is essential for viral infectivity [54][55]. The HIV envelope glycoproteins, gp 120 and gp 41, are involved in viral binding and fusion to cells.…”