Nitrogen-in-the-Ring Pyranoses and Furanoses: Structural Basis of Inhibition of Mammalian Glycosidases

Journal of Medicinal Chemistry
1994.0

Abstract

Seven pyranoses and three furanoses with a nitrogen in the ring were prepared by chemical synthesis, microbial conversion, and isolation from plants to investigate the contribution of epimerization, deoxygenation, and conformation to the potency of inhibition and specificity of mammalian glycosidases. The seven pyranoses are 1-deoxynojirimycin (1), the D-manno (2), D-allo (3), and D-galacto (4) isomers of 1, fagomine (1,2-dideoxynojirimycin, 5), and the D-allo (6) and D-galacto (7) isomers of 5, while the three furanoses are 2,5-dideoxy-2,5-imino-D-mannitol (8), 1,4-dideoxy-1,4-imino-D-arabinitol (9), and 1,4-dideoxy-1,4-imino-D-ribitol (10). The 2-deoxygenation and/or 3-epimerization of 1 enhanced the potency for rat intestinal lactase and bovine liver cytosolic beta-galactosidase. Especially compound 6 showed a potent inhibitory activity against both enzymes, and compound 8, a mimic of beta-D-fructofuranose, was a potent inhibitor of both beta-galactosidases as well. Compound 4, which has been known as a powerful alpha-galactosidase inhibitor, exhibited no significant inhibitory activity for most of mammalian beta-galactosidases. In addition, compound 6 fairly retained a potency of 1 toward rat intestinal isomaltase. In this study, compound 8, known as a processing alpha-glucosidase I inhibitor in cell culture, has been found to have no effect on processing alpha-glucosidase II, whereas 9 has been shown to be a good nonspecific inhibitor of intestinal isomaltase, processing alpha-glucosidase II, Golgi alpha-mannosidases I and II, and porcine kidney trehalase. It has been speculated that glycosidase inhibitors have structures which resemble those of the respective glycosyl cations. This Broad inhibitory activity of 9 toward various glycosidases suggest that it superimposes well on the various glycosyl cations.

Knowledge Graph

Similar Paper

Nitrogen-in-the-Ring Pyranoses and Furanoses: Structural Basis of Inhibition of Mammalian Glycosidases
Journal of Medicinal Chemistry 1994.0
N-Alkylated Nitrogen-in-the-Ring Sugars: Conformational Basis of Inhibition of Glycosidases and HIV-1 Replication
Journal of Medicinal Chemistry 1995.0
Homonojirimycin Isomers and N-Alkylated Homonojirimycins:  Structural and Conformational Basis of Inhibition of Glycosidases
Journal of Medicinal Chemistry 1998.0
Nitrogen-Containing Furanose and Pyranose Analogues from <i>Hyacinthus </i><i>orientalis</i>
Journal of Natural Products 1998.0
Nitrogen-Containing Furanose and Pyranose Analogues from <i>Hyacinthus </i><i>orientalis</i>
Journal of Natural Products 1998.0
Effect of five-membered sugar mimics on mammalian glycogen-degrading enzymes and various glucosidases
Bioorganic &amp; Medicinal Chemistry 2008.0
In vitro inhibition of glycogen-degrading enzymes and glycosidases by six-membered sugar mimics and their evaluation in cell cultures
Bioorganic &amp; Medicinal Chemistry 2008.0
α-1-C-Alkyl-1-deoxynojirimycin derivatives as potent and selective inhibitors of intestinal isomaltase: remarkable effect of the alkyl chain length on glycosidase inhibitory profile
Bioorganic &amp; Medicinal Chemistry Letters 2004.0
Isolation and SAR studies of bicyclic iminosugars from Castanospermum australe as glycosidase inhibitors
Phytochemistry 2015.0
Synthesis and α-glucosidase inhibitory activity evaluation of N-substituted aminomethyl-β-d-glucopyranosides
Bioorganic &amp; Medicinal Chemistry 2013.0