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

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.

Two Subsites on the Active Center of Pig Kidney Trehalase

“…They found that results with the five-membered-ring compound, 1,4-dideoxy-l,4-imino-D-arabinitol, superimpose well on the binding model on the basis of the mannosyl cation geometry. 1,4-Dideoxy-1,4-imino-D-arabinitol also superimposes well on the glucosyl cation, since it has two ring hydroxyl groups lying in the same region of space as C3 and C4 of a putative glucosyl cation, with the hydroxymethyl group also being topographically equivalent (Asano et al, 1994). 1,4-Dideoxy-l ,4-imino-D-arabinitoI is a good inhibitor of endoplasmic reticulum a-glucosidase I1 (K, = 9.7 pM) as well as Golgi a-mannosidase I1 (K, = 35 pM; Asano et al, 1994).…”

“…1,4-Dideoxy-1,4-imino-D-arabinitol also superimposes well on the glucosyl cation, since it has two ring hydroxyl groups lying in the same region of space as C3 and C4 of a putative glucosyl cation, with the hydroxymethyl group also being topographically equivalent (Asano et al, 1994). 1,4-Dideoxy-l ,4-imino-D-arabinitoI is a good inhibitor of endoplasmic reticulum a-glucosidase I1 (K, = 9.7 pM) as well as Golgi a-mannosidase I1 (K, = 35 pM; Asano et al, 1994). In this work, it more potently inhibited pig kidney trehalase than did I-deoxynojirimycin, with a K, value of 3.6 pM.…”

“…Pig kidney trehalase (0.7 U/mg protein), trehalose dihydrate, methyl a-D-glucoside, methyl p-D-glucoside, methyl a-D-mannoside and methyl P-D-mannoside were purchased from Sigma Chemical. 1 -Deoxynojirimycin (1,5-dideoxy-l,5-imino-D-glucitol), fagomine, 1 -deoxymannojirimycin (1,5-dideoxy-1,5-imino-~-mannito~), and 1,4-dideoxy-1,4-imino-D-arabinitol were purified according to published procedures (Asano et al, 1994). Validoxylamine A (Horii et al, 1972), Dgluco-dihydrovalidoxylamine A (Kameda et al, 1987) and validamine (Kameda et al, 1984) are known from the literature.…”

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

“…All these compounds inhibited a-l-fucosidases in a competitive manner. 2R,5R-Bis(hydroxymethyl)-3R,4R-Dihydroxypyrrolidine (DMDP, 2,5-dihydroxy-2,5-imino-d-mannitol), which was first isolated from the leaves of the legume Derris elliptica [14] and is now being reported in many disparate species of plants and microorganisms [15], has been shown to be a potent inhibitor of mammalian b-galactosidases [16]. The 6-deoxy derivative (6) of DMDP has been isolated from the seeds of A. pynaertii and reported to be a moderate inhibitor of Aspergillus niger b-mannosidase, with an IC 50 value of 380 mm [5].…”

Synthesis and Biological Activity of Novel Deoxynojirimycin Derivatives as Potent α-Glucosidase Inhibitors

“…Resembling D-glucose in structure as well as in the transition state of glucosidase-catalyzed reactions, DNJ is able to inhibit α-glucosidase in a competitive manner [9,10]. Given that DNJ showed good inhibitory activity against α-glucosidase [11], a number of DNJ derivatives have been synthesized in order to achieve significant potency of suppressing post-prandial elevation of the glucose level in blood. Successful results were first obtained with miglitol and emiglitate.…”