In vitro inhibition of glycogen-degrading enzymes and glycosidases by six-membered sugar mimics and their evaluation in cell cultures

An amyio-1, 6-glucosidase inhibitor enhanced inhibition of hepatic glucose production in combination with glycogen phosphorylase inhibitor. The inhibitory activity of 1-deoxynojirimycin ( 1) toward human maltase was identical to that of voglibose ( 10) of an anti-diabetic agent. l-Isofagomine ( 8),...

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Published in:Bioorganic & medicinal chemistry 2008-08, Vol.16 (15), p.7330-7336
Main Authors: Kuriyama, Chinami, Kamiyama, Ogusa, Ikeda, Kyoko, Sanae, Fujiko, Kato, Atsushi, Adachi, Isao, Imahori, Tatsushi, Takahata, Hiroki, Okamoto, Tadashi, Asano, Naoki
Format: Article
Language:English
Subjects:
Amylo-1,6-glucosidase
Animals
Biological and medical sciences
Caco-2
Caco-2 Cells
Carbohydrate Conformation
Cells, Cultured
Dose-Response Relationship, Drug
Fibroblasts - metabolism
Gaucher Disease - metabolism
Glycogen - metabolism
Glycogen phosphorylase
Glycoside Hydrolases - antagonists & inhibitors
Hepatocytes
Hepatocytes - drug effects
Humans
Imino Sugars - chemistry
Imino Sugars - pharmacology
Lysosomes - enzymology
Medical sciences
Miscellaneous
Noncompetitive inhibitor
Pharmacological chaperone
Pharmacology. Drug treatments
Rats
Six-membered sugar mimics
Structure-Activity Relationship
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Summary:An amyio-1, 6-glucosidase inhibitor enhanced inhibition of hepatic glucose production in combination with glycogen phosphorylase inhibitor. The inhibitory activity of 1-deoxynojirimycin ( 1) toward human maltase was identical to that of voglibose ( 10) of an anti-diabetic agent. l-Isofagomine ( 8), a noncompetitive inhibitor of lysosomal β-glucosidase. also showed a chaperoning activity in N370S Gaucher fibroblasts. We investigated in vitro inhibition of mammalian carbohydrate-degrading enzymes by six-membered sugar mimics and their evaluation in cell cultures. 1-Deoxynojirimycin (DNJ) showed no significant inhibition toward glycogen phosphorylase (GP) but was a potent inhibitor of another glycogen-degrading enzyme, amylo-1,6-glucosidase (1,6-GL), with an IC 50 value of 0.16 μM. In primary rat hepatocytes, the inhibition of glycogen breakdown by DNJ reached plateau at 100 μM with 25% inhibition and then remained unchanged. The potent GP inhibitor 1,4-dideoxy-1,4-imino- d-arabinitol ( d-AB1) inhibited hepatic glucose production with an IC 50 value of about 9 μM and the inhibition by d-AB1 was further enhanced in the presence of DNJ. DNJ and α-homonojirimycin (HNJ) are very potent inhibitors of rat intestinal maltase, with IC 50 values of 0.13 and 0.08 μM, respectively, and also showed a similar strong inhibition toward maltase in Caco-2 cell model system, with IC 50 value of 0.05 and 0.10 μM, respectively. d-Isofagomine ( d-IFG) and l-IFG are competitive and noncompetitive inhibitors of human lysosomal β-glucosidase (β-GL), respectively, with K i values of 8.4 nM and 6.9 μM. d-IFG increased intracellular β-GL activity by twofold at 10 μM in Gaucher N370S cell line as an ‘active-site-specific’ chaperone, and surprisingly a noncompetitive inhibitor l-IFG also increased intracellular β-GL activity by 1.6-fold at 500 μM.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2008.06.026