Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.20 (alpha-glucosidase)
 4,237 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-Alkylation of the alpha-glucosidase inhibitor 1-deoxynojirimycin (dNM) dramatically increases its inhibitory potency (Tan et al., J. Biol. Chem., 266, 14504-14510, 1991). However, the possibility of extending the alkyl chain to N-decyl-dNM is limited by an increase of detergent-like (amphiphilic) properties of long-chain alkylated dNM derivatives. Substitution of methylene groups in the N-decyl chain by oxygen reduced the amphiphilicity of N-decyl-dNM derivatives, while retaining their superior inhibitory properties. In intact HepG2 cells, the compound N-7-oxadecyl-dNM was found to result in the most pronounced retention of glucose residues on N-linked glycans. Permeabilization of the plasma membrane with the bacterial toxin Streptolysin O improves the inhibitory properties of the derivatives N-3,6,9-trioxadecyl-, N-7,10,13-trioxatetradecyl-, N-3-oxadecyl- and N-7-oxadecyl-dNM, but not those of dNM. These observations suggest differences in the mode of entry of the oxygen-substituted dNM derivatives in comparison with dNM. We observed that the dNM derivative N-3,6,9-trioxadecyl-dNM, devoid of inhibitory activity in intact cells, was inhibitory in Streptolysin O-permeabilized cells. Thus, the permeability barriers posed by plasma membrane and endoplasmic reticulum membrane are not equivalent. The use of a permeabilized cell system thus allows the elaboration of inhibitory principles for novel bioactive compounds where study of the isolated enzymes may not be possible, and where intact cells are not a suitable target due to permeability barriers.
 ...
PMID:Introduction of oxygen into the alkyl chain of N-decyl-dNM decreases lipophilicity and results in increased retention of glucose residues on N-linked oligosaccharides. 805 14

The synthesis of a series of analogues of the monosaccharide alpha-glucosidase I inhibitor N-decyl-1-deoxynojirimycin (1) is described. With the incorporation of a single oxygen atom particularly at position seven in the N-decyl side chain, i.e. to give N-7-oxadecyl-dNM (4), the therapeutic ratio (alpha-glucosidase I inhibitory activity over toxicity in HepG2 cells) increases considerably. N-7-Oxadecyl-dNM inhibits purified porcine liver alpha-glucosidase I with an IC50 value of 0.28 microM. The position of the oxygen atom in the N-decyl side chain is of importance since N-3-oxadecyl-dNM is less active and, moreover, is toxic to HepG2 cells at 3 mM. Subsequently, the synthesis of a disaccharide inhibitor of alpha-glucosidase I is described. The aminodisaccharide ManNH2 alpha 1,2Glc (12) inhibits alpha-glucosidase I with an IC50 value of 15.7 microM. Two closely related monosaccharide derivatives of 12 did not inhibit the enzyme at low microM concentrations (no inhibition at 5 microM), showing the additional effect of binding of the aglycon fragment of the molecule to the active site of alpha-glucosidase I. Next, the N-alkyl-dNM derivatives were analysed for antiviral and immunomodulatory activity in-vitro. It is found that the most potent alpha-glucosidase I inhibitor from this study, N-7-oxadecyl-dNM (4) inhibits HIV-1 induced syncytia formation and lymphocyte proliferation in-vitro. Finally, compound 4 was also investigated in-vivo. N-7-Oxadecyl-dNM (4) reduced adjuvant-induced arthritis in rats making this compound a potential candidate for treating autoimmune diseases like rheumatoid arthritis.
 ...
PMID:Synthesis of alpha-glucosidase I inhibitors showing antiviral (HIV-1) and immunosuppressive activity. 893 66

Alkylation of 1-azafagomine at the 2-N position was achieved by reductive amination of 1-N-acetyl-3,4,6-tri-O-benzyl-1-azafagomine by using aldehydes, palladium hydroxide, and hydrogen in EtOAc/water/acetic acid followed by deprotection. The 2-N-butyl, hexyl, heptyl, nonyl, decyl, and 3-phenylpropyl derivatives were made in this manner, and were tested for inhibition of alpha-glucosidase from yeast, and of beta-glucosidase from almonds. The new compounds were stronger beta-glucosidase inhibitors than 1-azafagomine, but weaker alpha-glucosidase inhibitors.
 ...
PMID:Anomer-selective glycosidase inhibition by 2-N-alkylated 1-azafagomines. 1735 29