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
| Autor: | Leon A. G. M. Van Den Broek, Agnes Tan, Hidde L. Ploegh, Liesbeth Pastoors, J G Bolscher, Dirk Jan Vermass, Constant A. A. van Boeckel |
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| Rok vydání: | 1994 |
| Předmět: |
Glycan
1-Deoxynojirimycin Carcinoma Hepatocellular Cell Membrane Permeability Molecular Sequence Data Oligosaccharides Biochemistry Cell Line Structure-Activity Relationship Tumor Cells Cultured Humans Structure–activity relationship Glycoproteins chemistry.chemical_classification Endoplasmic reticulum membrane biology Liver Neoplasms Glucose Enzyme Membrane Carbohydrate Sequence chemistry Cell culture Lipophilicity Chromatography Gel biology.protein Biophysics Streptolysin |
| Zdroj: | Glycobiology. 4:141-149 |
| ISSN: | 1460-2423 0959-6658 |
| DOI: | 10.1093/glycob/4.2.141 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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