title: 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.
abstract: 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.
authors.affiliation: Netherlands Cancer Institute, Division of Cellular Biochemistry, Amsterdam.
authors.forename: A
authors.initials: A
authors.lastname: Tan
authors.forename: L
authors.initials: L
authors.lastname: van den Broek
authors.forename: J
authors.initials: J
authors.lastname: Bolscher
authors.forename: D J
authors.initials: DJ
authors.lastname: Vermaas
authors.forename: L
authors.initials: L
authors.lastname: Pastoors
authors.forename: C
authors.initials: C
authors.lastname: van Boeckel
authors.forename: H
authors.initials: H
authors.lastname: Ploegh
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002240:Carbohydrate Sequence; D006528:Carcinoma, Hepatocellular; D002460:Cell Line; D002463:Cell Membrane Permeability; D002850:Chromatography, Gel; D005947:Glucose / Q000378:metabolism*; D006023:Glycoproteins / Q000096:biosynthesis*; D006801:Humans; D008113:Liver Neoplasms; D008969:Molecular Sequence Data; D009844:Oligosaccharides / Q000096:biosynthesis* / Q000737:chemistry / Q000302:isolation & purification; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D006023:Glycoproteins; D009844:Oligosaccharides; D017485:1-Deoxynojirimycin; D005947:Glucose