Synthesis of Cluster Galactosides with High Affinity for the Hepatic Asialoglycoprotein Receptor
| Autor: | Roelen Hc, van Berkel Tj, Beuting Dm, van de Marel Ga, E.A.L. Biessen, van Boom Jh |
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| Rok vydání: | 1995 |
| Předmět: |
Male
Stereochemistry Molecular Sequence Data Asialoglycoproteins Receptors Cell Surface Asialoglycoprotein Receptor chemistry.chemical_compound Galactosides Drug Discovery Galactose binding Animals Hepatic Asialoglycoprotein Receptor Rats Wistar Receptor Ligand Liver cell Galactoside Rats Carbohydrate Sequence Liver Biochemistry chemistry Molecular Medicine Asialoglycoprotein receptor Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 38:1538-1546 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00009a014 |
| Popis: | High-affinity ligands for the asialoglycoprotein receptor, which is uniquely localized on the parenchymal liver cell and recognizes oligoantennary galactosides, might be utilized as homing device to specifically target drugs or genes to parenchymal liver cells. In the present study, the synthesis of galactose-terminated triantennary glycosides, provided with various spacers between the beta-galactopyranosyl moieties and the branching point of the dendrite, is described. N-[Tris[[(methylthio)methoxy]methyl]methyl]-N alpha-[1-(6- methyladipy)]glycinamide (3b) was glycosylated with monogalactosyl derivatives, containing propanediol or ethylene glycol units as hydrophilic spacer moieties, to yield the corresponding cluster galactosides. To determine the affinity of the cluster galactosides for the asialoglycoprotein receptor, we have performed competition studies of [125I]ASOR binding, a specific ligand for the asialoglycoprotein receptor, to isolated parenchymal cells. The affinity for the asialoglycoprotein receptor significantly increased with increasing spacer length. N-[[[Tris-O-(beta-D-galactopyranosyl)-3,6,9-trioxaunde- canoxy]methoxy]methyl]-N-alpha-[1-(6-methyladipyl)]glycinami de (4e), a cluster galactoside provided with a 20 A spacer, possessed an at least 2000-fold higher affinity for the receptor than N-[[tris-O-(beta-D-galactopyranosyl)methyl]methyl]-N alpha-[1-(6- methyladipyl)]glycinamide (4a), a cluster galactoside lacking the spacer. It is concluded that vicinal galactosyl moieties within a cluster galactoside are more optimal recognized by the galactose binding sites of the asialoglycoprotein receptor upon proper spacing. The most potent galactoside, TG(20A), may constitute an attractive targeting device for the specific delivery of drugs and/or genes to the parenchymal liver cell. |
| Databáze: | OpenAIRE |
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