SYNTHESIS OF CLUSTER GALACTOSIDES WITH HIGH-AFFINITY FOR THE HEPATIC ASIALOGLYCOPROTEIN RECEPTOR

High-affinity Ligands for the asialoglycoprotein receptor, which is un iquely localized on the parenchymal liver cell and recognizes oligoant ennary galactosides, might be utilized as homing device to specificall y target drugs or genes to parenchymal liver cells. In the present stu dy, the synthesis of galactose-terminated triantennary glycosides, pro vided with various spacers between the beta-galactopyranosyl moieties and the branching point of the dendrite, is described. hyl]methyl]-N-a lpha-[1-(6-methyladipy)]glycinamide (3b) was glycosylated with monogal actosyl derivatives, containing propanediol or ethylene glycol units a s hydrophilic spacer moieties, to yield the corresponding cluster gala ctosides. To determine the affinity of the cluster galactosides for th e asialoglycoprotein receptor, we have performed competition studies o f [I-125]ASOR binding, a specific ligand for the asialoglycoprotein re ceptor, to isolated parenchymal cells. The affinity for the asialoglyc oprotein receptor significantly increased with increasing spacer lengt h. xy]methyl]-N-alpha-[1-(6-methyladipyl)]glycinamide (4e), a cluster galactoside provided with a 20 Angstrom spacer, possessed an at least 2000-fold higher affinity for the receptor than -O-(beta-D-galactopyra nosyl)methyl]methyl]-N-alpha -[1-(6-methyladipyl)]glycinamide (4a), a cluster galactoside lacking the spacer. It is concluded that vicinal g alactosyl moieties within a cluster galactoside are more optimal recog nized by the galactose binding sites of the asialoglycoprotein recepto r upon proper spacing. The most potent galactoside, TG(20 Angstrom), m ay constitute an attractive targeting device for the specific delivery of drugs and/or genes to the parenchymal liver cell.