STEPWISE SYNTHESIS OF A GALNAC-CONTAINING CLUSTER GLYCOSIDE LIGAND OFTHE ASIALOGLYCOPROTEIN RECEPTOR

A series of peptidylglycoside derivatives, including the tris(GalNAc-a minohexyl) glycoside of tyrosyl(glutamyl)glutamate (1) which is known to have sub-nanomolar affinity for the asialoglycoprotein receptor (AS GPr), have been synthesized using the protected tetra-O-acetyl aminohe xyl glycoside (9) of N-acetylgalactosamine. The N-succinyl derivative of 1 was also prepared, providing a derivative for bioconjugate format ion via carboxyl activation of the glycopeptide. Use of the protected glycoside 9 affords synthetic intermediates with increased solubility in organic solvents that are easier to purify and use in subsequent sy nthetic manipulations in comparison with compounds containing unprotec ted glycosides. These synthetic procedures will be generally applicabl e to the preparation of related compounds to probe binding to the ASCP r and the use of these cluster glycosides as ligands for targeted deli very to the liver. (C) Munksgaard 1994.