Stepwise synthesis of a GalNAc-containing cluster glycoside ligand of the asialoglycoprotein receptor.
A series of peptidylglycoside derivatives, including the tris(GalNAc-aminohexyl) glycoside of tyrosyl(glutamyl)-glutamate (1) which is known to have sub-nanomolar affinity for the asialoglycoprotein receptor (ASGPr), have been synthesized using the protected tetra-O-acetyl aminohexyl glycoside (9) of N-acetylgalactosamine. The N-succinyl derivative of 1 was also prepared, providing a derivative for bioconjugate formation 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 synthetic manipulations in comparison with compounds containing unprotected glycosides. These synthetic procedures will be generally applicable to the preparation of related compounds to probe binding to the ASGPr and the use of these cluster glycosides as ligands for targeted delivery to the liver.
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TargeTech Inc., Meriden, Connecticut.
D000116:Acetylgalactosamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D037263:Asialoglycoprotein Receptor; D002240:Carbohydrate Sequence; D006027:Glycosides / Q000138:chemical synthesis* / Q000378:metabolism*; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface / Q000378:metabolism*
D037263:Asialoglycoprotein Receptor; D006027:Glycosides; D011956:Receptors, Cell Surface; D000116:Acetylgalactosamine