title: Synthesis of sialic acid derivatives as ligands for the myelin-associated glycoprotein (MAG).
abstract: The trisaccharide substructure 13 of the ganglioside GQ1balpha shows a remarkable affinity for the myelin-associated glycoprotein (MAG). In the search for structurally simplified and pharmacokinetically improved mimics of 13, sialosides with modifications at the reducing and non-reducing end were synthesized. The biological evaluation of mimics 12a-o was performed in a competitive target-based assay. It was found that the relative inhibitory potency (rIP) of antagonist 12h was enhanced by more than 1000-fold in comparison to the reference trisaccharide 13, despite the former having a much simpler structure. In addition, the sialic acid derivatives, for example, 12h, have clearly improved pharmacokinetic properties due to the presence of aromatic moieties, a lower molecular weight, and a reduced number of polar hydroxy functions compared to the reference compound 13.
authors.affiliation: Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
authors.forename: Sachin V
authors.initials: SV
authors.lastname: Shelke
authors.forename: Gan-Pan
authors.initials: GP
authors.lastname: Gao
authors.forename: Stefanie
authors.initials: S
authors.lastname: Mesch
authors.forename: Heiko
authors.initials: H
authors.lastname: Gäthje
authors.forename: Soerge
authors.initials: S
authors.lastname: Kelm
authors.forename: Oliver
authors.initials: O
authors.lastname: Schwardt
authors.forename: Beat
authors.initials: B
authors.lastname: Ernst
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D020128:Inhibitory Concentration 50; D008024:Ligands; D015394:Molecular Structure; D018992:Myelin-Associated Glycoprotein / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019158:N-Acetylneuraminic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D018992:Myelin-Associated Glycoprotein; D019158:N-Acetylneuraminic Acid