Synthesis of sialic acid derivatives as ligands for the myelin-associated glycoprotein (MAG).
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.
Shelke
Sachin V
SV
Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
Gao
Gan-Pan
GP
Mesch
Stefanie
S
Gäthje
Heiko
H
Kelm
Soerge
S
Schwardt
Oliver
O
Ernst
Beat
B
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
D008024:Ligands; D018992:Myelin-Associated Glycoprotein; D019158:N-Acetylneuraminic Acid