Low micromolar inhibitors of galectin-3 based on 3'-derivatization of N-acetyllactosamine.
A strategy for generating potential galectin inhibitors was devised based on derivatization at the C-3' atom in 3'-amino-N-acetyllactosamine by using structural knowledge of the galectin carbohydrate recognition site. A collection of 12 compounds was prepared by N-acylations or N-sulfonylations. Hydrophobic tagging of the O-3 atom in the N-acetylglucosamine residue with a stearic ester allowed rapid and simple product purification. The compounds were screened in a galectin-3 binding assay and three compounds with significantly higher inhibitory activities compared to the parent N-acetyllactosaminide were found. These three best inhibitors all carried an aromatic amide at the C-3' position of the galactose moiety, which indicates that favorable interactions were formed between the aromatic group and galectin-3. The best inhibitor had an IC50 value (4.4 microM) about 50 times better than the parent N-acetyllactosaminide, which implies that it has potential as a valuable tool for studying galectin-3 biological functions and also as a lead compound for the development of galectin-3-blocking pharmaceuticals.
Sörme
Pernilla
P
Section MIG (Microbiology, Immunology, Glycobiology), Dept. of Laboratory Medicine, Lund University, Sölvegatan 23, 22362 Lund, Sweden.
Qian
Yuning
Y
Nyholm
Per-Georg
PG
Leffler
Hakon
H
Nilsson
Ulf J
UJ
D000606:Amino Sugars / Q000138:chemical synthesis / Q000494:pharmacology*; D000943:Antigens, Differentiation / Q000276:immunology*; D001665:Binding Sites; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D037502:Galectin 3
D000606:Amino Sugars; D000943:Antigens, Differentiation; D037502:Galectin 3; C000458:N-acetyllactosamine