1H-1,2,3-triazol-1-yl thiodigalactoside derivatives as high affinity galectin-3 inhibitors.
Galactose C3-triazole derivatives were synthesized by Cu(I)-catalyzed cycloaddition between acetylenes and galactose C3-azido derivatives. Evaluation against galectin-3, 7, 8N (N-terminal) and 9N (N-terminal) revealed 1,4-disubstituted triazoles to be high-affinity inhibitors of galectin-3 with selectivity over galectin-7, 8N, and 9N. Conformational analysis of 1,4-di- and 1,4,5-tri-substituted galactose C3-triazoles suggested that a triazole C5-substituent interfered sterically with the galectin proteins, which explained their poor affinities compared to the corresponding 1,4-disubstituted triazoles. Introduction of two 1,4-disubstituted triazole moieties onto thiodigalactoside resulted in affinities down to 29 nM for galectin-3.
Salameh
Bader A
BA
Chemistry Department, The Hashemite University, PO Box 150459, Zarka 13115, Jordan.
Cumpstey
Ian
I
Sundin
Anders
A
Leffler
Hakon
H
Nilsson
Ulf J
UJ
D002384:Catalysis; D037502:Galectin 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D013862:Thiogalactosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D037502:Galectin 3; D013862:Thiogalactosides; D014230:Triazoles; C031803:thiodigalactoside