1H-1,2,3-Triazol-1-yl thiodigalactoside derivatives as high affinity galectin-3 inhibitors |
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Authors: | Bader A Salameh Ian Cumpstey Anders Sundin Hakon Leffler Ulf J Nilsson |
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Institution: | 1. Chemistry Department, The Hashemite University, PO Box 150459, Zarka 13115, Jordan;2. Organic Chemistry, Lund University, PO Box 124, SE-221 00 Lund, Sweden;3. Section MIG, Department of Laboratory Medicine, University of Lund, Sölvegatan 23, SE-223 62 Lund, Sweden |
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Abstract: | 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. |
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