Abstract
Synthesis of doubly 3-O-coumarylmethyl-substituted thiodigalactosides from bis-3-O-propargyl-thiodigalactoside resulted in highly selective and high affinity galectin-3 inhibitors. Mutant studies, structural analysis, and molecular modeling revealed that the coumaryl substituents stack onto arginine side chains. One inhibitor displayed efficacy in a murine model of bleomycin-induced lung fibrosis similar to that of a known nonselective galectin-1/galectin-3 inhibitor, which strongly suggests that blocking galectin-3 glycan recognition is an important antifibrotic drug target.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bleomycin
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Coumarins / chemical synthesis
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Coumarins / chemistry*
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Coumarins / pharmacology
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Galactosides / chemical synthesis
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Galactosides / chemistry*
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Galactosides / pharmacology
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Galectin 3 / antagonists & inhibitors*
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Galectin 3 / genetics
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Galectin 3 / metabolism
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Humans
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Mice
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Models, Molecular
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Mutation
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Polysaccharides / metabolism*
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Protein Binding
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Pulmonary Fibrosis / chemically induced
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Pulmonary Fibrosis / metabolism*
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Pulmonary Fibrosis / pathology
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Structure-Activity Relationship
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Thiogalactosides / chemical synthesis
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Thiogalactosides / chemistry*
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Thiogalactosides / pharmacology
Substances
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Coumarins
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Galactosides
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Galectin 3
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Polysaccharides
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Thiogalactosides
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bis-3,3'-((2H-1-benzopyran-2-on-3-yl)-1,1'-sulfanediyldigalactopyranoside
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Bleomycin