Design, Synthesis, and Applications of Galectin Modulators in Human Health

Part of the Topics in Medicinal Chemistry book series (TMC, volume 12)


Over the last decade, the family of galectin proteins has been identified as key regulators of important biological processes. They bind β- d-galactopyranoside residues in glycoconjugates, and by presenting multiple binding sites, within one galectin or by forming dimers or multimers, they can cross-link glycoproteins and form galectin-glycoprotein lattices. Such lattices formed on the cell surface or in vesicles have been shown to control, for example, surface residence time and signaling by receptors. Hence, compounds modulating galectin binding to their glycoprotein ligands are of potential clinical interest. This chapter describes the design and development of disubstituted thiodigalactoside derivatives that form optimal interactions with the galectin-3 binding site resulting in double-digit nanomolar affinities. Studies are discussed in which such galectin-3-modulating compounds have been important in elucidating galectin-3 mechanisms, including galectin-3 trafficking, cancer, inflammation, fibrosis, and angiogenesis. Medically relevant models using the galectin-3 modulators in characterizing macrophage alternative activation and chronic inflammation, myofibroblast activation and fibrosis, and ocular angiogenesis are discussed in more detail. In summary, the high galectin-3 affinity and definitive effects in relevant models of the disubstituted thiodigalactosides identify them as promising as lead compounds for drug development, albeit leaving a challenge in terms of optimizing PK/ADME properties.


Angiogenesis Cancer CD98 Fibrosis Galectin Macrophage Modulator Myofibroblast Small molecule TGF-β VEGF 





Apolipoprotein E


Basic fibroblast growth factor


Cluster of differentiation 31 protein


Cluster of differentiation 8 protein


Cluster of differentiation 98 protein


Carbohydrate recognition domain




Epidermal growth factor


Epidermal growth factor receptor


Epithelial–mesenchymal transition


Food and Drug Administration


Galectin-3 C-terminal domain


Galectin-8 N-terminal domain


Galectin-9 N-terminal domain


Growth factor receptor-bound protein 2




Interleukin 4


Idiopathic pulmonary fibrosis


Insulin receptor substrate-1


Janus kinase


Dissociation constant




β1,6-N-acetylglucosaminyl transferase 5


Major histocompatibility complex 1


Merck molecular force field s


Phosphate buffer saline


Protein data bank


Phosphatidylinositide 3-kinase




Small interfering ribonucleic acid


Mothers against decapentaplegic homolog 2


Mothers against decapentaplegic homolog 3


Signal transducer and activator of transcription 6


T-cell receptor


Transforming growth factor β


Transforming growth factor β receptor 2


Type 2 helper T cell


Vascular epithelial growth factor


Vascular epithelial growth factor receptor


Vascular epithelial growth factor receptor 2


Wild type


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.MRC Centre for Inflammation Research, The Queen’s Medical Research InstituteUniversity of EdinburghEdinburghUK
  2. 2.Sackler School of Graduate Biomedical SciencesTufts UniversityBostonUSA
  3. 3.Section MIG (Microbiology, Immunology, Glycobiology), Department of Laboratory MedicineLund UniversityLundSweden
  4. 4.Department of Ophthalmology, New England Eye CenterTufts UniversityBostonUSA
  5. 5.Galecto Biotech AB, CobisCopenhagen, NDenmark
  6. 6.Department of Respiratory Medicine and AllergyKings CollegeLondonUK
  7. 7.Department of Chemistry, Centre for Analysis and SynthesisLund UniversityLundSweden

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