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Synergy of triazolyl substituents at C1 and C3 of galactose for high-affinity and selective galectin-4C inhibition

Dahlqvist, Alexander LU ; Go, Rob Marc ; Kishor, Chandan ; Leffler, Hakon LU ; Blanchard, Helen and Nilsson, Ulf J LU (2025) In RSC Chemical Biology 6(9). p.1437-1450
Abstract

Galectins are a family of carbohydrate-recognising proteins involved in regulation of cell adhesion and cell signaling, leading to roles in e.g. cancer progression, fibrosis, and ulcerative colitis. Glycomimetic galectin inhibitors based on different molecular scaffolds are known and have demonstrated effects from cell experiments to the clinic. Presented here is the synthesis and evaluation of 3-aryltriazolyl-C1-galactosyls leading to discovery of an unexpected synergy effect between C1 and C3 triazolyl substituents to give galectin-4C (C-terminal domain) inhibitors with affinities down to 9.5 μM and up to thirty-sevenfold selectivity for galectin-4C over other galectins. X-ray structural analysis of one inhibitor:galectin-4C complex... (More)

Galectins are a family of carbohydrate-recognising proteins involved in regulation of cell adhesion and cell signaling, leading to roles in e.g. cancer progression, fibrosis, and ulcerative colitis. Glycomimetic galectin inhibitors based on different molecular scaffolds are known and have demonstrated effects from cell experiments to the clinic. Presented here is the synthesis and evaluation of 3-aryltriazolyl-C1-galactosyls leading to discovery of an unexpected synergy effect between C1 and C3 triazolyl substituents to give galectin-4C (C-terminal domain) inhibitors with affinities down to 9.5 μM and up to thirty-sevenfold selectivity for galectin-4C over other galectins. X-ray structural analysis of one inhibitor:galectin-4C complex revealed that both the C1 and C3 arene-substituents engage in interactions with the galectin-4C binding site. These molecules have potential as lead compounds towards discovery of galectin-4-targeting compounds addressing inflammatory conditions, such as inflammatory bowel disease and ulcerative colitis.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
RSC Chemical Biology
volume
6
issue
9
pages
14 pages
publisher
Royal Society of Chemistry
external identifiers
  • pmid:40735388
  • scopus:105014271561
  • pmid:40735388
ISSN
2633-0679
DOI
10.1039/d5cb00106d
language
English
LU publication?
yes
id
929426ff-f8e3-4349-aa2c-b0349eb67128
date added to LUP
2025-07-31 17:35:04
date last changed
2025-10-20 14:46:03
@article{929426ff-f8e3-4349-aa2c-b0349eb67128,
  abstract     = {{<p>Galectins are a family of carbohydrate-recognising proteins involved in regulation of cell adhesion and cell signaling, leading to roles in e.g. cancer progression, fibrosis, and ulcerative colitis. Glycomimetic galectin inhibitors based on different molecular scaffolds are known and have demonstrated effects from cell experiments to the clinic. Presented here is the synthesis and evaluation of 3-aryltriazolyl-C1-galactosyls leading to discovery of an unexpected synergy effect between C1 and C3 triazolyl substituents to give galectin-4C (C-terminal domain) inhibitors with affinities down to 9.5 μM and up to thirty-sevenfold selectivity for galectin-4C over other galectins. X-ray structural analysis of one inhibitor:galectin-4C complex revealed that both the C1 and C3 arene-substituents engage in interactions with the galectin-4C binding site. These molecules have potential as lead compounds towards discovery of galectin-4-targeting compounds addressing inflammatory conditions, such as inflammatory bowel disease and ulcerative colitis.</p>}},
  author       = {{Dahlqvist, Alexander and Go, Rob Marc and Kishor, Chandan and Leffler, Hakon and Blanchard, Helen and Nilsson, Ulf J}},
  issn         = {{2633-0679}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{9}},
  pages        = {{1437--1450}},
  publisher    = {{Royal Society of Chemistry}},
  series       = {{RSC Chemical Biology}},
  title        = {{Synergy of triazolyl substituents at C1 and C3 of galactose for high-affinity and selective galectin-4C inhibition}},
  url          = {{http://dx.doi.org/10.1039/d5cb00106d}},
  doi          = {{10.1039/d5cb00106d}},
  volume       = {{6}},
  year         = {{2025}},
}