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Synthesis of β-d-C-galactopyranosyl compounds including constrained derivatives from clickable building blocks and evaluation as ligands for galectins

Dhara, Ashis ; Hever, Eoin LU ; Sjövall, Fredrik LU orcid ; Leffler, Hakon LU ; O'Malley, Ciaran ; Nilsson, Ulf J. LU orcid and Murphy, Paul V. (2026) In European Journal of Medicinal Chemistry 308.
Abstract
A set of nineteen C-galactopyranosyl ligands, which included constrained compounds based on a bicyclic trans-decalin type system. were synthesized via click chemistry from 2-(β-d-C-galactopyranosyl) ethylene azide intermediates. The compounds were evaluated for binding to various galectins and the most promising inhibitor from the series was a constrained 3-O-benzylated galactopyranose derivative, with a trifluorophenyltriazole appendage; the ligand showed a KD = 180 μM for Gal-4N, which is ∼7-fold better than lactose and ∼2-fold improved compared to thiodigalactoside; the compound was ∼5-fold selective for Gal-4N compared to Gal-4C. Molecular modelling suggested that the triazole C–H has... (More)
A set of nineteen C-galactopyranosyl ligands, which included constrained compounds based on a bicyclic trans-decalin type system. were synthesized via click chemistry from 2-(β-d-C-galactopyranosyl) ethylene azide intermediates. The compounds were evaluated for binding to various galectins and the most promising inhibitor from the series was a constrained 3-O-benzylated galactopyranose derivative, with a trifluorophenyltriazole appendage; the ligand showed a KD = 180 μM for Gal-4N, which is ∼7-fold better than lactose and ∼2-fold improved compared to thiodigalactoside; the compound was ∼5-fold selective for Gal-4N compared to Gal-4C. Molecular modelling suggested that the triazole C–H has potential to be involved in a non-classical H-bond with Glu87 carboxylate of Gal-4N, supported by increased affinity observed for trifluorophenyl substituted triazole when compared to fluorophenyl/phenyl derivatives. The modelling indicates that the benzyl aromatic ring may have Pi-Pi interactions with Phe/Trp, accounting for its ability to improve affinity. (Less)
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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
European Journal of Medicinal Chemistry
volume
308
article number
118613
pages
19 pages
publisher
Elsevier Masson SAS
external identifiers
  • pmid:41762924
  • scopus:105031250463
ISSN
0223-5234
DOI
10.1016/j.ejmech.2026.118613
language
English
LU publication?
yes
additional info
Copyright © 2026 The Authors. Published by Elsevier Masson SAS.. All rights reserved.
id
fc0c513d-9775-4ea0-9fb5-a6f94f62e3f1
date added to LUP
2026-03-05 20:50:12
date last changed
2026-05-15 15:56:50
@article{fc0c513d-9775-4ea0-9fb5-a6f94f62e3f1,
  abstract     = {{A set of nineteen C-galactopyranosyl ligands, which included constrained compounds based on a bicyclic <em>trans</em>-decalin type system. were synthesized via click chemistry from 2-(β-d-<em>C</em>-galactopyranosyl) ethylene azide intermediates. The compounds were evaluated for binding to various galectins and the most promising inhibitor from the series was a constrained 3-<em>O</em>-benzylated galactopyranose derivative, with a trifluorophenyltriazole appendage; the ligand showed a <em>K</em><sub>D</sub> = 180 μM for Gal-4N, which is ∼7-fold better than lactose and ∼2-fold improved compared to thiodigalactoside; the compound was ∼5-fold selective for Gal-4N compared to Gal-4C. Molecular modelling suggested that the triazole C–H has potential to be involved in a non-classical H-bond with Glu87 carboxylate of Gal-4N, supported by increased affinity observed for trifluorophenyl substituted triazole when compared to fluorophenyl/phenyl derivatives. The modelling indicates that the benzyl aromatic ring may have Pi-Pi interactions with Phe/Trp, accounting for its ability to improve affinity.}},
  author       = {{Dhara, Ashis and Hever, Eoin and Sjövall, Fredrik and Leffler, Hakon and O'Malley, Ciaran and Nilsson, Ulf J. and Murphy, Paul V.}},
  issn         = {{0223-5234}},
  language     = {{eng}},
  month        = {{01}},
  publisher    = {{Elsevier Masson SAS}},
  series       = {{European Journal of Medicinal Chemistry}},
  title        = {{Synthesis of β-d-C-galactopyranosyl compounds including constrained derivatives from clickable building blocks and evaluation as ligands for galectins}},
  url          = {{http://dx.doi.org/10.1016/j.ejmech.2026.118613}},
  doi          = {{10.1016/j.ejmech.2026.118613}},
  volume       = {{308}},
  year         = {{2026}},
}