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Aromatic heterocycle galectin-1 interactions for selective single-digit nM affinity ligands

Peterson, Kristoffer LU ; Collins, Patrick M.; Huang, Xiaoli LU ; Kahl-Knutsson, Barbro LU ; Essén, Sofia LU ; Zetterberg, Fredrik R.; Oredsson, Stina LU ; Leffler, Hakon LU ; Blanchard, Helen and Nilsson, Ulf J. LU (2018) In RSC Advances 8(44). p.24913-24922
Abstract

A series of 3-triazole-thiogalactosides and 3,3′-triazole-thiodigalactosides substituted with different five-membered heterocycles at the C-4 triazole position were found to have high selectivity for galectin-1. Initial studies on the 3-triazole-thiogalactosides indicated that five membered heterocycles in general gave increased affinity for galectin-1 and improved selectivity over galectin-3. The selectivity profile was similar for thiodigalactosides exemplified by 3,3′ substituted thien-3-yltriazole and thiazol-2-yltriazole, both having single-digit nM galectin-1 affinity and almost 10-fold galectin-1 selectivity. The binding interactions of a thiodigalactoside based galectin-1 inhibitor with two thien-3-yltriazole moieties were... (More)

A series of 3-triazole-thiogalactosides and 3,3′-triazole-thiodigalactosides substituted with different five-membered heterocycles at the C-4 triazole position were found to have high selectivity for galectin-1. Initial studies on the 3-triazole-thiogalactosides indicated that five membered heterocycles in general gave increased affinity for galectin-1 and improved selectivity over galectin-3. The selectivity profile was similar for thiodigalactosides exemplified by 3,3′ substituted thien-3-yltriazole and thiazol-2-yltriazole, both having single-digit nM galectin-1 affinity and almost 10-fold galectin-1 selectivity. The binding interactions of a thiodigalactoside based galectin-1 inhibitor with two thien-3-yltriazole moieties were studied with X-ray crystallography. One of the thiophene moieties was positioned deeper into the pocket than previously reported phenyltriazoles and formed close contacts with Val31, Ser29, Gly124, and Asp123. The affinity and structural analysis thus revealed that steric and electronic optimization of five-membered aromatic heterocycle binding in a narrow galectin-1 subsite confers high affinity and selectivity.

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author
organization
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type
Contribution to journal
publication status
published
subject
in
RSC Advances
volume
8
issue
44
pages
10 pages
publisher
Royal Society of Chemistry
external identifiers
  • scopus:85050076821
ISSN
2046-2069
DOI
10.1039/c8ra04389b
language
English
LU publication?
yes
id
530601ba-4541-437c-adab-4a71305d102e
date added to LUP
2018-08-03 08:33:08
date last changed
2018-11-21 21:41:00
@article{530601ba-4541-437c-adab-4a71305d102e,
  abstract     = {<p>A series of 3-triazole-thiogalactosides and 3,3′-triazole-thiodigalactosides substituted with different five-membered heterocycles at the C-4 triazole position were found to have high selectivity for galectin-1. Initial studies on the 3-triazole-thiogalactosides indicated that five membered heterocycles in general gave increased affinity for galectin-1 and improved selectivity over galectin-3. The selectivity profile was similar for thiodigalactosides exemplified by 3,3′ substituted thien-3-yltriazole and thiazol-2-yltriazole, both having single-digit nM galectin-1 affinity and almost 10-fold galectin-1 selectivity. The binding interactions of a thiodigalactoside based galectin-1 inhibitor with two thien-3-yltriazole moieties were studied with X-ray crystallography. One of the thiophene moieties was positioned deeper into the pocket than previously reported phenyltriazoles and formed close contacts with Val31, Ser29, Gly124, and Asp123. The affinity and structural analysis thus revealed that steric and electronic optimization of five-membered aromatic heterocycle binding in a narrow galectin-1 subsite confers high affinity and selectivity.</p>},
  author       = {Peterson, Kristoffer and Collins, Patrick M. and Huang, Xiaoli and Kahl-Knutsson, Barbro and Essén, Sofia and Zetterberg, Fredrik R. and Oredsson, Stina and Leffler, Hakon and Blanchard, Helen and Nilsson, Ulf J.},
  issn         = {2046-2069},
  language     = {eng},
  number       = {44},
  pages        = {24913--24922},
  publisher    = {Royal Society of Chemistry},
  series       = {RSC Advances},
  title        = {Aromatic heterocycle galectin-1 interactions for selective single-digit nM affinity ligands},
  url          = {http://dx.doi.org/10.1039/c8ra04389b},
  volume       = {8},
  year         = {2018},
}