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Systematic Tuning of Fluoro-galectin-3 Interactions Provides Thiodigalactoside Derivatives with Single-Digit nM Affinity and High Selectivity

Peterson, Kristoffer LU ; Kumar, Rohit LU ; Stenström, Olof LU ; Verma, Priya; Verma, Prashant R. LU ; Håkansson, Maria; Kahl-Knutsson, Barbro LU ; Zetterberg, Fredrik; Leffler, Hakon LU and Akke, Mikael LU , et al. (2018) In Journal of Medicinal Chemistry 61(3). p.1164-1175
Abstract

Symmetrical and asymmetrical fluorinated phenyltriazolyl-thiodigalactoside derivatives have been synthesized and evaluated as inhibitors of galectin-1 and galectin-3. Systematic tuning of the phenyltriazolyl-thiodigalactosides' fluoro-interactions with galectin-3 led to the discovery of inhibitors with exceptional affinities (Kd down to 1-2 nM) in symmetrically substituted thiodigalactosides as well as unsurpassed combination of high affinity (Kd 7.5 nM) and selectivity (46-fold) over galectin-1 for asymmetrical thiodigalactosides by carrying one trifluorphenyltriazole and one coumaryl moiety. Studies of the inhibitor-galectin complexes with isothermal titration calorimetry and X-ray crystallography revealed the... (More)

Symmetrical and asymmetrical fluorinated phenyltriazolyl-thiodigalactoside derivatives have been synthesized and evaluated as inhibitors of galectin-1 and galectin-3. Systematic tuning of the phenyltriazolyl-thiodigalactosides' fluoro-interactions with galectin-3 led to the discovery of inhibitors with exceptional affinities (Kd down to 1-2 nM) in symmetrically substituted thiodigalactosides as well as unsurpassed combination of high affinity (Kd 7.5 nM) and selectivity (46-fold) over galectin-1 for asymmetrical thiodigalactosides by carrying one trifluorphenyltriazole and one coumaryl moiety. Studies of the inhibitor-galectin complexes with isothermal titration calorimetry and X-ray crystallography revealed the importance of fluoro-amide interaction for affinity and for selectivity. Finally, the high affinity of the discovered inhibitors required two competitive titration assay tools to be developed: a new high affinity fluorescent probe for competitive fluorescent polarization and a competitive ligand optimal for analyzing high affinity galectin-3 inhibitors with competitive isothermal titration calorimetry.

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Journal of Medicinal Chemistry
volume
61
issue
3
pages
12 pages
publisher
American Chemical Society (ACS)
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  • scopus:85041902277
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0022-2623
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English
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31ae47bc-5a30-414f-b55f-43c2e9d663e7
date added to LUP
2018-02-20 14:42:48
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2018-06-10 05:27:01
@article{31ae47bc-5a30-414f-b55f-43c2e9d663e7,
  abstract     = {<p>Symmetrical and asymmetrical fluorinated phenyltriazolyl-thiodigalactoside derivatives have been synthesized and evaluated as inhibitors of galectin-1 and galectin-3. Systematic tuning of the phenyltriazolyl-thiodigalactosides' fluoro-interactions with galectin-3 led to the discovery of inhibitors with exceptional affinities (K<sub>d</sub> down to 1-2 nM) in symmetrically substituted thiodigalactosides as well as unsurpassed combination of high affinity (K<sub>d</sub> 7.5 nM) and selectivity (46-fold) over galectin-1 for asymmetrical thiodigalactosides by carrying one trifluorphenyltriazole and one coumaryl moiety. Studies of the inhibitor-galectin complexes with isothermal titration calorimetry and X-ray crystallography revealed the importance of fluoro-amide interaction for affinity and for selectivity. Finally, the high affinity of the discovered inhibitors required two competitive titration assay tools to be developed: a new high affinity fluorescent probe for competitive fluorescent polarization and a competitive ligand optimal for analyzing high affinity galectin-3 inhibitors with competitive isothermal titration calorimetry.</p>},
  author       = {Peterson, Kristoffer and Kumar, Rohit and Stenström, Olof and Verma, Priya and Verma, Prashant R. and Håkansson, Maria and Kahl-Knutsson, Barbro and Zetterberg, Fredrik and Leffler, Hakon and Akke, Mikael and Logan, Derek T. and Nilsson, Ulf J.},
  issn         = {0022-2623},
  language     = {eng},
  month        = {02},
  number       = {3},
  pages        = {1164--1175},
  publisher    = {American Chemical Society (ACS)},
  series       = {Journal of Medicinal Chemistry},
  title        = {Systematic Tuning of Fluoro-galectin-3 Interactions Provides Thiodigalactoside Derivatives with Single-Digit nM Affinity and High Selectivity},
  url          = {http://dx.doi.org/},
  volume       = {61},
  year         = {2018},
}