Systematic Tuning of Fluoro-galectin-3 Interactions Provides Thiodigalactoside Derivatives with Single-Digit nM Affinity and High Selectivity
(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.
(Less)
- author
- organization
- publishing date
- 2018-02-08
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Medicinal Chemistry
- volume
- 61
- issue
- 3
- pages
- 12 pages
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- scopus:85041902277
- pmid:29284090
- ISSN
- 0022-2623
- DOI
- 10.1021/acs.jmedchem.7b01626
- language
- English
- LU publication?
- yes
- id
- 31ae47bc-5a30-414f-b55f-43c2e9d663e7
- date added to LUP
- 2018-02-20 14:42:48
- date last changed
- 2024-06-24 10:06:01
@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 = {{The 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/10.1021/acs.jmedchem.7b01626}}, doi = {{10.1021/acs.jmedchem.7b01626}}, volume = {{61}}, year = {{2018}}, }