Galactose-amidine derivatives as selective antagonists of galectin-9
(2016) In Canadian Journal of Chemistry 94(11). p.936-939- Abstract
The family of galectin proteins involved in adhesion, growth regulation, immunity, and inflammatory events are important targets for development of small molecule antagonists. Here, N-sulfonyl amidine galactopyranoside derivatives obtained via a multicomponent reaction between galactose alkyne derivatives, sulfonyl azides, and amines were evaluated as antagonists of galectin-1,-2,-3,-4N (N-terminal domain),-4C (C-terminal domain),-8N,-9N, and-9C in a competitive fluorescence polarization assay. Highly selective compounds against galectin-9N with up to 30-fold improved affinity compared to the reference methyl β-d-galactopyranoside were identified. Molecular dynamics simulation suggested that the selectivity and affinity for galectin-9N... (More)
The family of galectin proteins involved in adhesion, growth regulation, immunity, and inflammatory events are important targets for development of small molecule antagonists. Here, N-sulfonyl amidine galactopyranoside derivatives obtained via a multicomponent reaction between galactose alkyne derivatives, sulfonyl azides, and amines were evaluated as antagonists of galectin-1,-2,-3,-4N (N-terminal domain),-4C (C-terminal domain),-8N,-9N, and-9C in a competitive fluorescence polarization assay. Highly selective compounds against galectin-9N with up to 30-fold improved affinity compared to the reference methyl β-d-galactopyranoside were identified. Molecular dynamics simulation suggested that the selectivity and affinity for galectin-9N originate from the N-sulfonyl amidine moieties forming tridentate hydrogen bonds to two asparagine side chains and one phenyl stacking edge-to-face to an arginine side chain. These selective galectin-9N antagonists are of significant value as chemical tools for studying galectin-9 biology and chemistry as well as possible starting structures for the discovery of galectin-9-targeting drugs influencing, e.g., immune regulation.
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- author
- Rajput, Vishal Kumar ; Sundin, Anders P. LU ; Leffler, Hakon LU ; Mukhopadhyay, Balaram and Nilsson, Ulf J. LU
- organization
- publishing date
- 2016-02-04
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Amidines, Antagonist, Galectin, Multicomponent reaction, N -sulfonyl
- in
- Canadian Journal of Chemistry
- volume
- 94
- issue
- 11
- pages
- 4 pages
- publisher
- NRC Research Press
- external identifiers
-
- wos:000388095300008
- scopus:84994652664
- ISSN
- 0008-4042
- DOI
- 10.1139/cjc-2015-0598
- language
- English
- LU publication?
- yes
- id
- 1d3e728f-9636-43ab-9d84-baf9e5923abd
- alternative location
- http://www.nrcresearchpress.com/doi/10.1139/cjc-2015-0598
- date added to LUP
- 2017-04-21 10:46:21
- date last changed
- 2024-03-31 06:30:35
@article{1d3e728f-9636-43ab-9d84-baf9e5923abd,
abstract = {{<p>The family of galectin proteins involved in adhesion, growth regulation, immunity, and inflammatory events are important targets for development of small molecule antagonists. Here, N-sulfonyl amidine galactopyranoside derivatives obtained via a multicomponent reaction between galactose alkyne derivatives, sulfonyl azides, and amines were evaluated as antagonists of galectin-1,-2,-3,-4N (N-terminal domain),-4C (C-terminal domain),-8N,-9N, and-9C in a competitive fluorescence polarization assay. Highly selective compounds against galectin-9N with up to 30-fold improved affinity compared to the reference methyl β-d-galactopyranoside were identified. Molecular dynamics simulation suggested that the selectivity and affinity for galectin-9N originate from the N-sulfonyl amidine moieties forming tridentate hydrogen bonds to two asparagine side chains and one phenyl stacking edge-to-face to an arginine side chain. These selective galectin-9N antagonists are of significant value as chemical tools for studying galectin-9 biology and chemistry as well as possible starting structures for the discovery of galectin-9-targeting drugs influencing, e.g., immune regulation.</p>}},
author = {{Rajput, Vishal Kumar and Sundin, Anders P. and Leffler, Hakon and Mukhopadhyay, Balaram and Nilsson, Ulf J.}},
issn = {{0008-4042}},
keywords = {{Amidines; Antagonist; Galectin; Multicomponent reaction; N -sulfonyl}},
language = {{eng}},
month = {{02}},
number = {{11}},
pages = {{936--939}},
publisher = {{NRC Research Press}},
series = {{Canadian Journal of Chemistry}},
title = {{Galactose-amidine derivatives as selective antagonists of galectin-9}},
url = {{http://dx.doi.org/10.1139/cjc-2015-0598}},
doi = {{10.1139/cjc-2015-0598}},
volume = {{94}},
year = {{2016}},
}