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Galactose-amidine derivatives as selective antagonists of galectin-9

Mandal, Santanu LU ; Rajput, Vishal Kumar; Sundin, Anders P. LU ; Leffler, Hakon LU ; Mukhopadhyay, Balaram and Nilsson, Ulf J. LU (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
organization
publishing date
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
  • scopus:84994652664
  • wos:000388095300008
ISSN
0008-4042
DOI
10.1139/cjc-2015-0598
language
English
LU publication?
yes
id
1d3e728f-9636-43ab-9d84-baf9e5923abd
date added to LUP
2017-04-21 10:46:21
date last changed
2017-11-05 05:16:31
@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       = {Mandal, Santanu and Rajput, Vishal Kumar and Sundin, Anders P. and Leffler, Hakon and Mukhopadhyay, Balaram and Nilsson, Ulf J.},
  issn         = {0008-4042},
  keyword      = {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},
  volume       = {94},
  year         = {2016},
}