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- Title
Galactose-amidine derivatives as selective antagonists of galectin-9.
- Authors
Mandal, Santanu; Rajput, Vishal K.; Sundin, Anders P.; Leffler, Hakon; Mukhopadhyay, Balaram; Nilsson, Ulf J.
- 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 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.
- Subjects
GALECTINS; GALACTOSE; AMIDINE derivatives; IMMUNOREGULATION; GROWTH regulators
- Publication
Canadian Journal of Chemistry, 2016, Vol 94, Issue 11, p936
- ISSN
0008-4042
- Publication type
Article
- DOI
10.1139/cjc-2015-0598