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Structure-Guided Design of d -Galactal Derivatives with High Affinity and Selectivity for the Galectin-8 N-Terminal Domain

Hassan, Mujtaba LU ; Baussière, Floriane ; Guzelj, Samo ; Sundin, Anders P. LU ; Håkansson, Maria ; Kovačič, Rebeka ; Leffler, Hakon LU ; Tomašič, Tihomir ; Anderluh, Marko LU and Jakopin, Žiga , et al. (2021) In ACS Medicinal Chemistry Letters 12(11). p.1745-1752
Abstract

Galectin-8 is a carbohydrate-binding protein that plays a crucial role in tumor progression and metastasis, antibacterial autophagy, modulation of the immune system, and bone remodeling. The design, synthesis, and protein affinity evaluation of a set of C-3 substituted benzimidazole and quinoline d-galactal derivatives identified a d-galactal-benzimidazole hybrid as a selective ligand for the galectin-8 N-terminal domain (galectin-8N), with a Kd of 48 μM and 15-fold selectivity over galectin-3 and even better selectivity over the other mammalian galectins. X-ray structural analysis of galectin-8N in complex with one benzimidazole- and one quinoline-galactal derivative at 1.52 and 2.1 Å together with molecular dynamics simulations and... (More)

Galectin-8 is a carbohydrate-binding protein that plays a crucial role in tumor progression and metastasis, antibacterial autophagy, modulation of the immune system, and bone remodeling. The design, synthesis, and protein affinity evaluation of a set of C-3 substituted benzimidazole and quinoline d-galactal derivatives identified a d-galactal-benzimidazole hybrid as a selective ligand for the galectin-8 N-terminal domain (galectin-8N), with a Kd of 48 μM and 15-fold selectivity over galectin-3 and even better selectivity over the other mammalian galectins. X-ray structural analysis of galectin-8N in complex with one benzimidazole- and one quinoline-galactal derivative at 1.52 and 2.1 Å together with molecular dynamics simulations and quantum mechanical calculations of galectin-8N in complex with the benzimidazole derivative revealed orbital overlap between a NH LUMO of Arg45 with electron rich HOMOs of the olefin and O4 of the d-galactal. Such overlap is hypothesized to contribute to the high affinity of the d-galactal-derived ligands for galectin-8N. A (3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay evaluation of the d-galactal-benzimidazole hybrid and an analogous galactoside derivative on a panel of cell lines with MTS assay showed no effect on cell viability up to 100 μM concentration. A subsequent functional assay using the MDA-MB-231 cell line demonstrated that the d-galactal-benzimidazole hybrid and the analogous galactoside derivative reduced the secretion of the proinflammatory cytokines interleukin-6 (IL-6) and IL-8 in a dose-dependent manner. Therefore, these compounds represent potential probes for galectin-8N pharmacology investigations and possibly promising leads for the design and synthesis of potent and selective galectin-8 inhibitors as potential antitumor and anti-inflammatory agents.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
benzimidazole, cytokine secretion, d -galactal, Galectin-8N, selectivity, X-ray crystallography
in
ACS Medicinal Chemistry Letters
volume
12
issue
11
pages
8 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:85119057227
  • pmid:34795863
ISSN
1948-5875
DOI
10.1021/acsmedchemlett.1c00371
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2021 The Authors. Published by American Chemical Society.
id
d01a4baf-8e48-4873-902f-e0d5bd657761
date added to LUP
2021-12-03 15:12:58
date last changed
2025-01-13 19:24:16
@article{d01a4baf-8e48-4873-902f-e0d5bd657761,
  abstract     = {{<p>Galectin-8 is a carbohydrate-binding protein that plays a crucial role in tumor progression and metastasis, antibacterial autophagy, modulation of the immune system, and bone remodeling. The design, synthesis, and protein affinity evaluation of a set of C-3 substituted benzimidazole and quinoline d-galactal derivatives identified a d-galactal-benzimidazole hybrid as a selective ligand for the galectin-8 N-terminal domain (galectin-8N), with a Kd of 48 μM and 15-fold selectivity over galectin-3 and even better selectivity over the other mammalian galectins. X-ray structural analysis of galectin-8N in complex with one benzimidazole- and one quinoline-galactal derivative at 1.52 and 2.1 Å together with molecular dynamics simulations and quantum mechanical calculations of galectin-8N in complex with the benzimidazole derivative revealed orbital overlap between a NH LUMO of Arg45 with electron rich HOMOs of the olefin and O4 of the d-galactal. Such overlap is hypothesized to contribute to the high affinity of the d-galactal-derived ligands for galectin-8N. A (3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay evaluation of the d-galactal-benzimidazole hybrid and an analogous galactoside derivative on a panel of cell lines with MTS assay showed no effect on cell viability up to 100 μM concentration. A subsequent functional assay using the MDA-MB-231 cell line demonstrated that the d-galactal-benzimidazole hybrid and the analogous galactoside derivative reduced the secretion of the proinflammatory cytokines interleukin-6 (IL-6) and IL-8 in a dose-dependent manner. Therefore, these compounds represent potential probes for galectin-8N pharmacology investigations and possibly promising leads for the design and synthesis of potent and selective galectin-8 inhibitors as potential antitumor and anti-inflammatory agents. </p>}},
  author       = {{Hassan, Mujtaba and Baussière, Floriane and Guzelj, Samo and Sundin, Anders P. and Håkansson, Maria and Kovačič, Rebeka and Leffler, Hakon and Tomašič, Tihomir and Anderluh, Marko and Jakopin, Žiga and Nilsson, Ulf J.}},
  issn         = {{1948-5875}},
  keywords     = {{benzimidazole; cytokine secretion; d -galactal; Galectin-8N; selectivity; X-ray crystallography}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{11}},
  pages        = {{1745--1752}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{ACS Medicinal Chemistry Letters}},
  title        = {{Structure-Guided Design of d -Galactal Derivatives with High Affinity and Selectivity for the Galectin-8 N-Terminal Domain}},
  url          = {{http://dx.doi.org/10.1021/acsmedchemlett.1c00371}},
  doi          = {{10.1021/acsmedchemlett.1c00371}},
  volume       = {{12}},
  year         = {{2021}},
}