Structure-Guided Design of d -Galactal Derivatives with High Affinity and Selectivity for the Galectin-8 N-Terminal Domain
(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.
(Less)
- author
- organization
- publishing date
- 2021-11-11
- 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
- 2024-06-15 22:11:16
@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}},
}