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Structure-Guided De...
Structure-Guided Design of d -Galactal Derivatives with High Affinity and Selectivity for the Galectin-8 N-Terminal Domain
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- Hassan, Mujtaba (författare)
- Lund University,Lunds universitet,Centrum för analys och syntes,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Centre for Analysis and Synthesis,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH,University of Ljubljana
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- Baussière, Floriane (författare)
- Lund University
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- Guzelj, Samo (författare)
- University of Ljubljana
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- Sundin, Anders P. (författare)
- Lund University,Lunds universitet,Centrum för analys och syntes,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Centre for Analysis and Synthesis,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH
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- Håkansson, Maria (författare)
- SARomics Biostructures AB
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- Kovačič, Rebeka (författare)
- SARomics Biostructures AB
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- Leffler, Hakon (författare)
- Lund University,Lunds universitet,Avdelningen för mikrobiologi, immunologi och glykobiologi - MIG,Institutionen för laboratoriemedicin,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Microbiology, Immunology and Glycobiology - MIG,Department of Laboratory Medicine,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Tomašič, Tihomir (författare)
- University of Ljubljana
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- Anderluh, Marko (författare)
- University of Ljubljana
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- Jakopin, Žiga (författare)
- University of Ljubljana
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- Nilsson, Ulf J. (författare)
- Lund University,Lunds universitet,Centrum för analys och syntes,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Centre for Analysis and Synthesis,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH
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(creator_code:org_t)
- 2021-11-02
- 2021
- Engelska 8 s.
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Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 12:11, s. 1745-1752
- Relaterad länk:
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http://dx.doi.org/10... (free)
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https://pubs.acs.org...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
Nyckelord
- benzimidazole
- cytokine secretion
- d -galactal
- Galectin-8N
- selectivity
- X-ray crystallography
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Hassan, Mujtaba
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Baussière, Flori ...
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Guzelj, Samo
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Sundin, Anders P ...
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Håkansson, Maria
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Kovačič, Rebeka
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visa fler...
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Leffler, Hakon
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Tomašič, Tihomir
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Anderluh, Marko
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Jakopin, Žiga
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Nilsson, Ulf J.
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visa färre...
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