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Structure-guided design of D-galactal derivatives with high affinity and selectivity for the galectin-8 n-terminal domainHassan, Mujtaba ...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.Vir: ACS Medicinal Chemistry Letters. - ISSN 1948-5875 (Vol. 12, iss. 11, 2021, str. 1745-1752)Vrsta gradiva - članek, sestavni del ; neleposlovje za odrasleLeto - 2021Jezik - angleškiCOBISS.SI-ID - 83202819
Avtor
Hassan, Mujtaba |
Baussière, Floriane |
Guzelj, Samo |
Sundin, Anders |
Håkansson, Maria |
Kovačič, Rebeka, 1990- |
Leffler, Hakon |
Tomašič, Tihomir |
Anderluh, Marko |
Jakopin, Žiga
Teme
Farmacevtska kemija |
Rak (medicina) |
Galectin-8N |
d-galactal |
benzimidazole |
selectivity |
X-ray crystallography |
cytokine secretion
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Hassan, Mujtaba | ![]() |
Baussière, Floriane | ![]() |
Guzelj, Samo | 52379 |
Sundin, Anders | ![]() |
Håkansson, Maria | ![]() |
Kovačič, Rebeka, 1990- | ![]() |
Leffler, Hakon | ![]() |
Tomašič, Tihomir | 28334 |
Anderluh, Marko | 21456 |
Jakopin, Žiga | 26496 |
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