Rational Design and Synthesis of Methyl-β-<scp>d</scp>-galactomalonyl Phenyl Esters as Potent Galectin-8<i>N</i> Antagonists

Patel, Bhavesh; Kishor, Chandan; Houston, Todd Ashley; Shatz-Azoulay, Hadas; Zick, Yehiel; Vinik, Yaron; Blanchard, Helen

doi:10.1021/acs.jmedchem.0c00602

Cited by 17 publications

(15 citation statements)

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“… 36 , 37 A recent study has shown that treatment of SUM159 breast cancer cells with exogenous galectin-8 stimulated the secretion of IL-6, IL-8 and IL-1β, while cotreatment with galectin-8 antagonists blocked this effect. 18 Since MDA-MB-231 cells express galectin-8 endogenously, we reasoned that inhibition of endogenous galectin-8 might reduce proinflammatory cytokine secretion in these cells. To this end, we treated MDA-MB-231 cells with compounds 6a and 1 at two different concentrations (10 and 100 μM).…”

Section: Results and Discussionmentioning

confidence: 99%

“…Achieving selectivity for galectin-8N over the other mammalian galectins has always been a challenging task, due to the substantial similarity of different galectin CRDs and even between 8N and 8C CRDs. The previously reported synthetic galectin-8N ligands include a coumarin-galactoside derivative ( K d = 200 μM), a methyl β- d -galactomalonyl phenyl ester ( K d = 5.7 μM), a quinoline-galactoside ( K d = 1.5 μM), and a recently reported benzimidazole-galactoside 1 ( K d = 1.8 μM) (Figure ). Of particular note is a recently reported tricyclic galactose-benzene hybrid 2 ( K d = 180 μM) which has about 2-fold selectivity over galectin-1 and a high 23-fold selectivity over galectin-3 (Figure ).…”

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confidence: 99%

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

Hassan

Baussière

Guzelj

et al. 2021

ACS Med. Chem. Lett.

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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 K d 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-(4sulfophenyl)-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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Section: Results and Discussionmentioning

confidence: 99%

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confidence: 99%

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

Hassan

Baussière

Guzelj

et al. 2021

ACS Med. Chem. Lett.

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“…Similarly, Gal-8 direct binding at the SARS-CoV-2 coronavirus RBD, might impede viral infection. Prototypes of Gal-8 inhibitors [ 146 , 147 ] are already available. Yet, further studies are required to unravel the role of Gal-8 in tumor growth and in the immunopathogenesis of COVID-19, before considering it as a potential therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

Galectin-8, cytokines, and the storm

Zick

2021

Biochemical Society Transactions

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Galectin-8 (Gal-8) belongs to a family of animal lectins that modulate cell adhesion, cell proliferation, apoptosis, and immune responses. Recent studies have shown that mammalian Gal-8 induces in an autocrine and paracrine manner, the expression and secretion of cytokines and chemokines such as RANKL, IL-6, IL-1β, SDF-1, and MCP-1. This involves Gal-8 binding to receptor complexes that include MRC2/uPAR/LRP1, integrins, and CD44. Receptors ligation triggers FAK, ERK, Akt, and the JNK signaling pathways, leading to induction of NF-κB that promotes cytokine expression. Indeed, immune-competent Gal-8 knockout (KO) mice express systemic lower levels of cytokines and chemokines while the opposite is true for Gal-8 transgenic animals. Cytokine and chemokine secretion, induced by Gal-8, promotes the migration of cancer cells toward cells expressing this lectin. Accordingly, Gal-8 KO mice experience reduced tumor size and smaller and fewer metastatic lesions when injected with cancer cells. These observations suggest the existence of a ‘vicious cycle’ whereby Gal-8 expression and secretion promotes the secretion of cytokines and chemokines that further promote Gal-8 expression. This ‘vicious cycle’ could enhance the development of a ‘cytokine storm’ which is a key contributor to the poor prognosis of COVID-19 patients.

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“…Another example is the recently described monosaccharide galactose-based antagonist of human Gal-8. This inhibitor has an affinity in the low micromolar range and is capable of inhibiting the secretion of cytokines by breast cancer cells [ 130 ].…”

Section: Approaches For Targeting and Delivery Of Galectinsmentioning

confidence: 99%

Galectins in Glioma: Current Roles in Cancer Progression and Future Directions for Improving Treatment

Ajarrag

St‐Pierre

2021

Cancers

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Traditional wisdom suggests that galectins play pivotal roles at different steps in cancer progression. Galectins are particularly well known for their ability to increase the invasiveness of cancer cells and their resistance to drug-induced cell death. They also contribute to the development of local and systemic immunosuppression, allowing cancer cells to escape the host’s immunological defense. This is particularly true in glioma, the most common primary intracranial tumor. Abnormally high production of extracellular galectins in glioma contributes to the establishment of a strong immunosuppressive environment that favors immune escape and tumor progression. Considering the recent development and success of immunotherapy in halting cancer progression, it is logical to foresee that galectin-specific drugs may help to improve the success rate of immunotherapy for glioma. This provides a new perspective to target galectins, whose intracellular roles in cancer progression have already been investigated thoroughly. In this review, we discuss the mechanisms of action of galectins at different steps of glioma progression and the potential of galectin-specific drugs for the treatment of glioma.

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Rational Design and Synthesis of Methyl-β-d-galactomalonyl Phenyl Esters as Potent Galectin-8N Antagonists

Cited by 17 publications

References 44 publications

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

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

Galectin-8, cytokines, and the storm

Galectins in Glioma: Current Roles in Cancer Progression and Future Directions for Improving Treatment

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