Synthesis and Screening of α-Xylosides in Human Glioblastoma Cells

Kalita, Mausam; Villanueva‐Meyer, Javier; Ohkawa, Yuki; Kalyanaraman, Chakrapani; Chen, Katharine; Mohamed, Esraa; Parker, Matthew F.L.; Jacobson, Matthew P.; Evans, Michael J.; Wilson, David M.

doi:10.1021/acs.molpharmaceut.0c00839

Cited by 5 publications

(3 citation statements)

References 48 publications

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“…For example, treatment of cells for 24 h with 0.3–1 mM 4-deoxy-4-fluoro-xyloside linked through a triazole to napthyl inhibited GAG biosynthesis by ∼ 80% [276] . Efforts are ongoing to generate prodrugs to achieve higher potency [277] . Caution should be exercised when using xyloside primers, as depletion of monosaccharides used in GAG biosynthesis can in some cases influence other glycosylation pathways.…”

Section: Glycosaminoglycan Inhibitorsmentioning

confidence: 99%

Small molecule inhibitors of mammalian glycosylation

Almahayni

Spiekermann

Fiore

et al. 2022

Matrix Biology Plus

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Section: Glycosaminoglycan Inhibitorsmentioning

confidence: 99%

Small molecule inhibitors of mammalian glycosylation

Almahayni

Spiekermann

Fiore

et al. 2022

Matrix Biology Plus

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“…It has also been reported the anti-angiogenic efficacy of two different fluoro-xylosides that by inhibiting HS synthesis in endothelial cells, ultimately inhibit tumour cells’ angiogenesis ( 134 ), which is in agreement with the previously mentioned role of HSPGs as important binding partners and co-receptors of pro-angiogenic factors, including VEGF and FGF. More recently, novel xyloside-derived compounds with potential to be used in therapy for glioblastoma were identified due to their ability of impairing endogenous GAG biosynthesis by binding to XYLT1 and β4GAL T7 active sites, and consequently decreasing glioblastoma cell viability ( 135 ). In a different study, Mani K. et al demonstrated that the use of the synthetic xyloside 2(6-hydroxynaphthyl)-β-D-xylopyranoside inhibited tumour cell growth in vitro , in human lung and hepatocellular carcinoma, and SV40-transformed mouse embryonic fibroblasts 3T3 cells, as well as in vivo , in human bladder carcinoma cells ( 136 ).…”

Section: Targeting Of Hs and Hs Biosynthetic Enzymesmentioning

confidence: 99%

Heparan Sulfate Biosynthesis and Sulfation Profiles as Modulators of Cancer Signalling and Progression

et al. 2021

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Heparan Sulfate Proteoglycans (HSPGs) are important cell surface and Extracellular Matrix (ECM) maestros involved in the orchestration of multiple cellular events in physiology and pathology. These glycoconjugates bind to various bioactive proteins via their Heparan Sulfate (HS) chains, but also through the protein backbone, and function as scaffolds for protein-protein interactions, modulating extracellular ligand gradients, cell signalling networks and cell-cell/cell-ECM interactions. The structural features of HS chains, including length and sulfation patterns, are crucial for the biological roles displayed by HSPGs, as these features determine HS chains binding affinities and selectivity. The large HS structural diversity results from a tightly controlled biosynthetic pathway that is differently regulated in different organs, stages of development and pathologies, including cancer. This review addresses the regulatory mechanisms underlying HS biosynthesis, with a particular focus on the catalytic activity of the enzymes responsible for HS glycan sequences and sulfation motifs, namely D-Glucuronyl C5-Epimerase, N- and O-Sulfotransferases. Moreover, we provide insights on the impact of different HS structural epitopes over HSPG-protein interactions and cell signalling, as well as on the effects of deregulated expression of HS modifying enzymes in the development and progression of cancer. Finally, we discuss the clinical potential of HS biosynthetic enzymes as novel targets for therapy, and highlight the importance of developing new HS-based tools for better patients’ stratification and cancer treatment.

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“…By these two mechanisms, xylosides act to block HSPG functions. Xylosides have been shown to inhibit glioblastoma cell viability [ 156 ], glioma cell invasion [ 157 ], tumor angiogenesis in vitro [ 158 ], and various tumor cell line growth in vitro and human bladder carcinoma growth in vivo [ 159 ]. These anti-HSPG strategies and available agents give great potential to future tauopathy treatments, exemplified by a recent study from Naini et al showing that surfen and oxalyl surfen decreased tau hyperphosphorylation and mitigated neuron deficits in vivo in a zebrafish model of tauopathy [ 160 ].…”

Section: Future Studies From the Hspg Aspectmentioning

confidence: 99%

Heparan Sulfate Proteoglycans in Tauopathy

et al. 2022

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Tauopathies are a class of neurodegenerative diseases, including Alzheimer’s disease, and are characterized by intraneuronal tau inclusion in the brain and the patient’s cognitive decline with obscure pathogenesis. Heparan sulfate proteoglycans, a major type of extracellular matrix, have been believed to involve in tauopathies. The heparan sulfate proteoglycans co-deposit with tau in Alzheimer’s patient brain, directly bind to tau and modulate tau secretion, internalization, and aggregation. This review summarizes the current understanding of the functions and the modulated molecular pathways of heparan sulfate proteoglycans in tauopathies, as well as the implication of dysregulated heparan sulfate proteoglycan expression in tau pathology and the potential of targeting heparan sulfate proteoglycan-tau interaction as a novel therapeutic option.

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Synthesis and Screening of α-Xylosides in Human Glioblastoma Cells

Abstract: Detailed experimental procedures, including chemical syntheses, MTT assays, IC 50 plots, and molecular modeling descriptions (PDF)

Cited by 5 publications

References 48 publications

Small molecule inhibitors of mammalian glycosylation

Small molecule inhibitors of mammalian glycosylation

Heparan Sulfate Biosynthesis and Sulfation Profiles as Modulators of Cancer Signalling and Progression

Heparan Sulfate Proteoglycans in Tauopathy

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