Design, synthesis and evaluation of carbamate-linked uridyl-based inhibitors of human ST6Gal I

Montgomery, Andrew P.; Dobie, Christopher; Szabo, Rémi; Hallam, Laura; Ranson, Marie; Yu, Haibo; Skropeta, Danielle

doi:10.1016/j.bmc.2020.115561

Cited by 16 publications

(11 citation statements)

References 71 publications

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“…More recently, Montgomery and colleagues developed a series of uridine-based compounds in which the α-hydroxyphosphonate was coupled with a 5′-amino-5′-deoxyuridine fragment instead of a cytidine [ 146 ]. The authors reported no cytotoxicity and higher potency of these compounds in inhibiting ST6GAL1 activity compared to their ancestors [ 146 ].…”

Section: Sialyltransferase Inhibitorsmentioning

confidence: 99%

Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention?

Pietrobono¹,

Stecca²

2021

Cancers

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Sialylation is an integral part of cellular function, governing many biological processes including cellular recognition, adhesion, molecular trafficking, signal transduction and endocytosis. Sialylation is controlled by the levels and the activities of sialyltransferases on glycoproteins and lipids. Altered gene expression of these enzymes in cancer yields to cancer-specific alterations of glycoprotein sialylation. Mounting evidence indicate that hypersialylation is closely associated with cancer progression and metastatic spread, and can be of prognostic significance in human cancer. Aberrant sialylation is not only a result of cancer, but also a driver of malignant phenotype, directly impacting key processes such as tumor cell dissociation and invasion, cell-cell and cell-matrix interactions, angiogenesis, resistance to apoptosis, and evasion of immune destruction. In this review we provide insights on the impact of sialylation in tumor progression, and outline the possible application of sialyltransferases as cancer biomarkers. We also summarize the most promising findings on the development of sialyltransferase inhibitors as potential anti-cancer treatments.

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Section: Sialyltransferase Inhibitorsmentioning

confidence: 99%

Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention?

Pietrobono¹,

Stecca²

2021

Cancers

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“…Interestingly, the neutral linkers were slightly more favorable than the charged phosphodiester moiety, suggesting that a carbamate or 1,2,3-triazole group may serve as a bioisostere of the phosphodiester group in the development of novel inhibitors. Thus, the same group recently published the synthesis and ST6Gal-I inhibition studies of 24 carbamate-linked uridyl-based compounds [ 134 ]. Among them, five promising compounds ( 46 – 50 ) ( Table 5 ) exhibited K i ’s in the range of 1–20 μM.…”

Section: Development Of Small Molecule Sialyltransferase Inhibitorsmentioning

confidence: 99%

Sialyltransferase Inhibitors for the Treatment of Cancer Metastasis: Current Challenges and Future Perspectives

Perez

2021

Molecules

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Potent, cell-permeable, and subtype-selective sialyltransferase inhibitors represent an attractive family of substances that can potentially be used for the clinical treatment of cancer metastasis. These substances operate by specifically inhibiting sialyltransferase-mediated hypersialylation of cell surface glycoproteins or glycolipids, which then blocks the sialic acid recognition pathway and leads to deterioration of cell motility and invasion. A vast amount of evidence for the in vitro and in vivo effects of sialyltransferase inhibition or knockdown on tumor progression and tumor cell metastasis or colonization has been accumulated over the past decades. In this regard, this review comprehensively discusses the results of studies that have led to the recent discovery and development of sialyltransferase inhibitors, their potential biomedical applications in the treatment of cancer metastasis, and their current limitations and future opportunities.

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“…Interestingly, these effects are enhanced due to nanoparticle-related inclusion and increased bioavailability [ 39 , 40 ]. In contrast to hypersialylation, the inhibition of sialylation in the most cancers improves their control by the immune system, as demonstrated by the increased level of CD 4+ cells, CD 8+T cells, and NK cells [ 41 , 42 ].…”

Section: Sialome As a Potential Target In Therapy Of Glioma And Other Human Cancersmentioning

confidence: 99%

Sialic Acid—Modified Nanoparticles—New Approaches in the Glioma Management—Perspective Review

Wielgat

Niemirowicz-Laskowska

Wilczewska

et al. 2021

IJMS

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The cell surface is covered by a dense and complex network of glycans attached to the membrane proteins and lipids. In gliomas, the aberrant sialylation, as the final stage of glycosylation, is an important regulatory mechanism of malignant cell behavior and correlates with worse prognosis. Better understanding of the role of sialylation in cellular and molecular processes opens a new way in the development of therapeutic tools for human brain tumors. According to the recent clinical observation, the cellular heterogeneity, activity of brain cancer stem cells (BCSCs), immune evasion, and function of the blood–brain barrier (BBB) are attractive targets for new therapeutic strategies. In this review, we summarize the importance of sialic acid-modified nanoparticles in brain tumor progression.

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Design, synthesis and evaluation of carbamate-linked uridyl-based inhibitors of human ST6Gal I

Cited by 16 publications

References 71 publications

Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention?

Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention?

Sialyltransferase Inhibitors for the Treatment of Cancer Metastasis: Current Challenges and Future Perspectives

Sialic Acid—Modified Nanoparticles—New Approaches in the Glioma Management—Perspective Review

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