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Potent Metabolic Sialylation Inhibitors Based on C-5-Modified Fluorinated Sialic Acids

[Image: see text] Sialic acid sugars on mammalian cells regulate numerous biological processes, while aberrant expression of sialic acid is associated with diseases such as cancer and pathogenic infection. Inhibition of the sialic acid biosynthesis may therefore hold considerable therapeutic potenti...

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Autores principales: Heise, Torben, Pijnenborg, Johan F. A., Büll, Christian, van Hilten, Niek, Kers-Rebel, Esther D., Balneger, Natasja, Elferink, Hidde, Adema, Gosse J., Boltje, Thomas J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2018
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348442/
https://www.ncbi.nlm.nih.gov/pubmed/30543426
http://dx.doi.org/10.1021/acs.jmedchem.8b01757
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author Heise, Torben
Pijnenborg, Johan F. A.
Büll, Christian
van Hilten, Niek
Kers-Rebel, Esther D.
Balneger, Natasja
Elferink, Hidde
Adema, Gosse J.
Boltje, Thomas J.
author_facet Heise, Torben
Pijnenborg, Johan F. A.
Büll, Christian
van Hilten, Niek
Kers-Rebel, Esther D.
Balneger, Natasja
Elferink, Hidde
Adema, Gosse J.
Boltje, Thomas J.
author_sort Heise, Torben
collection PubMed
description [Image: see text] Sialic acid sugars on mammalian cells regulate numerous biological processes, while aberrant expression of sialic acid is associated with diseases such as cancer and pathogenic infection. Inhibition of the sialic acid biosynthesis may therefore hold considerable therapeutic potential. To effectively decrease the sialic acid expression, we synthesized C-5-modified 3-fluoro sialic acid sialyltransferase inhibitors. We found that C-5 carbamates significantly enhanced and prolonged the inhibitory activity in multiple mouse and human cell lines. As an underlying mechanism, we have identified that carbamate-modified 3-fluoro sialic acid inhibitors are more efficiently metabolized to their active cytidine monophosphate analogues, reaching higher effective inhibitor concentrations inside cells.
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spelling pubmed-63484422019-01-29 Potent Metabolic Sialylation Inhibitors Based on C-5-Modified Fluorinated Sialic Acids Heise, Torben Pijnenborg, Johan F. A. Büll, Christian van Hilten, Niek Kers-Rebel, Esther D. Balneger, Natasja Elferink, Hidde Adema, Gosse J. Boltje, Thomas J. J Med Chem [Image: see text] Sialic acid sugars on mammalian cells regulate numerous biological processes, while aberrant expression of sialic acid is associated with diseases such as cancer and pathogenic infection. Inhibition of the sialic acid biosynthesis may therefore hold considerable therapeutic potential. To effectively decrease the sialic acid expression, we synthesized C-5-modified 3-fluoro sialic acid sialyltransferase inhibitors. We found that C-5 carbamates significantly enhanced and prolonged the inhibitory activity in multiple mouse and human cell lines. As an underlying mechanism, we have identified that carbamate-modified 3-fluoro sialic acid inhibitors are more efficiently metabolized to their active cytidine monophosphate analogues, reaching higher effective inhibitor concentrations inside cells. American Chemical Society 2018-12-13 2019-01-24 /pmc/articles/PMC6348442/ /pubmed/30543426 http://dx.doi.org/10.1021/acs.jmedchem.8b01757 Text en Copyright © 2018 American Chemical Society This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License (http://pubs.acs.org/page/policy/authorchoice_ccbyncnd_termsofuse.html) , which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes.
spellingShingle Heise, Torben
Pijnenborg, Johan F. A.
Büll, Christian
van Hilten, Niek
Kers-Rebel, Esther D.
Balneger, Natasja
Elferink, Hidde
Adema, Gosse J.
Boltje, Thomas J.
Potent Metabolic Sialylation Inhibitors Based on C-5-Modified Fluorinated Sialic Acids
title Potent Metabolic Sialylation Inhibitors Based on C-5-Modified Fluorinated Sialic Acids
title_full Potent Metabolic Sialylation Inhibitors Based on C-5-Modified Fluorinated Sialic Acids
title_fullStr Potent Metabolic Sialylation Inhibitors Based on C-5-Modified Fluorinated Sialic Acids
title_full_unstemmed Potent Metabolic Sialylation Inhibitors Based on C-5-Modified Fluorinated Sialic Acids
title_short Potent Metabolic Sialylation Inhibitors Based on C-5-Modified Fluorinated Sialic Acids
title_sort potent metabolic sialylation inhibitors based on c-5-modified fluorinated sialic acids
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348442/
https://www.ncbi.nlm.nih.gov/pubmed/30543426
http://dx.doi.org/10.1021/acs.jmedchem.8b01757
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