Potent metabolic sialylation inhibitors based on C-5 modified fluorinated sialic acids

Torben Heise; Johan Pijnenborg; Christian Büll; Niek van Hilten; Esther Kers-Rebel; Natasja Balneger; Hidde Elferink; Gosse J Adema; Thomas J Boltje

doi:10.1021/acs.jmedchem.8b01757

Potent metabolic sialylation inhibitors based on C-5 modified fluorinated sialic acids

Torben Heise, Johan Pijnenborg, Christian Büll, Niek van Hilten, Esther Kers-Rebel, Natasja Balneger, Hidde Elferink, Gosse J Adema, Thomas J Boltje

18 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	62
Udgave nummer	2
Sider (fra-til)	1014-1021
ISSN	0022-2623
DOI	https://doi.org/10.1021/acs.jmedchem.8b01757
Status	Udgivet - 24 jan. 2019
Udgivet eksternt	Ja

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10.1021/acs.jmedchem.8b01757Licens: CC BY-NC-ND

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abstract = "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.",

author = "Torben Heise and Johan Pijnenborg and Christian B{\"u}ll and {van Hilten}, Niek and Esther Kers-Rebel and Natasja Balneger and Hidde Elferink and Adema, {Gosse J} and Boltje, {Thomas J}",

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doi = "10.1021/acs.jmedchem.8b01757",

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T1 - Potent metabolic sialylation inhibitors based on C-5 modified fluorinated sialic acids

AU - Heise, Torben

AU - Pijnenborg, Johan

AU - Büll, Christian

AU - van Hilten, Niek

AU - Kers-Rebel, Esther

AU - Balneger, Natasja

AU - Elferink, Hidde

AU - Adema, Gosse J

AU - Boltje, Thomas J

PY - 2019/1/24

Y1 - 2019/1/24

N2 - 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.

AB - 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.

U2 - 10.1021/acs.jmedchem.8b01757

DO - 10.1021/acs.jmedchem.8b01757

M3 - Journal article

C2 - 30543426

SN - 0022-2623

VL - 62

SP - 1014

EP - 1021

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 2

ER -

Potent metabolic sialylation inhibitors based on C-5 modified fluorinated sialic acids

Abstract

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