Sulfonylurea Bioisosteres of Sulfonic Acid in JFD 00458‐Based ST6GAL1 Inhibitors Enhance Membrane Permeability
Abstract
Sialyltransferases catalyze the transfer of sialic acid to glycoconjugates within the Golgi apparatus, generating cell‐surface sialoglycans that regulate cell–cell and immune communication. This process can be modulated by inhibiting α−2,6‐sialyltransferase 1 (ST6GAL1), one of the most important sialyltransferases. Most β‐galactoside ST6GAL1 inhibitors are polar CMP‐Neu5Ac derivatives with limited membrane permeability, a limitation shared by the noncarbohydrate inhibitor JFD 00458 . Here, we designed JFD 00458 analogs to improve permeability while maintaining ST6GAL1 inhibition and direct target engagement. Incorporation of sulfonic‐acid bioisosteres, particularly sulfonylureas, improved passive permeability, as measured by parallel artificial membrane permeability assay, with the best analog reaching log(P_app [cm/s]) = −4.3. Potency was also improved in an expanded series of sulfonylureas, with the best inhibitor displaying an IC 50 of 1.9 µM. Microscale thermophoresis confirmed direct ST6GAL1 binding, with similar apparent K d values of approximately 22–25 µM for JFD 00458 and the optimized sulfonylureas. Saturation transfer difference NMR identified the substituted phenoxy phenyl core as a common ST6GAL1‐contacting epitope, while closer contacts from the sulfonylurea‐linked aromatic substituents in 6d and 6e were associated with the highest inhibitory potency across the series. These results establish sulfonylureas as membrane‐permeable sulfonic‐acid bioisosteres and provide a structure–activity framework for further ST6GAL1 inhibitor optimization.
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BibTeX
@article{koraj2026sulfonylurea,
title = {{Sulfonylurea Bioisosteres of Sulfonic Acid in JFD 00458‐Based ST6GAL1 Inhibitors Enhance Membrane Permeability}},
author = {Natan Koraj and Sushmaa Dangudubiyyam and Adelyn M. Betances‐mora and Ema Faganeli and Anne Harduin‐lepers and Jesús Angulo and Tan Khanh Nguyen and María Bort-Griñó and Ramon Hurtado‐guerrero and Marko Anderluh},
journal = {ChemMedChem},
year = {2026},
month = aug,
doi = {10.1002/cmdc.70465},
url = {https://lilloa.hal.science/hal-05840608v1},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Sulfonylurea Bioisosteres of Sulfonic Acid in JFD 00458‐Based ST6GAL1 Inhibitors Enhance Membrane Permeability
AU - Natan Koraj
AU - Sushmaa Dangudubiyyam
AU - Adelyn M. Betances‐mora
AU - Ema Faganeli
AU - Anne Harduin‐lepers
AU - Jesús Angulo
AU - Tan Khanh Nguyen
AU - María Bort-Griñó
AU - Ramon Hurtado‐guerrero
AU - Marko Anderluh
PY - 2026
DA - 2026/08/26
JO - ChemMedChem
DO - 10.1002/cmdc.70465
UR - https://lilloa.hal.science/hal-05840608v1
AB - Sialyltransferases catalyze the transfer of sialic acid to glycoconjugates within the Golgi apparatus, generating cell‐surface sialoglycans that regulate cell–cell and immune communication. This process can be modulated by inhibiting α−2,6‐sialyltransferase 1 (ST6GAL1), one of the most important sialyltransferases. Most β‐galactoside ST6GAL1 inhibitors are polar CMP‐Neu5Ac derivatives with limited membrane permeability, a limitation shared by the noncarbohydrate inhibitor JFD 00458 . Here, we designed JFD 00458 analogs to improve permeability while maintaining ST6GAL1 inhibition and direct target engagement. Incorporation of sulfonic‐acid bioisosteres, particularly sulfonylureas, improved passive permeability, as measured by parallel artificial membrane permeability assay, with the best analog reaching log(P_app [cm/s]) = −4.3. Potency was also improved in an expanded series of sulfonylureas, with the best inhibitor displaying an IC 50 of 1.9 µM. Microscale thermophoresis confirmed direct ST6GAL1 binding, with similar apparent K d values of approximately 22–25 µM for JFD 00458 and the optimized sulfonylureas. Saturation transfer difference NMR identified the substituted phenoxy phenyl core as a common ST6GAL1‐contacting epitope, while closer contacts from the sulfonylurea‐linked aromatic substituents in 6d and 6e were associated with the highest inhibitory potency across the series. These results establish sulfonylureas as membrane‐permeable sulfonic‐acid bioisosteres and provide a structure–activity framework for further ST6GAL1 inhibitor optimization.
SN - 1860-7179
SN - 1860-7187
ER -