N-Phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors

Auteur(s): Bouzriba, ChahrazedLarcher, LaurianeGagné-Boulet, MathieuFortin, Sébastien
Résumé: N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC50 = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
Type de document: Article de recherche
Date de publication: 14 septembre 2020
Date de la mise en libre accès: 14 septembre 2022
Version du document: AM
Licence Creative Commons: https://creativecommons.org/licenses/by-nc-nd/4.0
Lien permanent: http://hdl.handle.net/20.500.11794/74023
Ce document a été publié dans: Bioorganic and medicinal chemistry, Vol. 28 (22), 115739 (2020)
https://doi.org/10.1016/j.bmc.2020.115739
Elsevier
Autre version disponible: 10.1016/j.bmc.2020.115739
33007554
Collection :Articles publiés dans des revues avec comité de lecture

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