N-Phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors
DC Field | Value | Language |
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dc.contributor.author | Bouzriba, Chahrazed | - |
dc.contributor.author | Larcher, Lauriane | - |
dc.contributor.author | Gagné-Boulet, Mathieu | - |
dc.contributor.author | Fortin, Sébastien | - |
dc.date.accessioned | 2022-08-04T19:27:10Z | - |
dc.date.available | 2022-09-14T00:00:00Z | - |
dc.date.issued | 2020-09-14 | - |
dc.identifier.issn | 0968-0896 | fr |
dc.identifier.uri | http://hdl.handle.net/20.500.11794/74023 | - |
dc.description.abstract | 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. | fr |
dc.language | eng | fr |
dc.publisher | Elsevier | fr |
dc.subject | Anticancer agents | fr |
dc.subject | Human dihydroorotate dehydrogenase inhibitors | fr |
dc.subject | N-phenylureidobenzenesulfonates | fr |
dc.subject | PUB-SOs | fr |
dc.subject | SFOM-0046 | fr |
dc.title | N-Phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors | fr |
dc.type | COAR1_1::Texte::Périodique::Revue::Contribution à un journal::Article::Article de recherche | fr |
dcterms.bibliographicCitation | Bioorganic and medicinal chemistry, Vol. 28 (22), 115739 (2020) | fr |
dc.identifier.doi | 10.1016/j.bmc.2020.115739 | fr |
dc.identifier.pubmed | 33007554 | fr |
dc.subject.rvm | Anticancéreux | fr |
dc.subject.rvm | Cancer -- Chimiothérapie | fr |
dc.subject.rvm | Oxydoréductases -- Inhibiteurs | fr |
dc.subject.rvm | Uridine | fr |
rioxxterms.version | Accepted Manuscript | fr |
rioxxterms.version_of_record | https://doi.org/10.1016/j.bmc.2020.115739 | fr |
rioxxterms.project | NSERC, RGPIN-2016-05069 | fr |
rioxxterms.project.funder_name | Natural Sciences and Engineering Research Council of Canada | fr |
rioxxterms.project.funder_name | Fonds de Recherche du Québec - Santé | fr |
rioxxterms.project.funder_name | CHU de Québec. Centre de recherche | fr |
ali.license_ref | Attribution - Pas d'Utilisation Commerciale - Pas de Modification CC BY-NC-ND | fr |
ali.license_ref.start_date | 2022-09-14 | fr |
bul.rights.periodeEmbargo | 24 mois | fr |
bul.rights.addendum | Rien | fr |
Collection: | Articles publiés dans des revues avec comité de lecture |
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34. Bioorganic and Medicinal Chemistry 2020.pdf | 1.7 MB | Adobe PDF | Request a copy |
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