Phenyl 4-(2-oxopyrrolidin-1-yl)benzenesulfonates and phenyl 4-(2-oxopyrrolidin-1-yl)benzenesulfonamides as new antimicrotubule agents targeting the colchicine-binding site

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dc.contributor.authorGagné-Boulet, Mathieu-
dc.contributor.authorBouzriba, Chahrazed-
dc.contributor.authorChavez Alvarez, Atziri Corin-
dc.contributor.authorFortin, Sébastien-
dc.description.abstractWe recently designed and prepared new families of potent antimicrotubule agents designated as N-phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB–SOs) and phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamides (PIB–SAs). Our previous structure-activity relationship studies (SAR) focused on the aromatic ring B of PIB-SOs and PIB-SAs leaving the impact of the phenylimidazolidin-2-one moiety (ring A) on the binding to the colchicine-binding site (C-BS) poorly studied. Therefore, the aim of the present study was to evaluate the effect of replacing the imidazolidin-2-one (IMZ) group by a pyrrolidin-2-one moiety. To that end, 15 new phenyl 4-(2-oxopyrrolidin-1-yl)benzenesulfonate (PYB–SO) and 15 phenyl 4-(2-oxopyrrolidin-1-yl)benzenesulfonamide (PYB-SA) derivatives were designed, prepared, chemically characterised and biologically evaluated. PYB-SOs and PYB-SAs exhibit antiproliferative activity in the low nanomolar to low micromolar range (0.0087–8.6 μM and 0.056–21 μM, respectively) on human HT-1080, HT-29, M21 and MCF7 cancer cell lines. Moreover, they block cell cycle progression in G2/M phase. Immunofluorescence, tubulin affinity and tubulin polymerisation assays show that they cause microtubule depolymerisation by docking the C-BS. In addition, docking assays with the most potent derivatives show binding affinity toward the C-BS and they also exhibit weak or no toxicity toward chick embryos. Finally, physicochemical properties calculated using the SwissADME algorithm show that PYB-SOs and PYB-SAs are promising new families of antimicrotubule
dc.subjectAnticancer agentsfr
dc.subjectAntimicrotubule agentsfr
dc.subjectColchicine-binding site inhibitorsfr
dc.subjectPhenyl 4-(2-oxopyrrolidin-1-yl)benzenesulfonatesfr
dc.subjectPhenyl 4-(2-oxopyrrolidin-1-yl)benzenesulfonamidesfr
dc.titlePhenyl 4-(2-oxopyrrolidin-1-yl)benzenesulfonates and phenyl 4-(2-oxopyrrolidin-1-yl)benzenesulfonamides as new antimicrotubule agents targeting the colchicine-binding sitefr
dc.typeCOAR1_1::Texte::Périodique::Revue::Contribution à un journal::Article::Article de recherchefr
dcterms.bibliographicCitationEuropean journal of medicinal chemistry, Vol. 213, 113136 (2021)fr
dc.subject.rvmColchicine -- Inhibiteursfr
rioxxterms.versionAccepted Manuscriptfr
rioxxterms.projectNSERC, RGPIN-2016-05069fr
rioxxterms.project.funder_nameNatural Sciences and Engineering Research Council of Canadafr
rioxxterms.project.funder_nameFonds de Recherche du Québec - Santéfr
rioxxterms.project.funder_nameCHU de Québec. Centre de recherchefr
rioxxterms.project.funder_nameFonds d'enseignement et de recherche de la Faculté de Pharmacie de l'Université Lavalfr
ali.license_refAttribution - Pas d'Utilisation Commerciale - Pas de Modification CC BY-NC-NDfr
bul.rights.periodeEmbargo24 moisfr
Collection:Articles publiés dans des revues avec comité de lecture

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