2. Academic Validation
  3. Modification of the phenyl ring B of phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates by pyridinyl moiety leads to novel antimitotics targeting the colchicine-binding site

Modification of the phenyl ring B of phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates by pyridinyl moiety leads to novel antimitotics targeting the colchicine-binding site

  • Bioorg Med Chem Lett. 2024 Jun 1:105:129745. doi: 10.1016/j.bmcl.2024.129745.
Vincent Ouellette 1,  Chahrazed Bouzriba 2,  Atziri Corin Chavez Alvarez 3,  Geneviève Hamel-Côté 4,  Sébastien Fortin 5
Affiliations

Affiliations

  • 1 Centre de recherche du CHU de Québec-Université Laval, Axe Oncologie, Hôpital Saint-François d'Assise, 10 rue de l'Espinay, Québec, QC, G1L 3L5, Canada; Faculté de pharmacie, Université Laval, Pavillon Ferdinand-Vandry, 1050 avenue de la Médecine, Québec, QC, G1V 0A6, Canada. Electronic address: vincent.ouellette.2@ulaval.ca.
  • 2 Centre de recherche du CHU de Québec-Université Laval, Axe Oncologie, Hôpital Saint-François d'Assise, 10 rue de l'Espinay, Québec, QC, G1L 3L5, Canada; Faculté de pharmacie, Université Laval, Pavillon Ferdinand-Vandry, 1050 avenue de la Médecine, Québec, QC, G1V 0A6, Canada. Electronic address: chahrazed.bouzriba.1@ulaval.ca.
  • 3 Centre de recherche du CHU de Québec-Université Laval, Axe Oncologie, Hôpital Saint-François d'Assise, 10 rue de l'Espinay, Québec, QC, G1L 3L5, Canada; Faculté de pharmacie, Université Laval, Pavillon Ferdinand-Vandry, 1050 avenue de la Médecine, Québec, QC, G1V 0A6, Canada; Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval (IUCPQ), 2725 chemin Ste-Foy, Québec, QC, G1V 4G5, Canada. Electronic address: atziri-corin.chavez-alvarez.1@ulaval.ca.
  • 4 Centre de recherche du CHU de Québec-Université Laval, Axe Oncologie, Hôpital Saint-François d'Assise, 10 rue de l'Espinay, Québec, QC, G1L 3L5, Canada. Electronic address: genevieve.hamel-cote@crchudequebec.ulaval.ca.
  • 5 Centre de recherche du CHU de Québec-Université Laval, Axe Oncologie, Hôpital Saint-François d'Assise, 10 rue de l'Espinay, Québec, QC, G1L 3L5, Canada; Faculté de pharmacie, Université Laval, Pavillon Ferdinand-Vandry, 1050 avenue de la Médecine, Québec, QC, G1V 0A6, Canada. Electronic address: sebastien.fortin@pha.ulaval.ca.
PMID: 38614151 DOI: 10.1016/j.bmcl.2024.129745
Abstract

A series of 8 novel pyridinyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PYRIB-SOs) were designed, prepared and evaluated for their mechanism of action. PYRIB-SOs were found to have antiproliferative activity in the nanomolar to submicromolar range on several breast Cancer cell lines. Moreover, subsequent biofunctional assays indicated that the most potent PYRIB-SOs 1-3 act as antimitotics binding to the colchicine-binding site (C-BS) of α, β-tubulin and that they arrest the cell cycle progression in the G2/M phase. Microtubule immunofluorescence and tubulin polymerisation assay confirm that they disrupt the Cytoskeleton through inhibition of tubulin polymerisation as observed with microtubule-destabilising agents. They also show good overall theoretical physicochemical, pharmacokinetic and druglike properties. Overall, these results show that PYRIB-SOs is a new family of promising antimitotics to be further studied in vivo for biopharmaceutical and pharmacodynamic evaluations.

Keywords

Anticancer agents; Antimicrotubule agents; Antimitotics; Colchicine-binding site ligands; PYRIB-SOs; Pyridinyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates.

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