Design, synthesis and biological evaluation of new 2,6-difluorinated phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates as new antimicrotubule agents.

Autor: Bouzriba C; Centre de recherche du CHU de Québec-Université Laval, Axe oncologie, Québec, QC, Canada; Faculté de pharmacie, Université Laval, Pavillon Ferdinand-Vandry, 1050 avenue de la Médecine, Québec QC G1V 0A6, Canada; These authors contributed equally to this work. Electronic address: chahrazed.bouzriba.1@ulaval.ca., Gagné-Boulet M; Centre de recherche du CHU de Québec-Université Laval, Axe oncologie, Québec, QC, Canada; Faculté de pharmacie, Université Laval, Pavillon Ferdinand-Vandry, 1050 avenue de la Médecine, Québec QC G1V 0A6, Canada; These authors contributed equally to this work., Chavez Alvarez AC; Centre de recherche du CHU de Québec-Université Laval, Axe oncologie, Québec, QC, 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, 2725 chemin Ste-Foy, Québec QC G1V 4G5, Canada., Ouellette V; Centre de recherche du CHU de Québec-Université Laval, Axe oncologie, Québec, QC, Canada; Faculté de pharmacie, Université Laval, Pavillon Ferdinand-Vandry, 1050 avenue de la Médecine, Québec QC G1V 0A6, Canada., Laverdière I; Centre de recherche du CHU de Québec-Université Laval, Axe oncologie, Québec, QC, Canada; Faculté de pharmacie, Université Laval, Pavillon Ferdinand-Vandry, 1050 avenue de la Médecine, Québec QC G1V 0A6, Canada., Fortin S; Centre de recherche du CHU de Québec-Université Laval, Axe oncologie, Québec, QC, 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.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2024 May; Vol. 146, pp. 107299. Date of Electronic Publication: 2024 Mar 20.
DOI: 10.1016/j.bioorg.2024.107299
Abstrakt: We previously discovered a novel family of antimicrotubule agents designated as phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs). In this study, we evaluated the effect of the difluorination of the aromatic ring bearing the imidazolidin-2-one moiety (ring A) at positions 3, 5 and 2, 6 on their antiproliferative activity on four cancer cell lines, their ability to disrupt the microtubules and their toxicity toward chick embryos. We thus synthesized, characterized and biologically evaluated 24 new difluorinated PIB-SO derivatives designated as phenyl 3,5-difluoro-4-(2-oxoimidazolidin-1-yl)benzenesulfonates (3,5-PFB-SOs, 4-15) and phenyl 2,6-difluoro-4-(2-oxoimidazolidin-1-yl)benzenesulfonates (2,6-PFB-SOs, 16-27). The concentration of the drug required to inhibit cell growth by 50% (IC 50 ) of 3,5-PFB-SOs is over 1000 nM while most of 2,6-PFB-SOs exhibit IC 50 in the nanomolar range (23-900 nM). Furthermore, the most potent 2,6-PFB-SOs 19, 26 and 27 arrest the cell cycle progression in G2/M phase, induce cytoskeleton disruption and impair microtubule polymerization. Docking studies also show that the most potent 2,6-PFB-SOs 19, 21, 24, 26 and 27 have binding affinity toward the colchicine-binding site (C-BS). Moreover, their antiproliferative activity is not affected by antimicrotubule- and multidrug-resistant cell lines. Besides, they exhibit improved in vitro hepatic stability in the mouse, rat and human microsomes compared to their non-fluorinated counterparts. They also showed theoretical pharmacokinetic, physicochemical and drug-like properties suited for further in vivo assays. In addition, they exhibit low to no systemic toxicity toward chick embryos. Finally, our study evidences that PIB-SOs must be fluorinated in specific positions on ring A to maintain both their antiproliferative activity and their biological activity toward microtubules.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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