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

• Published in: European journal of medicinal chemistry 2021-03, Vol.213, p.113136, Article 113136
• Main Authors: Gagné-Boulet, Mathieu, Bouzriba, Chahrazed, Chavez Alvarez, Atziri Corin, Fortin, Sébastien
• Format: Article
• Language: English
• Subjects: Anticancer agents; Antimicrotubule agents; Antimitotics; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzenesulfonates - chemical synthesis; Benzenesulfonates - chemistry; Benzenesulfonates - pharmacology; Binding Sites - drug effects; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Colchicine - chemistry; Colchicine - pharmacology; Colchicine-binding site inhibitors; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Microtubules - drug effects; Microtubules - metabolism; Molecular Docking Simulation; Molecular Structure; Phenyl 4-(2-oxopyrrolidin-1-yl)benzenesulfonamides; Phenyl 4-(2-oxopyrrolidin-1-yl)benzenesulfonates; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.113136

We 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 agents. [Display omitted] •Modification of imidazolidin-2-one moiety leads to PYB-SOs and PYB-SAs.•PYB-SOs and PYB-SAs exhibit IC50 in the low nanomolar to low micromolar range.•They block the cell cycle progression in G2/M phase and disrupt microtubules.•In vitro and docking studies confirm that they bind to the colchicine-binding site.•They exhibit low or no toxicity toward chick embryos.