title: N-(2-methyl-indol-1H-5-yl)-1-naphthalenesulfonamide: A novel reversible antimitotic agent inhibiting cancer cell motility.
abstract: A series of compounds containing the sulfonamide scaffold were synthesized and screened for their in vitro anticancer activity against a representative panel of human cancer cell lines, leading to the identification of N-(2-methyl-1H-indol-5-yl)-1-naphthalenesulfonamide (8e) as a compound showing a remarkable activity across the panel, with IC50 values in the nanomolar-to-low micromolar range. Cell cycle distribution analysis revealed that 8e promoted a severe G2/M arrest, which was followed by cellular senescence as indicated by the detection of senescence-associated β-galactosidase (SA-β-gal) in 8e-treated cells. Prolonged 8e treatment also led to the onset of apoptosis, in correlation with the detection of increased Caspase 3/7 activities. Despite increasing γ-H2A.X levels, a well-established readout for DNA double-strand breaks, in vitro DNA binding studies with 8e did not support interaction with DNA. In agreement with this, 8e failed to activate the cellular DNA damage checkpoint. Importantly, tubulin staining showed that 8e promoted a severe disorganization of microtubules and mitotic spindle formation was not detected in 8e-treated cells. Accordingly, 8e inhibited tubulin polymerization in vitro in a dose-dependent manner and was also able to robustly inhibit cancer cell motility. Docking analysis revealed a compatible interaction with the colchicine-binding site of tubulin. Remarkably, these cellular effects were reversible since disruption of treatment resulted in the reorganization of microtubules, cell cycle re-entry and loss of senescent markers. Collectively, our data suggest that this compound may be a promising new anticancer agent capable of both reducing cancer cell growth and motility.
authors.affiliation: Cancer Cell Biology Laboratory, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les llles Balears, Palma, Illes Balears, Spain; Institut d'Investigació Sanitària de Palma (IdISPa), Palma, Illes Balears, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Aceves-Luquero
authors.affiliation: Departamento de Farmacia, Universidad CEU-Cardenal Herrera, Moncada, Valencia, Spain; Departamento de Química Orgánica, ICMoL, Universitat de València, Paterna, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Galiana-Roselló
authors.affiliation: Cancer Cell Biology Laboratory, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les llles Balears, Palma, Illes Balears, Spain; Institut d'Investigació Sanitària de Palma (IdISPa), Palma, Illes Balears, Spain.
authors.forename: Guillem
authors.initials: G
authors.lastname: Ramis
authors.affiliation: Departament de Química, Universitat de les llles Balears, Palma, Illes Balears, Spain.
authors.forename: Ruth
authors.initials: R
authors.lastname: Villalonga-Planells
authors.affiliation: Departamento de Química Inorgánica, ICMoL, Universitat de València, Paterna, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: García-España
authors.affiliation: Cancer Cell Biology Laboratory, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les llles Balears, Palma, Illes Balears, Spain; Departament de Biologia Fonamental i Ciències de la Salut, Universitat de les llles Balears, Palma, Illes Balears, Spain; Institut d'Investigació Sanitària de Palma (IdISPa), Palma, Illes Balears, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fernández de Mattos
authors.affiliation: Departamento de Química Farmacéutica, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Peláez
authors.affiliation: Departamento de Química Orgánica, ICMoL, Universitat de València, Paterna, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Llinares
authors.affiliation: Departamento de Farmacia, Universidad CEU-Cardenal Herrera, Moncada, Valencia, Spain. Electronic address: eugenia@uch.ceu.es.
authors.forename: M Eugenia
authors.initials: ME
authors.lastname: González-Rosende
authors.affiliation: Cancer Cell Biology Laboratory, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les llles Balears, Palma, Illes Balears, Spain; Departament de Biologia Fonamental i Ciències de la Salut, Universitat de les llles Balears, Palma, Illes Balears, Spain; Institut d'Investigació Sanitària de Palma (IdISPa), Palma, Illes Balears, Spain. Electronic address: priam.villalonga@uib.es.
authors.forename: Priam
authors.initials: P
authors.lastname: Villalonga
mesh_terms: D050256:Antimitotic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D019169:Jurkat Cells; D061986:MCF-7 Cells; D008870:Microtubules / Q000187:drug effects; D015394:Molecular Structure; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*; D014404:Tubulin / Q000187:drug effects
chemical_list: D050256:Antimitotic Agents; D007211:Indoles; C000618012:N-(2-methylindol-1H-5-yl)-1-naphthalenesulfonamide; D013449:Sulfonamides; D014404:Tubulin
keywords: Apoptosis; Cancer; Cell motility; Mitosis; Sulfonamides; Tubulin