title: New 5-Aryl-1H-imidazoles display in vitro antitumor activity against apoptosis-resistant cancer models, including melanomas, through mitochondrial targeting.
abstract: We designed and synthesized 48 aryl-1H-imidazole derivatives and investigated their in vitro growth inhibitory activity in cancer cell lines known to present various levels of resistance to proapoptotic stimuli. The IC50 in vitro growth inhibitory concentration of these compounds ranged from >100 μM to single digit μM. Among the most active compounds, 2i displayed similar in vitro growth inhibition in cancer cells independent of the cells' levels of resistance to proapoptotic stimuli and was found to be cytostatic in melanoma cell lines. Compound 2i was then tested by the National Cancer Institute Human Tumor Cell Line Anti-Cancer Drug Screen, and the NCI COMPARE algorithm did not reveal any correlation between its growth inhibition profiles with the NCI database compound profiles. The use of transcriptomically characterized melanoma models then enabled us to highlight mitochondrial targeting by 2i. This hypothesis was further confirmed by reactive oxygen production measurement and oxygen consumption analysis.
authors.affiliation: Laboratoire de Toxicologie, Faculté de Pharmacie, Université Libre de Bruxelles (ULB) , Boulevard du Triomphe, CP205/1, B-1050 Brussels, Belgium.
authors.forename: Véronique
authors.initials: V
authors.lastname: Mathieu
authors.forename: Emilie
authors.initials: E
authors.lastname: Van Den Berge
authors.forename: Justine
authors.initials: J
authors.lastname: Ceusters
authors.forename: Tomasz
authors.initials: T
authors.lastname: Konopka
authors.forename: Antonin
authors.initials: A
authors.lastname: Cops
authors.forename: Céline
authors.initials: C
authors.lastname: Bruyère
authors.forename: Christine
authors.initials: C
authors.lastname: Pirker
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.forename: Tran
authors.initials: T
authors.lastname: Trieu-Van
authors.forename: Didier
authors.initials: D
authors.lastname: Serteyn
authors.forename: Robert
authors.initials: R
authors.lastname: Kiss
authors.forename: Raphaël
authors.initials: R
authors.lastname: Robiette
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008545:Melanoma / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects*; D008954:Models, Biological; D009369:Neoplasms / Q000473:pathology*; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles