title: Benzo[b]thiophene-6-carboxamide 1,1-dioxides: inhibitors of human cancer cell growth at nanomolar concentrations.
abstract: Benzo[b]thiophenesulfonamide 1,1-dioxide derivatives (BTS) were described as candidate antineoplastic drugs. In the hope of finding new compounds with improved antitumour activity and reduced toxicity, we have designed and synthesized a small series of benzo[b]thiophene-6-carboxamide 1,1-dioxide derivatives (BTC) structurally related with the best reported BTS. Growth inhibition of HTB-54, CCRF-CEM and HeLa tumour cells lines at nanomolar concentrations was exhibited by some of the BTC. Hydrophobic substituents on the carboxamide group increased cytotoxicity but substitution by a hydroxy group diminished it, thus pointing to the electronic density on benzo[b]thiophene nucleus as a determinant factor. The process of cell death induced by BTC derivatives was further analyzed in CCRF-CEM cells, where these compounds induced apoptosis in a time and dose-dependent manner and cell cycle arrest at S phase. BTC derivatives also induced a significant increase in intracellular ROS levels in this cell line. Previous treatment of the cells with the antioxidant N-acetyl-cysteine abrogated the induction of apoptosis by BTC indicating that ROS generation is a previous event required to trigger the BTC induced apoptotic process.
authors.affiliation: Dpto de Ciencias de la Salud, Universidad Pública de Navarra, Avda. Barañain, 31008 Pamplona, Spain.
authors.forename: Aitziber A
authors.initials: AA
authors.lastname: Sagardoy
authors.forename: María J
authors.initials: MJ
authors.lastname: Gil
authors.forename: Raquel
authors.initials: R
authors.lastname: Villar
authors.forename: María J
authors.initials: MJ
authors.lastname: Viñas
authors.forename: Aranzazu
authors.initials: A
authors.lastname: Arrazola
authors.forename: Ignacio
authors.initials: I
authors.lastname: Encío
authors.forename: Victor
authors.initials: V
authors.lastname: Martinez-Merino
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use; D017209:Apoptosis; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D017382:Reactive Oxygen Species / Q000378:metabolism; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D013876:Thiophenes; C088015:benzothiophene