Benzo[b]thiophene-6-carboxamide 1,1-dioxides: Inhibitors of human cancer cell growth at nanomolar concentrations

• Published in: Bioorganic & medicinal chemistry 2010-08, Vol.18 (15), p.5701-5707
• Main Authors: Sagardoy, Aitziber A., Gil, María J., Villar, Raquel, Viñas, María J., Arrazola, Aranzazu, Encío, Ignacio, Martinez-Merino, Victor
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; Antitumour agents; Apoptosis; Benzo[b]thiophenecarboxamide 1,1-dioxide derivatives; Biological and medical sciences; Cell Line, Tumor; Cytotoxicity; Drug Screening Assays, Antitumor; General aspects; Humans; Medical sciences; Neoplasms - drug therapy; Pharmacology. Drug treatments; Reactive oxygen species (ROS); Reactive Oxygen Species - metabolism; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - therapeutic use
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.06.009

New BTC showed nM GI50 against HTB-54, CCRF-CEM and HeLa and sub-μM against K-562, MEL-AC and HT-29 tumour cell lines. BTC induced apoptosis in CCRF-CEM and a significant increase in the rate of intracellular ROS generation. 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.