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: Aitziber A Sagardoy, María J Gil, Raquel Villar, María J Viñas, Aranzazu Arrazola, Ignacio Encío, Victor Martinez-Merino
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 18 Issue 15 Pg. 5701-7 (Aug 01 2010) ISSN: 1464-3391 [Electronic] England
• PMID: 20615714 (Publication Type: Journal Article)
• Copyright: Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Reactive Oxygen Species
• Thiophenes
• benzothiophene

Topics

• Antineoplastic Agents (chemistry, therapeutic use)
• Apoptosis
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• Humans
• Neoplasms (drug therapy)
• Reactive Oxygen Species (metabolism)
• Thiophenes (chemical synthesis, chemistry, therapeutic use)