DNA strand cleaving properties and hypoxia-selective cytotoxicity of 7-chloro-2-thienylcarbonyl-3-trifluoromethylquinoxaline 1,4-dioxide.

Abstract

The heterocyclic N-oxide, 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, 1), shows promising antitumor activity in preclinical studies, but there is a continuing need to explore new compounds in this general structural category. In the work described here, we examined the properties of 7-chloro-2-thienylcarbonyl-3-trifluoromethylquinoxaline 1,4-dioxide (9h). We find that 9h causes redox-activated, hypoxia-selective DNA cleavage that mirrors the lead compound, tirapazamine, in both mechanism and potency. Furthermore, we find that 9h displays hypoxia-selective cytotoxicity against human cancer cell lines.

• Authors: Venkatraman Junnotula, Anuruddha Rajapakse, Leire Arbillaga, Adela López de Cerain, Beatriz Solano, Raquel Villar, Antonio Monge, Kent S Gates
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 18 Issue 9 Pg. 3125-32 (May 01 2010) ISSN: 1464-3391 [Electronic] England
• PMID: 20371184 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2010 Elsevier Ltd. All rights reserved.

Chemical References

• 7-chloro-2-thienylcarbonyl-3-trifluoromethylquinoxaline 1,4-dioxide
• Antineoplastic Agents
• Quinoxalines
• Triazines
• Tirapazamine
• NADP
• DNA
• Cytochrome P-450 Enzyme System

Topics

• Antineoplastic Agents (pharmacology)
• Chromatography, High Pressure Liquid
• Cytochrome P-450 Enzyme System (chemistry)
• DNA (chemistry, drug effects, metabolism)
• DNA Cleavage
• Humans
• Hypoxia
• Molecular Structure
• NADP (chemistry)
• Oxidation-Reduction
• Quinoxalines (chemistry, pharmacology)
• Tirapazamine
• Triazines (pharmacology)