title: 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.affiliation: Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA.
authors.forename: Venkatraman
authors.initials: V
authors.lastname: Junnotula
authors.forename: Anuruddha
authors.initials: A
authors.lastname: Rajapakse
authors.forename: Leire
authors.initials: L
authors.lastname: Arbillaga
authors.forename: Adela López
authors.initials: AL
authors.lastname: de Cerain
authors.forename: Beatriz
authors.initials: B
authors.lastname: Solano
authors.forename: Raquel
authors.initials: R
authors.lastname: Villar
authors.forename: Antonio
authors.initials: A
authors.lastname: Monge
authors.forename: Kent S
authors.initials: KS
authors.lastname: Gates
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D004247:DNA / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D053837:DNA Cleavage; D006801:Humans; D000860:Hypoxia; D015394:Molecular Structure; D009249:NADP / Q000737:chemistry; D010084:Oxidation-Reduction; D011810:Quinoxalines / Q000737:chemistry* / Q000494:pharmacology*; D000077704:Tirapazamine; D014227:Triazines / Q000494:pharmacology
chemical_list: C551967:7-chloro-2-thienylcarbonyl-3-trifluoromethylquinoxaline 1,4-dioxide; D000970:Antineoplastic Agents; D011810:Quinoxalines; D014227:Triazines; D000077704:Tirapazamine; D009249:NADP; D004247:DNA; D003577:Cytochrome P-450 Enzyme System