title: 1,2-Dithiolan-3-one 1-oxides: a class of thiol-activated DNA-cleaving agents that are structurally related to the natural product leinamycin.
abstract: Leinamycin is a recently discovered, thiol-dependent DNA-cleaving natural product. The mechanism of DNA cleavage by leinamycin is unknown. Inspired by this intriguing natural product, we have investigated the DNA-cleaving properties of three 1,2-dithiolan-3-one 1-oxides (1-3) that are structurally related to the suspected DNA-cleaving "core" of leinamycin. It was found that, similar to leinamycin, these three 1,2-dithiolan-3-one 1-oxides are thiol-dependent DNA-cleaving agents. At the concentrations of 1-3 used in these experiments (approximately 100 microM), efficient DNA cleavage is absolutely dependent on added thiol, with optimum cleavage occurring at 5-10 equiv (500 microM-1 mM) of added thiol. 2-Mercaptoethanol, glutathione, dithiothreitol, and thiophenol function with approximately equal efficiency as triggering agents for the cleavage reaction. DNA cleavage by 1-3 is not highly pH-dependent. Cleavage of DNA by these sulfur heterocycles is diminished by the removal of molecular oxygen from the reaction medium, by the radical scavengers methanol, ethanol, and mannitol, and by the enzyme catalase. Superoxide dismutase does not suppress DNA cleavage by these compounds. When diethylenetriaminepentaacetic acid is employed in these reactions as a chelator of adventitious trace metal ions, DNA cleavage is efficiently inhibited. The S-deoxy analog of 1 does not cleave DNA under conditions where 1 effects efficient thiol-mediated cleavage of DNA. These experiments indicate that, in concert with thiols, 1,2-dithiolan-3-one 1-oxides convert molecular oxygen to DNA-cleaving oxygen radicals. The marked effect of catalase further suggests that molecular oxygen is converted to hydrogen peroxide which ultimately cleaves DNA via a trace metal-dependent Fenton reaction. This work demonstrates that 1,2-dithiolan-3-one 1-oxides represent a general class of thiol-potentiated DNA-cleaving molecules.
authors.affiliation: Department of Chemistry, University of Missouri-Columbia 65211, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Behroozi
authors.forename: W
authors.initials: W
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Dannaldson
authors.forename: K S
authors.initials: KS
authors.lastname: Gates
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D007769:Lactams; D018942:Macrolides; D017382:Reactive Oxygen Species / Q000737:chemistry; D013438:Sulfhydryl Compounds / Q000737:chemistry; D013844:Thiazoles; D013871:Thiones; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D007769:Lactams; D018942:Macrolides; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D013844:Thiazoles; D013871:Thiones; D013876:Thiophenes; C059000:leinamycin; D004247:DNA