title: Stimulation of topoisomerase II-mediated DNA cleavage by ellipticine derivatives: structure-activity relationship.
abstract: Ellipticines are aromatic compounds that intercalate between DNA base pairs and display significant antitumor activity. The cytotoxicity of these compounds is mediated by DNA topoisomerase II, and the presence of a hydroxy group at position 9 of the pyridocarbazole ring system of ellipticines has been found to be essential for high levels of cytotoxicity. The ability of 13 ellipticine derivatives to stabilize the topoisomerase II-DNA covalent complex in vitro was studied, and the data obtained with five pairs of hydroxylated and nonhydroxylated analogues indicate that the hydroxy group at position 9 plays a crucial role in the stabilization of the complex. The influence, upon the complex stabilization, of various substituents at positions 1, 2, 5, and 6 of the pyridocarbazole ring system was investigated. The interaction with DNA of four ellipticine derivatives was studied in the topoisomerase II standard medium. Results suggest that the degree of unwinding might be a determinant of topoisomerase II-DNA-drug complex stability. In addition, the 5-ethyl derivative was observed to induce covalent complex stabilization by a cooperative mechanism.
authors.affiliation: Laboratoire de Biochimie-Enzymologie, CNRS URA147, INSERM U140, Institut Gustave Roussy, Villejuif, France.
authors.forename: P
authors.initials: P
authors.lastname: Fossé
authors.forename: B
authors.initials: B
authors.lastname: René
authors.forename: M
authors.initials: M
authors.lastname: Charra
authors.forename: C
authors.initials: C
authors.lastname: Paoletti
authors.forename: J M
authors.initials: JM
authors.lastname: Saucier
mesh_terms: D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004611:Ellipticines / Q000737:chemistry / Q000494:pharmacology*; D010957:Plasmids; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
chemical_list: D004611:Ellipticines; D059005:Topoisomerase II Inhibitors; C034192:ellipticine; D004250:DNA Topoisomerases, Type II