title: [In vitro stimulation by ellipticine derivatives of DNA cleavage induced by DNA topoisomerase II: a structure-activity relationship].
abstract: Ellipticines are intercalating planar polycyclic aromatic molecules that display antitumor activity. The cytotoxicity of these compounds is related to the presence of an hydroxy group at position 9 of the pyridocarbazole ring system and to their interaction with DNA topoisomerase II. The ability of 13 ellipticine derivatives to stabilize the topoisomerase II-DNA covalent complex in vitro is reported. The following observations emerge from our structure-activity relationship study: i) the hydroxy group at position 9 is essential for stabilizing the covalent complex, ii) the replacement of the methyl group at position 5 by an ethyl group (EPC) enhances the complex stabilization. The interaction of EPC and three other ellipticine analogues with DNA shows that the covalent complexes which are most stable have the lowest drug-DNA binding constants. In addition our study suggests that ellipticines induce covalent complex stabilization by a cooperative mechanism. A model is proposed to explain this stabilization by ellipticines. This study supports the idea that topoisomerase II is the primary target involved in the mechanisms of action of ellipticines.
authors.affiliation: Laboratoire de biochimie-enzymologie, CNRS URA 147, INSERM U 140, institut Gustave-Roussy, Villejuif, France.
authors.forename: P
authors.initials: P
authors.lastname: Fossé
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
authors.forename: B
authors.initials: B
authors.lastname: René
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000819:agonists / Q000378:metabolism*; D004611:Ellipticines / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008961:Models, Structural; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004611:Ellipticines; C027767:elliptinium; D004247:DNA; D004250:DNA Topoisomerases, Type II
vernacular_title: Stimulation in vitro par des dérivés de l'ellipticine des coupures de l'ADN induites par l'ADN topo-isomérase II: relation structure-activité.