title: Novel stable camptothecin derivatives replacing the E-ring lactone by a ketone function are potent inhibitors of topoisomerase I and promising antitumor drugs.
abstract: The E-ring lactone is the Achilles' heel of camptothecin derivatives: although it is considered necessary for the inhibition of the enzyme topoisomerase I (topo1), the opening of the lactone into a carboxylate abolishes the generation of topo1-mediated DNA breaks. S38809 is a novel camptothecin analog with a stable 5-membered E-ring ketone; therefore, it lacks the lactone function. DNA relaxation and cleavage assays revealed that S38809 functions as a typical topo1 poison by stimulating DNA cleavage at T downward arrow G sites. The activity was strongly dependent on the stereochemistry of the C-7 carbon atom that bears the hydroxy group. S38809 proved to be a potent cytotoxic agent, with a mean IC50 of 5.4 nM versus 11.6 nM for topotecan and 3.3 nM for SN38 (the active metabolite of irinotecan) on a panel of 31 human tumor cell lines. The cytotoxicity of S38809 and its ability to stabilize cleavable complexes was considerably reduced in camptothecin-resistant cells that express a mutated topo1, confirming that topo1 is its primary target. Cell death induced by topo1 poisoning requires the conversion of DNA single-strand breaks into double-strand breaks that can be detected by the formation of phosphorylated histone H2AX. In HCT116 cells, topotecan, SN38, and S38809 induced histone H2AX phosphorylation in S phase of the cell cycle, with S38809 being as potent as SN38 and 5-fold more potent than topotecan. In vivo, S38809 showed a marked antitumor activity against HCT116 xenografts. These findings open a new route for improving the pharmacological properties of camptothecin derivatives.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U837, Université de Lille 2, Facultéde Médecine, Institut de Médecine Prédictive et Recherche Thérapeutique, Lille, France. amelie.lansiaux@lille.inserm.fr
authors.forename: Amélie
authors.initials: A
authors.lastname: Lansiaux
authors.forename: Stéphane
authors.initials: S
authors.lastname: Léonce
authors.forename: Laurence
authors.initials: L
authors.lastname: Kraus-Berthier
authors.forename: Christine
authors.initials: C
authors.lastname: Bal-Mahieu
authors.forename: Romain
authors.initials: R
authors.lastname: Mazinghien
authors.forename: Sébastien
authors.initials: S
authors.lastname: Didier
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: David-Cordonnier
authors.forename: Patrick
authors.initials: P
authors.lastname: Hautefaye
authors.forename: Gilbert
authors.initials: G
authors.lastname: Lavielle
authors.forename: Christian
authors.initials: C
authors.lastname: Bailly
authors.forename: John A
authors.initials: JA
authors.lastname: Hickman
authors.forename: Alain
authors.initials: A
authors.lastname: Pierré
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020169:Caspases / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D010766:Phosphorylation; D059004:Topoisomerase I Inhibitors
chemical_list: D000970:Antineoplastic Agents; D004149:Dioxoles; D004791:Enzyme Inhibitors; C522460:S 38809; D059004:Topoisomerase I Inhibitors; D020169:Caspases; D002166:Camptothecin