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Novel stable camptothecin derivatives replacing the E-ring lactone by a ketone function are potent inhibitors of topoisomerase I and promising antitumor drugs.
Mol Pharmacol. 2007 Aug; 72(2):311-9.MP

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+Show Affiliations

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.frNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17494837

Citation

Lansiaux, Amélie, et al. "Novel Stable Camptothecin Derivatives Replacing the E-ring Lactone By a Ketone Function Are Potent Inhibitors of Topoisomerase I and Promising Antitumor Drugs." Molecular Pharmacology, vol. 72, no. 2, 2007, pp. 311-9.
Lansiaux A, Léonce S, Kraus-Berthier L, et al. Novel stable camptothecin derivatives replacing the E-ring lactone by a ketone function are potent inhibitors of topoisomerase I and promising antitumor drugs. Mol Pharmacol. 2007;72(2):311-9.
Lansiaux, A., Léonce, S., Kraus-Berthier, L., Bal-Mahieu, C., Mazinghien, R., Didier, S., David-Cordonnier, M. H., Hautefaye, P., Lavielle, G., Bailly, C., Hickman, J. A., & Pierré, A. (2007). Novel stable camptothecin derivatives replacing the E-ring lactone by a ketone function are potent inhibitors of topoisomerase I and promising antitumor drugs. Molecular Pharmacology, 72(2), 311-9.
Lansiaux A, et al. Novel Stable Camptothecin Derivatives Replacing the E-ring Lactone By a Ketone Function Are Potent Inhibitors of Topoisomerase I and Promising Antitumor Drugs. Mol Pharmacol. 2007;72(2):311-9. PubMed PMID: 17494837.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel stable camptothecin derivatives replacing the E-ring lactone by a ketone function are potent inhibitors of topoisomerase I and promising antitumor drugs. AU - Lansiaux,Amélie, AU - Léonce,Stéphane, AU - Kraus-Berthier,Laurence, AU - Bal-Mahieu,Christine, AU - Mazinghien,Romain, AU - Didier,Sébastien, AU - David-Cordonnier,Marie-Hélène, AU - Hautefaye,Patrick, AU - Lavielle,Gilbert, AU - Bailly,Christian, AU - Hickman,John A, AU - Pierré,Alain, Y1 - 2007/05/09/ PY - 2007/5/15/pubmed PY - 2007/9/6/medline PY - 2007/5/15/entrez SP - 311 EP - 9 JF - Molecular pharmacology JO - Mol. Pharmacol. VL - 72 IS - 2 N2 - 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. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/17494837/Novel_stable_camptothecin_derivatives_replacing_the_E_ring_lactone_by_a_ketone_function_are_potent_inhibitors_of_topoisomerase_I_and_promising_antitumor_drugs_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=17494837 DB - PRIME DP - Unbound Medicine ER -