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.
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 -