GUEDDOUDA, Nassima Meriem; HURTADO, Rosales Myanou; MOREAU, Stéphane; RONGA, Luisa; DAS, Rabindra Nath; SAVRIMOUTOU, Solène; RUBIO, Sandra; MARCHAND, Adrien; MENDOZA, Oscar; MARCHIVIE, Mathieu; ELMI, Lilian; CHANSAVANG, Albain; DESPLAT, Vanessa; GABELICA, Valérie; BOURDONCLE, Anne; MERGNY, Jean; GUILLON, Jean

doi:10.1002/cmdc.201600511

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GUEDDOUDA, Nassima Meriem
Acides Nucléiques : Régulations Naturelle et Artificielle [ARNA]

HURTADO, Rosales Myanou
Acides Nucléiques : Régulations Naturelle et Artificielle [ARNA]

MOREAU, Stéphane
Acides Nucléiques : Régulations Naturelle et Artificielle [ARNA]

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Article de revue

Ce document a été publié dans

ChemMedChem. 2017-01-20, vol. 12, n° 2, p. 146-160

Wiley-VCH Verlag

Résumé en anglais

Genomic sequences able to form guanine quadruplexes (G4) are found in oncogene promoters, in telomeres, and in 5'- and 3'-untranslated regions as well as introns of messenger RNAs. These regions are potential targets for drugs designed to treat cancer. Herein, we present the design and syntheses of ten new phenanthroline derivatives and characterization of their interactions with G4-forming oligonucleotides. We evaluated ligand-induced stabilization and specificity and selectivity of ligands for various G4 conformations using FRET-melting experiments. We investigated the interaction of compound 1 a (2,9-bis{4-[(3-dimethylaminopropyl)aminomethyl]phenyl}-1,10-phenanthroline), which combined the greatest stabilizing effect and specificity for G4, with human telomeric sequences using FRET, circular dichroism, and ESI-MS. In addition, we showed that compound 1 a interferes with the G4 helicase activity of Saccharomyces cerevisiae Pif1. Interestingly, compound 1 a was significantly more cytotoxic toward two human leukemic cell lines than to normal human blood mononuclear cells. These novel phenanthroline derivatives will be a starting point for further development and optimization of potent G4 ligands that have potential as anticancer agents.< Réduire

Mots clés en anglais

circular dichroism

phenanthroline

G-quadruplexes

G4 ligands

G-quadruplex

helicase assay

FRET-melting

DOI

http://dx.doi.org/10.1002/cmdc.201600511

Project ANR

Synthèse et évaluation cellulaire de ligands spécifiques de G-quadruplexes dérivés de porphyrines et salens - ANR-12-BSV8-0008

Origine

Importé de hal

Unités de recherche

Institut de Chimie de la Matière Condensée de Bordeaux (ICMCB) - UMR 5026