Design, Synthesis, and Evaluation of 2,9-Bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline Derivatives as G-Quadruplex Ligands.

Nassima Meriem Gueddouda (1) , Rosales Myanou Hurtado (1) , Stéphane Moreau (1) , Luisa Ronga (1) , Rabindra Nath Das (1) , Solène Savrimoutou (1) , Sandra Rubio (1) , Adrien Marchand (1) , Oscar Mendoza (1) , Mathieu Marchivie (2) , Lilian Elmi (1) , Albain Chansavang (1) , Vanessa Desplat (3) , Valérie Gabelica (1) , Anne Bourdoncle (1) , Jean Mergny (1) , Jean Guillon (1)

1 ARNA - Acides Nucléiques : Régulations Naturelle et Artificielle
2 ICMCB - Institut de Chimie de la Matière Condensée de Bordeaux
3 Cellules souches hématopoïétiques normales et leucémiques

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.

Mots clés: circular dichroism; phenanthroline; G-quadruplexes; G4 ligands; G-quadruplex; helicase assay; FRET-melting

Domaines: Matériaux

Nassima Meriem Gueddouda, Rosales Myanou Hurtado, Stéphane Moreau, Luisa Ronga, Rabindra Nath Das, et al.. Design, Synthesis, and Evaluation of 2,9-Bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline Derivatives as G-Quadruplex Ligands.. ChemMedChem, 2017, 12 (2), pp.146-160. ⟨10.1002/cmdc.201600511⟩. ⟨hal-01461586⟩