title: Design, Synthesis, and Evaluation of 2,9-Bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline Derivatives as G-Quadruplex Ligands.
abstract: 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.
authors.affiliation: Univ. Bordeaux, ARNA laboratory, CNRS UMR 5320, INSERM U1212, 33076, Bordeaux, France.
authors.forename: Nassima Meriem
authors.initials: NM
authors.lastname: Gueddouda
authors.affiliation: Univ. Bordeaux, ARNA laboratory, CNRS UMR 5320, INSERM U1212, 33076, Bordeaux, France.
authors.forename: Miyanou Rosales
authors.initials: MR
authors.lastname: Hurtado
authors.affiliation: Univ. Bordeaux, ARNA laboratory, CNRS UMR 5320, INSERM U1212, 33076, Bordeaux, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Moreau
authors.affiliation: Univ. Bordeaux, ARNA laboratory, CNRS UMR 5320, INSERM U1212, 33076, Bordeaux, France.
authors.forename: Luisa
authors.initials: L
authors.lastname: Ronga
authors.affiliation: Univ. Bordeaux, ARNA laboratory, CNRS UMR 5320, INSERM U1212, 33076, Bordeaux, France.
authors.forename: Rabindra Nath
authors.initials: RN
authors.lastname: Das
authors.affiliation: Univ. Bordeaux, ARNA laboratory, CNRS UMR 5320, INSERM U1212, 33076, Bordeaux, France.
authors.forename: Solène
authors.initials: S
authors.lastname: Savrimoutou
authors.affiliation: Univ. Bordeaux, ARNA laboratory, CNRS UMR 5320, INSERM U1212, 33076, Bordeaux, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rubio
authors.affiliation: Univ. Bordeaux, ARNA laboratory, CNRS UMR 5320, INSERM U1212, 33076, Bordeaux, France.
authors.forename: Adrien
authors.initials: A
authors.lastname: Marchand
authors.affiliation: Univ. Bordeaux, ARNA laboratory, CNRS UMR 5320, INSERM U1212, 33076, Bordeaux, France.
authors.forename: Oscar
authors.initials: O
authors.lastname: Mendoza
authors.affiliation: Univ. Bordeaux, ICMCB CNRS-UPR 9048, 33608, Pessac, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Marchivie
authors.affiliation: Univ. Bordeaux, ARNA laboratory, CNRS UMR 5320, INSERM U1212, 33076, Bordeaux, France.
authors.forename: Lilian
authors.initials: L
authors.lastname: Elmi
authors.affiliation: Univ. Bordeaux, ARNA laboratory, CNRS UMR 5320, INSERM U1212, 33076, Bordeaux, France.
authors.forename: Albain
authors.initials: A
authors.lastname: Chansavang
authors.affiliation: Univ. Bordeaux, UFR des Sciences Pharmaceutiques, Biothérapie des Maladies Génétiques Inflammatoires et Cancers, INSERM U1035, 33076, Bordeaux cedex, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Desplat
authors.affiliation: Univ. Bordeaux, ARNA laboratory, CNRS UMR 5320, INSERM U1212, 33076, Bordeaux, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Gabelica
authors.affiliation: Univ. Bordeaux, ARNA laboratory, CNRS UMR 5320, INSERM U1212, 33076, Bordeaux, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Bourdoncle
authors.affiliation: Univ. Bordeaux, ARNA laboratory, CNRS UMR 5320, INSERM U1212, 33076, Bordeaux, France.
authors.forename: Jean-Louis
authors.identifier: 0000-0003-3043-8401
authors.initials: JL
authors.lastname: Mergny
authors.affiliation: Univ. Bordeaux, ARNA laboratory, CNRS UMR 5320, INSERM U1212, 33076, Bordeaux, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Guillon
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002942:Circular Dichroism; D004265:DNA Helicases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015195:Drug Design; D031541:Fluorescence Resonance Energy Transfer; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D054856:G-Quadruplexes; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D008024:Ligands; D010618:Phenanthrolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D005656:Fungal Proteins; D008024:Ligands; D010618:Phenanthrolines; D004265:DNA Helicases; C025205:1,10-phenanthroline
keywords: G-quadruplexes; G4 ligands; circular dichroism; helicase assays; phenanthroline