Neomycin-capped aromatic platforms: quadruplex DNA recognition and telomerase inhibition

• Published in: Organic & biomolecular chemistry 2006-01, Vol.4 (6), p.1049-1057
• Main Authors: Kaiser, Markus, De Cian, Anne, Sainlos, Matthieu, Renner, Christian, Mergny, Jean-Louis, Teulade-Fichou, Marie-Paule
• Format: Article
• Language: English
• Subjects: Acridines - chemistry; Carbohydrate Conformation; DNA - chemistry; Fluorescence Resonance Energy Transfer; Hydrocarbons, Aromatic - chemistry; Kinetics; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Neomycin - chemistry; Neomycin - pharmacology; Phenanthrolines - chemistry; Quinacrine - chemistry; Taq Polymerase - metabolism; Telomerase - antagonists & inhibitors
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/b516378a

A series of aminoglycoside-capped macrocyclic structures has been prepared using intramolecular bis-tethering of neomycin on three aromatic platforms (phenanthroline, acridine, quinacridine). Based on NMR and calculations studies, it was found that the cyclic compounds adopt a highly flexible structure without conformational restriction of the aminoglycoside moiety. FRET-melting stabilization measurements showed that the series displays moderate to high affinity for the G4-conformation of human telomeric repeats, this effect being correlated with the size of the aromatic moiety. In addition, a FRET competition assay evidenced the poor binding ability of all macrocycles for duplex DNA and a clear binding preference for loop-containing intramolecular G4 structures compared to tetramolecular parallel G4 DNA. Finally, TRAP experiments demonstrated that the best G4-binder (quinacridine ) is also a potent and selective telomerase inhibitor with an IC(50) in the submicromolar range (200 nM).