Kaiser, Markus; De Cian, Anne; Sainlos, Matthieu; Renner, Christian; Mergny, Jean-Louis; Teulade-Fichou, Marie-Paule:

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

In: Organic & biomolecular chemistry : OBC ; an international journal of synthetic, physical and biomolecular organic chemistry, Jg. 4 (2007) ; Nr. 6, S. 1049-1057
ISSN: 1477-0520, 1477-1086
Zeitschriftenaufsatz / Fach: Biologie
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).