Neomycin-capped aromatic platforms: quadruplex DNA recognition and telomerase inhibition.
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).
Kaiser
Markus
M
Laboratoire de Chimie des Interactions Moléculaires, Collège de France, CNRS UPR 285, 11, place Marcelin Berthelot, 75005 Paris, France.
De Cian
Anne
A
Sainlos
Matthieu
M
Renner
Christian
C
Mergny
Jean-Louis
JL
Teulade-Fichou
Marie-Paule
MP
D000166:Acridines / Q000737:chemistry; D002236:Carbohydrate Conformation; D004247:DNA / Q000737:chemistry*; D031541:Fluorescence Resonance Energy Transfer; D006841:Hydrocarbons, Aromatic / Q000737:chemistry*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009355:Neomycin / Q000737:chemistry* / Q000494:pharmacology*; D010618:Phenanthrolines / Q000737:chemistry; D011796:Quinacrine / Q000737:chemistry; D019914:Taq Polymerase / Q000378:metabolism; D019098:Telomerase / Q000037:antagonists & inhibitors*
D000166:Acridines; D006841:Hydrocarbons, Aromatic; D010618:Phenanthrolines; D004247:DNA; D019914:Taq Polymerase; D019098:Telomerase; D011796:Quinacrine; D009355:Neomycin