Neomycin-capped aromatic platforms: Quadruplex DNA recognition and telomerase inhibition
Org. Biomol. Chem.. 2006-01-01; 4(6): 1049
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1. Org Biomol Chem. 2006 Mar 21;4(6):1049-57. Epub 2006 Jan 25.
Neomycin-capped aromatic platforms: quadruplex DNA recognition and telomerase
Kaiser M(1), De Cian A, Sainlos M, Renner C, Mergny JL, Teulade-Fichou MP.
(1)Laboratoire de Chimie des Interactions Moléculaires, Collège de France, CNRS
UPR 285, 11, place Marcelin Berthelot, 75005 Paris, France.
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
PMID: 16525549 [Indexed for MEDLINE]