Issue 6, 2006

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

Abstract

A series of aminoglycoside-capped macrocyclic structures 9–12 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 11) is also a potent and selective telomerase inhibitor with an IC50 in the submicromolar range (200 nM).

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

Article information

Article type
Paper
Submitted
17 Nov 2005
Accepted
04 Jan 2006
First published
25 Jan 2006

Org. Biomol. Chem., 2006,4, 1049-1057

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

M. Kaiser, A. De Cian, M. Sainlos, C. Renner, J. Mergny and M. Teulade-Fichou, Org. Biomol. Chem., 2006, 4, 1049 DOI: 10.1039/B516378A

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