Ethidium derivatives bind to G-quartets, inhibit telomerase and act as fluorescent probes for quadruplexes

The telomeric G-rich single-stranded DNA can adopt in vitro an intramolecul ar quadruplex structure, which has been shown to directly inhibit telomeras e activity. The reactivation of this enzyme in immortalized and most cancer cells suggests that telomerase is a relevant target in oncology, and telom erase inhibitors have been proposed as new potential anticancer agents. In this paper, we describe ethidiurn derivatives that stabilize G-quadruplexes . These molecules were shown to increase the melting temperature of an intr amolecular quadruplex structure, as shown by fluorescence and absorbance me asurements, and to facilitate the formation of intermolecular quadruplex st ructures. In addition, these molecules may be used to reveal the formation of multi-stranded DNA structures by standard fluorescence imaging, and ther efore become fluorescent probes of quadruplex structures. This recognition was associated with telomerase inhibition in vitro: these derivatives showe d a potent anti-telomerase activity, with IC50 values of 18-100 nM in a sta ndard TRAP assay.