2,7-Disubstituted Amidofluorenone Derivatives as Inhibitors of Human Telomerase

Abstract

Telomerase is a major new target for the rational design of novel anticancer agents. We have previously identified anthraquinone-based molecules capable of inhibiting telomerase by stabilizing G-quadruplex structures formed by the folding of telomeric DNA. In the present study we describe the synthesis and biological evaluation of a series of analogous fluorenone-based compounds with the specific aims of, first, determining if the anthraquinone chromophore is a prerequisite for activity and, second, whether the conventional cytotoxicity inherent to anthraquinone-based molecules may be reduced by rational design. This fluorenone series of compounds exhibits a broad range of telomerase inhibitory activity, with the most potent inhibitors displaying levels of activity (8-12 microM) comparable with other classes of G-quadruplex-interactive agents. Comparisons with analogous anthraquinone-based compounds reveal a general reduction in the level of cellular cytotoxicity. Molecular modeling techniques have been used to compare the interaction of fluorenone- and analogous anthraquinone-based inhibitors with a human G-quadruplex structure and to rationalize their observed biological activities.

Cell senescence and telomere shortening induced by a new series of specific G-quadruplex DNA ligands

“…Ligand 12459 was active against only two cell lines, and 5271 and 5352, were devoid of significant antiproliferative activity. Antiproliferative properties were correlated with the in vitro stabilization of G-quadruplexes, in contrast with other published G4 ligands (10,34). Ligand 115405 was found to induce major apoptosis within 24 h at micromolar concentrations in A549 cells (Fig.…”

“…A number of small molecules have been discovered to inhibit the function of telomerase by stabilizing G4-DNA structures (10)(11)(12)(13)(14). Triazines were compared at 1 M dye concentration, and the results are summarized on Fig.…”

“…1 A and B). Recent reports emphasize that specific recognition of G-quadruplexes may be achieved (5)(6)(7)(8)(9)(10)(11)(12). Agents that stabilize G-quadruplexes have the potential to interfere with telomere replication by blocking the elongation step catalyzed by telomerase (6) and can therefore act as antitumor agents (13)(14)(15)(16)(17).…”

Ascididemin and meridine stabilise G-quadruplexes and inhibit telomerase in vitro

“…The number of G4 ligands has grown rapidly over a few years: a range of molecules has been shown to inhibit telomerase through binding to its substrate [14,26,27,36,[44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59]. On the other hand, few natural products have been reported as G-quadruplex-mediated telomerase inhibitors, although one, telomestatin, is exceptionally potent with an IC50 of 5 nM against telomerase [25].…”

Telomere maintenance mechanisms as a target for drug development

“…We also demonstrated by using the direct telomerase assay that this compound inhibits telomerase through its interaction with the intramolecular Gquadruplex formed from the telomeric primer . A number of anthraquinone analogs have been recently identi®ed to interact with G-quadruplexes and inhibit telomerase, including some of the most potent small-molecule inhibitors of telomerase reported to date (Perry et al, 1999).…”