2,7-disubstituted amidofluorenone derivatives as inhibitors of human telomerase

Telomerase is a major new target for the rational design of novel anticance r agents. We have previously identified anthraquinone-based molecules capab le of inhibiting telomerase by stabilizing G-quadruplex structures formed b y the folding of telomeric DNA. In the present study we describe the synthe sis and biological evaluation of a series of analogous fluorenone-based com pounds with the specific aims of, first, determining if the anthraquinone c hromophore is a prerequisite for activity and, second, whether the conventi onal cytotoxicity inherent to anthraquinone-based molecules may be reduced by rational design. This fluorenone series of compounds exhibits a broad ra nge of telomerase inhibitory activity, with the most potent inhibitors disp laying levels of activity (8-12 mu M) comparable with other classes of G-qu adruplex-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 o f fluorenone- and analogous anthraquinone-based inhibitors with a human G-q uadruplex structure and to rationalize their observed biological activities .