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Toward the Development of Specific G‑Quadruplex Binders: Synthesis, Biophysical, and Biological Studies of New Hydrazone Derivatives

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journal contribution
posted on 25.05.2016, 00:00 by Jussara Amato, Rita Morigi, Bruno Pagano, Alessia Pagano, Stephan Ohnmacht, Alessio De Magis, Yee-Peng Tiang, Giovanni Capranico, Alessandra Locatelli, Alessandra Graziadio, Alberto Leoni, Mirella Rambaldi, Ettore Novellino, Stephen Neidle, Antonio Randazzo
G-Quadruplex-binding compounds are currently perceived as possible anticancer therapeutics. Here, starting from a promising lead, a small series of novel hydrazone-based compounds were synthesized and evaluated as G-quadruplex binders. The in vitro G-quadruplex-binding properties of the synthesized compounds were investigated employing both human telomeric and oncogene promoter G-quadruplexes with different folding topologies as targets. The present investigation led to the identification of potent G-quadruplex stabilizers with high selectivity over duplex DNA and preference for one G-quadruplex topology over others. Among them, selected derivatives have been shown to trap G-quadruplex structures in the nucleus of cancer cells. Interestingly, this behavior correlates with efficient cytotoxic activity in human osteosarcoma and colon carcinoma cells.