Mono-hydrazone based G-quadruplex selective ligands induce DNA damage and genome instability in human cancer cells.

摘要

Targeting G-quadruplex structures is currently viewed as a promising anticancer strategy. Searching for potent and selective G-quadruplex binders, here we describe a small series of new mono-hydrazone derivatives designed as analogues of a lead, which was proved to stabilize G-quadruplex structures and increase R loop levels in human cancer cells. To investigate the G-quadruplex binding properties of the new molecules, in vitro biophysical studies were performed employing both telomeric and oncogene promoter G-quadruplex forming sequences. The obtained results allowed the identification of a highly selective G-quadruplex ligand that, when studied in human cancer cells, proved to be able to stabilize both G-quadruplexes and R loops, and showed a potent cell killing activity associated with micronuclei formation, a clear sign of genome instability.

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