Monohydrazone Based G‑Quadruplex Selective Ligands Induce DNA Damage and Genome Instability in Human Cancer Cells

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 monohydrazone 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 the formation of micronuclei,
a clear sign of genome instability.