New acridone derivatives to target telomerase and oncogenes – an anticancer approach

In this work, two new acridone derivatives, <b>AcridPy</b> and <b>AcridPyMe</b>, were synthesized, for the first time, aiming to evaluate their potential as quadruplex stabilizers and anticancer agents. <b>AcridPy</b> was synthesized through a very straightforward one-pot sequential chemical reaction involving the Heck cross-coupling reaction of (<i>E</i>)-3-iodo-2-(4-methoxystyryl)-1-methylquinolin-4(1<i>H</i>)-one with a vinyl pyridine followed by <i>in situ</i> electrocyclization and oxidation, while the synthesis of <b>AcridPyMe</b> involved an additional <i>N</i>-methylation of the pyridine ring. Their ability to stabilize G-quadruplex DNA structures, which are associated with the regulation of oncogenes, was assessed using biophysical methods. Both compounds demonstrated significant quadruplex stabilization properties, showing selectivity to G-quadruplexes over duplex DNA. Molecular dynamics simulation experiments supported the preferential binding of <b>AcridPyMe</b> to MYC. The cytotoxicity of these derivatives was further evaluated <i>in vitro</i> in two distinct pancreatic tumor cell lines, PanC-1 and MIA PaCa-2, the lung tumor A549 cell line, the melanoma A375 cell line, and the immortalized human keratinocyte HaCaT cell line, through the evaluation of cell viability. For PanC-1 and MIA PaCa-2, the cell cycle dynamics and apoptotic cell death along with colocalization were also evaluated. The results revealed that <b>AcridPyMe</b> exhibited anticancer activity, correlated with its quadruplex stabilization ability and, although not exclusive, nuclear co-localization was observed. These findings suggest that the newly synthesized cationic acridone is a promising candidate for the development of novel anticancer therapies targeting G-quadruplex structures.