Novel ruthenium(II) complexes bearing polypyridyl and 1,2,4-oxadiazole ligands: from synthesis to in vitro and in vivo anticancer evaluation.

We report on the synthesis and characterization of four novel Ru(II) polypyridyl complexes incorporating bipyridine or phenanthroline ancillary ligands. Substituted 1,2,4-oxadiazoles are introduced here for the first time as chelating ligands for Ru(II), and the structure of a representative complex unequivocally established by single-crystal X-ray diffraction. The antiproliferative activity of the metal complexes in human colorectal (HCT116 and oxaliplatin- and BOLD-100-resistant derivatives) and ovarian (A2780 and A2780cis) cancer cell lines was evaluated. The presence of phenanthroline ancillary ligands induced the highest cytotoxicity, with platinum-resistant cells displaying enhanced sensitivity compared to parental lines. Cellular uptake of the metal complexes was quantified by ICP-MS. Finally, in vivo tests were conducted in BALB/c mice using the most promising compound, to evaluate its toxicity profile and its ability to inhibit CT-26 tumor growth. Interestingly, both duplex and G-quadruplex DNA can be excluded as potential molecular targets, as assessed by FRET-melting assays, UV-Vis spectroscopy, and circular dichroism.