Gold(III)- to Ruthenium(III)-metal exchange in dithiocarbmato complexes tunes their biological mode of action for cytotoxicity in cancer cells

Malignant tumors affect the human being since the pharaoh period, but in the last century the incidence of this disease has increased due to a large number of risk factors including deleterious lifestyle habits (i.e. smocking) and the higher longevity. Many efforts have been spent in the last decades for achieving an early-stage diagnosis of cancer and more effective cures, leading to a decline in age-standardized cancer mortality rates. In the last years, our research groups have developed new metal-based complexes with the aim to obtain a better selectivity for cancer cells and less side effects than the clinically established reference drug cisplatin. This work is focused on four novel Au(III) and Ru(III) complexes sharing the piperidine dithiocarbamato (pipe-DTC) as ligand in different molar ratio. The newly synthesized compounds [AuCl2(pipeDTC)], [Au(pipeDTC)2]Cl, [Ru(pipeDTC)3] and β-[Ru2(pipeDTC)5] have been synthesized and fully char-acterized by several chemical analyses. We have then investigated their biological properties in two different cell lines, namely AGS (gastric adenocarcinoma) and HCT116 (colon carcinomas), showing significant differences among the four compounds. First, the two gold-based compounds and β-[Ru2(pipeDTC)5] display IC50 in the µM range, significantly lower than cisplatin. Second, we showed that [AuCl2(pipeDTC)] and β-[Ru2(pipeDTC)5]Cl drive different molecular mechanisms. The first was able to induce the protein level of the DNA damage response factor p53 and the autophagy protein p62, in contrast to the second that induced ATF4 protein level but repressed p62 expression. This study highlights that the biological activity of different complexes bringing the same organic ligand, depends on the electronic and structural properties of the metal that are able to fine tune the biological properties, giving us precious information that can help to design more selective anticancer drugs.