Cytotoxic cis-ruthenium(iii) bis(amidine) complexes

In chemotherapy, the search for ruthenium compounds as alternatives to platinum compounds is proposed because of their unique properties. However, the geometry effect of ruthenium complexes is sparely investigated. In this paper, we report the synthesis of a series of bis(acetylacetonato)ruthenium(iii) complexes bearing two amidines (1-) in a cis configuration. These complexes are highly cytotoxic against various cancer cell lines, including a cisplatin-resistant cell line. In vitro studies suggested that the representative complex can induce cell cycle G0/G1 phase arrest, decrease the mitochondrial membrane potential, elevate the intracellular reactive oxygen species level, and cause DNA damage and caspase-mediated mitochondrial pathway apoptosis in NCI-H460 cells. In vivo, it can effectively inhibit tumor xenograft growth in nude mouse models with no body weight loss. In combination with the reported trans-bis(amidine)ruthenium(iii) complexes, we found that ruthenium(iii) bis(amidine) complexes could be cytotoxic in both trans and cis geometries, which is in contrast to platinum-based compounds.

Automated summary

In this paper, the synthesis of bis(acetylacetonato)ruthenium(iii) complexes bearing two amidines (1-) in a cis configuration is reported. These complexes exhibit high cytotoxicity against various cancer cell lines, even for cisplatin-resistant cell lines. The representative complex can induce cell cycle arrest, decrease mitochondrial membrane potential, increase reactive oxygen species level, cause DNA damage and apoptosis in cancer cells. Furthermore, it effectively inhibits tumor xenograft growth in mice without causing weight loss. The cytotoxicity of cis-ruthenium(iii) bis(amidine) complexes is comparable to that of trans-ruthenium(iii) bis(amidine) complexes, which is different from platinum-based compounds.