Our study demonstrates that four novel kinetically inert C,N-cyclometalated RuII complexes of the type [Ru(C^N)(N^N)2 ][PF6 ] containing a handle for functionalization on the C^N ligand are very potent cytotoxic agents against several different human cancer cell lines and are up to 400-fold more potent than clinically used cisplatin. In addition, the investigated ruthenium complexes are less cytotoxic in noncancerous cells, and exhibit higher selectivity for cancer cells than conventional platinum anticancer drugs. The high potency of the investigated ruthenium compounds can be attributed to several factors, including enhanced internalization and their capability to change mitochondrial transmembrane potential in cells. The new ruthenium complexes also interfere with protein synthesis with a markedly higher potency than conventional inhibitors of DNA translation. Notably, the latter mechanism has not been hitherto described for other cytotoxic Ru compounds and cisplatin.

Departamento de Química Inorgánica and Regional Campus of International Excellence Campus Mare Nostrum Universidad de Murcia and Biomedical Research Institute of Murcia 30071 Murcia Spain

Department of Biophysics Faculty of Science Palacky University 17 listopadu 12 77146 Olomouc Czech Republic

Institute of Biophysics Czech Academy of Sciences Kralovopolska 135 61265 Brno Czech Republic

SAI Universidad de Murcia 30071 Murcia Spain

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