Stronger Cytotoxicity for Cancer Cells Than for Fast Proliferating Human Stem Cells by Rationally Designed Dinuclear...

Cytostatic metallo-drugs mostly bind to the nucleobases of DNA. A new family of dinuclear transition metal complexes was rationally designed to selectively target the phosphate diesters of the DNA backbone by covalent bonding. The synthesis and characterization of the first dinuclear Ni^II₂ complex of this family are presented, and its DNA binding and interference with DNA synthesis in polymerase chain reaction (PCR) are investigated and compared to those of the analogous Cu^II₂ complex. The Ni^II₂ complex also binds to DNA but forms fewer intermolecular DNA cross-links, while it interferes with DNA synthesis in PCR at lower concentrations than Cu^II₂. To simulate possible competing phosphate-based ligands in vivo, these effects have been studied for both complexes with 100-200-fold excesses of phosphate and ATP, which provided no disturbance. The cytotoxicity of both complexes has been studied for human cancer cells and human stem cells with similar rates of proliferation. Cu^II₂ shows the lowest IC₅₀ values and a remarkable preference for killing the cancer cells. Three different assays show that the Cu^II₂ complex induces apoptosis in cancer cells. These results are discussed to gain insight into the mechanisms of action and demonstrate the potential of this family of dinuclear complexes as anticancer drugs acting by a new binding target.