TY - JOUR

T1 - Stronger Cytotoxicity for Cancer Cells Than for Fast Proliferating Human Stem Cells by Rationally Designed Dinuclear Complexes

AU - Schwarzbich, Sabrina

AU - Horstmann Née Gruschka, Claudia

AU - Simon, Jasmin

AU - Siebe, Lena

AU - Moreth, Alexander

AU - Wiegand, Christiane

AU - Lavrentieva, Antonina

AU - Scheper, Thomas

AU - Stammler, Anja

AU - Bögge, Hartmut

AU - Fischer Von Mollard, Gabriele

AU - Glaser, Thorsten

N1 - Funding Information: Funding of this work was provided by the DFG and Bielefeld University.

PY - 2020/10/5

Y1 - 2020/10/5

N2 - 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 NiII2 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 CuII2 complex. The NiII2 complex also binds to DNA but forms fewer intermolecular DNA cross-links, while it interferes with DNA synthesis in PCR at lower concentrations than CuII2. 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. CuII2 shows the lowest IC50 values and a remarkable preference for killing the cancer cells. Three different assays show that the CuII2 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.

AB - 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 NiII2 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 CuII2 complex. The NiII2 complex also binds to DNA but forms fewer intermolecular DNA cross-links, while it interferes with DNA synthesis in PCR at lower concentrations than CuII2. 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. CuII2 shows the lowest IC50 values and a remarkable preference for killing the cancer cells. Three different assays show that the CuII2 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.

UR - http://www.scopus.com/inward/record.url?scp=85092046796&partnerID=8YFLogxK

U2 - 10.1021/acs.inorgchem.0c02255

DO - 10.1021/acs.inorgchem.0c02255

M3 - Article

C2 - 32951424

AN - SCOPUS:85092046796

VL - 59

SP - 14464

EP - 14477

JO - Inorganic chemistry

JF - Inorganic chemistry

SN - 0020-1669

IS - 19

ER -