Evaluation of the binding mode of a cytotoxic dinuclear nickel complex to two neighboring phosphates of the DNA backbone

Simon J, Gruschka CHN, Mix A, et al. Evaluation of the binding mode of a cytotoxic dinuclear nickel complex to two neighboring phosphates of the DNA backbone. Dalton Transactions. 2022.A family of dinuclear complexes based on 2,7-disubstituted 1,8-naphthalenediol-ligands has been designed to bind covalently to two neighboring phosphate diester groups in the backbone of DNA. The dinuclear Cu-II and Ni-II complexes bind to DNA resulting in the inhibition of DNA synthesis in PCR experiments and in a cytotoxicity that is stronger for human cancer cells than for human stem cells of the same proliferation rate. These experiments support but cannot prove that the dinuclear complexes bind as intended to two neighboring phosphate ester groups of the DNA backbone. Here, we evaluate the potential binding mode of the cytotoxic dinuclear Ni-II complex using simple phosphate diester models (dimethyl phosphate and diphenyl phosphate). Depending on the reaction conditions, the phosphate diesters bind to the Ni-II ions in a bridging or in a terminal coordination mode. The latter occurs by substitution of two coordinated acetates by the phosphate diesters. This reaction has been followed by NMR spectroscopy, which demonstrates that the substitution of acetate by phosphate is thermodynamically strongly favored, while the exchange with excess phosphate is fast on the NMR time scale. The molecular structure of the Ni-II complex with two coordinated diphenyl phosphates served as a model for the computational evaluation of the binding to the DNA backbone. This combined experimental and computational study suggests a monodentate coordination mode of the DNA phosphate diesters to the Ni-II ions that is assisted by hydrogen bonds with water ligands

Rational design of a cytotoxic dinuclear Cu2 complex that binds by molecular recognition at two neighboring phosphates of the DNA backbone

Jany T, Moreth A, Gruschka C, et al. Rational design of a cytotoxic dinuclear Cu2 complex that binds by molecular recognition at two neighboring phosphates of the DNA backbone. Inorganic chemistry. 2015;54(6):2679-2690.The mechanism of the cytotoxic function of cisplatin and related anticancer drugs is based on their binding to the nucleobases of DNA. The development of new classes of anticancer drugs requires establishing other binding modes. Therefore, we performed a rational design for complexes that target two neighboring phosphates of the DNA backbone by molecular recognition resulting in a family of dinuclear complexes based on 2,7-disubstituted 1,8-naphthalenediol. This rigid backbone preorganizes the two metal ions for molecular recognition at the distance of two neighboring phosphates in DNA of 6-7 Å. Additionally, bulky chelating pendant arms in the 2,7-position impede nucleobase complexation by steric hindrance. We successfully synthesized the Cu(II)2 complex of the designed family of dinuclear complexes and studied its binding to dsDNA by independent ensemble and single-molecule methods like gel electrophoresis, precipitation, and titration experiments followed by UV-vis spectroscopy, atomic force microscopy (AFM), as well as optical tweezers (OT) and magnetic tweezers (MT) DNA stretching. The observed irreversible binding of our dinuclear Cu(II)2 complex to dsDNA leads to a blocking of DNA synthesis as studied by polymerase chain reactions and cytotoxicity for human cancer cells

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

Schwarzbich S, Horstmann Nee Gruschka C, Simon J, et al. Stronger Cytotoxicity for Cancer Cells Than for Fast Proliferating Human Stem Cells by Rationally Designed Dinuclear Complexes. Inorganic chemistry. 2020;59(19):14464–14477.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

Rational Design of a Cytotoxic Dinuclear Cu₂ Complex That Binds by Molecular Recognition at Two Neighboring Phosphates of the DNA Backbone

The mechanism of the cytotoxic function of cisplatin and related anticancer drugs is based on their binding to the nucleobases of DNA. The development of new classes of anticancer drugs requires establishing other binding modes. Therefore, we performed a rational design for complexes that target two neighboring phosphates of the DNA backbone by molecular recognition resulting in a family of dinuclear complexes based on 2,7-disubstituted 1,8-naphthalenediol. This rigid backbone preorganizes the two metal ions for molecular recognition at the distance of two neighboring phosphates in DNA of 6–7 Å. Additionally, bulky chelating pendant arms in the 2,7-position impede nucleobase complexation by steric hindrance. We successfully synthesized the Cu^II₂ complex of the designed family of dinuclear complexes and studied its binding to dsDNA by independent ensemble and single-molecule methods like gel electrophoresis, precipitation, and titration experiments followed by UV–vis spectroscopy, atomic force microscopy (AFM), as well as optical tweezers (OT) and magnetic tweezers (MT) DNA stretching. The observed irreversible binding of our dinuclear Cu^II₂ complex to dsDNA leads to a blocking of DNA synthesis as studied by polymerase chain reactions and cytotoxicity for human cancer cells

Rational Design of a Cytotoxic Dinuclear Cu₂ Complex That Binds by Molecular Recognition at Two Neighboring Phosphates of the DNA Backbone

The mechanism of the cytotoxic function of cisplatin and related anticancer drugs is based on their binding to the nucleobases of DNA. The development of new classes of anticancer drugs requires establishing other binding modes. Therefore, we performed a rational design for complexes that target two neighboring phosphates of the DNA backbone by molecular recognition resulting in a family of dinuclear complexes based on 2,7-disubstituted 1,8-naphthalenediol. This rigid backbone preorganizes the two metal ions for molecular recognition at the distance of two neighboring phosphates in DNA of 6–7 Å. Additionally, bulky chelating pendant arms in the 2,7-position impede nucleobase complexation by steric hindrance. We successfully synthesized the Cu^II₂ complex of the designed family of dinuclear complexes and studied its binding to dsDNA by independent ensemble and single-molecule methods like gel electrophoresis, precipitation, and titration experiments followed by UV–vis spectroscopy, atomic force microscopy (AFM), as well as optical tweezers (OT) and magnetic tweezers (MT) DNA stretching. The observed irreversible binding of our dinuclear Cu^II₂ complex to dsDNA leads to a blocking of DNA synthesis as studied by polymerase chain reactions and cytotoxicity for human cancer cells

Rational Design of a Cytotoxic Dinuclear Cu₂ Complex That Binds by Molecular Recognition at Two Neighboring Phosphates of the DNA Backbone

The mechanism of the cytotoxic function of cisplatin and related anticancer drugs is based on their binding to the nucleobases of DNA. The development of new classes of anticancer drugs requires establishing other binding modes. Therefore, we performed a rational design for complexes that target two neighboring phosphates of the DNA backbone by molecular recognition resulting in a family of dinuclear complexes based on 2,7-disubstituted 1,8-naphthalenediol. This rigid backbone preorganizes the two metal ions for molecular recognition at the distance of two neighboring phosphates in DNA of 6–7 Å. Additionally, bulky chelating pendant arms in the 2,7-position impede nucleobase complexation by steric hindrance. We successfully synthesized the Cu^II₂ complex of the designed family of dinuclear complexes and studied its binding to dsDNA by independent ensemble and single-molecule methods like gel electrophoresis, precipitation, and titration experiments followed by UV–vis spectroscopy, atomic force microscopy (AFM), as well as optical tweezers (OT) and magnetic tweezers (MT) DNA stretching. The observed irreversible binding of our dinuclear Cu^II₂ complex to dsDNA leads to a blocking of DNA synthesis as studied by polymerase chain reactions and cytotoxicity for human cancer cells