Rational Design of Dinuclear Complexes Binding at Two Neighboring Phosphate Esters of DNA

Thorsten Glaser, Gabriele Fischer von Mollard, Dario Anselmetti

This microreview summarizes a study aiming at the development of a novel family of metal complexes that binds to the phosphate esters of the DNA backbone inspired by the cytotoxicity of the anticancer drug cisplatin and by the phosphate ester cleaving reactivity of metalloenzymes and their biomimetic model complexes. A rational design is presented that is based on the requirements to establish a molecular recognition for the phosphate esters of the DNA backbone and to suppress binding to the less exposed nucleobases. Two phosphate binding sites should be preoriented and fixed by a rigid backbone to the distance of two neighboring phosphate ester in the DNA backbone of 6-7 Å. Sterical demand close to the phosphate binding sites should inhibit coordination to the nucleobases. This was molecularly translated into an unprecedented family of dinuclear complexes based on 1,8-naphthalenediol ligands with sterically demanding chelate arms in 2,7-position. The synthesis of the ligand and its first dinuclear CuII2 complex is described. The binding of this complex to DNA has been studied by biochemical ensemble methods and biophysical single-molecule methods. The incubation of DNA with the CuII2 complex results in interstrand interactions forming aggregates that prevent the DNA to enter the gel in the electrophoresis experiments. AFM experiments show an increase of the DNA diameter and local entanglements of the DNA by intrastrand interactions. The stretching of a single DNA molecule by optical tweezers exhibits distinct force peaks upon treatment with the complex necessary to break the intrastrand interactions. Torsional measurements of a single DNA molecule by magnetic tweezers showed a shortening of the effective DNA length due to the intrastrand interactions. Incubation with the CuII2 complex suggests inhibition of DNA synthesis in polymerase chain reaction experiments and strong cytotoxicity to human HeLa cancer cells, both at lower concentration than with cisplatin. A coherent model is provided that explains all experimental observations by the intended binding of the CuII2 complex to two neighboring phosphates of the DNA backbone and the formation of intra- or interstrand interactions by π-π interactions of the outward oriented and freely exposed naphthalene rings.

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