Simulations of Copper-1,10-Phenanthroline Complexes Binding the DNA

Robertazzi A;VARGIU, ATTILIO VITTORIO;RUGGERONE, PAOLO;Magistrato A;de Hoog P;arloni P;Reedijk J.

2009-01-01

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Abstract

Copper complexes of 1,10-phenanthroline (phen) are chemical nucleases employed as footprinting reagents for determining ligand binding sites. The cleavage activity of the parent complex, Cu(phen)2, occurs according to the following mechanism: a) reduction of Cu(phen)22+ to Cu(phen)2+; b) non-coordinative binding of Cu(phen)2+ to DNA; c) Cu(phen)2+ oxidation to Cu(phen)22+ by H2O2, and formation of Cu-“oxo” and/or Cu-“hydroxyl” species; d) oxidative attack leading to DNA-cleavage. However, the potential clinical use of the parent compound is mainly prevented by two drawbacks: i) the low binding constant of the second phenanthroline; ii) the modest sequence selective DNA cleavage. To improve Cu(phen)2 efficiency, Pitié et al. used a serinol bridge to link the two phen rings leading to Cu(2-Clip-phen) and Cu(3-Clip-phen) derivatives, which cleave the DNA 2 and 60 times more efficiently than Cu(phen)2. To address the modest sequence selectivity, the amine group of the serinol bridge was functionalized with sequence specific DNA minor/major-groove binding ligands such as cisplatin- and distamycin-like compounds, leading to encouraging results. In this work, a combination of theoretical methods, including DFT, Docking and Molecular Dynamics, was employed to i) characterize the DNA binding of these complexes and ii) to determine the origin of their diverse DNA-cleavage efficiency. Our simulations clearly revealed that several factors such as planarity of the ligand, better interaction with DNA and minor-groove fit, contribute to the enhanced efficiency of Cu(3-Clip-phen) compared to the other structurally similar complexes.