Influence of the Copper Coordination Geometry on the DNA Cleavage Activity of Clip‐Phen Complexes Studied by DFT

Abstract

Six different Cu(Clip‐Phen)2+/+ complexes, with or without a coordinating chloride ligand, have been investigated by DFT calculations to evaluate the influence of the length and functional substituents of the bridge linking the two phenanthroline units on the DNA cleavage activity. The changes of the structural and energetic profiles imposed by the bridge of these complexes have been analyzed by comparison with the well studied nuclease active agent Cu(phen)22+/+. The present studies show that the bridge length of these complexes is critical for the consequent geometry, and both the strain and ligand binding energies. Upon reduction (needed for the DNA cleavage activity), the geometry of Cu(phen)2 changes drastically. The behavior of the complexes with a 4‐ or 5‐carbon bridge resembles the behavior of Cu(phen)22+/+. However, the geometries of the complexes with two‐ or three‐carbon bridges are markedly different from the one of unbridged Cu(phen)2+, as a result of constraints enforced by the short bridge. The results suggest that the cleaving activities of these bis‐phenanthroline complexes are influenced by the different ligand environment geometries imposed by the bridge, and not by the change of the redox properties. It appears that the influence of the different bridges on the redox properties of the complexes is minor.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Copper Complexes as Anticancer Agents

“…In an effort to overcome these limits, Pitié et al [181] used a serinol bridge (abbreviated as Clip) to link two phen ligands on positions 2, resulting in [Cu(2-Clip-phen)] 2+ (51) and 3, resulting in [Cu(3-Clip-phen)] 2+ (52) [182]. The reason for this increase in DNA-cleavage activity was not completely clear, but it was supposed to arise from structural characteristics [185] rather than from electronic properties [182]. The reason for this increase in DNA-cleavage activity was not completely clear, but it was supposed to arise from structural characteristics [185] rather than from electronic properties [182].…”

Study on potential antitumor mechanism of a novel Schiff Base copper(II) complex: Synthesis, crystal structure, DNA binding, cytotoxicity and apoptosis induction activity

“…Schiff base Cu(II) complexes can show their antibacterial and antiproliferative activities because of the properties of the metal center or the coordinate ligands alone, as well as the structural and electronic properties which is ascribed to the coordination [27][28][29][30]. Recently, Reedjik and co-workers reported a novel Schiff base class of DNA binding and cleaving agents [31][32][33][34]. The Cu(II) Schiff base complex, [Cu II (pyrimol)Cl] (2) (Scheme 1), could catalytically cleave DNA in the absence of reductant and show high to modest cytotoxicity against selected cancer cell lines.…”

Evaluations of AMBER force field parameters by MINA approach for copper-based nucleases

“…However, the mechanism of metallonucleases cleaving DNA is complicated and still poorly understood [11]. Copper is a bioessential element which plays a key role in biological processes, for instance, copper-based complexes are very important in anticancer drugs development serving as specific DNA binding or cleaving reagents [12][13][14][15][16][17]. Even the DNA cleavage activity of some copper nucleases have been demonstrated by experimental results [18,19], the understanding of the mechanism of interaction of copper nucleases with DNA is still limited at the molecular level.…”