Mapping the DNA Damaging Effects of Polypyridyl Copper Complexes with DNA Electrochemical Biosensors

Abstract

Several classes of copper complexes are known to induce oxidative DNA damage that mediates cell death. These compounds are potentially useful anticancer agents and detailed investigation can reveal the mode of DNA interaction, binding strength, and type of oxidative lesion formed. We recently reported the development of a DNA electrochemical biosensor employed to quantify the DNA cleavage activity of the well-studied [Cu(phen)2]2+ chemical nuclease. However, to validate the broader compatibility of this sensor for use with more diverse—and biologically compatible—copper complexes, and to probe its use from a drug discovery perspective, analysis involving new compound libraries is required. Here, we report on the DNA binding and quantitative cleavage activity of the [Cu(TPMA)(N,N)]2+ class (where TPMA = tris-2-pyridylmethylamine) using a DNA electrochemical biosensor. TPMA is a tripodal copper caging ligand, while N,N represents a bidentate planar phenanthrene ligand capable of enhancing DNA interactions through intercalation. All complexes exhibited electroactivity and interact with DNA through partial (or semi-) intercalation but predominantly through electrostatic attraction. Although TPMA provides excellent solution stability, the bulky ligand enforces a non-planar geometry on the complex, which sterically impedes full interaction. [Cu(TPMA)(phen)]2+ and [Cu(TPMA)(DPQ)]2+ cleaved 39% and 48% of the DNA strands from the biosensor surface, respectively, while complexes [Cu(TPMA)(bipy)]2+ and [Cu(TPMA)(PD)]2+ exhibit comparatively moderate nuclease efficacy (ca. 26%). Comparing the nuclease activities of [Cu(TPMA)(phen)] 2+ and [Cu(phen)2]2+ (ca. 23%) confirms the presence of TPMA significantly enhances chemical nuclease activity. Therefore, the use of this DNA electrochemical biosensor is compatible with copper(II) polypyridyl complexes and reveals TPMA complexes as a promising class of DNA damaging agent with tuneable activity due to coordinated ancillary phenanthrene ligands

Biomimetic Radical Chemistry and Applications

“…Six articles report new experimental data on targeting DNA damage [ 11 , 12 , 13 , 14 , 15 , 16 ]. Guanine radicals generated in single, double, and G-quadruplex oligonucleotides are studied by nanosecond transient absorption spectroscopy [ 11 ].…”

“…Several classes of copper complexes prepared in the past were explored for their chemical nuclease activity both biologically and chemically [ 20 ]. Two studies include the mechanism of copper artificial metallo-nuclease to induce superoxide-mediated cleavage via the minor groove [ 15 ], and the DNA binding and quantitative cleavage activity of the [Cu(TPMA)( N , N )] 2+ class (where TPMA = tris-2-pyridylmethylamine) using a DNA electrochemical biosensor [ 16 ].…”

Anti-Proliferation and DNA Cleavage Activities of Copper(II) Complexes of N3O Tripodal Polyamine Ligands

“…The ligand platform plays a pivotal role in modulating the properties of the metal and its interaction (mode and strength) with DNA. Polypyridyl ligands have been widely used for designing copper nucleases because pyridines can intercalate into DNA and give rise to Cu II /Cu I redox potentials adequate for oxidative cleavage when engaged in coordination [16,17]. They are mostly based on bipyridine [18][19][20], phenanthroline [18,19,[21][22][23][24][25][26][27], terpyridine [28], phenanthrene [1,29], and tripodal structures [17,[30][31][32][33].…”

“…Polypyridyl ligands have been widely used for designing copper nucleases because pyridines can intercalate into DNA and give rise to Cu II /Cu I redox potentials adequate for oxidative cleavage when engaged in coordination [16,17]. They are mostly based on bipyridine [18][19][20], phenanthroline [18,19,[21][22][23][24][25][26][27], terpyridine [28], phenanthrene [1,29], and tripodal structures [17,[30][31][32][33]. These moieties can be further engineered for adding functionalities [34,35].…”