A phosphate-targeted dinuclear Cu(II) complex combining major groove binding and oxidative DNA cleavage

Abstract

Free radical generation is an inevitable consequence of aerobic existence and is implicated in a wide variety of pathological conditions including cancer, cardiovascular disease, ageing and neurodegenerative disorder. Free radicals can, however, be used to our advantage since their production is catalysed by synthetic inorganic molecules—termed artificial metallonucleases—that cut DNA strands by oxidative cleavage reactions. Here, we report the rational design and DNA binding interactions of a novel di-Cu2+ artificial metallonuclease [Cu2(tetra-(2-pyridyl)-NMe-naphthalene)Cl4] (Cu2TPNap). Cu2TPNap is a high-affinity binder of duplex DNA with an apparent binding constant (Kapp) of 107 M(bp)−1. The agent binds non-intercalatively in the major groove causing condensation and G-C specific destabilization. Artificial metallonuclease activity occurs in the absence of exogenous reductant, is dependent on superoxide and hydrogen peroxide, and gives rise to single strand DNA breaks. Pre-associative molecular docking studies with the 8-mer d(GGGGCCCC)2, a model for poly[d(G-C)2], identified selective major groove incorporation of the complex with ancillary Cu2+-phosphate backbone binding. Molecular mechanics methods then showed the d(GGGGCCCC)2 adduct to relax about the complex and this interaction is supported by UV melting experiments where poly[d(G-C)2] is selectively destabilized.

Polypyridyl‐Based Copper Phenanthrene Complexes: A New Type of Stabilized Artificial Chemical Nuclease

“…OH and H 2 O 2 . To the best of our knowledge, this DNA oxidation profile is unique for mononuclear systems and the closest examples are from the dinuclear [Cu 2 {tetra‐(2‐pyridyl)‐NMe‐naphthalene)Cl 4 }] (Cu 2 TPNap) complex and some other multinuclear systems . Additionally, considering that the .…”

“…These findings contrast with the DNA damagem echanism of Cu-Phen-typec omplexes in which the most prevalent speciesg enerateda re COH and H 2 O 2 . [24] To the best of our knowledge, this DNA oxidation profile is unique for mononuclear systems andt he closeste xamples are from the dinuclear [Cu 2 {tetra-(2-pyridyl)-NMe-naphthalene)Cl 4 }] (Cu 2 TPNap)c omplex [25] and some other multinuclear systems. [33,37] Additionally,c onsidering that the COH radical is not significant in this case, AMN activity departs from classical Fenton-type or Haber-Weiss pathways.…”

“…Significantly, the presence of phenazine ligands did not alter the electrochemical profile or ROS catalysis when compared with Cu‐Phen. We, as well as others, have identified the value of polynuclearity in providing enhanced cleavage capability and recently demonstrated that TA/TA and AT/AT oligonucleotide steps can be discriminated by a di‐Cu II ‐Phen complex containing an octanedioate bridge . Despite these developments, a limiting factor of Cu‐Phen systems is their poor stability in solution, in which speciation, ligand dissociation, and transmetalation occur.…”

CuII and AuIII Complexes with Glycoconjugated Dithiocarbamato Ligands for Potential Applications in Targeted Chemotherapy

“…The metal centers Au III and Cu II were chosen owing to their well‐known low‐micromolar cytotoxic effects, when complexed with DTCs or other appropriate ligands, against a wide panel of human tumor cell lines. In this regard, different mechanisms of action have been recognized in the literature over the last years: for example, while reactivity toward the selenoenzyme thioredoxin reductase, aquaporins, proteasome, or PARP‐1 has been detected for Au III compounds, induced oxidative DNA or mitochondrial damage has been observed for Cu II counterparts …”

“…In this regard, different mechanisms of action have been recognized in the literature over the last years:f or example, while reactivity toward the selenoenzyme thioredoxin reductase, aquaporins, proteasome, or PARP-1 has been detected for Au III compounds, [27][28][29][30][31] induced oxidative DNA or mitochondrial damage has been observed for Cu II counterparts. [26,32] DTCs are bidentate anions forming very stable coordination compounds. [33] The strong chelating effect can prevent ligand substitutions, thusf avoring the application of this class of complexes for biomedical purposes.…”