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Intercalation processes of copper complexes in DNA.

ABSTRACT: The family of anticancer complexes that include the transition metal copper known as Casiopeínas® shows promising results. Two of these complexes are currently in clinical trials. The interaction of these compounds with DNA has been observed experimentally and several hypotheses regarding the mechanism of action have been developed, and these include the generation of reactive oxygen species, phosphate hydrolysis and/or base-pair intercalation. To advance in the understanding on how these ligands interact with DNA, we present a molecular dynamics study of 21 Casiopeínas with a DNA dodecamer using 10 ?s of simulation time for each compound. All the complexes were manually inserted into the minor groove as the starting point of the simulations. The binding energy of each complex and the observed representative type of interaction between the ligand and the DNA is reported. With this extended sampling time, we found that four of the compounds spontaneously flipped open a base pair and moved inside the resulting cavity and four compounds formed stacking interactions with the terminal base pairs. The complexes that formed the intercalation pocket led to more stable interactions.

SUBMITTER: Galindo-Murillo R

PROVIDER: S-EPMC4477671 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Intercalation processes of copper complexes in DNA.

Galindo-Murillo Rodrigo R García-Ramos Juan Carlos JC Ruiz-Azuara Lena L Cheatham Thomas E TE Cortés-Guzmán Fernando F

Nucleic acids research 20150509 11

The family of anticancer complexes that include the transition metal copper known as Casiopeínas® shows promising results. Two of these complexes are currently in clinical trials. The interaction of these compounds with DNA has been observed experimentally and several hypotheses regarding the mechanism of action have been developed, and these include the generation of reactive oxygen species, phosphate hydrolysis and/or base-pair intercalation. To advance in the understanding on how these ligand ...[more]

PMID: 25958394

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Project description: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.

Project description:Alkali ion intercalation is fundamental to battery technologies for a wide spectrum of potential applications that permeate our modern lifestyle, including portable electronics, electric vehicles, and the electric grid. In spite of its importance, the Nernstian nature of the charge transfer process describing lithiation of carbon has not been described previously. Here we use the ultrathin few-layer graphene (FLG) with micron-sized grains as a powerful platform for exploring intercalation and co-intercalation mechanisms of alkali ions with high versatility. Using voltammetric and chronoamperometric methods and bolstered by density functional theory (DFT) calculations, we show the kinetically facile co-intercalation of Li+ and K+ within an ultrathin FLG electrode. While changes in the solution concentration of Li+ lead to a displacement of the staging voltammetric signature with characteristic slopes ca. 54-58 mV per decade, modification of the K+/Li+ ratio in the electrolyte leads to distinct shifts in the voltammetric peaks for (de)intercalation, with a changing slope as low as ca. 30 mV per decade. Bulk ion diffusion coefficients in the carbon host, as measured using the potentiometric intermittent titration technique (PITT) were similarly sensitive to solution composition. DFT results showed that co-intercalation of Li+ and K+ within the same layer in FLG can form thermodynamically favorable systems. Calculated binding energies for co-intercalation systems increased with respect to the area of Li+-only domains and decreased with respect to the concentration of -K-Li- phases. While previous studies of co-intercalation on a graphitic anode typically focus on co-intercalation of solvents and one particular alkali ion, this is to the best of our knowledge the first study elucidating the intercalation behavior of two monovalent alkali ions. This study establishes ultrathin graphitic electrodes as an enabling electroanalytical platform to uncover thermodynamic and kinetic processes of ion intercalation with high versatility.

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Intercalation processes of copper complexes in DNA.

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Intercalation processes of copper complexes in DNA.

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