A theoretical study of Ru(II) polypyridyl DNA intercalators

Ambrosek, David; Loos, Pierre‐François; Assfeld, Xavier; Daniel, Chantal

doi:10.1016/j.jinorgbio.2010.04.002

Cited by 69 publications

(45 citation statements)

References 45 publications

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“…Computational studies of dppz complexes intercalated into a dinucleotide step also support the notion of very small differences in intercalation energetics from the two grooves. 18 In this intercalative binding mode, the dppz ligand is positioned inside the base stack also in a head-on fashion. The intercalation of the dppz ligand is so deep that the end most distal from the ruthenium center protrudes into the major groove.…”

Section: Resultsmentioning

confidence: 99%

“…12 Extensive studies in solution have established that these complexes bind to DNA by intercalation through the planar dppz ligand. 13-17 Some possible structures have been put forward through theoretical calculations; 18-19 however, due to the lack of site-specificity in DNA binding, solution and crystal structures have largely remained elusive. Although the discovery of the unique photophysical properties of this class of complexes was made over two decades ago, the first crystal structure of a dppz complex bound to DNA was not obtained until very recently, but it did not capture dppz intercalation into a native DNA duplex.…”

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confidence: 99%

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Crystal structure of Δ-[Ru(bpy)2dppz]2+ bound to mismatched DNA reveals side-by-side metalloinsertion and intercalation

2012

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DNA mismatches represent a novel target in developing diagnostics and therapeutics for cancer, since deficiencies in DNA-mismatch repair (MMR) are implicated in many cancers and cells that are MMR-deficient show a high frequency of mismatches. We use metal complexes with bulky intercalating ligands serve as probes for DNA mismatches. Here, we report the high resolution (0.92 Å) crystal structure of the ruthenium ‘light switch’ complex Δ-Ru(bpy)2dppz2+ (bpy = 2,2′-bipyridine and dppz = dipyridophenazine), known to show luminescence on binding to duplex DNA, bound to both mismatched and well matched sites in the oligonucleotide 5′-(dCGGAAATTACCG)2-3′ (underline denotes AA mismatches). Two crystallographically independent views reveal that the complex binds mismatches through metalloinsertion, where the dppz inserts into the duplex through the minor groove, ejecting both mispaired adenosines. Additional ruthenium complexes are intercalated at well-matched sites, creating an array of complexes in the minor groove stabilized through stacking interactions between bpy ligands and extruded adenosines. This structure attests to the generality of metalloinsertion and metallointercalation as DNA binding modes.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Crystal structure of Δ-[Ru(bpy)2dppz]2+ bound to mismatched DNA reveals side-by-side metalloinsertion and intercalation

2012

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“…The presence of a dark 3 IL dppz state in the vicinity of the 3 MLCT states is also evidenced and its position is very sensitive to solvent effects. In previous studies, we performed theoretical studies based on DFT and TD‐DFT and mixed quantum mechanics/molecular mechanics (QM/MM) methods for the UV/Vis spectroscopy of [Ru(bpy) 2 (dppz)] 2+ , [Ru(phen) 2 (dppz)] 2+ , and [Ru(tap) 2 (dppz)] 2+ 35–38. When intercalated into guanine–cytosine base pairs, or into a pentadecamer model treated at the QM/MM level, the absorption spectra of bpy‐, phen‐, and tap‐substituted complexes are characterized by low‐lying 1 MLCT anc (anc=ancillary) states localized on the ancillary ligands, in contrast to what is found in vacuum, water, and acetonitrile, in which the MLCT anc and MLCT dppz states are largely mixed.…”

Section: Introductionmentioning

confidence: 99%

Photophysical Properties of Ruthenium(II) Polypyridyl DNA Intercalators: Effects of the Molecular Surroundings Investigated by Theory

Véry

Ambrosek

Otsuka

et al. 2014

Chemistry A European J

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The environmental effects on the structural and photophysical properties of [Ru(L)2 (dppz)](2+) complexes (L=bpy=2,2'-bipyridine, phen=1,10-phenanthroline, tap=1,4,5,8-tetraazaphenanthrene; dppz=dipyrido[3,3-a:2',3'-c]phenazine), used as DNA intercalators, have been studied by means of DFT, time-dependent DFT, and quantum mechanics/molecular mechanics calculations. The electronic characteristics of the low-lying triplet excited states in water, acetonitrile, and DNA have been investigated to decipher the influence of the environment on the luminescent behavior of this class of molecules. The lowest triplet intra-ligand (IL) excited state calculated at λ≈800 nm for the three complexes and localized on the dppz ligand is not very sensitive to the environment and is available for electron transfer from a guanine nucleobase. Whereas the lowest triplet metal-to-ligand charge-transfer ((3)MLCT) states remain localized on the ancillary ligand (tap) in [Ru(tap)2 (dppz)](2+), regardless of the environment, their character is drastically modified in the other complexes [Ru(phen)2 (dppz)](2+) and [Ru(bpy)2 (dppz)](2+) upon going from acetonitrile (MLCTdppz/phen or MLCTdppz/bpy) to water (MLCTdppz) and DNA (MLCTphen and MLCTbpy). The change in the character of the low-lying (3) MLCT states accompanying nuclear relaxation in the excited state controls the emissive properties of the complexes in water, acetonitrile, and DNA. The light-switching effect has been rationalized on the basis of environment-induced control of the electronic density distributed in the lowest triplet excited states.

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“…[22][23][24][25] Another important aspect is the selectivity of cisplatin: it should attack DNA rather than react with other biomolecules such as proteins. 32,33 For instance, Platts and co-workers have used quantum mechanics/ molecular mechanics (QM/MM) partition to investigate the structures and binding energies of platinum complexes on singleand double-stranded fragments of DNA. 3 Theoretical calculations confirm that the N7 center is the most reactive position for DNA metallation as discussed by Burda et al, [26][27][28] who also explored the cisplatin affinity towards sulfur donors present in proteins.…”

Section: Introductionmentioning

confidence: 99%

Cisplatin cytotoxicity: a theoretical study of induced mutations

Cerón‐Carrasco

Jacquemin

Cauët

2012

Phys. Chem. Chem. Phys.

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We investigate possible mutations in the genetic code induced by cisplatin with an approach combining molecular dynamics (MD) and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. Specifically, the impact of platination on the natural tautomeric equilibrium in guanine-cytosine (GC) base pairs is assessed to disclose the possible role played by non-canonical forms in anti-tumour activity. To obtain valuable predictions, the main interactions present in a real DNA environment, namely hydration and stacking, are simultaneously taken into account. According to our results, the Pt-DNA adduct promotes a single proton transfer reaction in GC in the DNA sequence AG[combining low line]G[combining low line]C. Such rare tautomers might play an important role in the cisplatin biological activity since they meet the stability requirements necessary to promote a permanent mutation.

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A theoretical study of Ru(II) polypyridyl DNA intercalators

Cited by 69 publications

References 45 publications

Crystal structure of Δ-[Ru(bpy)2dppz]2+ bound to mismatched DNA reveals side-by-side metalloinsertion and intercalation

Crystal structure of Δ-[Ru(bpy)2dppz]2+ bound to mismatched DNA reveals side-by-side metalloinsertion and intercalation

Photophysical Properties of Ruthenium(II) Polypyridyl DNA Intercalators: Effects of the Molecular Surroundings Investigated by Theory

Cisplatin cytotoxicity: a theoretical study of induced mutations

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