Reactivity of hexaruthenium assemblies towards nucleotides and DNA (original) (raw)
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Binding of the Δ- and Λ-Enantiomers of [Ru(dmphen) 2 dpq] 2+ to the Hexanucleotide d(GTCGAC) 2
Inorganic Chemistry, 1999
1 H NMR spectroscopy and viscosity measurements have been used to study the oligonucleotide binding of the ∆and Λ-enantiomers of the metal complex [Ru(dmphen) 2 dpq] 2+ (dmphen ) 2,9-dimethyl-1,10-phenanthroline and dpq ) dipyrido[3,2-f:2′,3′-h]quinoxaline). The addition of either enantiomer to d(GTCGAC) 2 induced large upfield shifts and significant broadening for the hexanucleotide imino and metal complex dpq resonances. These data coupled with the observed increase in the melting transition midpoint of the hexanucleotide duplex upon addition of either enantiomer suggests that both ∆-and Λ-[Ru(dmphen) 2 dpq] 2+ bind by intercalation. A significant number of metal complex to hexanucleotide NOE contacts were observed in NOESY spectra of d(GTCGAC) 2 with added ∆-or Λ-[Ru(dmphen) 2 dpq] 2+ . The observed intermolecular NOEs were consistent with both enantiomers intercalating between the G 4 A 5 bases of one strand and the T 2 C 3 bases of the complementary strand. Intermolecular NOEs from the dmphen protons were only observed to protons located in the hexanucleotide minor groove. Alternatively, NOE contacts from the dpq protons were observed to both major and minor groove protons. The NOE data suggest that the dpq ligand of the ∆-enantiomer intercalates deeply into the hexanucleotide base stack while the Λ-enantiomer can only partially intercalate. Viscosity measurements were consistent with the proposed intercalation binding models. The addition of the ∆-enantiomer increased the relative viscosity of the DNA solution, while a decrease in the relative viscosity of the DNA was observed upon addition of the Λ-metal complex. These results confirm our proposal that octahedral metallointercalators can intercalate from the minor groove. In addition, the results demonstrate that the left-handed enantiomer of [Ru(dmphen) 2 dpq] 2+ prefers to intercalate from the narrow minor groove despite only being able to partially insert a polycyclic aromatic ligand into the DNA base stack.
Frontiers in Chemistry, 2019
Lawsone itself exhibits interesting biological activities, and its complexation with a metal center can improve the potency. In this context a cytotoxic Ru-complex, [Ru(law)(dppb)(bipy)] (law = lawsone, dppb = 1,4-bis(diphenylphosphino)butane and bipy = 2,2 ′-bipyridine), named as CBLAU, was prepared as reported. In this work, NMR binding-target studies were performed to bring to light the most accessible interaction sites of this Ru-complex toward Calf-Thymus DNA (CT-DNA, used as a model), in a similar approach used for other metallic complexes with anti-cancer activity, such as cisplatin and carboplatin. Advanced and robust NMR binding-target studies, among them Saturation Transfer Difference (STD)-NMR and longitudinal relaxometry (T 1), were explored. The 1 H and 31 P-NMR data indicate that the structure of Ru-complex remains preserved in the presence of CT-DNA, and some linewidth broadening is also observed for all the signals, pointing out some interaction. Looking at the binding efficiency, the T 1 values are highly influenced by the formation of the CBLAU-DNA adduct, decreasing from 11.4 s (without DNA) to 1.4 s (with DNA), where the difference is bigger for the lawsone protons. Besides, the STD-NMR titration experiments revealed a stronger interaction (K D = 5.9 mM) for CBLAU-DNA in comparison to non-complexed lawsone-DNA (K D = 34.0 mM). The epitope map, obtained by STD-NMR, shows that aromatic protons from the complexed lawsone exhibits higher saturation transfer, in comparison to other Ru-ligands (DPPB and bipy), suggesting the supramolecular contact with CT-DNA takes place by the lawsone face of the Ru-complex, possibly by a spatial π-π stacking involving π-bonds on nucleic acids segments of the DNA chain and the naphthoquinone group.
Chemistry & Biology, 2005
We have designed a synthetic oligodeoxyribonucleotide duplex TGT(20), whose sequence is shown in . The pyrimidine-rich top strand of this duplex contained only one G residue in the sequence TGT in the center (printed bold in the ). This top strand was modified by the complexes Ru-THA and Ru-CYM ( ) so that it contained a single monofunctional adduct of these ruthenium complexes at the single central G residue. The monoadducted top strand of the duplex TGT(20) was hybridized with the complementary strand. The samples of the ruthenated TGT(20) duplexes in which the upper strand only was 5'-end labeled with 32 P were treated (or mixed) with DMS, which does not react with ruthenated G because the N7 position is no longer accessible [1, 2]. The adducts were removed by NaCN [3-5] and then the sample was treated with piperidine. In the nonmodified duplexes, the central G residue in the top strands was reactive with DMS (not shown). It was no longer reactive in both ruthenated duplexes. This observation confirms that the single G residue in the upper strand remained ruthenated even after the duplex was formed [1, 2].
Biochemistry, 2003
Modifications of natural DNA in a cell-free medium by antitumor monodentate Ru(II) arene compounds of the general formula [(η 6 -arene)Ru(en)Cl] + (arene ) biphenyl, dihydroanthracene, tetrahydroanthracene, p-cymene, or benzene; en ) ethylenediamine) were studied by atomic absorption, melting behavior, transcription mapping, circular and linear dichroism, plasmid unwinding, competitive ethidium displacement, and differential pulse polarography. The results indicate that these complexes bind preferentially to guanine residues in double-helical DNA. The data are consistent with DNA binding of the complexes containing biphenyl, dihydroanthracene, or tetrahydroanthracene ligands that involves combined coordination to G N7 and noncovalent, hydrophobic interactions between the arene ligand and DNA, which may include arene intercalation and minor groove binding. In contrast, the single hydrocarbon rings in the p-cymene and benzene ruthenium complexes cannot interact with double-helical DNA by intercalation. Interestingly, the adducts of the complex containing p-cymene ligand, which has methyl and isopropyl substituents, distort the conformation and thermally destabilize double-helical DNA distinctly more than the adducts of the three multiring ruthenium arene compounds. It has been suggested that the different character of conformational alterations induced in DNA, and the resulting thermal destabilization, may affect differently further "downstream" effects of damaged DNA and consequently may result in different biological effects of this new class of metal-based antitumor compounds. The results point to a unique profile of DNA binding for Ru(II) arene compounds, suggesting that a search for new anticancer compounds based on this class of complexes may also lead to an altered profile of biological activity in comparison with that of metal-based antitumor drugs already used in the clinic or currently on clinical trials. -dC), polymer of alternating dG and dC residues; poly(dA-dT), polymer of alternating dA and dT residues; r b, the number of metal atoms bound per nucleotide residue; ri, the molar ratio of free metal complex to nucleotide-phosphates at the onset of incubation with DNA.; THA, tetrahydroanthracene; t m, DNA melting temperature; transplatin, trans-diamminedichloroplatinum(II).
Bifunctional Amine-Tethered Ruthenium(II) Arene Complexes Form Monofunctional Adducts on DNA
Inorganic Chemistry, 2007
The tethered Ru II half-sandwich complexes [η 6 :η 1 -C 6 H 5 (CH 2 ) n NH 2 )RuCl 2 ] 1 (n ) 3) and 2 (n ) 2) have been synthesized as potential bifunctional anticancer complexes, and their X-ray crystal structures have been determined. They hydrolyze rapidly in aqueous solution to give predominantly mono-aqua mono-chlorido species. Mono-9EtG adducts, where 9EtG ) 9-ethylguanine, form rapidly, but the second 9EtG binds more slowly and more weakly.
Reactions of a cytotoxic hexanuclear arene ruthenium assembly with biological ligands
Journal of Organometallic Chemistry, 2013
Reactions between the cytotoxic hexacationic arene ruthenium assembly [(p-cymene) Ru 6 (oxa) 3 (tpt) 2 ] 6þ ([1] 6þ ) (tpt ¼ 2,4,6-tri(pyridin-4-yl)-1,3,5-triazine and oxa ¼ oxalato) (IC 50 ¼ 0.96 mM against A2780 human ovarian cancer cells) and a large range of amino acids (AA) as well as the tripeptide glutathione (GSH) were monitored in aqueous solution at 37 C by NMR spectroscopy and ESI mass spectrometry. These reactions were undertaken in order to establish the nature of the species that are presumably transported into the cell, to determine possible mechanisms of detoxification, as well as to identify potential cellular targets that may be related to the cytotoxicity. Formation of degradation products with the general formula [(p-cymene)Ru(AA)] þ could be observed with all amino acids tested in which the amino acid acts as bidentate (N,N or N,O) or tridentate (N,N,O, N,O,O or N,S,O) chelating ligand.
Inorganica Chimica Acta, 2006
A series of mixed ligand Ru(II) complexes of 5,6-dimethyl-1,10-phenanthroline (5,6-dmp) as primary ligand and 1,10-phenanthroline (phen), 2,2 0-bipyridine (bpy), pyridine (py) and NH 3 as co-ligands have been prepared and characterized by X-ray crystallography, elemental analysis and 1 H NMR and electronic absorption spectroscopy. The X-ray crystal structure of the complex [Ru(phen) 2 (bpy)]Cl 2 reveals a distorted octahedral coordination geometry for the RuN 6 coordination sphere. The DNA binding constants obtained from the absorption spectral titrations decrease in the order, tris(5,6-dmp)Ru(II) > bis(5,6-dmp)Ru(II) > mono(5,6-dmp)Ru(II), which is consistent with the trend in apparent emission enhancement of the complexes on binding to DNA. These observations reveal that the DNA binding affinity of the complexes depend upon the number of 5,6-dmp ligands and hence the hydrophobic interaction of 5,6-dimethyl groups on the DNA surface, which is critical in determining the DNA binding affinity and the solvent accessibility of the exciplex. Among the bis(5,6-dmp)Ru(II) complexes, those with monodentate py (4) or NH 3 (5) co-ligands show DNA binding affinities slightly higher than the bpy and phen analogues. This reveals that they interact with DNA through the co-ligands while both the 5,6-dmp ligands interact with the exterior of the DNA surface. All these observations are supported by thermal denaturation and viscosity measurements. Two DNA binding modes-surface/electrostatic and strong hydrophobic/partial intercalative DNA interaction-are suggested for the mixed ligand complexes on the basis of time-resolved emission measurements. Interestingly, the 5,6-dmp ligands promote aggregation of the complexes on the DNA helix as a helical nanotemplate, as evidenced by induced CD signals in the UV region. The ionic strength variation experiments and competitive DNA binding studies on bis(5,6-dmp)Ru(II) complexes reveal that EthBr and the partially intercalated and kinetically inert [Ru(phen) 2 (dppz)] 2+ (dppz = dipyrido[3,2-a:2 0 ,3 0-c]phenazine) complexes revert the CD signals induced by exciton coupling of the DNA-bound complexes with the free complexes in solution.
Dalton Transactions, 2009
Diastereomeric oligopyridine-ruthenium(II)-amino acid conjugated complexes of the general formulas K-and D-[Ru(bpy) 2 (4,4¢(CO 2 Y) 2 -bpy)] 2+ , where Y = L-AlaCONH 2 , L-LysCONH 2 , L-HisCONH 2 , L-TyrCONH 2 ), were synthesized and characterized. Their binding properties with ct-DNA and the oligonucleotide duplex d(5¢CGCGCG-3¢) 2 , by means of circular dichroism (CD), NMR spectroscopy and DNA thermal denaturation (T m ) curves were studied. CD and T m data indicate that all diastereomeric complexes bind to the DNA major groove, D-diastereomers in a similar manner, while K-diastereomers in dependence of the nature of the amino acid. NMR studies of d(5¢CGCGCG-3¢) 2 , and the complexes D-1, D-2, K-1 and K-2 indicate that D-1 and D-2 were bound having the ancillary bpy ligands towards the DNA groove, while the corresponding K-1 and K-2 were orientated in a similar way, facing the ligand 4,4¢(CO 2 Y) 2 bpy towards the DNA major groove. Photoinduced DNA cleavage was observed in all cases studied, which take place through singlet oxygen production. D-4 and K-4 show the lower photoinduced cleavage yield, probably because the singlet oxygen ( 1 O 2 ) oxidizes not only the DNA phosporodiesteric bonds but the tyrosine's phenolic OH bond as well.