Synthesis, characterization, and reaction pathways for the formation of a GMP adduct of a cytotoxic thiocyanato ruthenium arene complex

The organoruthenium complex [(η⁶-hmb)Ru(en)(Cl)][PF₆] (hmb is hexamethylbenzene, en is ethylenediamine) undergoes facile aquation and then reacts with KSCN in unbuffered solution to give the S-coordinated thiocyanato product [(η⁶-hmb)Ru(en)(S-SCN)]⁺ which slowly converts to the thermodynamically favored N-bound complex [(η⁶-hmb)Ru(en)(N-NCS)]⁺ (1 ⁺). Complex 1 was synthesized and characterized by X-ray crystallography and mass spectrometry. Despite its lack of hydrolysis over 24 h, complex 1 exhibits moderate cytotoxicity (IC₅₀ 24 μM) towards the human ovarian cancer cell line A2780, comparable with that of the chlorido analogue which is thought to be activated (towards potential target DNA) via a rapid aquation (Wang et. al. in Proc Natl Acad Sci USA 102:18269–18274, 2005). Detailed kinetic studies suggest that complex 1 binds to guanosine 5′-monophosphate (GMP) through direct N7 substitution of the N-bound SCN ligand. In the presence of a high concentration of chloride (104 mM), however, complex 1 may bind partly to GMP via Cl substitution.     

Competitive reactions of a ruthenium arene anticancer complex with histidine, cytochrome c and an oligonucleotide

The ruthenium arene anticancer complex [(⁶-bip)Ru(en)Cl][PF₆] (1) (bip is biphenyl, en is ethylenediamine) reacted slowly with the amino acid L-histidine (L-His) in aqueous solution at 310 K. Two L-His adducts of 1 were separated by high-performance liquid chromatography and identified by electrospray ionisation mass spectrometry and NMR: an imidazole N-bound complex [(⁶-bip)Ru(en)(N–L-His)]²⁺, and an N-bound complex [(⁶-bip)Ru(en)(N–L-His)]²⁺. At 310 K, after 24 h only about 22% of complex 1 (2 mM) reacted with L-His, and of the unreacted 1, 59% had hydrolysed. In the presence of 100 mM NaCl, approximately 90% of 1 remained unreacted. In aqueous solution or triethylammonium acetate (TEAA) buffer (pH 7.6), ¹⁵N-labelled 1 reacted with cytochrome c to give two monoruthenated protein adducts. The reaction reached equilibrium within 2 h by which time approximately 50% of cytochrome c was ruthenated. On the basis of [¹H, ¹⁵N] NMR data, one adduct may have Ru bound to the N-terminus, and the other to a carboxylate group on the protein. In TEAA buffer and at 310 K, more than 90% of the 14-mer oligonucleotide d(TATGTACCATGTAT) reacted with 2 mol Eq of 1 to give rise to monoruthenated and diruthenated oligonucleotide adducts. The presence of cytochrome c (1 mol Eq) or L-His (4 mol Eq) had little effect on the course of the reaction with the oligonucleotide. In cells, DNA (or RNA) may be a favoured reaction site for this Ru anticancer complex.Electronic supplementary material is available for this article at .

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Metabolization of [Ru(η6-C6H5CF3)(pta)Cl2]: a cytotoxic RAPTA-type complex with a strongly electron withdrawing arene ligand

Abstract  

The anticancer ruthenium–arene compound [Ru(η⁶-C₆H₅CF₃)(pta)Cl₂] (where pta is 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane), termed RAPTA-CF3, with the electron-withdrawing α,α,α-trifluorotoluene ligand, is one of the most cytotoxic RAPTA compounds known. To rationalize the high observed cytotoxicity, the hydrolysis of RAPTA-CF3 in water and brine (100 mM sodium chloride) and its reactions with the protein ubiquitin and a double-stranded oligonucleotide (5′-GTATTGGCACGTA-3′) were studied using NMR spectroscopy, high-resolution Fourier transform ion cyclotron resonance mass spectrometry, and gel electrophoresis. The aquation of the ruthenium–chlorido complex was accompanied by a loss of the arene ligand, independent of the chloride concentration, which is a special property of the compound not observed for other ruthenium–arene complexes with relatively stable ruthenium–arene bonds. Accordingly, the mass spectra of the biomolecule reaction mixtures contained mostly [Ru(pta)]–biomolecule adducts, whereas [Ru(pta)(arene)] adducts typical of other RAPTA compounds were not observed in the protein or DNA binding studies. Gel electrophoresis experiments revealed a significant degree of decomposition of the oligonucleotide, which was more pronounced in the case of RAPTA-CF3 compared with RAPTA-C. Consequently, facile arene loss appears to be responsible for the increased cytotoxicity of RAPTA-CF3.     

Organometallic indolo[3,2-c]quinolines versus indolo[3,2-d]benzazepines: synthesis, structural and spectroscopic characterization, and biological efficacy

The synthesis of ruthenium(II) and osmium(II) arene complexes with the closely related indolo[3,2-c]quinolines N-(11H-indolo[3,2-c]quinolin-6-yl)-ethane-1,2-diamine (L ¹ ) and N′-(11H-indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1,2-diamine (L ² ) and indolo[3,2-d]benzazepines N-(7,12-dihydroindolo-[3,2-d][1]benzazepin-6-yl)-ethane-1,2-diamine (L ³ ) and N′-(7,12-dihydroindolo-[3,2-d][1]benzazepin-6-yl)-N,N-dimethylethane-1,2-diamine (L ⁴ ) of the general formulas [(η⁶-p-cymene)M^II(L ¹ )Cl]Cl, where M is Ru (4) and Os (6), [(η⁶-p-cymene)M^II(L ² )Cl]Cl, where M is Ru (5) and Os (7), [(η⁶-p-cymene)M^II(L ³ )Cl]Cl, where M is Ru (8) and Os (10), and [(η⁶-p-cymene)M^II(L ⁴ )Cl]Cl, where M is Ru (9) and Os (11), is reported. The compounds have been comprehensively characterized by elemental analysis, electrospray ionization mass spectrometry, spectroscopy (IR, UV–vis, and NMR), and X-ray crystallography (L ¹ ·HCl, 4·H₂O, 5, and 9·2.5H₂O). Structure–activity relationships with regard to cytotoxicity and cell cycle effects in human cancer cells as well as cyclin-dependent kinase (cdk) inhibition and DNA intercalation in cell-free settings have been established. The metal-free indolo[3,2-c]quinolines inhibit cancer cell growth in vitro, with IC₅₀ values in the high nanomolar range, whereas those of the related indolo[3,2-d]benzazepines are in the low micromolar range. In cell-free experiments, these classes of compounds inhibit the activity of cdk2/cyclin E, but the much higher cytotoxicity and stronger cell cycle effects of indoloquinolines L ¹ and 7 are not paralleled by a substantially higher kinase inhibition compared with indolobenzazepines L ⁴ and 11, arguing for additional targets and molecular effects, such as intercalation into DNA.     

Synthesis, characterization and reactivity of polypyridyl ruthenium(II) carbonyl complexes with phosphine derivatives: Ruthenium-carbon bond labilization based on steric and electronic effects

Ruthenium phosphine complexes with a CO ligand [Ru(tpy)(PR₃)(CO)Cl]⁺ (tpy = 2,2′:6′,2″-terpyridine, R = Ph or p-tolyl), were prepared by introduction of CO gas to the corresponding dichloro complexes at room temperature. New carbonyl complexes were characterized by various methods including structural analyses. They were shown to release CO following the addition of several N-donors to form the corresponding substituted complexes. The kinetic data and structural results observed in this study indicated that the CO release reactions proceeded in an interchange mechanism. The molecular structures of [Ru(tpy)(PPh₃)(CO)Cl]PF₆, [Ru(tpy)(P(p-tolyl)₃)(CO)Cl]PF₆ and [Ru(tpy)(PPh₃)(CH₃CN)Cl]PF₆ were determined by X-ray crystallography.     

Interactions of arene-Ru(II)-chloroquine complexes of known antimalarial and antitumor activity with human serum albumin (HSA) and transferrin

The interactions of π-arene-Ru(II)-chloroquine complexes with human serum albumin (HSA), apotransferrin and holotransferrin have been studied by circular dichroism (CD) and UV-Visible spectroscopies, together with isothermal titration calorimetry (ITC). The data for [Ru(η⁶-p-cymene)(CQ)(H₂O)Cl]PF₆ (1), [Ru(η⁶-benzene)(CQ)(H₂O)Cl]PF₆ (2), [Ru(η⁶-p-cymene)(CQ)(H₂O)₂][PF₆]₂ (3), [Ru(η⁶-p-cymene)(CQ)(en)][PF₆]₂ (4), [Ru(η⁶-p-cymene)(η⁶-CQDP)][BF₄]₂ (5) (CQ: chloroquine; DP: diphosphate; en: ethylenediamine), in comparison with CQDP and [Ru(η⁶-p-cymene)(en)Cl][PF₆] (6) as controls demonstrate that 1, 2, 3, and 5, which contain exchangeable ligands, bind to HSA and to apotransferrin in a covalent manner. The interaction did not affect the α-helical content in apotransferrin but resulted in a loss of this type of structure in HSA. The binding was reversed in both cases by a decrease in pH and in the case of the Ru-HSA adducts, also by addition of chelating agents. A weaker interaction between complexes 4 and 6 and HSA was measured by ITC but was not detectable spectroscopically. No interactions were observed for complexes 4 and 6 with apotransferrin or for CQDP with either protein. The combined results suggest that the arene-Ru(II)-chloroquine complexes, known to be active against resistant malaria and several lines of cancer cells, also display a good transport behavior that makes them good candidates for drug development.     

Synthesis, characterization, photophysics and intramolecular energy transfer process in bimetallic rhenium(I)-ruthenium(II) complexes

Two new heterobimetallic complexes of rhenium(I) and ruthenium(II) [(CO)₃(NN)Re(4,4′-bpy)Ru(NN)₂Cl](PF₆)₂ and already known monometallic complexes [Cl(NN)₂Ru(4,4′-bpy)](PF₆) and [(CO)₃(NN)Re(4,4′-bpy)](PF₆) and bimetallic complexes [Cl(NN)₂Ru(4,4′-bpy)Ru(NN)₂Cl](PF₆)₂, [(CO)₃(NN)Re(4,4′-bpy)Re(NN)(CO)₃](PF₆)₂ (NN = 2,2′-bipyridine, 1,10-phenanthroline; 4,4′-bpy = 4,4′-bipyridine) are synthesized and characterized by spectral techniques. The photophysical properties of all the complexes are studied. It is found that attachment of rhenium(I) altered the photophysical characteristics of ruthenium(II). Excited state energy transfer from the rhenium(I) chromophore to the ruthenium(II) is observed upon excitation at 355 nm.     

Combined arene ruthenium porphyrins as chemotherapeutics and photosensitizers for cancer therapy

Mononuclear 5-(4-pyridyl)-10,15,20-triphenylporphyrin and 5-(3-pyridyl)-10,15,20-triphenylporphyrin as well as tetranuclear 5,10,15,20-tetra(4-pyridyl)porphyrin (tetra-4-pp) and 5,10,15,20-tetra(3-pyridyl)porphyrin) (tetra-3-pp) arene ruthenium(II) derivatives (arene is C₆H₅Me or p-Pr ⁱ C₆H₄Me) were prepared and evaluated as potential dual photosensitizers and chemotherapeutics in human Me300 melanoma cells. In the absence of light, all tetranuclear complexes were cytotoxic (IC₅₀ ≤ 20 μM), while the mononuclear derivatives were not (IC₅₀ ≥ 100 μM). Kinetic studies of tritiated thymidine and tritiated leucine incorporations in cells exposed to a low concentration (5 μM) of tetranuclear p-cymene derivatives demonstrated a rapid inhibition of DNA synthesis, while protein synthesis was inhibited only later, suggesting arene ruthenium–DNA interactions as the initial cytotoxic process. All complexes exhibited phototoxicities toward melanoma cells when exposed to laser light of 652 nm. At low concentration (5 μM), LD₅₀ of the mononuclear derivatives was between 5 and 10 J/cm², while for the tetranuclear derivatives LD₅₀ was approximately 2.5 J/cm² for the [Ru₄(η⁶-arene)₄(tetra-4-pp)Cl₈] complexes and less than 0.5 J/cm² for the [Ru₄(η⁶-arene)₄(tetra-3-pp)Cl₈] complexes. Examination of cells under a fluorescence microscope revealed the [Ru₄(η⁶-arene)₄(tetra-4-pp)Cl₈] complexes as cytoplasmic aggregates, whereas the [Ru₄(η⁶-arene)₄(tetra-3-pp)Cl₈] complexes were homogenously dispersed in the cytoplasm. Thus, these complexes present a dual synergistic effect with good properties of both the arene ruthenium chemotherapeutics and the porphyrin photosensitizer.     

Synthesis, spectral and structural studies of water soluble arene ruthenium (II) complexes containing 2,2′-dipyridyl-N-alkylimine ligand

A series of water soluble complexes of general formula [(η⁶-arene)Ru{(C₅H₄N)₂CNRi}Cl]PF₆ have been prepared by the reaction of [{(η⁶-arene)RuCl₂}₂] with appropriate 2,2′-dipyridyl-N-alkylimine ligands (dpNRi) in the presence of NH₄PF₆ (where; R = Me or Et; arene = p-cymene, C₆Me₆, C₆H₆). The 2,2′-dipyridyl-N-alkylimine ligands are prepared by reaction of 2,2′-dipyridyl ketone with the corresponding alkylamine. The complexes are readily obtained as air stable yellow to dark brown solids by simple stirring at room temperature. The complexes are isolated as their hexafluorophosphate salts and characterized on the basis of spectroscopic data. The molecular structure of representative complex [(η⁶-C₆Me₆)Ru{(C₅H₄N)₂CN-Me}Cl]PF₆ has been determined by single crystal X-ray diffraction studies.     

Communication of metal ions in the dinuclear ruthenium complexes containing 4,4′-bipyridine, 1,4-diisocyanobenzene, and pyrazine bridging ligands: Synthesis, characterization and structure determination

Reaction of [Ru(2,2′-bipyridine)(2,2′:6′,2″-terpyridine)Cl]PF₆ (abbreviated to [Ru(bipy)(terpy)Cl]PF₆) with 0.5 equiv of the bidentate ligand L produces the dinuclear complexes [{Ru(bipy)(terpy)}₂(μ-L)](PF₆)₄ (L = 4,4′-bipyridine 1, 1,4-diisocyanobenzene 2 and pyrazine 3) in moderate yields. Treating [Ru(bipy)(terpy)Cl]PF₆ with equal molar of 1,4-diisocyanobenzene affords [Ru(bipy)(terpy)(CNC₆H₄NC)](PF₆)₂ (2a). These new complexes have been characterized by mass, NMR, and UV-Vis spectroscopy, and the structures of 1-3 determined by an X-ray diffraction study. Cyclic voltammetric studies suggest that metal communication between the two ruthenium ions increases from 1 to 2 to 3.     

Novel mononuclear η-pentamethylcyclopentadienyl complexes of platinum group metals bearing pyrazolylpyridazine ligands: Syntheses and spectral studies

Condensation of 3,6-dichloropyridazine with 3,5-dimethylpyrazole in 1:1 ratio yielded one side substituted pyrazolylpyridazine ligand 3-chloro-6-(3,5-dimethylpyrazolyl)pyridazine (L) while condensation of 3,6-dichloropyridazine with substituted pyrazoles in 1:2 ratio yielded both side substituted pyrazolylpyridazine ligands such as 3,6-bis(pyrazolyl)pyridazine (L1), 3,6-bis(3-methylpyrazolyl)pyridazine (L2) and 3,6-bis(3,5-dimethylpyrazolyl)pyridazine (L3). A new series of cationic mononuclear complexes of the type [(η⁵-Cp)M_a(L)(PPh₃)]PF₆, [(η⁵-Cp*)M_b(L)Cl]PF₆, [(η⁵-Cp*)Ru(L′)(PPh₃)]PF₆ and [(η⁵-Cp*)M_b(L′)Cl]⁺ (where M_a = Ru, Os; M_b = Rh, Ir and L′ = L1, L2, L3) bearing pyrazolylpyridazine and η⁵-cyclopentadienyl ligands are reported. The complexes have been completely characterized by spectral studies. The molecular structures of representative complexes have been determined by single crystal X-ray crystallography.     

The ruthenium(II)–arene compound RAPTA-C induces apoptosis in EAC cells through mitochondrial and p53–JNK pathways

An investigation of the molecular mechanism of the anticancer activity demonstrated by the ruthenium(II)–arene compound [Ru(η⁶-p-cymene)Cl₂(pta)] (pta is 1,3,5-triaza-7-phosphaadamantane), termed “RAPTA-C”, in Ehrlich ascites carcinoma (EAC) bearing mice is described. RAPTA-C exhibits effective cell growth inhibition by triggering G₂/M phase arrest and apoptosis in cancer cells. Cell cycle arrest is associated with increased levels of p21 and reduced amounts of cyclin E. RAPTA-C treatment also enhances the levels of p53, and its treatment triggers the mitochondrial apoptotic pathway, as shown by the change in Bax to Bcl-2 ratios, resulting in cytochrome c release and caspase-9 activation. c-Jun NH₂-terminal kinase (JNK) is a critical mediator in RAPTA-C-induced cell growth inhibition. Activation of JNK by RAPTA-C increases significantly during apoptosis. Overall, these results suggest a critical role for JNK and p53 in RAPTA-C-induced G₂/M arrest and apoptosis of EAC-bearing mice. Consequently, RAPTA-C treatment results in a significant inhibition in the progression of cancer in an animal model, which emulates the human disease, and does so with remarkably low general toxicity; hence, RAPTA-C has potential for clinical application.     

Identification of (η6-arene)ruthenium(II) protein binding sites in E. coli cells by combined multidimensional liquid chromatography and ESI tandem mass spectrometry: specific binding of [(η6- p -cymene)RuCl2(DMSO)] to stress-regulated proteins and to helicases

An automated multidimensional protein identification technology, which combines biphasic liquid chromatography with electrospray ionisation tandem mass spectrometry (MS/MS), was employed to analyse tryptic peptides from Escherichia coli cells treated with the antiproliferation agent [(η⁶-p-cymene)RuCl₂(DMSO)], where DMSO is dimethyl sulfoxide. MS/MS spectra were recorded for molecular ions generated by neutral loss of p-cymene from intensive peptide ions coordinated by the (η⁶-p-cymene)Ru^II fragment. Matching of the MS/MS spectra of the ruthenated peptides to spectra of proteins in the E. coli database enabled the identification of five protein targets for [(η⁶-p-cymene)RuCl₂(DMSO)]. One of these is the constitutive cold-shock protein cspC, which regulates the expression of genes encoding stress-response proteins, and three of the other targets, ppiD, osmY and sucC, are proteins of the latter type. The DNA damage-inducible helicase dinG was likewise established as a protein target. Aspartate carboxylate functions were identified as the probable Ru binding sites in cspC, ppiD and dinG, and threonine and lysine side chains in osmY and sucC, respectively. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Mononuclear arene ruthenium complexes containing 5,6-diphenyl-3-(pyridine-2-yl)-1,2,4-triazine as chelating ligand: Synthesis and molecular structure

The mononuclear cations of the general formula [(η⁶-arene)RuCl(pdpt)]⁺ (pdpt = 5,6-diphenyl-3-(pyridine-2-yl)-1,2,4-triazine; arene = C₆H₆ (1); C₆H₅Me (2); p-PrⁱC₆H₄Me (3); C₆Me₆ (4)) have been synthesised from 5,6-diphenyl-3-(pyridine-2-yl)-1,2,4-triazine (pdpt) and the corresponding chloro complexes [(η⁶-C₆H₆)Ru(μ-Cl)Cl]₂, [(η⁶-C₆H₅Me)Ru(μ-Cl)Cl]₂, [(η⁶p-PrⁱC₆H₄Me)Ru(μ-Cl)Cl]₂ and [(η⁶-C₆Me₆)Ru(μ-Cl)Cl]₂, respectively. The X-ray crystal structure analyses of [1][PF₆] · (C₆H₆)_2.5 and [2][PF₆] · (CH₃CN)₂ reveal a typical piano-stool geometry around the metal centre and in the crystal packing a complexed networks of intermolecular interactions.     

Development of DNA electrochemical biosensor based on immobilization of ssDNA on the surface of nickel oxide nanoparticles modified glassy carbon electrode

A sensitive electrochemical method for DNA hybridization based on immobilization of DNA probe and [Ru(NH₃)₅Cl]PF₆ complex onto nickel oxide nanomaterials (NiOx_np) modified glassy carbon electrode was developed. Due to strong affinity of NiOx_np for phosphate groups, oligonucleotides probe with a terminal 5′-phosphate group was attached to the surface of the modified electrode. DNA immobilization and hybridization were characterized by electrochemical impedance spectroscopy (EIS) and differential pulse voltammetry using K₃Fe(CN)₆/K₄Fe(CN)₆ and [Ru(NH₃)₅Cl]PF₆ as probe and indicator, respectively. The Ru-complex current response indicates only the complementary sequence showing an obvious current signal in comparison to non-complementary and three or single point mismatched sequences. The fabricated biosensor possessed good selectivity and sensitivity for complementary probe, taxon: 32630 tumor necrosis factor (TNF). The linear dynamic range, sensitivity and detection limit of the proposed biosensor were 4 × 10⁻¹⁰ M to 1 × 10⁻⁸ M, 34.32 nA nM⁻¹ and 6.8 × 10⁻¹¹ M, respectively. Excellent reproducibility and stability, quite simple and inexpensive preparation are the other advantages of proposed biosensor.     

Synthesis and characterization of Pt(II) and Pt(II)/Ru(II) complexes with the bidentate bridging ligand dipyrido(2,3-a:3′,2′-h)phenazine (dpop)

Three new complexes [Pt(dpop)(Cl)₂], [(Cl)₂Pt(dpop)Pt(Cl)₂] and [(bpy)₂Ru(dpop)Pt(Cl)₂](PF₆)₂ (dpop = dipyrido(2,3-a:3′,2′-h)phenazine) were prepared and studied. The electronic absorption spectra of the complexes display Pt dπ → dpop π* and Ru dπ → dpop π* MLCT transitions at longer wavelengths than for previously reported similar complexes. Results of cyclic voltammograms show reversible dpop centered reductions while for the mixed metal [(bpy)₂Ru(dpop)Pt(Cl)₂]²⁺ an irreversible Pt(II) oxidative wave precedes the Ru(II) oxidation/reduction couple. Spectroelectrochemical results show that all oxidative and reductive processes are completely reversible. The [(Cl)₂Pt(dpop)Pt(Cl)₂] complex cleaves in solution with pseudo-first order kinetics resulting in loss of the Pt dπ → dpop π* MLCT transition at 545 nm.     

Cyclodextrins improve the antimicrobial activity of the chloride salt of Ruthenium(II) chloro-phenanthroline-trithiacyclononane

The complex [Ru([9]aneS₃)phenCl]Cl (phen = 1,10-phenanthroline) and its synthetic precursor [Ru([9]aneS₃)dmsoCl₂] were immobilized in permethylated β-cyclodextrin (TRIMEB). A new crystalline structure of the precursor, obtained from a batch ethanol solution at low temperature (4°C), is fully described from single-crystal X-ray diffraction data. [Ru([9]aneS₃)phenCl]Cl was also encapsulated in native β-cyclodextrin for comparison with the TRIMEB compound. All three compounds were obtained with a 1:1 host:guest stoichiometry and were studied by powder X-ray diffraction (including synchrotron radiation data), thermogravimetric analysis (TGA), ¹³C{¹H} CP/MAS NMR and FTIR spectroscopies. The bacterial growth inhibitory action of the complex [Ru([9]aneS₃)phenCl]Cl and its two cyclodextrin compounds was tested on Gram-negative (Salmonella, Escherichia) and Gram-positive strains (Bacillus, Listeria, Enterococcus and Staphilococcus) and results show a positive effect of cyclodextrin immobilization on the antimicrobial properties. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Enhanced DNA photocleavage properties of Ru(II) terpyridine complexes upon incorporation of methylphenyl substituted terpyridine and/or the polyazine bridging ligand dpp (2,3-bis(2-pyridyl)pyrazine)

The heteroleptic complexes, [(MePhtpy)RuCl(dpp)](PF₆) and [(tpy)RuCl(dpp)](PF₆), have been synthesized, characterized, and investigated with respect to their photophysical, redox, and DNA photocleavage properties (where MePhtpy = 4′-(4-methylphenyl)-2,2′:6′,2′′-terpyridine and dpp = 2,3-bis(2-pyridyl)pyrazine, tpy = 2,2′:6′,2′′-terpyridine). The X-ray crystal structure confirms the identity of the new [(MePhtpy)RuCl(dpp)](PF₆) complex. These heteroleptic complexes were found to photocleave DNA in the presence of oxygen, unlike the previously studied complex, [Ru(tpy)₂](PF₆)₂. The photophysical, redox, and DNA photocleavage properties of the heteroleptic complexes were compared with those of the homoleptic complexes, [Ru(MePhtpy)₂](PF₆)₂ and [Ru(tpy)₂](PF₆)₂. The heteroleptic complexes showed intense metal to ligand charge transfer (MLCT) transition at lower energy ([(MePhtpy)RuCl(dpp)](PF₆), 522 nm; [(tpy)RuCl(dpp)](PF₆), 516 nm) and longer excited state lifetimes as compared to the homoleptic complexes. The [Ru(MePhtpy)₂]²⁺ complex was found to photocleave DNA in contrast to [Ru(tpy)₂]²⁺. The introduction of a methylphenyl group on the tepyridine ligand not only enhances the ³MLCT excited state lifetime but also increases the lipophilicity and thereby the DNA binding ability of the molecule. An increase in lipophilicity upon addition of a methylphenyl group on the 2,2′:6′,2′′-terpyridine ligand was confirmed by determination of the partition coefficient ([(MePhtpy)RuCl(dpp)](PF₆), log P = +1.16; [(tpy)RuCl(dpp)](PF₆), log P = −1.27). The heteroleptic complexes photocleave DNA more efficiently than the homoleptic complexes, with the greatest activity being observed for the newly prepared [(MePhtpy)RuCl(dpp)](PF₆) complex.     

New ruthenium(II) mixed metallocene derived complexes: Synthesis, characterization by X-ray diffraction and evaluation on DNA interaction by atomic force microscopy

A new family of Ru(II) mixed metallocene complexes of the type [Ru(η⁵-C₅H₅)(η⁶-arene)][PF₆] has been synthesized and fully characterized by NMR and UV-Vis spectroscopy. X-ray analysis of single crystal was achieved for all the complexes and revealed the presence of two enantiomers expected for planar chirality originated by the η⁶ coordination of the arene prochiral ligands. Studies of interaction of the new complexes with pBR322 DNA by atomic force microscopy showed very strong and different types of interaction. Antiproliferative tests were examined on human leukemia cancer cells (HL-60) using the MTT assay, and the IC₅₀ values revealed low antiproliferative activity compared to cisplatin.     

Mixed-ligand complexes of ruthenium(II) containing new photoactive or electroactive ligands: synthesis, spectral characterization and DNA interactions

Mixed-ligand ruthenium(II) complexes of three photoactive ligands, viz., (E)-1-[2-(4-methyl-2-pyridyl)-4-pyridyl]-2-(1-naphthyl)-1-ethene (mppne), (E)-1-(9-anthryl)-2-[2-(4-methyl-2-pyridyl)-4-pyridyl]-1-ethene (mppae) and (E)-1-[2-(4-methyl-2-pyridyl)-4-pyridyl]-2-(1-pyrenyl)-1-ethene (mpppe), in which a 2,2′-bipyridyl unit is linked via an ethylinic linkage to either a naphthalene, an anthracene or a pyrene chromophore and three electroactive ligands, viz., 4-(4-pyridyl)-1,2-benzenediol (catpy), 5,6-dihydroxy-1,10-phenanthroline (catphen) and 1,2-benzenediol (cat), were synthesized in good to moderate yields. Complexes [Ru(bpy)₂(mppne)]²⁺ (bpy is 2, 2′–bipyridyl), [Ru(bpy)₂(mppae)]²⁺, [Ru(bpy)₂(mpppe)]²⁺, [Ru(bpy)₂(sq-py)]⁺, [Ru(bpy)₂(sq-phen)]⁺ and [Ru(phen)₂(bsq)]⁺ (phen is 1,10-phenanthroline) were fully characterized by elemental analysis, IR, ¹H NMR, fast-atom bombardment or electron-impact mass, UV–vis and cyclic voltammetric methods. In the latter three complexes, the ligands catpy, catphen and cat are actually bound to the metal center as the corresponding semiquinone species, viz., 4-(4-pyridyl)-1,2-benzenedioleto(+I) (sq-py), 1,10-phenanthroline-5,6-dioleto(+I) (sq-phen) and 1,2-benzenedioleto(+I) (bsq), thus making the overall charge of the complexes formally equal to + 1 in each case. These three complexes are electron paramagnetic resonance active and exhibit an intense absorption band between 941 and 958 nm owing to metal-to-ligand charge transfer (MLCT, d _Ru→π*_sq) transitions. The other three ruthenium(II) complexes containing three photoactive ligands, mppne, mppae and mpppe, exhibit MLCT (d _Ru→π*_bpy ) bands in the 454–461-nm region and are diamagnetic. These can be characterized by the ¹H NMR method. [Ru(bpy)₂(mppne)]²⁺, [Ru(bpy)₂(mppae)]²⁺ and [Ru(bpy)₂(mpppe)]²⁺ exhibit redox waves corresponding to the Ru^III/Ru^II couple along with the expected ligand (bpy and substituted bpy) based ones in their cyclic and differential pulse voltammograms (CH₃CN, 0.1 M tetrabutylammonium hexafluorophosphate)—corresponding voltammograms of [Ru(bpy)₂(sq-py)]⁺, [Ru(bpy)₂(sq-phen)]⁺ and [Ru(phen)₂(bsq)]⁺ are mainly characterized by waves corresponding to the quinone/semiquinone (q/sq) and semiquinone/1,2-diol (sq/cat) redox processes. The results of absorption and fluorescence titration as well as thermal denaturation studies reveal that [Ru(bpy)₂(mppne)]²⁺ and [Ru(bpy)₂(mppae)]²⁺ are moderate-to-strong binders of calf thymus DNA with binding constants ranging from 10⁵ to 10⁶ M⁻¹. Under the identical conditions of drug and light dose, the DNA (supercoiled pBR 322) photocleavage activities of these two complexes follow the order:[Ru(bpy)₂(mppne)]²⁺>[Ru(bpy)₂(mppae)]²⁺, although the emission quantum yields follow the reverse order. The other ruthenium(II) complexes containing the semiquinone-based ligands are found to be nonluminescent and inefficient photocleavage agents of DNA. However, experiments shows that [Ru(bpy)₂(sq)]⁺-based complexes oxidize the sugar unit and could be used as mild oxidants for the sugar moiety of DNA. Possible explanations for these observations are presented.Electronic Supplementary Material Supplementary material is available for this article at .