Organometallic ruthenium(II)-arene complexes with triphenylphosphine amino acid bioconjugates: Synthesis,characterization and biological properties

(p-Cymene)-ruthenium bioconjugates ML (1) and ML₂ (2), bearing phosphane ligands substituted with chiral or non-chiral amino acid esters, L, were synthetized and characterized by instrumental methods (NMR, CD, MS) and DFT calculations (using the wB97xD functional). Cytotoxic activity of complexes 1 and 2 was investigated by using human cervical carcinoma cell line (HeLa) and MTT assay. Four (2_pG, 2_pA, 2_mG and 2_mA) out of ten synthesized ruthenium complexes showed significant toxicity, with IC₅₀ values of 5–30 μM. Evaluation of the potential biomolecular targets of bioconjugates 2 by UV–Vis, fluorescence and CD spectroscopy revealed no measurable interaction with DNA, but micromolar affinity for proteins. The cytotoxicity of bioconjugates 2 is in correlation with their BSA binding constants, i. e. bioconjugates with lower IC₅₀ values show higher binding affinities towards BSA. Compound 2_mG with value of IC₅₀ 16 μM was selected for further biological characterization. The higher level of toxicity towards tumor compared to normal cell lines indicates its selective activity, important characteristic for potential medical use. It was detected 2_mG caused increase of cells in the S phase of cell cycle and consequential decrease of cells in G0/G1 phase. Additionally, 2_mG caused dose- and time-dependent increase of SubG0/G1 cell population, suggesting its ability to induce programmed cell death. Further investigation determined autophagy as the mode of cell death. The role of GSH in HeLa cells response to investigated organometallic ruthenium complexes was confirmed using specific regulators of GSH synthesis, buthionine sulfoximine and N-acetyl-cysteine. Pre-treatment of cells with ethacrynic acid and probenecid emphasized the role of GSH in detoxification of 2_mG compound. The amount of total ruthenium accumulation in the cell did not correlate with toxicity of 2_pG, 2_pA, 2_mG and 2_mA, suggesting structure dependent differences in either cell uptake or kinetics of ruthenium complexes detoxification. We speculate that ruthenium complexes bind protein-based biomolecules further triggering cell death. Based on the gained knowledge, the synthesis and development of more tumor-specific ruthenium-based complexes as potential anticancer drugs can be expected.     

Substituent effect of 8-quinolinolato ligands on photo-induced isomerization for linear nitrosylruthenium(II) complexes - Experimental study

cis-1 [RuCl(QN)(QN′)NO] (HQN or HQN′ = 8-quinolinol, 5-chloro-, 5,7-dichloro-, 2-isopropyl-, 2-ethyl-, 2,4-dimethyl- or 2-methyl-8-quinolinol) complexes and the corresponding trans complexes were prepared. The cis-1 to trans and the trans to cis-1 photo-induced isomerizations were carried out to investigate the substituent effect of the 8-quinolinolato ligands on the isomerization and to elucidate the mechanism. The molar ratio of trans to cis-1 isomer for the isomerization was compared among [RuCl(QN)(QN′)NO], [RuCl(QN′)₂NO] and [RuCl(QN)₂NO]. The results clearly indicate that the chloro group and bulkiness of the alkyl group in the 8-quinolinolato ligands influence on the isomerization.     

Electrogenerated chemiluminescence of (bis-bipyridyl)ruthenium(II) acetylacetonate complexes

The synthesis, electrochemistry, spectroscopy and electrogenerated chemiluminescence (ECL) of five bis-bipyridine ruthenium(II) complexes containing acetylacetonate complexes are reported. More specifically, (bpy)₂Ru(BA)₂(PF₆) (bpy = 2,2′-bipyridine; BA = benzoylacetonate), (bpy)₂Ru(TTFA)(PF₆) (TTFA =  thenoyltrifluoroacetonate), (bpy)₂Ru(TFPB)(PF₆) (TFPB = 4,4,4-trifluoro-1-phenyl-1,3-butanedionate), (bpy)₂Ru(TFPD)(PF₆) (TFPD =  1,1,1-trifluoro-2-4-pentanedionate), and (bpy)₂Ru(DBM)(PF₆) (DBM = dibenzoylmethide) display UV-Vis, photoluminescence, electrochemical and ECL properties characteristic of ruthenium bipyridyl complexes. All complexes display absorptions in the UV and visible regions of the spectra, with visible absorptions ranging from 350 to 700 nm, typical of metal-to-ligand charge transfer (MLCT) transitions. Photoluminescence emission maxima are also characteristic of MLCT transitions with wavelength maxima from 575 to 600 nm depending on the nature of the acetylacetonate ligand. ECL efficiencies for the complexes (?_ecl ∼ 0.013-0.051) are much lower than a standard (?_ecl = 1) with electron-withdrawing substituents resulting in lower efficiencies.     

Synthesis and properties of trinuclear polypyridyl complexes Ru(II)-Co(II)-Ru(II) and Ru(II)-Co(III)-Ru(II): Their photoinduced interconversion

The trinuclear [{Ru^II(bpy)₂(bpy-terpy)}₂Co^II]⁶⁺ complex (1⁶⁺) in which a Co(II)-bis-terpyridine-like centre is covalently linked to two Ru(II)-tris-bipyridine-like moieties by a bridging bipyridine-terpyridine ligand has been synthesised and characterised. Its electrochemical, photophysical and photochemical properties have been investigated in CH₃CN. The cyclic voltammetry exhibits two successive reversible oxidation processes, corresponding to the Co^III/Co^II and Ru^III/Ru^II redox couples at E_1/2 = −0.06 and 0.91 V vs Ag/Ag⁺ 10 mM, respectively. The one-electron oxidized form of the complex, [{Ru^II(bpy)₂(bpy-terpy)}₂Co^III]⁷⁺ (1⁷⁺) obtained after exhaustive electrolysis carried out at 0.2 V is fully stable. 1⁶⁺ and 1⁷⁺ are only poorly luminescent, indicating that the covalent linkage of the Ru(II)-tris-bipyridine centre to the cobalt subunit leads to a strong quenching of the Ru^II excited state by an intramolecular process. Luminescence lifetime experiments carried out at different temperatures indicate that the transfer is more efficient for 1⁷⁺ compare to 1⁶⁺ due to lower activation energy. Continuous irradiation of 1⁷⁺ performed at 405 nm in the presence of P(Ph)₃ acting as sacrificial electron donor leads to its quantitative reduction into 1⁶⁺, whereas similar experiment starting from 1⁶⁺ with a sulfonium salt as sacrificial electron acceptor converts 1⁶⁺ into 1⁷⁺ with a slower rate and a maximum yield of 80%. These photoinduced electron transfers were followed by UV-Visible spectroscopy and compared with those obtained with a simple mixture of both mononuclear parent complexes i.e. [Ru^II(bpy)₃]²⁺ and [Co^II(tolyl-terpy)₂]²⁺ or [Co^III(tolyl-terpy)₂]³⁺ (tolyl-terpy = 4′-(4-methylphenyl)-2,2′:6′,2′′-terpyridine).     

Linkage isomerism of pentaammine(dimethylsulfoxide)ruthenium(II/III) complexes: A theoretical study

Density functional theory (DFT) calculations have been performed for understanding the linkage isomerism of [Ru^II/III(NH₃)₅(dmso)]^2+/3+ (dmso = dimethylsulfoxide) from a theoretical point of view. In particular, we focus on the interchange between O-bonded and S-bonded structures of the dmso ligand by oxidation/reduction. We have examined five different exchange-correlation functionals (SVWN, BP86, mPWPW91, B3PW91, and B3LYP) in our DFT calculations and found that the relative stabilities of the O-bonded and S-bonded structures are largely dependent on the functional employed. From detailed analyses of atomic charge distributions, it has been found that the calculated atomic charges on the central metal ions are strongly correlated with the relative energies. We also studied the effect of solvation on the linkage isomerism using continuum solvation models.     

Ruthenium (II) thiacrown complexes as hydrogen-transfer reduction catalysts

An investigation into the potential of a series of Ruthenium (II) thiacrown complexes with general formula [Ru([9]aneS₃)Cl₂(L)] and [Ru([n]aneS₄)Cl(L)]⁺, where L = DMSO or Ph₃P, n = 12, 14, or 16, as hydrogen transfer reduction catalysts is reported. As part of these studies two new complexes incorporating [Ru([12]aneS₄)] and [Ru([16]aneS₄)] metal centres have been synthesised and fully characterised. The X-ray structure of one of these complexes is also reported. The UV/Vis spectra of these complexes are dominated by π → π* transitions, with weaker d → d transitions also being apparent. Using these eight structurally related complexes, studies on the transfer hydrogenation of acetophenone using propan-2-ol as the hydride source were carried out. This work revealed that the complexes displayed catalytic activity in the presence of a base promoter. Although the activity of these complexes were considerably lower than that of structurally related mixed-donor ligand systems, there was some evidence that the flexibility of the ligand did have an effect on initial catalytic activity.     

Preparation of ruthenium(II) chloride complexes of polybasic amines

The reactions of RuCl₂[P(C₆H₅)₃]₃, RuCl₂(tmeda)₂, and RuCl₂(1,5-COD)(tmeda) with polybasic amines such as pyrazole have been studied. From the phosphine complex, a binuclear complex has been isolated in which one pyrazole has been incorporated, while reactions of the latter two with excess pyrazole lead to the replacement of a tmeda ligand by two pyrazoles.     

DNA-binding studies of mixed-ligand (ethylenediamine)ruthenium(II) complexes

A series of mixed-ligand ruthenium(II) complexes of the type [Ru(en)(2)bpy](2+) (bpy=2,2-bipyridine; 1), [Ru(en)(2)phen](2+) (phen=1,10-phenantroline; 2), [Ru(en)(2)IP](2+) (IP=imidazo[4,5-f][1,10]phenanthroline; 3), and [Ru(en)(2)PIP](2+) (PIP=2-phenylimidazo[4,5-f][1,10]phenanthroline; 4) have been isolated and characterized by UV/VIS, IR, and (1)H-NMR spectral methods. The binding of the complexes with calf thymus DNA has been investigated by absorption, emission spectroscopy, viscosity measurements, DNA melting, and DNA photo-cleavage. The spectroscopic studies together with viscosity measurements and DNA melting studies support that complexes 1 and 2 bind to CT DNA (=calf thymus DNA) by groove mode. Complex 2 binds more avidly to CT DNA than complex 1, complexes 3 and 4 bind to CT DNA by intercalation mode, 4 binds more avidly to CT DNA than 3. Noticeably, the four complexes have been found to be efficient photosensitisers for strand scissions in plasmid DNA.     

Synthesis of cyclopentadienyl ruthenium(II) complexes containing tethered functionalities

The reaction of [C₅H₄(CH₂)_nX]Tl (1: n = 2, X = NMe₂, OMe, CN; n = 3, X = NMe₂) with [(η⁶-C₆H₆)RuCl(μ-Cl)]₂, 2, afforded the sandwich compounds [{η⁵-C₅H₄(CH₂)_nX}Ru(η⁶-C₆H₆)]PF₆, 3, and [η⁵-C₅H₄(CH₂)_nX]₂Ru, 4. Photolytic cleavage of 3 in acetonitrile afforded the tethered products [{η⁵:κN-C₅H₄(CH₂)_nX}Ru(CH₃CN)₂]PF₆, 5.     

Substitution kinetics of tetracarbonyl(η-alkene)ruthenium complexes: ALKENE = ethene and methyl acrylate

The kinetics in heptane of displacement of the alkene ligands ethene and methyl acrylate from Ru(CO)₄(η²-alkene) by P(OEt)₃ have been measured. The reactions occur by reversible dissociation of the alkenes, and activation parameters are compared with those for dissociation of CO from Ru(CO)₅ and for reactions of the corresponding Os complexes. A linear free energy relationship for ligand dissociation from Ru(CO)₅, Ru(CO)₄(C₂H₄) and Ru(CO)₄(MA) has a gradient close to unity, indicating virtually complete bond breaking in the transition states. Competition parameters for reactions of what is probably a solvated Ru(CO)₄S intermediate have been measured for the alkenes and P(OEt)₃, and for eleven other P-donor nucleophiles. Correlations with the electronic and steric properties of the P-donors show negligible dependence on the electron donicity of the nucleophiles and a small but significant dependence on their sizes. The sizes were quantified by Tolman cone angles or by ‘cone angle equivalents’ derived directly from Brown's ligand repulsion energies (E_r). These correlations compared with those, reported elsewhere, for reactions of the probably solvated intermediates Co₂(CO)₅(μ²-C₂Ph₂) and H₃Re₃(CO)₁₁ formed by ligand dissociative processes. In all cases the discrimination between nucleophiles by the intermediates is weak confirming their high reactivity and the borderline nature of the mechanisms of these bimolecular reactions between I_d and I_a.     

One-pot syntheses of alkenyl-phosphonio complexes of ruthenium(II), rhodium(III) and iridium(III) bearing p-cymene or pentamethylcyclopentadienyl groups

Reaction of [(p-cymene)RuCl₂(PPh₃)] (1) or [Cp^∗MCl₂(PPh₃)] (Cp^∗ = C₅Me₅) (3a: M = Rh; 4a: M = Ir) with 1-alkynes and PPh₃ were carried out in the presence of KPF₆, generating the corresponding alkenyl-phosphonio complexes, [(p-cymene)RuCl(PPh₃){CHCR(PPh₃)}](PF₆) (2a: R = Ph; 2b: R = p-tolyl) or [Cp^∗MCl(PPh₃){CHCPh(PPh₃)}](PF₆) (5: M = Rh; 6: M = Ir). Similar reactions of complexes [Cp^∗RhCl₂(L¹)] (3a: L¹ = PPh₃; 3c: L¹ = P(OMe)₃) with L² (L² = PPh₃, PMePh₂, P(OMe)₃) gave [Cp^∗RhCl(L¹)(L²)](PF₆) (7bb: L¹ = L² = PMePh₂; 7ca: L¹ = P(OMe)₃, L² = PPh₃; 7cc: L¹ = L² = P(OMe)₃). Alkenyl-phosphonio complex 5 was treated with P(OMe)₃ or 2,6-xylyl isocyanide, affording [Cp^∗RhCl(L){CHCPh(PPh₃)}](PF₆) (8a: L = P(OMe)₃; 8b: L = 2,6-xylNC). X-ray structural analyses of 2a, 6 and 8a revealed that the phosphonium moiety bonded to the C_β atom of the alkenyl group are E configuration.     

DNA conformational changes and cleavage by ruthenium(II) nitrofurylsemicarbazone complexes

Metal complexes that establish interactions with DNA are being studied not only because of their potential use as therapeutic agents but also as tools for biochemistry and molecular biology. Searching for drugs with anti-trypanosome activity, we previously synthesized a series of ruthenium mixed ligand dimethyl sulfoxide complexes of the type [Ru(II)Cl(2)(DMSO)(2)L], where L is 5-nitrofurylsemicarbazone derivatives and DMSO is dimethyl sulfoxide. Though they present the ability to bind DNA, no activity against parasites in cell culture was observed. Considering their potential application as molecular tools we further analyzed the interactions with DNA through an electrophoretic approach. Non covalent withdrawal of superhelicity and a rapid nicking activity upon covalent interaction was observed. Inhibition of both effects was observed in the presence of distamycin suggesting the involvement of the DNA minor groove in the interaction with the nitrofurylsemicarbazone ruthenium complexes. In addition cleavage inhibition by dimethyl sulfoxide suggests an oxidative mechanism of action.     

Unusual phenomenon in the chemistry of orthometalated ruthenium (II) complexes

Yellow cyclometalatated ruthenium (II) complexes [Ru(o-X-2-py)(MeCN)₄]PF₆ (1, X = C₆H₄ (a) or 4-MeC₆H₃ (b)) react readily with 1,10-phenanthroline (LL) in MeCN to give brownish-red species cis-[Ru(o-X-2-py)(LL)(MeCN)₂]PF₆ in high yields. The same reaction of the same complexes under the same conditions with 2,2′-bipyridine results in a significant color change from yellow to brownish-orange suggesting a formation of new species. Surprisingly, X-ray structural studies of these two complexes showed that they are structurally indistinguishable from the starting complexes 1. Referred to as complexes 4a,b, the new compounds are slightly more stable in the air though their spectral characteristics in solution are similar to 1a,b. The diffuse reflectance spectroscopy is so far the only technique that indicated differences between 1 and 4.     

Spectroelectrochemical studies of some ruthenium(II) complexes with polypyridyl bridging ligands

Ruthenium(II) bis(2,2″-pyridyl) complexes with bridging ligands: 6,7-dichloro-2,3-di(2-pyridyl)quinoxaline; 2,3-di(2-pyridyl)-quinoxaline; 5-methyl-2,3-di(2-pyridyl) quinoxaline; 6,7-dibenzo-2,3-di(2-pyridyl)quinoxaline have been prepared. The electrochemical and spectroscopic properties of these complexes are reported. The resonance Raman spectroelectrochemical results indicate the presence of oxidation state sensitive marker bands in the resonance Raman spectra of the oxidized complexes. The spectroscopic data for the reduced complexes is similar for all four species. The resonance Raman data for the reduced species are dominated by 2,2″-bipyridyl vibrations.     

Supported organometallic complexes part 39: cationic diamine(ether-phosphine)ruthenium(II) complexes as precursors for the hydrogenation of trans-4-phenyl-3-butene-2-one

Treatment of RuCl₂(η¹-Ph₂PCH₂CH₂OCH₃)₂(diamine) (1L₁-1L₇) with one equivalent of AgX (X=OTf, BF₄) in CH₂Cl₂ results in the formation of the monocationic ruthenium(II) complexes [RuCl(η¹-Ph₂PCH₂CH₂OCH₃)(η²-Ph₂PCH₂CH₂OCH₃)(diamine)]⁺X⁻ (2L₁-2L₇). These complexes were characterized by NMR, and mass spectroscopy as well as by elemental analyses, 2L₁ additionally by an X-ray structural analysis. Complex 2L₁ crystallizes in the monoclinic space group C2/c with Z=8. The monocationic and neutral complexes were applied as catalysts in the selective hydrogenation of trans-4-phenyl-3-butene-2-one. With the exception of 1L₃/1L₇ and 2L₃/2L₇ all catalysts showed high activities and selectivities toward the hydrogenation of the carbonyl group under mild conditions. However, the activity of the cationic catalysts is only half of that of their neutral congeners.     

Synthesis and characterization of iron and ruthenium complexes bearing P-N ligands based on 8-hydroxyquinoline

The synthesis of bidentate aminophosphine ligands (PN^quin) based on 8-hydroxyquinoline is described. These ligands react with cis-Fe(CO)₄Br₂ to give selectively octahedral complexes of the type cis,cis-Fe(PN^quin)(CO)₂Br₂. There is only one isomer formed where the two CO and the two bromide ligands adopt a cis configuration. The reaction of [RuCp(CH₃CN)₃]PF₆ with PN^quin ligands affords the halfsandwich complexes [RuCp(PN^quin)(CH₃CN)]PF₆ in high isolated yields. Likewise, treatment of [Ru(η⁶-p-cymene)(μ-Cl)Cl]₂ with PN^quin in the presence of AgCF₃SO₃ affords halfsandwich complexes of the type [Ru(η⁶-p-cymene)(PN^quin)Cl]CF₃SO₃. All ligands and complexes are characterized by NMR and IR spectroscopy. The X-ray structure of representative compounds is reported. In addition, the relative stability of isomeric structures and conformers of Fe(PN^quin-Ph)(CO)₂Br₂ is studied by means of DFT calculations.     

Synthesis and characterization of Ru(II), Rh(III) and Ir(III) complexes of the “Daniphos” ligands and their application in the hydrogen transfer catalysis

The synthesis of arene-ruthenium(II) and C₅Me₅-rhodium(III) and -iridium(III) complexes of chiral arene-chromium-tricarbonyl-based P^∧P and P^∧N ligands is described. Three complexes were characterized in the solid state by X-ray structural analysis. The complexes were tested in the catalytic hydrogen transfer reactions as well as in the kinetic resolution of racemic alcohols, where some complexes showed good conversion, but low enantioselectivity.     

Benzothiazole bipyridine complexes of ruthenium(II) with cytotoxic activity

A series of benzothiazole-substituted trisbipyridine ruthenium(II) analogues {[Ru(bpy)₂(4,5′-bbtb)]²⁺, [Ru(bpy)₂(5,5′-bbtb)]²⁺ and [Ru(bpy)₂(5-mbtb)]²⁺ [bpy is 2,2′-bipyridine, bbtb is bis(benzothiazol-2-yl)-2,2′-bipyridine, 5-mbtb is 5-(benzothiazol-2-yl),5′-methyl-2,2′-bipyridine]} have been prepared and compared with the complex [Ru(bpy)₂(4,4′-bbtb)]²⁺ reported previously. From the UV–vis spectral studies, substitution at the 5-position of the bpy causes the ligand-centred transitions to occur at considerably lower energy than for those with the functionality at the 4-position, while at the same time causing the emission to be effectively quenched. However, substitution at the 4-position causes the metal-to-ligand charge transfer to occur at lower energies. Fluorescent intercalator displacement studies indicate that the doubly substituted complexes displace ethidium bromide from a range of oligonucleotides, with the greater preference shown for bulge and hairpin sequences by the Λ enantiomer. Since the complexes only show small variation in the UV–vis spectra on the introduction of calf thymus DNA and a small increase in fluorescence they do not appear to be intercalators, but appear to associate within one of the grooves. All of the reported bisbenzothiazole complexes show reasonable cytotoxicity against a range of human cancer cell lines. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

New mono and dinuclear arene ruthenium chloro complexes containing ester substituents

The dinuclear arene ruthenium complexes [RuCl₂{C₆H₅(CH₂)₃OCO-p-C₆H₄-OC₈H₁₇}]₂ (1) and [RuCl₂{p-C₆H₄(CH₂COOCH₂CH₃)₂}]₂ (2) have been obtained by dehydrogenation of the corresponding cyclohexadiene derivative with ruthenium chloride hydrate. The single-crystal X-ray structure analysis of 2 shows the arene ligands to be involved in slipped-parallel π-π stacking interactions with neighbouring molecules, thus forming infinite chains along the b-axis. The dinuclear complexes 1 and 2 react with two equivalents of triphenylphosphine (PPh₃) to give in excellent yield the corresponding mononuclear phosphine complexes [RuCl₂{C₆H₅(CH₂)₃OCO-p-C₆H₄-OC₈H₁₇}(PPh₃)] (3) and [RuCl₂{p-C₆H₄(CH₂COOCH₂CH₃)₂}(PPh₃)] (4), respectively. The single-crystal X-ray structure analysis of 4 reveals the formation of a dimer through two C-H?Cl interactions in the solid state.