The nature of Ru-NO bonds in ruthenium tetraazamacrocycle nitrosyl complexes-a computational study

Ruthenium complexes including nitrosyl or nitrite complexes are particularly interesting because they can not only scavenge but also release nitric oxide in a controlled manner, regulating the NO-level in vivo. The judicious choice of ligands attached to the [RuNO] core has been shown to be a suitable strategy to modulate NO reactivity in these complexes. In order to understand the influence of different equatorial ligands on the electronic structure of the Ru-NO chemical bonding, and thus on the reactivity of the coordinated NO, we propose an investigation of the nature of the Ru-NO chemical bond by means of energy decomposition analysis (EDA), considering tetraamine and tetraazamacrocycles as equatorial ligands, prior to and after the reduction of the {RuNO}(6) moiety by one electron. This investigation provides a deep insight into the Ru-NO bonding situation, which is fundamental in designing new ruthenium nitrosyl complexes with potential biological applications.

The In Vitro and In Vivo Antitumour Activities of Nitrosyl Ruthenium Amine Complexes

Ruthenium compounds of the type trans-[Ru(NO)(NH3)(4)(L)] X-3, L = N-heterocyclic ligands, P(OEt)(3), SO32-, X BF4- or PF6-, or [Ru(NO)Hedta], were tested for antitumour activity in vitro against murine melanoma and human tumour cells. The ruthenium complexes induced DNA fragmentation and morphological alterations suggestive of necrotic tumour cell death. The calculated IC50 values were lower than 100 mu M. Complexes for which L = isn or imN were partially effective in vivo in a syngeneic model of murine melanoma B16F10, increasing animal survival. In addition, the same ruthenium complexes effectively inhibited angiogenesis of HUVEC cells in vitro. The results suggest that these nitrosyl complexes are a promising platform to be explored for the development of novel antitumour agents.

Cytotoxic peptide conjugates of dinuclear arene ruthenium trithiolato complexes

In order to improve the water-solubility of dinuclear thiolato-bridged arene ruthenium complexes, a new series was synthesized by conjugating octaarginine, octalysine, and cyclo[Lys-Arg-Gly-Asp-D-Phe] using chloroacetyl thioether (ClAc) ligation, resulting in cytotoxic conjugates against A2780 human ovarian cancer cells (IC50 = 2–8 μM) and against the cisplatin resistant line A2780cisR (IC50 = 7–15 μM). These metal complexes represent, to the best of our knowledge, the most cytotoxic ruthenium bioconjugates reported so far.

Tuning the in vitro cell cytotoxicity of dinuclear arene ruthenium trithiolato complexes: Influence of the arene ligand

A new series of cationic dinuclear arene ruthenium complexes bridged by three thiophenolato ligands, [(η6-arene)2Ru2(μ2-SR)3]+ with arene = indane, R = met: 1 (met = 4-methylphenyl); R = mco: 4 (mco = 4-methylcoumarin-7-yl); arene = biphenyl, R = met: 2; R = mco: 5; arene = 1,2,3,4-tetrahydronaphthalene, R = met: 3; R = mco: 6, have been prepared from the reaction of the neutral precursor [(η6-arene)Ru(μ2-Cl)Cl]2 and the corresponding thiophenol RSH. All cationic complexes have been isolated as chloride salts and fully characterized by spectroscopic and analytical methods. The molecular structure of 1, solved by X-ray structure analysis of a single crystal of the chloride salt, shows the two ruthenium atoms adopting a pseudo-octahedral geometry without metal–metal bond in accordance with the noble gas rule. All complexes are stable in H2O at 37 °C, but only 1 remains soluble in a 100 mM aqueous NaCl solution, while significant percentages (30–60 %) of 2–6 precipitate as chloride salts under these conditions. The 4-methylphenylthiolato complexes (R = met) are highly cytotoxic towards human ovarian cancer cells, the IC50 values being in the sub-micromolar range, while the 4-methylcoumarin-7-yl thiolato complexes (R = mco) are only slightly cytotoxic. Complexes 1 and 3 show the highest in vitro anticancer activity with IC50 values inferior to 0.06 μM for the A2780 cell line. The results demonstrate that the arene ligand is an important parameter that should be more systematically evaluated when designing new half-sandwich organometallic complexes.

Hydrolytic behaviour of mono-and dithiolato-bridged dinuclear arene ruthenium complexes and their interactions with biological ligands

The hydrolysis and the reactivity of two dinuclear p-cymene ruthenium monothiolato complexes, [(η6-p-MeC6H4Pri)2Ru2Cl2(µ-Cl)(µ-S-m-9-B10C2H11)] (1) and [(η6-p-MeC6H4Pri)2¬Ru2Cl2(µ-Cl)¬(µ-S¬CH2-p-C6H4-NO2)] (2), and of two dinuclear p-cymene ruthenium dithiolato complexes, [(η6-p-MeC6H4Pri)2Ru2(µ-SCH2CH2Ph)2Cl2] (3) and [(η6-p-Me¬C6H4¬Pri)2¬Ru2(S¬CH2¬C6H4-p-O¬Me)2¬Cl2] (4) towards amino acids, nucleotides, and a single-stranded DNA dodecamer were studied using NMR and mass spectrometry. In aqueous solutions at 37 °C, the monothiolato com¬plexes 1 and 2 undergo rapid hydrolysis, irrespective of the pH value, the predominant species in D2O/acetone-d6 solution at equilibrium being the neutral hydroxo complexes [(η6-p-Me¬C6H4¬Pri)2Ru2(OD)2(µ-OD)(µ-SR)]. The dithiolato complexes 3 and 4 are stable in water under acidic conditions, but undergo slow hydrolysis under neutral and basic conditions. In both cases, the cationic hydroxo complexes [(η6-p-MeC6H4Pri)2Ru2(µ-SR)2¬(OD)¬(CD3CN)]+ are the only spe¬cies observed in D2O/CD3CN at equilibrium. Surprisingly, no adducts are observed upon addition of an excess of L-methionine or L-histidine to the aqueous solutions of the complexes. Upon addition of an excess of L-cysteine, on the other hand, 1 and 2 form the unusual cationic trithiolato complexes [(η6-p-MeC6H4Pri)2¬Ru2{µ-SCH2CH(NH2)COOH}2(µ-SR)]+ containing two bridging cysteinato li¬gands, while 3 and 4 yield cationic trithiolato complexes [(η6-p-MeC6H4Pri)2Ru2[µ-SCH2CH¬(NH2)COOH](µ-SR)2]+ containing one bridging cysteinato ligand. A representative of catio¬nic trithiolato complexes containing a cysteinato bridge of this type, [(η6-p-MeC6H4Pri)2¬Ru2[µ-S¬CH2CH(NH2)COOH](µ-SCH2-p-C6H4-But)2]+ (6) could be synthesised from the di¬thiolato complex [(η6-p-Me¬C6H4¬Pri)2-Ru2(S¬CH2¬C6H4-p-But)2Cl2] (5), isolated as the tetra¬fluo¬ro¬borate salt and fully characterised. Moreover, the mono- and dithiolato complexes 1 - 4 are inert toward nucleotides and DNA, suggesting that DNA is not a target of cytotoxic thiolato-bridged arene ruthenium complexes. In contrast to the trithiolato complexes, monothiolato and dithio¬lato complexes hydrolyse and react with L-cysteine. These results may have im¬portant implications for the mode of action of thiolato-bridged dinuclear arene ruthenium drug candidates, and suggest that their modes of action are different to those of other arene ruthenium complexes.