Nitric oxide species as oxidising agents and adducts for soft scorpionates

Bis-(κ³-H,S,S-dihydrobis-(methimazolyl)borato)ruthenium(II), [Ru(Bm^Me)₂], has been prepared and tested as a nitric oxide scavenger using NO, NOBF₄ and NOBr. The products isolated show that, NO and NO⁺ are good one electron oxidising agents towards the ruthenium complexes but NO is not coordinated to the metal. The oxidised species, [Ru(Bm^Me)₂]BF₄ has been isolated and characterised. Reaction of “Ru(NO)Cl₃” with NaBm^Me results in the removal of the borohydride from the ligand and formation of [Ru(mtH)₃(mt)(NO)Cl]⁺.     

Cationic Ruthenium‐Cyclopentadienyl‐Diphosphine Complexes as Catalysts for the Allylation of Phenols with Allyl Alcohol; Relation between Structure and Catalytic Performance in O‐ vs. C‐Allylation

A new catalytic method has been investigated to obtain either O‐ or C‐allylated phenolic products using allyl alcohol or diallyl ether as the allyl donor. With the use of new cationic ruthenium(II) complexes as catalyst, both reactions can be performed with good selectivity. Active cationic Ru(II) complexes, having cyclopentadienyl and bidentate phosphine ligands are generated from the corresponding Ru(II) chloride complexes with a silver salt. The structures of three novel (diphosphine)Ru(II)CpCl catalyst precursor complexes are reported. It appears that the structure of the bidentate ligand has a major influence on catalytic activity as well as chemoselectivity. In addition, a strong cocatalytic effect of small amounts of acid is revealed. Model experiments are described that have been used to build a reaction network that explains the origin and evolution in time of both O‐allylated and C‐allylated phenolic products. Some mechanistic implications of the observed structure vs. performance relation of the [(diphosphine)RuCp]⁺ complexes and the cocatalytic role of added protons are discussed.     

Arene–RuII Complexes of Curcumin Exert Antitumor Activity via Proteasome Inhibition and Apoptosis Induction

Organometallic ruthenium(II) complexes of general formula [(η⁶‐arene)Ru(curcuminato)Cl], with arene being p‐iPrC₆H₄Me ( 1 ), C₆H₆ ( 2 ), and C₆Me₆ ( 3 ), were synthesized, characterized, and evaluated for their antitumor effects. Specifically, we explored their ability to regulate the proteasome, a validated pharmacological target in cancer treatment. Ruthenium complexes inhibited isolated proteasomes to various extents, with the biological activity of these complexes depending on the nature of the bound arene; in particular, [(η⁶‐arene)Ru(curcuminato)Cl] 2 suppressed proteasomal activities more potently than 1 , 3 , or free curcumin. Each complex also inhibited proteasomes in cultured colon cancer cells and consequently triggered apoptosis, with the [(η⁶‐benzene)Ru(curcuminato)Cl] complex 2 being the most active. The influence on the oxidative status of HCT116 cells and the DNA binding ability of the [(η⁶‐arene)Ru(curcuminato)Cl] complexes were studied. Complex 2 showed the highest antioxidant capacity; moreover, complexes 1 and 2 were shown to bind isolated DNA with higher affinity (up to threefold) than free curcumin. Collectively, our results demonstrate that the complexation of curcumin with ruthenium(II) is a promising starting point for the development of curcumin‐based anticancer drugs.     

Aldehyde-decorated 2,2′-bipyridine and 2,2′:6′,2″-terpyridine ruthenium(II) complexes: Convenient scaffolds for supramolecular chemistry

Two new aldehyde-decorated tpy and bpy-containing ruthenium(II) complexes, [Ru(1)(bpy)₂][PF₆]₂ and [Ru(1)(tpy)Cl][PF₆] in which 1 is 5,5′-bis(4-formylphenyl)-2,2′-bipyridine, have been prepared and fully characterized. The packing in both solid state structures involves extensive O_aldehyde···HC_pyridine contacts, but π-stacking interactions are important only between [Ru(1)(tpy)Cl]⁺ cations.     

Design, synthesis, and in vitro antifungal activity of 1-[(4-substituted-benzyl)methylamino]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ols

As part of our studies focused on the design of 1‐[((hetero)aryl‐ and piperidinylmethyl)amino]‐2‐phenyl‐3‐(1H‐1,2,4‐triazol‐1‐yl)propan‐2‐ols as antifungal agents, we report the development of new extended benzylamine derivatives substituted at the para position by sulfonamide or retrosulfonamide groups linked to alkyl or aryl chains. These molecules have broad‐spectrum antifungal activities not only against Candida spp., including fluconazole‐resistant strains, but also against a filamentous species (A. fumigatus). Concerning fluconazole resistance, selected compounds exhibit the capacity to overcome CDR and ERG11 gene upregulation and to maintain antifungal activity despite a recognized critical CYP51 substitution in C. albicans isolates. Synthesis, investigation of the mechanism of action by sterol analysis in a C. albicans strain, and structure–activity relationships (SARs) are reported.     

Arene ruthenium(II) p-chloroacetophenone phenylthiosemicarbazone complex mediated transfer hydrogenation of ketones

A series of cationic half-sandwich arene ruthenium(II) complexes of general formula [Ru(η⁶-p-cymene)Cl(L)]Cl have been synthesized from the reaction of [Ru(η⁶-p-cymene)Cl₂]₂ with thiosemicarbazone derivatives (L). Characterization of the complexes were accomplished by analytical and spectral (FT-IR, UV–Vis, ¹H NMR) methods. Single crystal structure determination reveals the presence of a pseudooctahedral three-legged piano stool conformation. All the complexes exhibit a quasi-reversible one electron reduction in the range from ?0.75 to ?0.85 V. Further, the catalytic activity of the titled complex has been investigated in the transfer hydrogenation of ketones in the presence of isopropanol/NaOH.     

Chemoselective Ruthenium‐Catalyzed Reduction of Acid Chlorides to Aldehydes with Dimethylphenylsilane

A variety of aromatic and alkyl acid chlorides can be selectively converted into aldehydes using dimethylphenyl silane (HSiMe₂Ph) as the reducing reagent in the presence of the cationic ruthenium catalyst {Cp[(i‐Pr)₃P]Ru(NCMe)₂}⁺ [PF₆]⁻. The reactions proceed under very mild conditions and are tolerant to many functional groups.     

Increased Lipophilicity of Halogenated Ruthenium(II) Polypyridyl Complexes Leads to Decreased Phototoxicity in vitro when Used as Photosensitizers for Photodynamic Therapy

In the fight against cancer, photodynamic therapy is generating great interest thanks to its ability to selectively kill cancer cells without harming healthy tissues. In this field, ruthenium(II) polypyridyl complexes, and more specifically, complexes with dipyrido[3,2-a:2’,3’-c]phenazine (dppz) as a ligand are of particular interest due to their DNA-binding and photocleaving properties. However, ruthenium(II) polypyridyl complexes can sometimes suffer from low lipophilicity, which hampers cellular internalisation through passive diffusion. In this study, four new [Ru(dppz-X₂)₃]²⁺ complexes (X=H, F, Cl, Br, I) were synthesized and their lipophilicity (logP), cytotoxicity and phototoxicity on cancerous and noncancerous cell lines were assessed. This study shows that, counterintuitively, the phototoxicity of these complexes decreases as their lipophilicity increases; this could be due solely to the atomic radius of the halogen substituents.     

Mitochondrial Fragmentation Is an Important Cellular Event Induced by Ruthenium(II) Polypyridyl Complexes in Osteosarcoma Cells

A series of ruthenium(II) polypyridyl complexes were synthesized and evaluated for their in vitro anticancer activities. The results showed that ruthenium polypyridyl complexes, especially [Ru(bpy)₂(p‐tFPIP)]²⁺ ( 2 a ; bpy=bipyridine, tFPIP=2‐(2‐trifluoromethane phenyl)imidazole[4,5‐f][1,10]phenanthroline), exhibited novel anticancer activity against human cancer cell lines, but with less toxicity to a human normal cell line. The results of flow cytometry and caspase activities analysis indicated that the 2 a ‐induced growth inhibition against MG‐63 osteosarcoma cells was mainly caused by mitochondria‐mediated apoptosis. DNA fragmentation and nuclear condensation as detected by TUNEL–DAPI co‐staining further confirmed 2 a ‐induced apoptotic cell death. Further, fluorescence imaging revealed that ruthenium(II) polypyridyl complexes could target mitochondria to induce mitochondrial fragmentation, accompanied by depletion of mitochondrial membrane potential. Taken together, these findings suggest a potential application of theses ruthenium(II) complexes in the treatment of cancers.     

Convenient General Asymmetric Synthesis of Roche Ester Derivatives through Catalytic Asymmetric Hydrogenation: Steric and Electronic Effects of Ligands

An efficient and concise asymmetric hydrogenation of acrylate esters promoted by the cationic ruthenium monohydride complex [Ru(H)(η⁶‐cot)SYNPHOS]⁺BF₄⁻ is reported. A full investigation of the effects of catalyst precursors, solvents, temperature, hydrogen pressure, substrates as well as steric and electronic properties of ligands was carried out. The corresponding valuable Roche ester derivatives were obtained in good to excellent isolated yields and high enantioselectivities under mild conditions. The robustness and practicability of this highly enantioselective hydrogenation was demonstrated by the synthesis of the 3‐hydroxy‐2‐methylpropanoic acid tert‐butyl ester on a multigram scale, resulting in excellent yield and ee up to 94%.     

Investigation of inducing apoptosis in human lung cancer A549 cells and related mechanism of a ruthenium(II) polypyridyl complex

Two Ru(II) polypyridyl complexes [Ru(bpy)₂(pztp)]^2 + (Ru1) and [Ru(bpy)₂(pytp)]^2 + (Ru2) were synthesized and characterized. Our data demonstrated that Ru2 displayed relatively higher cytotoxic activity against lung cancer A549 cells and had higher selectivity between tumor and normal cells in comparison with cisplatin. Studies on the molecular mechanism revealed that Ru2 caused cell cycle arrest at G2/M in A549 cells and induced apoptosis through a ROS-mediated mitochondrial dysfunction pathway. The further studies by comet assay at single cell level indicated that DNA damage in A549 cells was triggered by Ru2, following with the up-regulation of phosphorylated ATM (Ser1984), Histone H2A.X (Ser139) and p53 (Ser15). Western blot analysis suggested that MAPKs signaling pathways, especially ERK, were involved in Ru2-induced apoptosis. Moreover, both DNA damage and MAPKs signaling pathways were regulated by the level of ROS. To our knowledge, this is the first report of the ruthenium (II) polypyridyl complex which induces apoptosis partly through the activation of ERK.     

Exploring the Molecular Mechanisms Underlying the in vitro Anticancer Effects of Multitarget-Directed Hydrazone Ruthenium(II)–Arene Complexes

The molecular targets and the modes of action behind the cytotoxicity of two structurally established N,O- or N,N-hydrazone ruthenium(II)–arene complexes were explored in human breast adenocarcinoma cells (MCF-7) and paralleled in non-cancerous and cisplatin-resistant counterparts (MCF-10A and MCF-7CR respectively). Both complexes, [Ru(hmb)(L1)Cl] ( 1 , L1=4-((2-(2,4-dinitrophenyl)hydrazono)(phenyl)methyl)-3-methyl-1-phenyl-1H-pyrazol-5-olate) and [Ru(cym)(L2)Cl] ( 2 , L2=1-((3-methyl-5-oxo-1-phenyl-1H-pyrazol-4(5H)-ylidene)(phenyl)methyl)-2-(pyridin-2-yl)hydrazin-1-ide), reversibly interact with moderate-to-high affinity with a number of molecular targets in cell-free assays, namely serum albumin, DNA, the 20S proteasome and hydroxymethylglutaryl-CoA reductase. Most interestingly, only 2 readily crosses the cell membrane and preserves its binding/modulatory ability toward the targets of interest upon rapid cellular internalization. The resulting action at multiple levels of the cancer cascade is likely the cause for the selective sensitization of tumour cells to p27-mediated apoptotic death, and for the ability of 2 to overcome the drug resistance problem.     

Electropolymerization and characterization of terpyridinyl iron (II) and ruthenium (II) complexes

Electroactive 2,2′: 6,2″-terpyridinyl ligands ( 3, 5, 6 ) and their iron(II) ( 7a–9a ) and ruthenium(II) complexes ( 7b–9b ) were synthesized. Bis[3-(aminophenyl)-2,2′ :6,2″-terpyridinyl]metal(II) complexes ( 7a, 7b ) and bis[2-(hydroxyphenyl)-2,2′ :6,2″-terpyridinyl]metal(II) complexes ( 8a, 8b ) were electropolymerized on to the surface of Pt or In-SnO₂ (ITO) electrodes in acetonitrile containing Bu₄NCIO₄ by scanning the potential between O and + 1.6V (for 7a and 7b ), and ?0.8 and +1.6V (for 8a and 8b ) versus saturated calomel electrode. The electrodes obtained by electropolymerization exhibited reversible electrochromism based on Fe(II)/Fe(III) or Ru(II)/Ru(III) redox couple. Photoresponses to visible light were found in the modified electrode obtained by electropolymerization of ruthenium complex 7b in an aqueous LiClO₄ solution containing methylviologen (cation MV²⁺) under an O₂ atmosphere. The mechanism for the photoresponded cathodic current was explained in terms of an excitation of bis(terpyridinyl)ruthenium(II) complex [Ru(terpy)²₂⁺] by visible light, an electron transfer from the excited state [Ru(terpy)^2+*₂] to MV²⁺, reduction of Ru(terpy)³⁺₂ at an electrode, and oxidation of MV^+* with O₂.     

Organometallic ruthenium complexes with thiosemicarbazone ligands: Synthesis,structure and cytotoxicity of [(η6-p-cymene)Ru(NS)Cl]+ (NS = 9-anthraldehyde thiosemicarbazones)

A series of half-sandwich arene ruthenium complexes containing bidentate thiosemicarbazone ligands have been synthesized and their biological activity investigated. The compounds have the general formula [(6-p-cymene)Ru(R-ATSC)Cl]X (ATSC = 9-anthraldehyde thiosemicarbazone and R = H, CH₃ and C₆H₅). The crystal structure of [(6-p-cymene) Ru(MeATSC)Cl]Cl have been determined and represents the first structurally characterized arene–ruthenium half-sandwich complex with a thiosemicarbazone ligand. The complexes show good cytotoxic profiles against MCF-7 and MDA-MB-231 (breast adenocarcinoma) as well as HCT 116 and HT-29 (colorectal carcinoma) cell lines.     

Direct Amide Synthesis from Alcohols and Amines by Phosphine‐Free Ruthenium Catalyst Systems

Amides are synthesized directly from alcohols and amines in high yields using an in situ generated catalyst from easily available ruthenium complexes such as the (p‐cymene)ruthenium dichloride dimer, [Ru(p‐cymeme)Cl₂]₂, or the (benzene)ruthenium dichloride dimer, [Ru(benzene)Cl₂]₂, an N‐heterocyclic carbene (NHC) ligand, and a nitrogen containing L‐type ligand such as acetonitrile. The phosphine‐free catalyst systems showed improved or comparable activity compared to previous phosphine‐based catalytic systems. The in situ generated catalyst from [Ru(benzene)Cl₂]₂, an NHC ligand, and acetonitrile showed excellent activity toward reactions with cyclic secondary amines such as piperidine and morpholine.     

Homonuclear tris-dithiocarbamato ruthenium(III) complexes as single-molecule precursors for the synthesis of ruthenium(III) sulfide nanoparticles

Tris(N-phenyldithiocarbamato) ruthenium(III) complexes, [Ru(L¹)₃] (1); tris(N-(4-methylphenyl)dithiocarbamato)) ruthenium(III), [Ru(L²)₃] (2); and tris(N-(4-methoxyphenyl)dithiocarbamato)) ruthenium(III), [Ru(L³)₃] (3) were synthesized and characterized by elemental analysis, thermogravimetric analysis, FTIR, UV–VIS and NMR spectroscopy. TGA analyses show major degradation of all complexes in the range 120–350°C, leading to the formation of residual weight corresponding to ruthenium (III) sulfides. The ¹H-NMR spectra of the ligands and complexes are in agreement with the proposed structures. FTIR studies confirmed that the ligands coordinate the Ru³⁺ ion in a bidentate chelating mode. The complexes were thermolysed at 180°C to prepare hexadecylamine-capped Ru₂S₃ nanoparticles. Powder X-ray diffraction patterns revealed the formation of hexagonal-phase Ru₂S₃ nanoparticles with average crystallite sizes ranging from 8.3 to 9.5?nm. TEM images showed the crystalline clusters with shapes ranging from square to hexagonal, while SEM images elucidated that the particles were agglomerated. Energy-dispersive X-ray spectra confirmed the presents of Ru₂S₃ nanoparticles.     

Investigation of antitumor mechanism of the chiral ruthenium complex Λ-[Ru(phen)2p-MOPIP]2 + in human gastric cancer MGC-803 cells

There has been a vast increase in telomerase inhibition research over the past several years, which was demonstrated as an attractive anti-tumor strategy. Our previous study found that the chiral ruthenium complex, [Ru(phen)₂p-MOPIP]^2 + (Phen = 1,10-phenanthroline, p-MOPIP = 2-(4-methoxyphenyl)-imidazo[4,5f] Markman (2003), Janaratne et al. (2007) phenanthroline) (dl-OMe) and its enantiomer Δ/Λ-[Ru(phen)₂p-MOPIP]^2 + (Δ/Λ-OMe) could bind to and stabilize G-quadruplex DNA structure in telomeres, and inhibit telomerase activity. In this study, cytotoxic activity of these Ru complexes was studied by MTT assay. The anti-tumor mechanisms of Λ-OMe were investigated using TRAP assay, Western blot analysis, flow cytometry, Hochest staining, and RT-PCR. Results showed that among several Ru complexes, Λ-OMe demonstrated a better anti-tumor activity against gastric cancer cell line (MGC-803), and had less effect on normal gastric epithelial cell. Λ-OMe effectively inhibited the cell growth by inhibiting cellular telomerase activity, triggering cell cycle arrest, and inducing apoptosis of MGC-803 cells. The inhibitory effect on telomerase activity was associated with the altered expression of telomere-related proteins TRF1 and TRF2. Cell-cycle arrest was associated with increased levels of P21 mRNA. Apoptosis of MGC-803 cell was triggered by modulating the expression of apoptosis-related genes Bax, Bcl-2, and caspase-3. Overall, the results suggest that Λ-OMe may be a new promising agent for human gastric cancer therapy.     

Synthesis,characterization and catalytic activities of ruthenium complexes containing triphenylphosphine/triphenylarsine and tetradentate Schiff bases

Ruthenium(II) complexes of the type [Ru(CO)(B)(L)] (B=AsPh₃, pyridine, piperidine or morpholine; L=dianion of tetradentate Schiff bases) have been synthesized and characterized by physico-chemical methods. These complexes are found to be effective catalysts in the oxidation of primary and secondary alcohols using N-methylmorpholine-N-oxide as oxidant. The catalytic activity of these triphenylarsine complexes have been compared with that of triphenylphosphine complexes and with similar ruthenium(III) complexes. The formation of high valent Ruⁿ⁺²O species as catalytic intermediate is proposed for the catalytic processes.     

Structural Optimization of Berberine as a Synergist to Restore Antifungal Activity of Fluconazole against Drug‐Resistant Candida albicans

We have conducted systematic structural modification, deconstruction, and reconstruction of the berberine core with the aim of lowering its cytotoxicity, investigating its pharmacophore, and ultimately, seeking novel synergistic agents to restore the effectiveness of fluconazole against fluconazole‐resistant Candida albicans. A structure–activity relationship study of 95 analogues led us to identify the novel scaffold of N‐(2‐(benzo[d][1,3]dioxol‐5‐yl)ethyl)‐2‐(substituted phenyl)acetamides 7 a – l , which exhibited remarkable levels of in vitro synergistic antifungal activity. Compound 7 d (N‐(2‐(benzo[d][1,3]dioxol‐5‐yl)ethyl)‐2‐(2‐fluorophenyl)acetamide) significantly decreased the MIC₈₀ values of fluconazole from 128.0 μg mL^?1 to 0.5 μg mL^?1 against fluconazole‐resistant C. albicans and exhibited much lower levels of cytotoxicity than berberine toward human umbilical vein endothelial cells.     

Synthesis of Sunflower Oil Based Bimetallic Polymer and Its Antifungal Studies

Bimetallic oil based polymer was prepared by condensation polymerization reaction. FTIR and ¹H NMR have been used to support structure of the polymers. Thermal behavior of the polymer was established by thermogravimetry/differential thermal analysis (TG/DTA). The polymers were examined for their antifungal properties by performing minimum inhibitory concentration assessment, growth curve studies, and H⁺ extrusion studies using Candida species as model organisms. Growth and sensitivity of the organisms were significantly effected by test polymers at different concentrations. Insight studies to mechanism suggested that the synthesized polymers exerts their antifungal activity by targeting H⁺-ATPase mediated H⁺-pumping, inhibition of H⁺-ATPase leads to intracellular acidification and cell death.