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Prospective anticancer metallodrugs should consider target-specific components in their design in order to overcome the limitations of the current chemotherapeutics. The inclusion of vitamins, which receptors are overexpressed in many cancer cell lines, has proven to be a valid strategy. Therefore, in this paper we report the synthesis and characterization of a set of new compounds [Ru(η 5 -C 5 H 5 )(P(C 6 H 4 R) 3 )(4,4'-R'-2,2'-bpy)] + (R = F and R' = H, 3 ; R = F and R' = biotin, 4 ; R = OCH 3 and R' = H, 5 ; R = OCH 3 and R' = biotin, 6 ), inspired by the exceptional good results recently obtained for the analogue bearing a triphenylphosphane ligand. The precursors for these syntheses were also described following modified literature procedures, [Ru(η 5 -C 5 H 5 )(P(C 6 H 4 R) 3 ) 2 Cl], where R is -F ( 1 ) or -OCH 3 ( 2 ). The structure of all compounds is fully supported by spectroscopic and analytical techniques and by X-ray diffraction studies for compounds 2 , 3 , and 5 . All cationic compounds are cytotoxic in the two breast cancer cell lines tested, MCF7 and MDA-MB-231, and much better than cisplatin under the same experimental conditions. The cytotoxicity of the biotinylated compounds seems to be related with the Ru uptake by the cells expressing biotin receptors, indicating a potential mediated uptake. Indeed, a biotin-avidin study confirmed that the attachment of biotin to the organometallic fragment still allows biotin recognition by the protein. Therefore, the biotinylated compounds might be potent anticancer drugs as they show cytotoxic effect in breast cancer cells at low dose dependent on the compounds' uptake, induce cell death by apoptosis and inhibit the colony formation of cancer cells causing also less severe side effects in zebrafish.

Ruthenium complexes hold a great potential in chemotherapy as an alternative to the classical platinum based drugs. The organometallic compounds studied in the present work were previously found to exhibit important anticancer activities. Here we have investigated the binding of three ruthenium compounds, namely [Ru(η(5)-C5H5)(PPh3)(bopy)][CF3SO3] 1, [Ru(η(5)-C5H5)(PPh3)(2-ap)][CF3SO3] 2, and [Ru(η(5)-C5H5)(PPh3)(isoquinpk)][CF3SO3] 3 (bopy=2-benzoylpyridine; 2-ap=2-acetylpyridine; isoquinpk=1-isoquinolinyl phenyl ketone) to fatty acid human serum albumin (HSA) and fatty acid-free human serum albumin (HSA(faf)) at physiological pH7.4. The influence of the substituent groups on the heteroaromatic (N,O) coordinated ligand was also studied by fluorescence spectroscopy to get information about this binding. The Stern-Volmer quenching constants (KSV) were calculated at 293, 298 and 310K, with the corresponding thermodynamic parameters ∆G, ∆H and ∆S as well. The fluorescence quenching method was used to determine the number of binding sites (n) and association constants (Ka) at the same temperatures. The binding site to HSA was confirmed by competitive studies of the ruthenium compounds with warfarin., (© 2013.)

In this work we explored the possibility of improving the selectivity of a cytotoxic Ru complex [RuCp(PPh3)(2,2′-bipy)][CF3SO3] (where Cp = η5-cyclopentadienyl) TM34 towards FGFR(+) breast cancer cells. Molecular dynamics (MD) simulations of TM34 in a phosphatidylcholine membrane model pinpointed the cyclopentadienyl group as a favorable derivatization position for the peptide conjugation approach. Three new Ru(II) complexes presenting a functionalized η5-cyclopentadienyl were synthesized, namely [Ru(η5-C5H4COOH)(2,2′-bipy)(PPh3)][CF3SO3] (TM281) and its precursors, [Ru(η5-C5H4COOCH2CH3)(η2-2,2′-bipy)(PPh3)][CF3SO3] (3) and [Ru(η5-C5H4COOCH2CH3)(PPh3)2Cl] (2). Complex TM281 was prepared by the hydrolysis of the ethyl ester group appended to the η5-cyclopentadienyl ligand of complex 3 with K2CO3 in water/acetonitrile, followed by mild protonation using an ion exchange resin. The newly synthesized complexes were fully characterized by NMR, FTIR and UV-vis spectroscopic techniques. Also, electrochemical studies were carried out by means of cyclic voltammetry in order to evaluate the stability of the compounds. Single crystal X-ray diffraction studies were carried out for compounds 3 and TM281 which crystallized in the monoclinic system, space group P21/n. The unprecedented synthesis and characterization of three half-sandwich ruthenium(II)-cyclopentadienyl peptide conjugates and their preliminary biological evaluation against human FGFR(+) and FGFR(−) breast cancer cells are also reported. [ABSTRACT FROM AUTHOR]

Four cationic ruthenium(II) complexes with the formula [Ru(η5 -C5H5)(PPh3)2]+, with L = 5-phenyl-1H-tetrazole (TzH) 1, imidazole (ImH) 2, benzo[1,2-b;4,3-b'] dithio-phen-2-carbonitrile (Bzt) 3, and [5-(2-thiophen-2-yl)-vinyl]-thiophene-2- carbonitrile] (Tvt) 4 were prepared and characterized in view to evaluate their potentialities as antitumor agents. Studies by Circular Dichroism indicated changes in the secondary structure of ct-DNA. Changes in the tertiary structure of pBR322 plasmid DNA were also observed in gel electrophoresis experiment and the images obtained by atomic force microscopy (AFM) suggest strong interaction with pBR322 plasmid DNA; the observed decreasing of the viscosity with time indicates that the complexes do not intercalate between DNA base pairs. Compounds 1, 2, and 3 showed much higher cytotoxicity than the cisplatin against human leukaemia cancer cells (HL-60 cells). [ABSTRACT FROM AUTHOR]

Abstract: A systematic series of η5-monocyclopentadienylruthenium(II) complexes with substituted thiophene nitrile ligands of general formula [Ru(η5-C5H5)(P_P)(NC{SC4H2} n NO2)][PF6] (P_P=dppe, (+)-diop; n =1–3) has been synthesized and characterized. Spectroscopic and electrochemical data were used in order to get an insight on the molecular nonlinear optical properties of these complexes when compared to those found for the reported thiophene iron(II) and p-benzonitrile or 1,2-di-(2-thienyl)-ethene derived iron(II)/ruthenium(II) related complexes. The compound [Ru(η5-C5H5)(dppe)(NC{SC4H2}2NO2)][PF6] was also characterized by X-ray diffraction. The solid state nonlinear optical properties of the chiral compounds were also evaluated by Kurtz powder technique with a Nd:YAG laser emitting at 1064nm. [Copyright &y& Elsevier]

Abstract: A new family of three-legged piano stool structured organometallic compounds containing the η5-cyclopentadienylruthenium(II)/iron(II) fragments {M(η5-C5H5) (DPPE)}+, {Ru(η5-C5H5)(PPh3)2}+ and {Ru(η5-C5H5)(TMEDA)}+ with coordinated thiophene based chromophores, namely 5-(2-thiophen-2-yl-vinyl)-thiophene-2-carbonitrile (L1) and 5-[2-(5-Nitro-thiophen-2-yl)-vinyl]-thiophene-2-carbonitrile (L2) has been synthesized and fully characterized by 1H, 13C, 31P NMR, IR and UV–Vis spectroscopies. Also, electrochemical studies were carried out by cyclic voltammetry and all experimental data are interpreted and compared with related compounds under the scope of NLO properties. Compounds [Ru(η5-C5H5)(DPPE)(NC(C4H2S)C(H)C(H)(C4H3S))][CF3SO3] (1′Ru) [Fe(η5-C5H5)(DPPE)(NC(C4H2S)C(H)C(H)(C4H3S))] [PF6] (1Fe) and [Ru(η5-C5H5)(DPPE)(NC(C4H2S)C(H)C(H)(C4H2S)NO2)][CF3SO3] (4′Ru) were also crystallographically characterized. [Copyright &y& Elsevier]

A novel family of Ru II -arene compounds with the general formula of [Ru II (η 6 -(2-phenoxyethanol))(L)Cl] + (L: 2,2′-bipyridine (bpy) ( 3 ), 4,4′-dimethyl-2,2′-bipyridine ( 4 ) and 4,4′-diyldimethanol-2,2′-bipyridine ( 5 )) was synthesized and characterized by standard spectroscopic and analytical methods. Complex 3 was further studied by single-crystal X-ray diffraction analysis, showing a pseudo octahedral geometry and strong π-π lateral stacking interactions in the crystal packing. Effect of the substituents on the electrochemical properties and on the aqueous solution stability was monitored by cyclic voltammetry, UV–Vis and 1 H NMR spectroscopy. Complexes 3 – 5 presented multiple irreversible redox processes according to their cyclic voltammograms recorded in acetonitrile, and their Ru II → Ru III oxidation peaks were found at ca. +1.6 V. Hydrolysis of the binuclear [Ru II (η 6 -(2-phenoxyethanol))(μ 2 -Cl)Cl] 2 precursor ( 1 ) resulted in binuclear hydroxido bridged species [(Ru II (η 6 -(2-phenoxyethanol))) 2 (μ-OH) 3 ] + and [(Ru II (η 6 -(2-phenoxyethanol))) 2 (μ-OH) 2 Z 2 ] (Z = H 2 O/Cl − ) in the presence of chloride ions in water. The hydrolytic behaviour of this Ru II precursor is similar to that of the analogous species [Ru II (η 6 - p -cymene)(μ 2 -Cl)Cl] 2 regarding the hydrolysis products and their stability constants. Formation of complexes 3 – 5 by reaction of the Ru II precursor with the (N,N) bidentate ligands was found to be relatively slow in aqueous solution. The complexation is complete already at pH 1 due to the formation of [Ru II (η 6 -(2-phenoxyethanol))(L)Z] complexes of significantly high stability in all cases, which are predominant species up to pH 6. However, besides the formation of the mixed hydroxido species [Ru II (η 6 -(2-phenoxyethanol))(L)(OH)] + at neutral and basic pH values, the slow oxidation of the Ru II centre takes place as well leading to the partial loss of the arene moiety. The rate of these processes depends on the pH and its maximum was found at pH 8–9. Additionally the chlorido/aqua co-ligand exchange processes of the [Ru II (η 6 -(2-phenoxyethanol))(L)Cl] + species were also monitored and only ∼5% of the chlorido ligand was found to be replaced by water in 0.1 M chloride ion containing aqueous solutions at pH 5. [ABSTRACT FROM AUTHOR]

Abstract: A novel water soluble organometallic compound, [RuCp(mTPPMSNa)(2,2′-bipy)][CF3SO3] (TM85, where Cp=η5-cyclopentadienyl, mTPPMS=diphenylphosphane-benzene-3-sulfonate and 2,2′-bipy=2,2′-bipyridine) is presented herein. Studies of interactions with relevant proteins were performed to understand the behavior and mode of action of this complex in the biological environment. Electrochemical and fluorescence studies showed that TM85 strongly binds to albumin. Studies carried out to study the formation of TM85 which adducts with ubiquitin and cytochrome c were performed by electrospray ionization mass spectrometry (ESI-MS). Antitumor activity was evaluated against a variety of human cancer cell lines, namely A2780, A2780cisR, MCF7, MDAMB231, HT29, PC3 and V79 non-tumorigenic cells and compared with the reference drug cisplatin. TM85 cytotoxic effect was reduced in the presence of endocytosis modulators at low temperatures, suggesting an energy-dependent mechanism consistent with endocytosis. Ultrastructural analysis by transmission electron microscopy (TEM) revealed that TM85 targets the endomembranar system disrupting the Golgi and also affects the mitochondria. Disruption of plasma membrane observed by flow cytometry could lead to cellular damage and cell death. On the whole, the biological activity evaluated herein combined with the water solubility property suggests that complex TM85 could be a promising anticancer agent. [Copyright &y& Elsevier]

Abstract: A series of new ruthenium(II) complexes of the general formula [Ru(η5-C5H5)(PP)(L)][PF6] (PP = DPPE or 2PPh3, L = 4-butoxybenzonitrile or N-(3-cyanophenyl)formamide) and the binuclear iron(II) complex [Fe(η5-C5H5)(PP)(μ-L)(PP)(η5-C5H5)Fe][PF6]2 (L = (E)-2-(3-(4-nitrophenyl)allylidene)malononitrile, that has been also newly synthesized) have been prepared and studied to evaluate their potential in the second harmonic generation property. All the new compounds were fully characterized by NMR, IR and UV–Vis spectroscopies and their electrochemistry behaviour was studied by cyclic voltammetry. Quadratic hyperpolarizabilities (β) of three of the complexes have been determined by hyper-Rayleigh scattering (HRS) measurements at fundamental wavelength of 1500 nm and the calculated static β 0 values are found to fall in the range 65–212 × 10−30 esu. Compound presenting β 0 = 212 × 10−30 esu has revealed to be 1.2 times more efficient than urea standard in the second harmonic generation (SHG) property, measured in the solid state by Kurtz powder technique, using a Nd:YAG laser (1064 nm). [Copyright &y& Elsevier]

Abstract: Anticancer activity of the new [Ru(η5-C5H5)(PPh3)(Me2bpy)][CF3SO3] (Me2bpy = 4,4′-dimethyl-2,2′-bipyridine) complex was evaluated in vitro against several human cancer cell lines, namely A2780, A2780CisR, HT29, MCF7, MDAMB231 and PC3. Remarkably, the IC50 values, placed in the nanomolar and sub-micromolar range, largely exceeded the activity of cisplatin. Binding to human serum albumin, either HSA (human serum albumin) or HSAfaf (fatty acid-free human serum albumin) does not affect the complex activity. Fluorescence studies revealed that the present ruthenium complex strongly quench the intrinsic fluorescence of albumin. Cell death by the [Ru(η5-C5H5)(PPh3)(Me2bpy)][CF3SO3] complex was reduced in the presence of endocytosis modulators and at low temperature, suggesting an energy-dependent mechanism consistent with endocytosis. On the whole, the biological activity evaluated herein suggests that the complex could be a promising anticancer agent. [Copyright &y& Elsevier]

Abstract: Ruthenium complexes hold great potential as alternatives to cisplatin in cancer chemotherapy. We present results on the in vitro antitumor activity of an organometallic ‘RuIICp’ complex, [RuIICp(bipy)(PPh3)][CF3SO3], designated as TM34 (PPh3 = triphenylphosphine; bipy = 2,2′-bipyridine), against a panel of human tumor cell lines with different responses to cisplatin treatment, namely ovarian (A2780/A2780cisR, cisplatin sensitive and resistant, respectively), breast (MCF7) and prostate (PC3) adenocarcinomas. TM34 is very active against all tumorigenic cell lines, its efficacy largely surpassing that of cisplatin (CisPt). The high activity of TM34 towards CisPt resistant cell lines possibly suggests a mechanism of action distinct from that of CisPt. The effect of TM34 on the activity of the enzyme poly(ADP-ribose) polymerase 1 (PARP-1) involved in DNA repair mechanisms and apoptotic pathways was also evaluated, and it was found to be a strong PARP-1 ruthenium inhibitor in the low micromolar range (IC50 =1.0±0.3μM). TM34 quickly binds to human serum albumin forming a 1:1 complex with a conditional stability constant (log K′~4.0), comparable to that of the RuIII complex in clinical trial KP1019. This indicates that TM34 can be efficiently transported by this protein, possibly being involved in its distribution and delivery if the complex is introduced in the blood stream. Albumin binding does not affect TM34 activity, yielding an adduct that maintains cytotoxic properties (against A2780 and A2780cisR cells). Altogether, the properties herein evaluated suggest that TM34 could be an anticancer agent of highly relevant therapeutic value. [Copyright &y& Elsevier]

Abstract: A new family of “RuCp” (Cp=η5-C5H5) derivatives with bidentate N,O and N,N′-heteroaromatic ligands revealed outstanding cytotoxic properties against several human cell lines namely, A2780, A2780CisR, HT29, MCF7, MDAMB231, and PC3. IC50 values were much lower than those found for cisplatin. Crystal structure of compound 4 was determined by X-ray diffraction studies. Density functional theory (DFT) calculations performed for compound 1 showed electronic flow from the ruthenium center to the coordinated bidentate ligand, in agreement with the electrochemical studies and the existence of a metal-to-ligand charge-transfer (MLCT) band evidenced by spectroscopic data. [Copyright &y& Elsevier]

Abstract: A series of ruthenium(II) complexes with the general formula [Ru(η5-C5H5) (η6-substituted arene)]+[PF6]− (substituted arene=2-phenylpyridine (1), dibenzosuberone (2) and toluene (3)), in combination with isopropyl alcohol were used for the polymerization of ɛ-caprolactone. The polymerization was found to be quantitative and controlled, with PDI in the range 1.1–1.3. By means of MALDI-ToF analyses, functionalization studies with d,l-lactide and NMR monitoring techniques, it has been found that the polymerization proceeds via a living Activated Monomer mechanism (AM) involving an η6–η4 change of the coordination mode of the arene. These experimental results were corroborated by DFT studies. The growth of several polymer chains per ruthenium atom highlights interesting potentialities for molecular weight control and catalyst economy. The stability of the ruthenium complexes allows their recovery at the end of the polymerization, which can be viewed as a further advance in a green chemistry frame. [Copyright &y& Elsevier]

Abstract: Four ruthenium(II) complexes with the formula [Ru(η5-C5H5)(PP)L][CF3SO3], being (PP=two triphenylphosphine molecules), L=1-benzylimidazole, 1 ; (PP=two triphenylphosphine molecules), L=2,2′bipyridine, 2 ; (PP=two triphenylphosphine molecules), L=4-Methylpyridine, 3 ; (PP=1,2-bis(diphenylphosphine)ethane), L=4-Methylpyridine, 4 , were prepared, in view to evaluate their potentialities as antitumor agents. The compounds were completely characterized by NMR spectroscopy and their crystal and molecular structures were determined by X-ray diffraction. Electrochemical studies were carried out giving for all the compounds quasi-reversible processes. The images obtained by atomic force microscopy (AFM) suggest interaction with pBR322 plasmid DNA. Measurements of the viscosity of solutions of free DNA and DNA incubated with different concentrations of the compounds confirmed this interaction. The cytotoxicity of compounds 1 2 3 4 was much higher than that of cisplatin against human leukemia cancer cells (HL-60 cells). IC50 values for all the compounds are in the range of submicromolar amounts. Apoptotic death percentage was also studied resulting similar than that of cisplatin. [ABSTRACT FROM AUTHOR]