Search

The pharmacological properties of any drug are related to its ability to interact with macromolecular blood components. The interaction of human serum albumin (HSA) and apotransferrin (ATf) with six RuII complexes containing ketoconazole (KTZ), which we have previously reported to be active against Leishmania major and Trypanosoma cruzi, has been investigated by monitoring the tryptophan fluorescence intensity of each protein upon incremental addition of the complexes. All the Ru-KTZ derivatives, namely cis-fac-[RuIICl2(DMSO)3(KTZ)] (1), cis-[RuIICl2(bipy)(DMSO)(KTZ)] (2), [RuII(η6-p-cymene)Cl2(KTZ)] (3), [RuII(η6-p-cymene)(en)(KTZ)][BF4]2 (4), [RuII(η6-p-cymene)(bipy)(KTZ)][BF4]2 (5), and [RuII(η6-p-cymene)(acac)(KTZ)][BF4] (6) are able to quench the intrinsic fluorescence of HSA and ATf at 27 ºC. Analysis of the spectroscopic data using Stern-Volmer plots indicates that in both cases the quenching takes place principally through a static mechanism involving the formation of Ru complex-protein adducts; further analysis of the fluorescence data allowed the estimation of apparent association constants and the number of binding sites for each protein and each compound. The results indicate that both HSA and ATf are possible effective transporters for Ru-KTZ antiparasitic drugs.

A series of organometallic ruthenium(II) complexes containing iminophosphorane ligands have been synthesized and characterized. Cationic compounds with chloride as counterion are soluble in water (70–100 mg/mL). Most compounds (especially highly water-soluble 2) are more cytotoxic to a number of human cancer cell lines than cisplatin. Initial mechanistic studies indicate that the cell death type for these compounds is mainly through canonical or caspase-dependent apoptosis, nondependent on p53, and that the compounds do not interact with DNA or inhibit protease cathepsin B. In vivo experiments of 2 on MDA-MB-231 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (shrinkage) of 56% after 28 days of treatment (14 doses of 5 mg/kg every other day) with low systemic toxicity. Pharmacokinetic studies showed a quick absorption of 2 in plasma with preferential accumulation in the breast tumor tissues when compared to kidney and liver, which may explain its high efficacy in vivo.

A new catalyst composed of Rh nanoparticles supported on magnesium oxide was prepared by mild hydrogenation of a pre-adsorbed organometallic precursor, and characterized by TEM, XRD, XPS, and hydrogen chemisorption measurements. The catalyst contains 5 wt% Rh as ∼50 nm metallic nanoparticles uniformly distributed on the surface of MgO, in turn made up of smaller (∼2 nm) particles. This material is an efficient catalyst for the hydrogenation of arenes, N-heteroaromatic compounds, and alkenes under moderate reaction conditions. Analogous catalysts containing Rh nanoparticles on other rare earth oxide supports display similar catalytic properties and the hydrogenation activity correlates with the basicity of the support in the case of N-heterocycles, following the trend Rh/MgO

The development of catalysts capable of promoting hydrogenation of aromatics while being resistant to poisoning by nitrogen- and sulfur-containing species is of much interest in connection with hydrotreating of fossil fuels. We report a catalyst composed of ruthenium nanoparticles supported on magnesia, designed to promote heterolytic hydrogen splitting and surface ionic hydrogenation pathways. The catalyst, prepared through a one-pot procedure, promotes the hydrogenation of mono- and poly-cyclic arenes, as well as N- and S-heteroaromatics representative of fossil fuels components. Of particular significance are the superior activity and wider substrate scope of the catalyst, in relation to other known supported noble metals, and the excellent recyclability and long catalyst lifetime. Based on our experimental data, a dual-site catalyst structure and an associated dual-pathway mechanism are proposed, which may have interesting implications for the development of new poison-tolerant noble metal catalytic systems.

A new hybrid compound 5 containing a ruthenocene, a 4-aminoquinoline, and a 1,2,4-trioxane within a single molecular structure has been synthesized and evaluated for antimalarial potential. In order to ascertain the role of each component of hybrid 5, its antimalarial activity has been measured against chloroquine-resistant and chloroquine-sensitive strains of Plasmodium falciparum in comparison with those of chloroquine, artemisinin, a ruthenocene-trioxane compound 9 not containing an aminoquinoline, the precursor trioxane ketone 4, and a trioxane dimer 10. Hybrid 5 displays high antimalarial activity, in the mid to low nanomolar IC50 range, and low cytotoxicity toward healthy mammalian cells, which translates into good selectivity indexes. The potency of 5 is consistently higher than those of chloroquine, the parent metal-free trioxane, and compound 9, the structural intermediate featuring a ruthenocene moiety bound to the trioxane but lacking the aminoquinoline. These results validate our hypothesis that it is the combination of the aminoquinoline, the ruthenocenyl moiety, and the trioxane in a single molecule that provides the enhanced antiplasmodial activity, and highlight the concept of hybrid compounds as a strategy that deserves further attention.

In previous studies we reported a novel series of organometallic compounds, RuII complexed with clotrimazole, displaying potent trypanosomatid activity with unnoticeable toxicity toward normal mammalian cells. In view of the promising activity of Ru-clotrimazole complexes against Leishmania major (L. major), the present work sought to investigate the anti-leishmanial activity of the AM162 complex in the murine model of cutaneous leishmaniasis. In addition, to facilitate the design of new therapeutic strategies against this disease, we investigated the mode of action of two Ru-clotrimazole complexes in L. major promastigotes. Overall, we demonstrate that AM162 significantly reduced the lesion size in mice exposed to L. major infection. In addition, Ru-clotrimazole compounds are able to induce a mitochondrial dependent apoptotic-like death in the extracellular form of the parasite based on labeling of DNA fragments, mitochondrial depolarization, cell cycle alteration profile and plasma membrane phospholipid externalization. Our findings reveal a promising efficacy of the Ru-clotrimazole AM162 complex for the treatment of cutaneous leishmaniasis, as well as pro-apoptotic activity and thus guarantees further evaluation in pre-clinical studies.

The complexes [Rh(PhBP3)(cod)] (1) and [{Ru(PhBP3)(μ-Cl)}2] (8), containing the tripodal phosphanoborate ligand [PhB(CH2PPh2)3]−, are efficient catalysts for the selective hydrogenation of cinnamaldehyde to the corresponding allyl alcohol. Complex 8 is one of the most efficient catalysts reported to date for this reaction, in terms of activity (TOF 527 h−1) and selectivity (≥97%) under mild reaction conditions (6.8 atm H2, 75 °C). The rhodium system also displays good catalytic features in the hydrogenation of cinnamaldehyde (TOF 219 h−1), particularly a high selectivity (81%) for this metal in the reduction of the C═O bond. Crotonaldehyde can also be reduced, although the selectivities are not as high as for cinnamaldehyde; 2-cyclohexenone is rapidly and specifically reduced to cyclohexanone by both catalysts. The ruthenium catalyst 8 operates via heterolytic activation of hydrogen, involving monohydride intermediates and possibly ionic hydrogen transfer, while the rhodium complex 1 involves oxidative addition of dihydrogen to form dihydride intermediates and follows a substrate route. Indeed, complex 1 reacts with hydrogen in acetonitrile to give the dihydride complex [Rh(PhBP3)(H)2(NCMe)] (3), while protonation of one of the phosphane arms of the ligand occurs on treatment of complex 1 with HBF4 to give the cationic species [Rh{PhB(PH)P2}(cod)]BF4. The hydride ligands in 3 are easily removed as molecular hydrogen by reaction with CO under atmospheric pressure to give the rhodium(I) complex [Rh(PhBP3)(CO)2]. In this reaction, the replacement of acetonitrile by CO takes place previously to the elimination of hydrogen, which indicates that substrates can coordinate to the metal in 3 by replacement of the labile acetonitrile ligand. Under an atmosphere of argon, complex 3 reacts with chloroform to give an equimolecular mixture of the cis and trans isomers of [{Rh(PhBP3)(H)(μ-Cl)}2] and, eventually, complex [Rh(PhBP3)Cl2] in one day., We thank The Petroleum Research Fund of the American Chemical Society (Grant #47472-AC3 to R.A.S.-D.), the MICINN/FEDER (Project CTQ2008-03860), and Gobierno de Aragón (ARMOIN, Group E70) for generous financial support. S.J. thanks GA for a fellowship.

We have measured water/n-octanol partition coefficients, pK(a) values, heme binding constants, and heme aggregation inhibition activity of a series of ruthenium-pi-arene-chloroquine (CQ) complexes recently reported to be active against CQ-resistant strains of Plasmodium falciparum. Measurements of heme aggregation inhibition activity of the metal complexes near water/n-octanol interfaces qualitatively predict their superior antiplasmodial action against resistant parasites, in relation to CQ; we conclude that this modified method may be a better predictor of antimalarial potency than standard tests in aqueous acidic buffer. Some interesting tendencies emerge from our data, indicating that the antiplasmodial activity is related to a balance of effects associated with the lipophilicity, basicity, and structural details of the compounds studied.

A new family of rhodium and iridium compounds with the bulky tris(ortho-methoxyphenyl) phosphine (PAn3) was synthesized and characterized by NMR methods. The X-ray crystal structures of RhCl(PAn3)(COD) (1) and Ir[(PBz3)(PAn3)(COD)]PF6 (4) have been determined. A stabilizing agostic interaction has been crystallographically observed in both compounds, due to the steric hindrance of the ortho-substituted phosphine ligand and its presence has been associated to the fluxional behavior shown by the complexes on the NMR timescale in solution. Iridium complexes containing PBz3 and/or PAn3 have been evaluated as catalyst precursors for the hydrogenation of trans-cinnamaldehyde (CNA), and their activities have also been compared to those of other iridium complexes containing bulky phosphine ligands, such as PTol3 (tris-ortho-tolyl-phosphine). The catalytic experiments show that irrespectively of the phosphine combination, all of the evaluated catalysts prevalently hydrogenate the C C moiety. However, the product selectivity can be tuned by changing either the substrate/catalyst ratio or the phosphine ligand at the metal center. The catalyst with PAn3 proved to be more efficient and also gave higher yields of the enol product, indicating that stereoelectronic effects are responsible for the changes in selectivity.

The new RuII chloroquine complexes [Ru(η6-arene)(CQ)Cl2] (CQ = chloroquine; arene = p-cymene 1, benzene 2), [Ru(η6-p-cymene)(CQ)(H2O)2][BF4]2 (3), [Ru(η6-p-cymene)(CQ)(en)][PF6]2 (en = ethylenediamine) (4), and [Ru(η6-p-cymene)(η6-CQDP)][BF4]2 (5, CQDP = chloroquine diphosphate) have been synthesized and characterized by use of a combination of NMR and FTIR spectroscopy with DFT calculations. Each complex is formed as a single coordination isomer: in compounds 1–4 chloroquine binds to ruthenium in the η1-N mode through the quinoline nitrogen atom whereas in complex 5 an unprecedented η6 bonding through the carbocyclic ring is observed. Compounds 1, 2, 3, and 5 are active against CQ-resistant (Dd2, K1 and W2) and CQ-sensitive (FcB1, PFB, F32 and 3D7) malaria parasites (Plasmodium falciparum); importantly, the potency of these complexes against resistant parasites is consistently higher than that of the standard drug chloroquine diphosphate. Complexes 1 and 5 also inhibit the growth of colon cancer cells, independently of the p53 status and of liposarcoma tumor cell lines with the latter showing increased sensitivity, especially to complex 1 (IC50 8 µM); this is significant because this type of tumor does not respond to currently employed chemotherapies.

The mechanism of antimalarial action of the ruthenium-chloroquine complex [RuCl(2)(CQ)](2) (1), previously shown by us to be active in vitro against CQ-resistant strains of Plasmodium falciparum and in vivo against P. berghei, has been investigated. The complex is rapidly hydrolyzed in aqueous solution to [RuCl(OH(2))(3)(CQ)](2)[Cl](2), which is probably the active species. This compound binds to hematin in solution and inhibits aggregation to beta-hematin at pH approximately 5 to a slightly lower extent than chloroquine diphosphate; more importantly, the heme aggregation inhibition activity of complex 1 is significantly higher than that of CQ when measured at the interface of n-octanol-aqueous acetate buffer mixtures under acidic conditions modeling the food vacuole of the parasite. Partition coefficient measurements confirmed that complex 1 is considerably more lipophilic than CQ in n-octanol-water mixtures at pH approximately 5. This suggests that the principal target of complex 1 is the heme aggregation process, which has recently been reported to be fast and spontaneous at or near water-lipid interfaces. The enhanced antimalarial activity of complex 1 is thus probably due to a higher effective concentration of the drug at or near the interface compared with that of CQ, which accumulates strongly in the aqueous regions of the vacuole under those conditions. Furthermore, the activity of complex 1 against CQ-resistant strains of P. falciparum is probably related to its greater lipophilicity, in line with previous reports indicating a lowered ability of the mutated transmembrane transporter PfCRT to promote the efflux of highly lipophilic drugs. The metal complex also interacts with DNA by intercalation, to a comparable extent and in a similar manner to uncomplexed CQ and therefore DNA binding does not appear to be an important part of the mechanism of antimalarial action in this case.

A series of catalysts composed of ruthenium nanoparticles immobilized on poly(4-vinylpyridine) was prepared by NaBH(4) reduction of RuCl(3).3H(2)O in methanol in the presence of the polymer; TEM measurements of a 10 wt % Ru/P4VPy material indicate that ruthenium particles of 1-2 nm predominate. This catalyst is efficient for the selective hydrogenation of quinoline to 1,2,3,4-tetrahydroquinoline at 100-120 ºC and 30-40 bar H(2). The activity increases with hydrogen pressure up to 40 bar but is essentially independent of quinoline concentration. Polar solvents, triethylamine, and acetic acid enhance catalytic performance, suggesting an ionic mechanism involving heterolytic hydrogen activation.

A kinetic study of the homogeneous hydroformylation of 1-hexene to the corresponding aldehydes (heptanal and 2-methyl-hexanal) was carried out using a rhodium catalyst formed by addition of 1 equiv. of 1,2-bis(diphenylphosphino)ethane (dppe) to Rh(acac)(CO) 2 under mild reaction conditions (80 °C, 1–7 atm H 2 and 1–7 atm CO) in toluene; in all cases linear to branched ratios were close to 2. The reaction rate is first-order in dissolved hydrogen concentration at pressures below 3 atm, but independent of this parameter at higher pressures. In both regimes (low and high H 2 pressure), the initial rate was first-order with respect to the concentration of Rh and fractional order with respect to 1-hexene concentration. Increasing CO pressure had a positive effect on the rate up to a threshold value above which inhibition of the reaction was observed; the range of positive order on CO concentration is smaller when the total pressure is increased. The kinetic data and related coordination chemistry are consistent with a mechanism involving RhH(CO)(dppe) as the active species initiating the cycle, hydrogenolysis of the acyl intermediate as the rate-determining step of the catalytic cycle at low hydrogen pressure, and migratory insertion of the olefin into the metal-hydride bond as rate limiting at high hydrogen pressure. This catalytic cycle is similar to the one commonly accepted for RhH(CO)(PPh 3 ) 3 but different from previous proposals for Rh-diphosphine catalysts.

The new water soluble complex [HRu(CO)(CH3CN)(TPPTS)3]BF4 (TPPTS = tris[(m-sulfonated)phenyl]phosphine P(m-C6H4SO3Na)3) has been synthesized by ligand exchange techniques from the corresponding PPh3 derivative in a methoxyethanol–water mixture. The new complex was characterized by FTIR, UV–vis, and 1H NMR and 31P {1H} NMR spectroscopy and used as catalyst precursor for the aqueous biphasic hydroformylation of several olefins and their mixtures under moderate reaction conditions. The catalytic activity order found was: 1-hexene > allylbenzene > 2,3-dimethyl-1-butene > styrene > cyclohexene. The sulphur tolerance of this complex was also investigated using thiophene as a model molecule; it was found that the new complex maintains its activity when the thiophene concentration is below 500 ppm. The mercury test in independent experiments showed no interference of the Hg at all with the evolution of the reaction, demonstrating that the catalysis is performed by molecular species. The recyclable nature of the complex was demonstrated during 1-hexene hydroformylation where at the end of each catalytic reaction all the metal remains in the aqueous phase.

New rhodium and iridium complexes, with the formula [MCl(PBz 3 )(cod)] [M = Rh ( 1 ), Ir ( 2 )] and [M(PBz 3 ) 2 (cod)]PF 6 [M = Rh ( 3 ), Ir ( 4 )] (cod = 1,5-cyclooctadiene), stabilized by the tribenzylphosphine ligand (PBz 3 ) were synthesized and characterized by elemental analysis and spectroscopic methods. The molecular structures of 1 and 2 were determined by single-crystal X-ray diffraction. The addition of pyridine to a methanol solution of 1 or 2 , followed by metathetical reaction with NH 4 PF 6 , gave the corresponding derivatives [M(py)(PBz 3 )(cod)]PF 6 [M = Rh ( 5 ), Ir ( 6 )]. At room temperature in CHCl 3 solution, 4 converted spontaneously to the ortho -metallated complex [IrH(PBz 3 )(cod){η 2 - P , C -(C 6 H 4 CH 2 )PBz 2 }]PF 6 ( 7 ) as a mixture of cis / trans isomers via intramolecular C–H activation of a benzylic phenyl ring. The reaction of 3 or 4 with hydrogen in coordinating solvents gave the dihydrido bis(solvento) derivative [M(H) 2 (S) 2 (PBz 3 ) 2 ]PF 6 (M = Rh, Ir; S = acetone, acetonitrile, THF), that transformed into the corresponding dicarbonyls [M(H) 2 (CO) 2 (PBz 3 ) 2 ]PF 6 by treatment with CO. Analogous cis -dihydrido complexes [M(H) 2 (THF) 2 (py)(PBz 3 ) 2 ]PF 6 (M = Rh, Ir) were observed by reaction of the py derivatives 5 and 6 with H 2 .

The iridium complexes [Ir(PBz3)2(COD)]PF6 and [Ir(py)(PBz3)(COD)]PF6 are effective catalyst precursors for the homogeneous hydrogenation of N-(β-naphthylmethylene)aniline (NβNA) to naphthalene-2-ylmethylphenylamine (PBz3 = tribenzylphosphine; COD = 1,5-cyclooctadiene; py = pyridine). For comparative purposes, other iridium and rhodium catalysts modified with either PBz3 or PPh3 have been tested as catalysts for NβNA hydrogenation. A kinetic study of this reaction catalyzed by [Ir(PBz3)2(COD)]PF6, [Ir(py)(PBz3)(COD)]PF6, and [Rh(PPh3)2(COD)]PF6, together with in situ NMR experiments, has led us to propose catalytic cycles for the three precursors.

The new water-soluble rhodium complex [Rh(μ-Pz)(CO)(TPPTS)] 2 ( I ) with TPPTS tris- meta -sulfonatophenylphosphine and Pz = pyrazolate ligand, has been synthesized by the reaction of the rhodium precursor [Rh(acac)(CO) 2 ] with TPPTS and pyrazol in aqueous solution under inert atmosphere and characterized by FT-IR, UV–vis, 1 H NMR, 31 P{ 1 H} NMR. This complex ( I ) shows high solubility and stability in water for long periods of time as demonstrated by UV–vis studies. The new rhodium complex was used as catalyst precursor during the two-phase catalytic hydroformylation of different olefins under the following reactions conditions: 373 K, 4981.3 kPa (CO/H 2 = 1:1), 600 rpm and S / C = 100/1, obtaining as reaction order: 1-hexene > styrene > allylbenzene > 2,3-dimethyl-1-butene > cyclohexene. The catalytic activity of the complex ( I ) in the equimolar and real mixture of olefins with or without the presence of thiophene was also studied and practically no change in the total conversion to aldehydes was observed. This experiments shows that the binuclear complex ( I ) is resistant to possible sulphur poisons present in refinery cuts.

The hydroformylation of medium-chain C6 olefins and of allyl alcohol was achieved with paraformaldehyde in dioxane solution using rhodium catalysts with mono-, bi-, and tri-dentate phosphine ligands. The highest activities with n/i ratios around 2, were obtained for a system derived from [Rh(dppe)2]+, prepared in situ by reaction of Rh(acac)(CO)2 with 2 eq of dppe.

The complexes RhH(CO)L3, where L = PPh3, P(m-C6H4SO3Na)3 (TPPTS), and (C6H5)2P(m-C6H4SO3Na) (TPPMS) were used as catalyst precursors for a comparative study of the catalytic hydroformylation of several C6 alkenes and alkene mixtures under moderate reaction conditions in homogeneous (PPh3) and aqueous-biphasic (TPPTS, TPPMS) media. The biphasic systems are efficient for the hydroformylation of hex-1-ene, 2,3-dimethyl-1-butene, styrene, cyclohexene, and mixtures thereof, in water/n-heptane at 80 °C. The main problem associated with these catalysts is their tendency to promote alkene isomerization if the effective syngas concentration in the liquid phases is low, but this side-reaction can be suppressed by using higher CO/H2 pressures (54 atm). The selectivity of both water-soluble catalysts for linear products of hex-1-ene and for branched products of styrene is modest in comparison with the homogeneous system, which may limit their utility for classical oxo uses, but this is not a disadvantage for other interesting applications related to the hydroformylation of alkene mixtures and particularly to naphtha upgrading where linear and branched products are equally useful. The catalysts can be recycled without significant loss of activity and are resistant to the presence of benzothiophene in the mixture.

Ketoconazole (KTZ) has been used as a second-line agent in hormone-refractory cancer therapy. Since transition metal complexes including those of Ru(III), show important anticancer activity with limited toxicity, we investigated the potential antitumor efficacy of Ru(II) complexed to KTZ or clotrimazole (CTZ) compared to Ru(II) alone or uncomplexed azoles. RuCl2(KTZ)2 exerted greater apoptosis- associated caspase-3 activation than RuCl2(CTZ)2, KTZ, CTZ or RuCl2(MeCN)4 against several human tumor cell monolayers. PARP cleavage and a decrease in S+G2 cells were evident after RuCl2(KTZ)2 treatment in genetically matched C8161 melanoma monolayers with unequal p53 functional status. Release of mitochondrial cytochrome c and Mn-SOD suggest mitochondria as a target of RuCl2(KTZ)2. Treatment of WM164 melanoma monolayers with 25 microM of cisplatin or RuCl2(KTZ)2 showed that the latter is more effective than cisplatin at inducing PARP fragmentation and proapoptotic Bak expression. Such results suggest that these Ru(II) and Pt(II) metal complexes are unequally effective and act through alternative signaling pathways. In studies with multicellular spheroids, which frequently are more resistant to cytotoxic anticancer drugs than monolayers, those from wt p53 C8161 melanoma underwent PARP fragmentation in response to RuCl2(KTZ)2. In contrast, spheroids of mut p53 A431 carcinoma overexpressing EGF receptor were resistant to either RuCl2(KTZ)2 or anti-EGF receptor C225 MAb. However, joint treatment with both agents restored growth arrest and apoptosis in these spheroids. In contrast to the antitumor action of cisplatin, which is known to be hampered by p53 dysfunction, we show that RuCl2(KTZ)2 is active irrespective of p53 functional status against several adherent tumor cells and synergizes with anti-EGF receptor C225 MAb to kill tumor spheroids resistant to either agent.

The water-soluble complex Ru(H)2(CO)(TPPMS)3 where TPPMS: (C6H5)2P(m-C6H4SO3Na) was obtained by phosphine ligand exchange from the corresponding PPh3 derivative in a water–toluene mixture and characterized by FTIR, UV-Vis, and 1 H NMR and 31 P { 1 H } spectroscopy. The complex was used as a catalyst precursor for the aqueous-biphasic catalytic hydroformylation of several alkenes and alkene mixtures under moderate reaction conditions. The activity trend observed was: 1-hexene > cyclohexene > 2,3-dimethyl-1-butene and the catalyst was shown to be resistant to possible sulphur poisons.

Complexes of the type [Ru(II)Cl2(DMSO)2L], where L are 5-nitrofurylsemicarbazone derivatives, were prepared in an effort to combine the potential anti-tumor activity of the metal and the free ligands. The new complexes are excellent DNA binding agents for calf thymus DNA. So, their in vitro anti-tumor activity was tested in cellular models and the complexes were found to be non-cytotoxic on the tumor cell lines assayed, neither in aerobic conditions nor in the bio-reductive assay performed. Redox behavior, lipophilicity and stability were studied in order to explain the lack of cellular cytotoxic effects. The complexes resulted 10–100 times more hydrophilic than the parent ligands thus the bio-activity of these compounds would be compromised by their inadequate lipophilic properties.

The synthesis and characterization of the first two Re complexes with semicarbazone ligands is presented. Selected ligands are 5-Nitro-2-furaldehyde semicarbazone (Nitrofurazone) (L1) and its derivative 3-(5-Nitrofuryl)acroleine semicarbazone (L2). Complexes of general formula [ReVOCl2(PPh3)L], where L = L1 and L2, were prepared in good yields and high purity by reaction of [ReVOCl3(PPh3)2] with L in ethanol or methanol solutions. The complexes formula and molecular structures were supported by elemental analyses and electronic, FTIR, 1H, 13C and 31P NMR spectroscopies. In addition, the crystal and molecular structure of [ReVOCl2(PPh3)L2] was determined by X-ray diffraction methods. [ReOCl2(PPh3)(3-(5-Nitrofuryl)acroleine semicarbazone)] crystallizes in the space group P-1 with a = 11.2334(2), b = 11.3040(2), c = 12.5040(2) A, α = 81.861(1), β = 63.555(1), γ = 83.626(1)°, and Z = 2. The Re(V) ion is in a distorted octahedral environment, equatorially coordinated to a deprotonated semicarbazone molecule acting as a bidentate ligand through its carbonylic oxygen and azomethynic nitrogen atoms, to an oxo ligand and a chlorine atom. The six-fold coordination is completed by another chlorine atom and a triphenylphosphine ligand at the axial positions. Neue Rhenium(V)-Nitrofuryl-semicarbazon-Komplexe. Kristallstruktur von [ReOCl2(PPh3){3-(5-Nitrofuryl)acrolein-semibarbazon}] Die Synthese und die Charakterisierung der ersten beiden Re-Komplexe mit Semicarbazon-Liganden wird beschrieben. Die ausgewahlten Liganden sind 5-Nitro-2-furaldehyd-semicarbazon (Nitrofurazon) (L1) und sein Derivat 3-(5-Nitrofuryl)acrolein-semicarbazon (L2). Die Komplexe der allgemeinen Formel [ReVOCl2(PPh3)L] mit L = L1 und L2 wurden in guten Ausbeuten und hoher Reinheit durch Reaktion von [ReVOCl3(PPh3)2] mit L in Ethanol- oder Methanollosungen hergestellt. Die Komplexformeln und die Molekulstrukturen werden durch Elementaranalysen und Elektronen-FTIR-, 1H-, 13C- und 31P-NMR-Spektroskopie gestutzt. Zusatzlich wird die Kristall- und Molekulstruktur von [ReVOCl2(PPh3)L2] durch Rontgenmethoden ermittelt. [ReOCl2(PPh3){3-(5-Nitrofuryl)acrolein-semicarbazon}] kristallisiert in der Raumgruppe P1¯ mit a = 11, 2334(2); b = 11, 3040(2); c = 12.5040(2) A; α = 81, 861(1); β = 63, 555(1); γ = 83, 626(1)° und Z = 2. Das Rheniumatom befindet sich in verzerrt oktaedrischer Umgebung, es ist aquatorial durch den deprotonierten, als zweizahnig fungierenden Semicarbazon-Liganden mittels des Carbonylsauerstoffatoms und des Azomethin-Stickstoffatoms koordiniert sowie durch den Oxo- und einen Chloroliganden. Die Sechsfachkoordination wird durch ein weiteres Chloratom und durch den Triphenylphosphin-Liganden in den Axialpositionen erganzt.

International audience; The efficacy of chloroquine, once the drug of choice in the fight against Plasmodium falcipa-rum, is now severely limited due to widespread resistance. Amodiaquine is one of the most potent antimalarial 4-aminoquinolines known and remains effective against chloroquine-resistant parasites, but toxicity issues linked to a quinone-imine metabolite limit its clinical use. In search of new compounds able to retain the antimalarial activity of amodiaquine while circumventing quinone-imine metabolite toxicity, we have synthesized five 4-amino-quinolines that feature rings lacking hydroxyl groups in the side chain of the molecules and are thus incapable of generating toxic quinone-imines. The new compounds displayed high in vitro potency (low nanomolar IC 50), markedly superior to chloroquine and comparable to amodiaquine, against chloroquine-sensitive and chloroquine-resistant strains of P. falcipa-rum, accompanied by low toxicity to L6 rat fibroblasts and MRC5 human lung cells, and metabolic stability comparable or higher than that of amodiaquine. Computational studies indicate a unique mode of binding of compound 4 to heme through the HOMO located on a biphenyl moeity, which may partly explain the high antiplasmodial activity observed for this compound.

Nucleophilic attack of the β-carbon of an Ir I I I -alkenyl functionality onto the α-carbon of a coordinated nitrile- or aldehyde occurs intramoleculary to yield initially iridacyclic structures. Nitriles give rise to isolable complexes that contain delocalized five-membered rings (iridapyrroles, e.g. 3'-8') in a reaction catalyzed by H 2 O (for some of these syntheses, Ir I I I -η 3 -allyl derivatives may be used as the source of the Ir I I I -alkenyl moiety). In contrast. the alkenyl-to-aldehyde C-C coupling gives transient iridacycles that evolve by a fast alkyl-to-alkylidene migration and β-H elimination. The end products (13* and 14*) contain an elaborated chelating alkoxide-olefin ligand. Addition of [H(OEt 2 ) 2 ](BAr' 4 ] to the iridapyrroles effects stereospecific protonation of the β-ring carbon. Those iridapyrroles which contain an additional metal-alkyl functionality (e.g. 3a*, alkyl=C 2 H 5 ) afford highly reactive cationic alkyl-alkylidene intermediates that evolve instantaneously by migratory insertion/β-H elimination. The end products also contain an elaborated, chelating ligand, although this time with an olefin and imine terminus compared with the previous ligand. Contrary to this result, protonation of the hydride-iridapyrrole complex 8a* in weakly coordinating solvents permits isolation of two unusual cationic cis-hydride-alkylidene compounds 11*, which undergo reversible 1,2-H shifts.

The complexes [Cu(CTZ)4]Cl2·2H2O (1), [Cu(CTZ)Cl2]2 (2), [Cu(KTZ)3Cl2] (3), and [Cu(KTZ)Cl2]2·2H2O (4) were prepared by reaction of CuCl2 with CTZ and KTZ (where CTZ = 1-[[(2-chlorophenyl)diphenyl]methyl]-1H-imidazole and KTZ = cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine), respectively, in acetonitrile at different ligand to metal molar ratios. Gold complexes [Au(PPh3)(CTZ)]PF6 (5) and [Au(PPh3)(KTZ)]PF6·H2O (6) were synthesized by reaction of AuClPPh3, with KPF6 and CTZ or KTZ in acetonitrile. All the new compounds were characterized by NMR spectroscopy and microanalytical methods, and for the paramagnetic species EPR spectroscopy and DC magnetic susceptibility measurements were also employed. The solid-state structure of 1 has been determined by X-ray crystallography. 1 crystallizes in the triclinic space group P1, with a = 12.773(2) A, b = 15.326(4) A, c = 11.641(2) A, V = 1957.4(7) A3, Z = 1, and Dcalcd = 1.284 g/cm3. The structure...

The role of transition metal complexes as catalysts for homogeneous hydrogenation reactions has been extensively investigated during the last few decades. This paper reviews recently disclosed work by a number of research laboratories including ours, which shows that the study of the kinetics of such processes is a particularly important tool which, if used in combination with spectroscopic techniques, isotope labeling, isolation of stable analogues and theoretical calculations, allows the elucidation of the mechanisms operating in a variety of homogeneous catalytic hydrogenation reactions.

The ruthenium(II) tris-acetonitrile complex [(triphos)Ru(MeCN)3]BPh4 (1) is an extremely efficient catalyst precursor for the regioselective hydrogenation of benzo[b]thiophene (BT) to 2,3-dihydrobenzo[b]thiophene (DHBT) in homogeneous phase under mild reaction conditions (THF, 40−100 °C, 1−30 bar H2) [triphos = MeC(CH2PPh2)3]. At 30 bar of H2 and 100 °C, BT is converted to DHBT with an average rate of 500 mol of product (mol of cat)-1 h-1. During the catalytic reactions with PH2 > 5 bar, the acetonitrile ligands in 1 are transformed into a mixture of NHEt2, NEt3, and NH3, while the termination ruthenium products are the monohydrido complexes [(triphos)Ru(H)(NH3)2]BPh4, [(triphos)Ru(H)(NH3)(NH2Et)]BPh4, and [(triphos)Ru(H)(NH3)(η1-S-DHBT)]BPh4. Below 5 bar of H2, no hydrogenation of MeCN occurs and all of the ruthenium is recovered as [(triphos)Ru(H)(NCMe)(η1-S-DHBT)]BPh4. All of these Ru(II) hydrido complexes catalyze the hydrogenation of BT to DHBT as efficiently as 1. The substitution of D2 for H2 in a ...

The pharmacological properties of any drug are related to their ability to interact with macromolecular blood components. The interaction of human serum albumin (HSA) and apotransferrin (ATf) with six RuII complexes containing ketoconazole (KTZ), which we have previously reported to be active against Leishmania major and Trypanosoma cruzi, has been investigated by monitoring the tryptophan fluorescence intensity of each protein upon incremental addition of the complexes. All the Ru-KTZ derivatives, namely cis-fac-[RuIICl2(DMSO)3(KTZ)] (1), cis-[RuIICl2(bipy)(DMSO)(KTZ)] (2), [RuII(η6-p-cymene)Cl2(KTZ)] (3), [RuII(η6-p-cymene)(en)(KTZ)][BF4]2 (4), [RuII(η6-p-cymene)(bipy)(KTZ)][BF4]2 (5), and [RuII(η6-p-cymene)(acac)(KTZ)][BF4] (6) are able to quench the intrinsic fluorescence of HSA and ATf at 27 °C. Analysis of the spectroscopic data using Stern-Volmer plots indicates that in both cases the quenching takes place principally through a static mechanism involving the formation of Ru complex-protein adducts; further analysis of the fluorescence data allowed the estimation of apparent association constants and the number of binding sites for each protein and each compound. The results indicate that both HSA and ATf are possible effective transporters for Ru-KTZ antiparasitic drugs.

The complexes [M(COD)(PPh3)2]PF6 (M = Rh, 1a; Ir, 1b) are highly efficient precatalysts for the homogeneous hydrogenation of benzo[b]thiophene (BT) to 2,3-dihydrobenzo[b]thiophene (DHBT). Both complexes react rapidly with BT and H2 to produce the corresponding [M(H)2(η1(S)-BT)2(PPh3)2]PF6 (M = Rh, 2a; Ir, 2b), which enter the catalytic cycle. In the case of Ir, the catalysis is more conveniently carried out by use of 2b, which is stable enough to be isolated pure. Kinetic and mechanistic studies of BT hydrogenation were carried out by using 1a and 2b as the catalyst precursors in 1,2-dichloroethane solution at 40 °C. For both complexes, the reaction proceeds according to the rate law r = kcat [M] [H2], where kcat = k1K3/(1 + K3[H2]). All of the experimental data are consistent with a general mechanism in which the transfer of the hydrides to coordinated BT in [M(H)2(η2(CC)-BT)(PPh3)2]PF6 is the rate-determining step of the catalytic cycle. The complex [Ir(H)2(η1(S)-DHBT)2(PPh3)2]PF6 was obtained as a stab...

NMR data for two Ru-TPPMS complexes previously described as unsaturated monomeric species have led to their reformulation as the chloro-bridged dimers [RuCl(TPPMS)2(μ-Cl)]2(1) and [RuH(TPPMS)2(μ-Cl)]2(2); three new water-soluble complexes OsH4(TPPMS)3(3), OsHCl(CO)(TPPMS)2(4), and [OsCl(TPPMS)2(μ-Cl)]2(5) have been synthesized and characterized. Complexes 1–5, as well as mixtures of Ru and Os salts with TPPMS and TPPTS catalyze the hydrogenation of cinnamaldehyde under mild reaction conditions in aqueous biphasic systems; the activities and selectivities of these catalysts have been compared with those of homogeneous PPh3 analogues. In general there is a clear advantage in using the aqueous biphasic mixtures over their analogous homogeneous solutions, since catalyst recovery and recycling are easy and because the regioselectivity towards the production of the α, β-unsaturated alcohol is considerably enhanced on going from the homogeneous PPh3 to the biphasic TPPMS and TPPTS systems, particularly in the case of Ru.

Ruthenium-based compounds have intriguing anti-cancer properties and some of these novel compounds are currently in clinical trials. To continue the development of new metal-based drug combinations, we coupled ruthenium (Ru) with the azole compounds ketoconazole (KTZ) and clotrimazole (CTZ), which are well-known antifungal agents that also display anticancer properties. We report the activity of a series of twelve Ru-KTZ and Ru-CTZ compounds against three prostate tumor cell lines with different androgen sensitivity, as well as cervical cancer and lymphoblastic lymphoma cell lines. In addition, human cell lines were used to evaluate the toxicity against non-transformed cells and to establish selectivity indexes. Our results indicate that the combination of ruthenium and KTZ/CTZ in a single molecule results in complexes that are more cytotoxic than the individual components alone, displaying in some cases low micromolar CC50 values and high selectivity indexes. Additionally, all compounds are more cytotoxic against prostate cell lines with lower cytotoxicity against non-transformed epidermal cell lines. Some of the compounds were found to primarily induce cell death via apoptosis yet weakly interact with DNA. Our studies also demonstrate that the cytotoxicity induced by our Ru-based compounds is not directly related to their ability to interact with DNA.

The carbonylation and cyclization of N-alkylallylamines to γ-butyrolactams is efficiently achieved by use of RhCl 3 · 3 H 2 O PPh 3 or RhCl(CO)(PPh3)2 as catalyst precursors under mild conditions (70°C, 10 bar) when CO H 2 (4:1) mixtures are used instead of pure CO. Mechanistic studies on the Rh and the analogous Ir system allowed the deduction of a major catalytic cycle in which the active species is RhCl(CO)2(PPh3)2 and the role of H2 is the decomposition of an intermediate containing a coordinated carbamoyl fragment derived from a nucleophilic attack of the amine to a coordinated CO.

The complexes Ru(PPh3)2Cl2(L)2 (L = 4-But-py, 4-vinyl-py, 4-CN-py, 4-Me-py, 3-Me-py, L2 = 4,4′-bipy) have been prepared by reaction of RuCl2(PPh3)3 with the appropriate ligand under mild conditions and characterized by elemental analysis, IR, NMR (1H and 31P) and UV-vis spectra; the RuII derivatives display a RuP2Cl2N2 core with a trans, cis, cis arrangement of the donor atoms. Ru(PPh3)2Cl2(4-But-py)2 is an efficient catalyst precursor for the homogeneous hydrogenation of cyclohexene and benzaldehyde under moderate conditions. A kinetic study of the hydrogenation of cyclohexene led to a rate law r = kcat[Ru][H2], which corresponds to a mechanism involving a fast coordination of cyclohexene to an electronically unsaturated hydride RuHCl(PPh3)2(4-But-py), followed by a rate-limiting oxidative addition of H2 and rapid reductive elimination of the product.

Chloroquine free base (CQ) reacts with [Rh(COD)Cl]2 (COD = 1,5-cyclooctadiene) and RuCl3.-3H2O/Zn to yield Rh(COD)(CQ)Cl (1) and [RuCl2(CQ)]2 (2), respectively. The two novel metal- CQ complexes, which were characterized mainly by 1D and 2D NMR spectroscopy, were tested against Plasmodium berghei. The in vitro activity of 1 was comparable to that of chloroquine diphosphate (CQDP), whereas 2 was about 5 times more active. In in vivo tests at equivalent concentrations of free CQ, CQDP reduced the parasitemia by 55%, while for complexes 1 and 2 the reduction reached 73% and 94%, respectively, without any sign of acute toxicity being observed up to 30 days after treatment. The Ru derivative 2 was further evaluated against two chloroquine-resistant strains of Plasmodium falciparum, and it was found to be 2-5 times more active than CQDP.

A new catalyst composed of Pd nanoparticles supported on MgO has been prepared by the room temperature NaBH(4) reduction of Na(2)PdCl(4) in methanol in the presence of the support. TEM measurements reveal well-dispersed Pd particles of mean diameter 1.7 nm attached to the MgO surface. Further characterization was achieved by ICP-AES, XPS, XRD, H(2) pulse chemisorption and H(2)-TPR. The new catalyst is efficient for the regioselective hydrogenation of the heterocyclic ring of quinolines, as well as for the mild reduction of a variety of alkenes representative of fuel components, and the partial saturation of biodiesel. The new material is considerably more reactive than commercial Pd/SiO(2) and Pd/Al(2)O(3) catalysts under analogous reaction conditions.

Eight new ruthenium complexes of clotrimazole (CTZ) with high antiparasitic activity have been synthesized, cis,fac-[Ru(II)Cl(2)(DMSO)(3)(CTZ)] (1), cis,cis,trans-[Ru(II)Cl(2)(DMSO)(2)(CTZ)(2)] (2), Na[Ru(III)Cl(4)(DMSO)(CTZ)] (3), Na[trans-Ru(III)Cl(4)(CTZ)(2)] (4), [Ru(II)(η(6)-p-cymene)Cl(2)(CTZ)] (5), [Ru(II)(η(6)-p-cymene)(bipy)(CTZ)][BF(4)](2) (6), [Ru(II)(η(6)-p-cymene)(en)(CTZ)][BF(4)](2) (7), and [Ru(II)(η(6)-p-cymene)(acac)(CTZ)][BF(4)] (8) (bipy = bipyridine; en = ethlylenediamine; acac = acetylacetonate). The crystal structures of compounds 4-8 are described. Complexes 1-8 are active against promastigotes of Leishmania major and epimastigotes of Trypanosoma cruzi. Most notably, complex 5 increases the activity of CTZ by factors of 110 and 58 against L. major and T. cruzi, with no appreciable toxicity to human osteoblasts, resulting in nanomolar and low micromolar lethal doses and therapeutic indexes of 500 and 75, respectively. In a high-content imaging assay on L. major-infected intraperitoneal mice macrophages, complex 5 showed significant inhibition on the proliferation of intracellular amastigotes (IC(70) = 29 nM), while complex 8 displayed some effect at a higher concentration (IC(40) = 1 μM).

International audience; In the search for new therapeutic tools against neglected diseases produced by trypanosomatid parasites, and particularly against African Trypanosomiasis, whose etiological agent is Trypanosoma brucei, organoruthenium compounds with bioactive nitrofuran containing thiosemicarbazones (L) as co-ligands were obtained. Four ruthenium(II) complexes with the formula [Ru(2)(p-cymene)(2)(L)(2)]X(2), where X = Cl or PF(6), were synthesized and the crystal structures of two of them were solved by X-ray diffraction methods. Two of the complexes show significant in vitro growth inhibition activity against Trypanosoma brucei brucei and are highly selective towards trypanosomal cells with respect to mammalian cells (J774 murine macrophages). These promising results make the title organoruthenium compounds good lead candidates for further developments towards potential antitrypanosomal organometallic drugs.

In spite of the large scale industrial applications of the hydrodesulfurization (HDS) process, and of the considerable number of studies of this reaction on heterogeneous catalysts, the mechanisms involved are not yet clearly understood. In this article we first summarize the main mechanistic pathways that have been proposed to occur on surfaces for HDS of thiophenes, and then review those aspects of coordination and organometallic chemistry that are most pertinent to the activation, desulfurization and hydrogenation of thiophenes on metal complexes. The examples described constitute excellent molecular analogues of the species and reactions that are thought to intervene in heterogeneous catalysis, and thus complement surface studies and contribute to the understanding of this important reaction.

A nanostructured catalyst composed of Ru nanoparticles immobilized on poly(4-vinylpyridine) (PVPy) has been synthesized by NaBH(4) reduction of RuCl(3)·3H(2)O in the presence of the polymer in methanol at room temperature. TEM measurements show well-dispersed Ru nanoparticles with an average diameter of 3.1 nm. Both powder XRD patterns and XPS data indicate that the Ru particles are predominantly in the zerovalent state. The new catalyst is efficient for the hydrogenation of a wide variety of aromatic hydrocarbons and N-heteroaromatic compounds representative of components of petroleum-derived fuels. The experimental data indicate the existence of two distinct active sites in the nanostructure that lead to two parallel hydrogenation pathways, one for simple aromatics involving conventional homolytic hydrogen splitting on Ru and a second one for N-heteroaromatics taking place via a novel heterolytic hydrogen activation on the catalyst surface, assisted by the basic pyridine groups of the support.

Three platinum-chloroquine complexes, trans-Pt(CQDP)(2)(I)(2) [1], trans-Pt(CQDP)(2)(Cl)(2) [2] and trans-Pt(CQ)(2)(Cl)(2) [3], were prepared and their most probable structure was established through a combination of spectroscopic analysis and density functional theory (DFT) calculations. Their interaction with DNA was studied and their activity against 6 tumor cell lines was evaluated. Compounds 1 and 2 interact with DNA primarily through electrostatic contacts and hydrogen bonding, with a minor contribution of a covalent interaction, while compound 3 binds to DNA predominantly in a covalent fashion, with weaker secondary electrostatic interactions and possibly hydrogen bonding, this complex also exerted greater cytotoxic activity against the tumor cell lines.

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(η(6)-p-cymene)(CQ)(H(2)O)Cl]PF(6) (1), [Ru(η(6)-benzene)(CQ)(H(2)O)Cl]PF(6) (2), [Ru(η(6)-p-cymene)(CQ)(H(2)O)(2)][PF(6)](2) (3), [Ru(η(6)-p-cymene)(CQ)(en)][PF(6)](2) (4), [Ru(η(6)-p-cymene)(η(6)-CQDP)][BF(4)](2) (5) (CQ: chloroquine; DP: diphosphate; en: ethylenediamine), in comparison with CQDP and [Ru(η(6)-p-cymene)(en)Cl][PF(6)] (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.

The complexes [IrH 2 (η 1 S-Th) 2 (PPh 2 ) 2 ]PF 6 (Th=thiophene (2), benzo[b]thiophene (3), dibenzothiophene (4) tetrahydrothiophene (5)) have been synthesized in high yields by hydrogenation of [Ir(COD)(PPh 3 ) 2 ]PF 6 (COD =1,5-cyclooctadiene) in the presence of the appropriate thiophene. The structures of 2 and 5 have been determined by X-ray diffraction