Synthesis, characterization and cytotoxic activities of the [RuCl(2)(NO)(dppp)(L)]PF(6) complexes

The synthesis and characterization of ruthenium compounds of the type [RuCl(2)(NO)(dppp)(L)]PF(6) [dppp = 1,3-bis(diphenylphosphino)propane; L = pyridine, 4-methylpyridine, 4-phenylpyridine and dimethyl sulfoxide] are described. The complexes were characterized by elemental analysis, UV/Vis and infrared spectroscopy, cyclic voltammetry, and X-ray crystallography for the complexes with the pyridine and 4-methylpyridine ligands. In vitro evaluation of these nitrosyl complexes revealed cytotoxic activity from 7.1 to 19.0 mu M against the MDA-MB-231 breast tumor cells and showed that, in this case, they are more active than the reference metallodrug cisplatin. The 1,3-bis(diphenylphosphino)propane and the N-heterocyclic ligands alone failed to show cytotoxic activities at the concentrations tested (maximum concentration utilized = 200 mu M). (C) 2009 Elsevier Inc. All rights reserved.

Ruthenium(II) complexes containing N(4)-tolyl-2-acetylpyridine thiosemicarbazones and phosphine ligands: NMR and electrochemical studies of cis-trans isomerization

[Ru(HL)(PPh3)(2)Cl]Cl complexes have been obtained in which HL = N(4)-ortho (complex 1), N(4)-meta (complex 2) and N(4) pctratolyl 2-acetylpyridine thiosemicarbazone (complex 3). NMR and electrochemical studies indicate that both cis and trans isomers exist in solution, and that the cis isomers are converted into the trans isomers with time. Crystal structure determination of (1) reveals that the traps isomer is formed in the solid state. (c) 2007 Elsevier B.V. All rights reserved.

Ruthenium (II) phosphine/picolinate complexes as antimycobacterial agents

The synthesis, characterization and the anti-Mycobacterium tuberculosis (MTB) activities of three ruthenium complexes containing the 2-pyridinecarboxylic acid anion (picolinate), with formulae cis-[Ru(pic)(dppm)(2)]PF(6) (1), Cis- [Ru(pic)(dppe)(2)]PF(6) (2) and [Ru(pic)(2)(PPh(3))(2)] (3) [pic = 2-pyridinecarboxylate; dppm = bis(diphenylphosphino)methane: dppe = 1,2-bis(diphenylphosphino)ethane; PPh(3) = triphenylphosphine] are reported in this article. The complexes were characterized by elemental analysis, spectroscopic and electrochemical techniques. Their in vitro anti mycobacterial activity was determinated as the Minimum Inhibitory Concentration (MIC) for MTB cell growth, measured by the REMA method. The best MICs were found for complexes (1) and (2), with values of 0.78 and 0.26 mu g/mL, respectively. The results are comparable to or better than ""first line"" or ""second line"" drugs commonly used in the treatment of TB. (C) 2009 Elsevier Masson SAS. All rights reserved.

Diruthenium(II, III) complexes of ibuprofen, aspirin, naproxen and indomethacin non-steroidal anti-inflammatory drugs: Synthesis, characterization and their effects on tumor-cell proliferation

[Ru-2(dNSAID)(4)Cl] and novel [Ru-2(dNSAID)(4)(H2O)(2)]PF6 complexes, where dNSAID = deprotonated carboxylate from the non-steroidal anti-inflammatory drugs (NSIDs), respectively: ibuprofen, Hibp (1) and aspirin, Hasp (2); naproxen, Hnpx (3) and indomethacin, Hind (4), have been prepared and characterized by optical spectroscopic methods. All of the compounds exhibit mixed valent Ru-2(II, III) cores where metal-metal bonds are stabilized by four drug-carboxylate bridging ligands in paddlewheel type structures. The diruthenium complexes and their parent NSAIDs showed no significant effects for Hep2 human larynx or T24/83 human bladder tumor. In contrast, the coordination of Ru-2(II,III) core led to synergistic effects that increased significantly the inhibition of C6 rat glioma proliferation in relation to the organic NSAIDs naproxen and ibuprofen, The possibility that the complexes Ru-2-ibp and Ru-2-npx may exert effects (anti-angiogenic and anti-matrix metalloprotease) that are similar to those exhibited by NAMI-A opens new horizons for in vivo C6 glioma model studies. (C) 2007 Elsevier Ltd. All rights reserved.

Coordination of nitro-thiosemicarbazones to ruthenium(II) as a strategy for anti-trypanosomal activity improvement

Complexes [RuCl(H4NO(2)Fo4M)(bipy)(dppb)]PF(6) (1), [RuCl(H4NO(2)Fo4M)(Mebipy)(dppb)]PF(6) (2), [RuCl(H4NO(2)Fo4M)(phen)(dppb)]PF(6) (3), [RuCl(H4NO(2)Ac4M)(bipy)(dppb)]PF(6) (4), [RuCl(H4NO(2)Ac4M)(Mebipy)(dppb)]PF(6) (5) and [RuCl(H4NO(2)Ac4M)(phen)(dppb)]PF(6) (6) with N(4)-methyl-4-nitrobenzalde hyde thiosemicarbazone (H4NO(2)Fo4M) and N(4)-methyl-4-nitroacetophenone thiosemicarbazone (H4NO(2) Ac4M) were obtained from [RuCl(2)(bipy)(dppb)], [RuCl(2)(Mebipy)(dppb)], and [RuCl(2)(phen)(dppb)], (dppb = 1,4-bis(diphenylphospine)butane; bipy = 2,2`-bipyridine: Mebipy = 4,4`-dimethyl-2,2`-bipyridine: phen = 1,10-phenanthroline). In all cases the thiosemicarbazone is attached to the metal center through the sulfur atom. Complexes (1-6), together with the corresponding ligands and the Ru precursors were evaluated for their ability to in vitro suppress the growth of Trypanosoma cruzi. All complexes were more active than their corresponding ligands and precursors. Complexes (1-3) and (5) revealed to be the most active among all studied compounds with ID(50) = 0.6-0.8 mu M. In all cases the association of the thiosemicarbazone with ruthenium, dppb and bipyridine or phenanthroline in one same complex proved to be an excellent strategy for activity improvement. (C) 2010 Elsevier Masson SAS. All rights reserved.

Nitrosyl ethylenediaminetetraacetate ruthenium(II) complex promotes cellular growth and could be used as nitric oxide donor in plants

Over recent years nitric oxide (NO) not only has appeared as an important endogenous signaling molecule in plants and as a mediator in many developmental and physiological processes, but has also received recognition as a plant hormone. The impressive recent achievements in elucidating the role of NO in plants have come about by the application of NO donors. The aim herein was to study the effects of the different NO donors, sodium nitroprusside (SNP) and the nitrosyl ethylenediaminetetraacetate ruthenium(II) ([Ru(NO)(Hedta)]) complex on cellular growth in embryogenic suspension cultures of Araucaria angustifolia. Appraisal of our data revealed that [Ru(NO)(Hedta)] stimulated about 60% of cellular growth in embryogenic suspension cultures of A. angustifolia, with results similar to those observed with the SNP donor. Nevertheless, application of the NO scavenger PTIO (2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide) inhibited this cellular growth in both. Cellular growth was correlated with an increase in endogenous NO levels after 21 days of culture, especially in treatments with NO donors. Our results demonstrated that the [Ru(NO)Hedta] complex could possibly be used as a NO donor in plants. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

New Ni(II)-sulfonamide complexes: Synthesis, structural characterization and antibacterial properties. X-ray diffraction of [Ni(sulfisoxazole)(2)(H2O)(4)] center dot 2H(2)O and [Ni(sulfapyridine)(2)]

The synthesis, structural characterization, voltammetric experiments and antibacterial activity of [Ni(sulfisoxazole)(2)(H2O)(4)] center dot 2H(2)O and [Ni(sulfapyridine)(2)] were studied and compared with similar previously reported copper complexes. [Ni(sulfisoxazole)(2)(H2O)(4)] center dot 2H(2)O crystallized in a monoclinic system, space group C2/c where the nickel ion was in a slightly distorted octahedral environment, coordinated with two sulfisoxazole molecules through the heterocyclic nitrogen and four water molecules. [Ni(sulfapyridine)(2)] crystallized in a orthorhombic crystal system, space group Pnab. The nickel ion was in a distorted octahedral environment, coordinated by two aryl amine N from two sulfonamides acting as monodentate ligands and four N atoms (two sulfonamidic N and two heterocyclic N) from two different sulfonamide molecules acting as bidentate ligands. Differential pulse voltammograms were recorded showing irreversible peaks at 1040 and 1070 mV, respectively, attributed to Ni(II)/Ni(III) process. [Ni(sulfisoxazole)(2)(H2O)(4)] center dot 2H(2)O and [Ni(sulfapyridine)(2)] presented different antibacterial behavior against Staphylococcus aureus and Escherichia coli from the similar copper complexes and they were inactive against Mycobacterium tuberculosis. (c) 2007 Elsevier Inc. All rights reserved.

Perspectives for Novel Mixed Diruthenium-Organic Drugs as Metallopharmaceuticals in Cancer Therapy

Ruthenium compounds have been actively studied as metallodrugs for cancer therapy. Representatives of ruthenium-based antitumor drugs are the classes of ruthenium(III)-chlorido-(N-ligand)complexes, including the drugs namely NAMI-A and KP1019 in clinical trials, and ruthenium(II)-arene organometallics, with some compounds currently undergoing advanced preclinical testing. An alternative approach for tumor-inhibiting metallodrugs is the coordination of metal ions to organic pharmaceuticals. The combination of antitumor-active ruthenium ion with biologically-active pro-ligands in single compounds can result in the enhancement of activity, for example through synergistic effects. In the present article, some developments in the ruthenium-based antitumor drugs field are briefly highlighted and recent studies on mixed diruthenium-organic drugs as metallopharmaceuticals in cancer therapy are described. Novel organic pharmaceuticals-containing diruthenium(II, III)complexes have shown promising antitumor activity for C6 rat glioma - a model for glioblastoma multiforme (GBA).

The reduction of Cu(II)/neocuproine complexes by some polyphenols: Total polyphenols determination in wine samples

A new method is presented for spectrophotometric determination of total polyphenols content in wine. The procedure is a modified CUPRAC method based on the reduction of Cu(II), in hydroethanolic medium (pH 7.0) in the presence of neocuproine (2,9-dimethyl-1,10-phenanthroline), by polyphenols, yielding a Cu(I) complexes with maximum absorption peak at 450 nm. The absorbance values are linear (r = 0.998, n = 6) with tannic acid concentrations from 0.4 to 3.6 mu mol L(-1). The limit of detection obtained was 0.41 mu mol L(-1) and relative standard deviation 1.2% (1 mu mol L(-1); n = 8). Recoveries between 80% and 110% (mean value of 95%) were calculated for total polyphenols determination in 14 commercials and 2 synthetic wine samples (with and without sulphite). The proposed procedure is about 1.5 more sensitive than the official Folin-Ciocalteu method. The sensitivities of both methods were compared by the analytical responses of several polyphenols tested in each method. (C) 2010 Elsevier Ltd. All rights reserved.

Synthesis, characterization, X-ray structure and in vitro anti mycobacterial and antitumoral activities of Ru(II) phosphine/diimine complexes containing the ""SpymMe(2)"" ligand, SpymMe(2)=4,6-dimethyl-2-mercaptopyrimidine

The reaction of cis-[RuCl2(dppb)(N-N)], dppb = 1,4-bis(diphenylphosphino)butane, complexes with the ligand HSpymMe(2), 4,6-dimethyl-2-mercaptopyrimidine, yielded the cationic complexes [Ru(SpymMe(2))(dppb)(N-N)]PF6, N-N = bipy (1) and Me-bipy (2), bipy = 2,2`-bipyridine and Me-bipy = 4,4`dimethyl-2,2`-bipyridine, which were characterized by spectroscopic and electrochemical techniques and X-ray crystallography and elemental analysis. Additionally, preliminary in vitro tests for antimycobacterial activity against Mycobacterium tuberculosis H37Rv ATCC 27264 and antitumor activity against the MDA-MB-231 human breast tumor cell line were carried out on the new complexes and also on the precursors cis-[RuCl2(dppb)(N-N)], N-N = bipy (3) and Me-bipy (4) and the free ligands dppb, bipy, Me-bipy and SpymMe(2). The minimal inhibitory concentration (MIC) of compounds needed to kill 90% of mycobacterial cells and the IC50 values for the antitumor activity were determined. Compounds 1-4 exhibited good in vitro activity against M. tuberculosis, with MIC values ranging between 0.78 and 6.25 mu g/mL, compared to the free ligands (MIC of 25 to >50 mu g/mL) and the drugs used to treat tuberculosis. Complexes I and 2 also showed promising antitumor activity, with IC50 values of 0.46 +/- 0.02 and 0.43 +/- 0.08 mu M, respectively, against MDA-MB-231 breast tumor cells. (C) 2008 Elsevier Inc. All rights reserved.

Dependence of the product on the P-P ligand in reactions of [RuCl(3)(NO)(P-P)] complexes (P-P = aromatic diphosphines) with 2-mercaptopyridine

This study presents the syntheses and characterization of 2-mercaptopyridine (pyS(-)) complexes containing ruthenium(II) with the following general formula [Ru(pyS)(2)(P-P)], P-P = (c-dppen) = cis-1,2-bis(diphenylphosphino)ethylene) (1); (dppe)=1,2-bis(diphenylphosphino)ethane (2); (dppp)=1,3-bis(diphenylphosphino)propane (3) and (dppb) = 1,4-bis(diphenylphosphino)butane (4). The complexes were synthesized from the mer- or fac-[RuCl(3)(NO)(P-P)] precursors in the presence of triethylamine in methanol solution with dependence of the product on the P-P ligand. The reaction of pyS- with a ruthenium complex containing a bulky aromatic diphosphine dppb disclosed a major product with a dangling coordinated dppbO-P, the [Ru(pyS)(2)(NO)(eta(1)-dppbO-P)]PF(6) (5). In addition, this work also presents and discusses the spectroscopic and electrochemical behavior of 1-5. and report the X-ray structures for I and S. (C) 2009 Elsevier Ltd. All rights reserved.

On the synthesis and structures of the complexes [RuCl(L)(dppb)(N-N)]PF(6) (L = CO, py or 4-NH(2)py; dppb=1,4-bis(diphenylphosphino)butane; N-N=2,2 `-bipyridine or 1,10-phenanthroline) and [(dppb)(CO)Cl(2)-Ru-pz-RuCl(2)(CO)(dppb)] (pz = pyrazine)

The ""Ru(P-P)"" unit (P-P = diphosphine) is recognized to be an important core in catalytic species for hydrogenation of unsaturated organic substrates. Thus, in this study we synthesized six new complexes containing this core, including the binuclear complex [(dppb)(CO)Cl(2)Ru-pz-RuCl(2)(CO)(dPPb)] (pz = pyrazine) which can be used as a precursor for the synthesis of cationic carbonyl species of general formula [RuCl(CO)(dppb)(N-N)]PF(6) (N-N = diimine). Complexes with the formula (RuCl(py)(dppb)(N-N)]PF(6) were synthesized by exhaustive electrolysis of these carbonyl compounds or from the precursors [RuCl(2)(dppb)(N-N)]. The new complexes were characterized by microanalysis, conductivity measurements, IR and (31)P{(1)H)} NMR spectroscopy, cyclic voltammetry and X-ray crystallography. (C) 2010 Elsevier Ltd. All rights reserved.

Effect of some antioxidants on oxidative DNA damage induced by autoxidation of microquantities of sulfite in the presence of Ni(II)/Gly-Gly-L-His

Ni(II)GGH (GGH, glycylglycyl-L-histidine) reacts rapidly with S(IV), in air-saturated solution, to produce Ni(III)GGH. A mechanism is proposed where Ni(III) oxidizes SO(3)(2-) to SO(3)(center dot-), which reacts with dissolved oxygen to produce SO(5)(center dot-), initiating radical chain reactions. DNA strand breaks and 8-oxo-7,8-dihydro-20-deoxyguanosine (8-oxodGuo) formation were observed in air-saturated solutions containing micromolar concentrations of nickel(II) and S(IV). The efficacies of melatonin, (-)-epigallocatechin-gallate (from green tea), resveratrol, tannic, and ascorbic acids in terms of their inhibitory activities of DNA strand breaks and 8-oxodGuo formation were evaluated.

Spectroscopic Investigation on the Formation of a Dinuclear Me(2)SO-Ru(2)-Mercaptopyridine Bridged Complex: [Ru(2)Cl(3)(mu-pyS)(mu-dmso)(dmso)(4)]center dot 2H(2)O

A dinuclear ruthenium(II) complex double-bridged by an N-aromatic ligand 2-mercaptopyridine (2-pyridinethiol or 2-pyridyl mercaptan) and a methyl sulfoxide (dmso) have been characterized by X-ray crystallography. The reported compound with formula [Ru(2)Cl(3) (mu-pyS)(mu-dmso)(dmso)(4)] center dot 2H(2)O, [C(15)H(36)Cl(3)NO(7)S(6)Ru(2)] (P2/c, a = 13.8175(2) angstrom, b = 10.5608(2) angstrom, c = 21.3544 (3) angstrom, beta = 106.090(1)degrees, V = 2,994.05(8) angstrom(3), Z = 4) represents a seven-membered ring system with both rutheniums in an octahedral geometry. All the hydrogen bonds (C-H-Cl) and the van der Waals contacts give rise to three-dimensional network in the structure and add stability to the dinuclear compound. To our knowledge, this is the first time that the formation of a dinuclear ruthenium(II) complex double-bridged by an N-aromatic ligand 2-mercaptopyridine and dmso have been reported. The study also provided valuable insight into bioinorganic chemistry as continuing efforts are being made to develop metal-based cancer chemotherapeutics. A major feature of this paper is the resolution of a double bridged ruthenium structure which contributes to a better understanding of ruthenium reactivity.

Functional Analysis of saxophone, the Drosophila Gene Encoding the BMP Type I Receptor Ortholog of Human ALK1/ACVRL1 and ACVR1/ALK2

In metazoans, bone morphogenetic proteins (BMPS) direct a myriad of developmental and adult homeostatic evens through their heterotetrameric type I and type II receptor complexes. We examined 3 existing and 12 newly generated mutations in the Drosophila type I receptor gene, saxophone (sax), the ortholog of the human Activin Receptor-Like. Kinasel and -2 (ALK1/ACVR1 and ALK2/ACVR1) genes. Our genetic analyses identified two distinct classes of sax alleles. The first class consists of homozygous viable gain-of-function (GOF) alleles that exhibit (1) synthetic lethality in combination with mutations in BMP pathway components, and (2) significant maternal effect lethality that can be rescued by an increased dosage of the BMP encoding gene, dpp(+). In contrast, the second class consists of alleles that are recessive lethal and do not exhibit lethality in combination with mutations in other BMP pathway components. The alleles in this second class are clearly loss-of-function (LOF) with both complete and partial loss-of-function mutations represented. We find that one allele in the second class of recessive lethals exhibits dominant-negative behavior, albeit distinct from the GOF activity of the first class of viable alleles. On the basis of the fact that the first class of viable alleles can be reverted to lethality and on our ability to independently generate recessive lethal sat mutations, our analysis demonstrates that sax is an essential gene. Consistent with this conclusion, we find that a normal sax transcript is produced by sax(P), a viable allele previously reported to be mill, and that this allele can be reverted to lethality. Interestingly, we determine that two mutations in the first: class of sax alleles show the same amino acid substitutions as mutations in the human receptors ALK1/ACVR1-1 and ACVR1/ALK2, responsible for cases of hereditary hemorrhagic telangiectasia type 2 (HHT2) and fibrodysplasia ossificans progressiva (FOP), respectively. Finally, the data presented here identify different functional requirements for the Sax receptor, support the proposal that Sax participates in a heteromeric receptor complex, and provide a mechanistic framework for future investigations into disease states that arise from defects in BMP/TGF-beta signaling.