Gold complexes inhibit mitochondrial thioredoxin reductase: consequences on mitochondrial functions

The effects of gold(I) complexes (auranofin, triethylphosphine gold and aurothiomalate), gold(III) complexes ([Au(2,2'-diethylendiamine)Cl]Cl(2), [(Au(2-(1,1-dimethylbenzyl)-pyridine) (CH(3)COO)(2)], [Au(6-(1,1-dimethylbenzyl)-2,2'-bipyridine)(OH)](PF(6)), [Au(bipy(dmb)-H)(2,6-xylidine)](PF(6))), metal ions (zinc and cadmium acetate) and metal complexes (cisplatin, zinc pyrithione and tributyltin) on mitochondrial thioredoxin reductase and mitochondrial functions have been examined. Both gold(I) and gold(III) complexes are extremely efficient inhibitors of thioredoxin reductase showing IC(50) ranging from 0.020 to 1.42 microM while metal ions and complexes not containing gold are less effective, exhibiting IC(50) going from 11.8 to 76.0 microM. At variance with thioredoxin reductase, auranofin is completely ineffective in inhibiting glutathione peroxidase and glutathione reductase, while gold(III) compounds show some effect on glutathione peroxidase. The mitochondrial respiratory chain is scarcely affected by gold compounds while the other metal complexes and metal ions, in particular zinc ion and zinc pyrithione, show a more marked inhibitory effect that is reflected on a rapid induction of membrane potential decrease that precedes swelling. Therefore, differently from gold compounds, the various metal ions and metal complexes exert their effect on different targets indicating a lower specificity. It is concluded that gold compounds are highly specific inhibitors of mitochondrial thioredoxin reductase and this action influences other functions such as membrane permeability properties. Metal ions and metal complexes markedly inhibit the activity of thioredoxin reductase although to an extent lower than that of gold compounds. They also inhibit mitochondrial respiration, decrease membrane potential and, finally, induce swelling.     

Mechanistic studies on two dinuclear organogold(III) compounds showing appreciable antiproliferative properties and a high redox stability

Two dinuclear oxo-bridged organogold(III) compounds, namely [(N,N,C)(2)Au(2)(μ-O)][PF(6)](2) (with N,N,CH = 6-(1-methylbenzyl)-2,2'-bipyridine, Au(2)O1; or 6-(1,1-dimethylbenzyl)-2,2'-bipyridine, Au(2)O2), were previously prepared and characterised. Their solution chemistry under physiological-like conditions has been investigated here as well as their in vitro antiproliferative properties. Notably, these compounds reveal a marked redox stability even in the presence of effective biological reductants such as ascorbic acid and glutathione. The two dinuclear gold(iii) compounds were evaluated for cytotoxic actions against a representative panel of 12 human tumor cell lines, in comparison to respective mononuclear parent compounds [(N,N,C)AuOH][PF(6)], and appreciable biological activity could be highlighted. The reactions of Au(2)O1 and Au(2)O2 with a few model proteins were studied and the ability to form metallodrug-protein adducts monitored through ESI MS methods. Typical adducts were identified where the protein is associated to monometallic gold fragments; in these adducts gold remains in the oxidation state +3 and conserves its organic ligand. A direct comparison of the biological profiles of these binuclear organogold(III) compounds with those previously reported for a series of dinuclear oxo-bridged complexes [(N,N)(2)Au(2)(μ-O)(2)][PF(6)](2) (N,N = 6(6')-substituted 2,2'-bipyridines) named Auoxo's was carried out. It emerges that the greater cytotoxicity of the latter is mainly due to the greater oxidising power of their gold(III) centres and to propensity to generate gold(i) species; in contrast, the here described bimetallic organogold(III) complexes manifest a far higher redox stability in the biological milieu coupled to lower, but still significant, antiproliferative properties. Different molecular mechanisms are thus hypothesised for these two classes of dinuclear gold(III) agents.     

Solution chemistry and cytotoxic properties of novel organogold(III) compounds

The solution behaviour of some novel organogold(III) compounds was investigated, and their cytotoxic properties evaluated against a few human tumour cell lines (A2780/S, A2780/R, MCF7, HT29 and A549). Specifically, the following compounds were considered: [Au(bipy(dmb)-H)(2,6-xylidine-H)][PF(6)] (AuXyl) and [Au(bipy(dmb)-H)(p-toluidine-H)][PF(6)] (AuTol) (in which bipy(dmb)=6-(1,1-dimethylbenzyl)-2,2'-bipyridine), [Au(py(dmb)-H)(AcO)(2)] (AuPyAcO) (in which py(dmb)=2-(1,1-dimethylbenzyl)-pyridine) and [Au(pz(Ph)-H)Cl(3)]K (AuPzCl) (in which pz(Ph)=1-phenylpyrazole). The solution chemistry of these compounds, under physiological-like conditions, was investigated through UV-vis absorption and (1)H NMR spectroscopies. Significant cytotoxic effects in vitro were observed in selected cases.     

Half-sandwich Ru II[9]aneS3 complexes structurally similar to antitumor-active organometallic piano-stool compounds: preparation, structural characterization and in vitro cytotoxic activity

The preparation, structural characterization, and chemical behavior in aqueous solution of a series of new Ru[9]aneS3 half-sandwich complexes of the type [Ru([9]aneS3)Cl(NN)][CF3SO3] and [Ru([9]aneS3)(dmso-S)(N-N)][CF3SO3]2 (5-15, NN=substituted bpy or 2x1-methylimidazole) are described. The X-ray structures of [Ru([9]aneS3)Cl(3,3'-H2dcbpy)][CF3SO3] (9) (3,3'-H2dcbpy=3,3'-dicarboxy-2,2'-bipyridine), [Ru([9]aneS3)Cl(4,4'-dmobpy)][CF3SO3] (13) (4,4'-dmobpy=4,4'-dimethoxy-2,2'-bipyridine), and [Ru([9]aneS3)Cl(1-MeIm)2][CF3SO3] (15) (1-MeIm=1-methylimidazole) were also determined. The new compounds are structurally similar to anticancer-active organometallic half-sandwich complexes of formula [Ru(eta6-arene)Cl(NN)][PF6]. Three chloro compounds (5, 9, 15) were tested in vitro for cytotoxic activity against two human cancer cell lines in comparison with the previously described [Ru([9]aneS3)Cl(en)][CF3SO3] (1, en=ethylenediamine), [Ru([9]aneS3)Cl(bpy)][CF3SO3] (2), and with their common dmso precursor [Ru([9]aneS3)Cl(dmso-S)2][CF3SO3] (3). Only the ethylenediamine complex 1 showed some antiproliferative activity, ca. one order of magnitude lower than the reference organometallic half-sandwich compound RM175 that contains biphenyl instead of [9]aneS3. This compound was further tested against a panel of human cancer cell lines (including one resistant to cisplatin).     

Characterization of synthetic oxomanganese complexes and the inorganic core of the O2-evolving complex in photosystem II: evaluation of the DFT/B3LYP level of theory

The capabilities and limitations of the Becke-3-Lee-Yang-Parr (B3LYP) hybrid density functional are investigated as applied to studies of mixed-valent multinuclear oxomanganese complexes. Benchmark calculations involve the analysis of structural, electronic and magnetic properties of di-, tri- and tetra-nuclear Mn complexes, previously characterized both chemically and spectroscopically, including the di-mu-oxo bridged dimers [Mn(III)Mn(IV)(mu-O)(2)(H(2)O)(2)(terpy)(2)](3+) (terpy=2,2':6,2'-terpyridine) and [Mn(III)Mn(IV)(mu-O)(2)(phen)(4)](3+) (phen=1,10-phenanthroline), the Mn trimer [Mn(3)O(4)(bpy)(4)(H(2)O)(2)](4+) (bpy=2,2'-bipyridine), and the tetramer [Mn(4)O(4)L(6)](+) with L=Ph(2)PO(2)(-). Furthermore, the density functional theory (DFT) B3LYP level is applied to analyze the hydrated Mn(3)O(4)CaMn cluster completely ligated by water, OH(-), Cl(-), carboxylate and imidazole ligands, analogous to the '3+1 Mn tetramer' of the oxygen-evolving complex of photosystem II. It is found that DFT/B3LYP predicts structural and electronic properties of oxomanganese complexes in pre-selected spin-electronic states in very good agreement with X-ray and magnetic experimental data, even when applied in conjunction with rather modest basis sets. However, it is conjectured that the energetics of low-lying spin-states is beyond the capabilities of the DFT/B3LYP level, constituting a limitation to mechanistic studies of multinuclear oxomanganese complexes where until now the performance of DFT/B3LYP has raised little concern.     

Interactions of selected gold(III) complexes with calf thymus DNA

DNA represents the primary target for platinum antitumor metal complexes and is the probable target for newly developed cytotoxic gold(III) complexes. To test this hypothesis the reactions with calf thymus DNA of five representative gold(III) complexes--namely [Au(en)(2)]Cl(3), [Au(dien)Cl]Cl(2), [Au(cyclam)](ClO(4))(2)Cl, [Au(terpy)Cl]Cl(2) and [Au(phen)Cl(2)]Cl--were analyzed in vitro through various physicochemical techniques including circular dichroism, absorption spectroscopy, DNA melting, and ultradialysis. It is shown that all tested complexes interact with DNA and modify significantly its solution behavior. The solution conformation of DNA is affected to variable extents by the individual complexes as shown by CD titration experiments. Notably, in all cases, the gold(III) chromophore is not largely perturbed by addition of calf thymus DNA ruling out occurrence of gold(III) reduction. Ultradialysis experiments point out that the binding affinity of the various complexes for the DNA double helix is relatively low; in most cases the gold(III)/DNA interaction is electrostatic in nature and reversible. The implications of these findings for the mechanism of action of antitumor gold(III) complexes are discussed.     

Effects of aurothiomalate and gold(III) complexes on spontaneous motility of isolated human oviduct

Organic gold complexes have different biological activity, depending on their potential for interactions with key functional molecules.The aim of this study was to investigate potential of several newly synthesized organic gold complexes to influence spontaneous motility of the Fallopian tubes.The effects of [Au(bipy)Cl(2)](+) (dichloride(2,2'-bipyridyl)aurate(III)-ion), aurothiomalate, [Au(DMSO)(2)Cl(2)]Cl and DMSO on spontaneous motility of Fallopian tubes were tested on the isolated tube segments in vitro. Aurothiomalate (from 2.9?×?10(-9) to 4.9?×?10(-4)?M/l), [Au(bipy)Cl(2)]Cl (from 3.3?×?10(-9) to 4.2?×?10(-5)?M/l) and DMSO (from 1.9?×?10(-8) to 1.0?×?10(-5)?M/l) did not affect spontaneous contractions of the isolated Fallopian tube ampulla, while [Au(DMSO)(2)Cl(2)]Cl (from 2.9?×?10(-9) to 4.2?×?10(-5)?M/l) showed concentration-dependent increase (stimulation) of spontaneous contractions of the isolated Fallopian tube isthmus, and remained without effect on the isolated ampulla.The drugs designed as organic gold complexes with weaker bonds between the gold itself and organic part of a molecule could adversely affect motility of the Fallopian tubes, and theoretically fertility of women taking such drugs in their reproductive age.     

Redox and ligand exchange reactions of potential gold(I) and gold(III)-cyanide metabolites under biomimetic conditions

Biomimetic pathways for the oxidation of [Au(CN)(2)](-), a gold metabolite, and further cyanation of the gold(III) products to form Au(CN)(4)(-) were investigated using 13C NMR and UV-Visible spectroscopic methods. Hypochlorite ion, an oxidant released during the oxidative burst of immune cells, was employed. The reaction generates mixed dicyanoaurate(III) complexes, trans-[Au(CN)(2)X(2)](-), where X(-) represents equilibrating hydroxide and chloride ligands, and establishes the chemical feasibility of dicyanoaurate oxidation by OCl(-) to gold(III) species. This oxidation reaction suggests a new procedure for synthesis of H[Au(CN)(2)Cl(2)]. Reaction of trans-[Au(CN)(2)X(2)](-) (X(-)=Cl(-) and Br(-)) or [AuCl(4)](-) with HCN in aqueous solution at pH 7.4 leads directly to [Au(CN)(4)](-) without detection of the anticipated [Au(CN)(x)X(4-x)](-)intermediates, which is attributed to the cis- and trans-accelerating effects of the cyanides. The reduction of [Au(CN)(4)](-) by glutathione and other thiols is a complex, pH-dependent process that proceeds through two intermediates and ultimately generates [Au(CN)(2)](-). These studies provide further insight into the possible mechanisms of an immunogenically generated gold(I)/gold(III) redox cycle in vivo.     

Proton-linked bi- and tri-metallic gold cyanide complexes observed by ESI-MS spectrometry

Electrospray ionization spectra of potential cyanide-containing gold-drug metabolites revealed additional, weak, unanticipated peaks at approximately twice the mass of the gold(I) and gold(III) cyanide complexes. The exact masses correspond to proton-linked bimetallic complexes, [H[Au(CN)(m)](2)](-), (m=2,4). Further investigation revealed a total of 12 examples, including trimetallic complexes, [H(2)[Au(CN)(m)](3)](-); mixed species with two complexes, [H[Au(CN)(2)][Au(CN)(4)]](-); and thiolato species, [H[(RS)Au(CN)(3)](2)](-). trans-[AuX(2)(CN)(2)Cl(2)](-) and trans-[AuX(2)(CN)(2)Br(2)](-) generated (35)Cl/(37)Cl and (79)Br/(81)Br isotopic patterns for the protonated bi- and tri-metallic analogues which were in good agreement with the presence of four or six halide ligands, respectively. Concentration-dependent studies demonstrated that the signals are independent of the solution concentrations of mono-metallic precursors, suggesting formation in the gas phase during or following droplet desolvation.     

Intercalation into the DNA double helix and in vivo biological activity of water-soluble planar [Pt(diimine)(N,N-dihydroxyethyl-N'-benzoylthioureato)]+Cl- complexes: a study of their thermal stability, their CD spectra and their gel mobility

The interaction of newly synthesised water-soluble planar complexes of general structure [Pt(diimine)(N,N-dihydroxyethyl-N'-benzoylthioureato)]+Cl- with DNA was investigated by means of DNA melting studies, CD spectroscopy, and DNA gel mobility studies. Addition of stoichometric amounts of [Pt(diimine)H2L-S,O]Cl complexes to polynucleotides caused a significant increase in the melting temperature of poly(dA-dT) and calf-thymus DNA, respectively, indicating that these complexes interacted with DNA and stabilised the double helical structure. The CD spectra confirmed the relatively strong binding of three related Pt(II) complexes ([Pt(2,2'-bipyridine)H2L-S,O]Cl, [Pt(4,4'-dimethyl-2,2'-bipyridine)H2L-S,O]Cl, and [Pt(1,10-phenanthroline)H2L-S,O]Cl), to DNA. Comparison with the published CD spectra of ethidium bromide/DNA complex suggests a similar intercalation mode of binding. cis-[(4,4'-di-tert-butyl-2,2'-bipyridyl)N,N-di(2-hydroxyethyl)-N'-benzoylthioureatoplatinum(II)] chloride, with its very bulky tert-butyl groups, did not intercalate into the polynucleotide double helix. In DNA mobility studies in the presence of the four [Pt(diimine)H2L-S,O]Cl complexes, only [Pt(2,2'-bipyridine)H2L-S,O]Cl affected the DNA mobility to any detectable extent. Finally, in vivo studies on the biological activity of the complexes, using an Escherichia coli DNA excision repair deficient uvrA mutant strain, indicated that only the [Pt(2,2'-bipyridine)H2L-S,O]Cl complex showed significant cellular toxicity and that this was, in part, linked to DNA damage.     

DNA-binding and photocleavage studies of cobalt(III) mixed-polypyridyl complexes containing 2-(2-chloro-5-nitrophenyl)imidazo [4,5-f][1,10]phenanthroline

The ligand 2-(2-chloro-5-nitrophenyl)imidazo[4,5-f][1,10]phenanthroline(CNOIP) and its complexes [Co(bpy)(2)(CNOIP)](3+) (1) and [Co(phen)(2)(CNOIP)](3+) (2) (bpy=2,2'-bipyridine; phen=1,10-phenanthroline) have been synthesized and characterized. Binding of the two complexes with calf thymus DNA has been investigated by spectroscopic methods, cyclic voltammetry, viscosity, and electrophoresis measurements. The experimental results indicate that both complexes bind to DNA through an intercalative mode. In comparison with their parent complexes containing PIP ligand (PIP=2-phenylimidazo[4,5-f][1,10]phenanthroline), the introduction of NO(2) and Cl groups to the PIP ligand decreased the binding affinity of complexes 1 and 2 to CT DNA. Both complexes have also been found to promote the photocleavage of plasmid pBR 322 DNA, the hydroxyl radical (OH*) is suggested to be the reactive species responsible for the cleavage.     

Synthesis, characterization, and DNA-binding of chiral complexes delta- and lambda-[Ru(bpy)2(pyip)]2+

New chiral Ru(II) complexes delta and lambda-[Ru(bpy)(2)(pyip)](PF(6))(2) [(bpy = 2,2'-bipyridine; pyip = (2-(1-pyrenyl)-1H-imidazo[4,5-f] [1,10]phenanthroline] were synthesized and characterized by elemental analysis, (1)H NMR, ESI-MS, IR, and CD spectra. Their DNA-binding properties were studied by means of UV-vis, emission spectra, CD spectra and viscosity measurements. A subtle but detectable difference was observed in the interaction of both enantiomer with CT-DNA. Spectroscopy experiments indicated that each of these complexes could interact with the DNA. The DNA-binding of the Delta-enantiomer was stronger than that of Lambda-enantiomer. DNA-viscosity experiments provided evidence that both Delta- and Lambda-[Ru(bpy)(2)(pyip)](PF(6))(2) bound to DNA by intercalation. At the same time, the DNA-photocleavage properties of the complexes were investigated too. Under irradiation with UV light, Ru(II) complexes showed different efficiency of cleaving DNA.     

Cyclometalated ruthenium(II) complexes as efficient redox mediators in peroxidase catalysis

Cyclometalated ruthenium(II) complexes, [Ru(II)(C~N)(N~N)(2)]PF(6) [HC~N=2-phenylpyridine (Hphpy) or 2-(4'-tolyl)pyridine; N~N=2,2'-bipyridine, 1,10-phenanthroline, or 4,4'-dimethyl-2,2'-bipyridine], are rapidly oxidized by H(2)O(2) catalyzed by plant peroxidases to the corresponding Ru(III) species. The commercial isoenzyme C of horseradish peroxidase (HRP-C) and two recently purified peroxidases from sweet potato (SPP) and royal palm tree (RPTP) have been used. The most favorable conditions for the oxidation have been evaluated by varying the pH, buffer, and H(2)O(2) concentrations and the apparent second-order rate constants ( k(app)) have been measured. All the complexes studied are oxidized by HRP-C at similar rates and the rate constants k(app) are identical to those known for the best substrates of HRP-C (10(6)-10(7) M(-1) s(-1)). Both cationic (HRP-C) and anionic (SPP and RPTP) peroxidases show similar catalytic efficiency in the oxidation of the Ru(II) complexes. The mediating capacity of the complexes has been evaluated using the SPP-catalyzed co-oxidation of [Ru(II)(phpy)(bpy)(2)]PF(6) and catechol as a poor peroxidase substrate as an example. The rate of enzyme-catalyzed oxidation of catechol increases more than 10000-fold in the presence of the ruthenium complex. A simple routine for calculating the rate constant k(c) for the oxidation of catechol by the Ru(III) complex generated enzymatically from [Ru(II)(phpy)(bpy)(2)](+) is proposed. It is based on the accepted mechanism of peroxidase catalysis and involves spectrophotometric measurements of the limiting Ru(II) concentration at different concentrations of catechol. The calculated k(c) value of 0.75 M(-1) s(-1) shows that the cyclometalated Ru(II) complexes are efficient mediators in peroxidase catalysis.     

Iron(III) complexes of certain meridionally coordinating tridentate ligands as models for non-heme iron enzymes: the role of carboxylate coordination

The iron(III) complexes [Fe(pda)Cl(H(2)O)(2)] (1), [Fe(tpy)Cl(3)] (2), and [Fe(bbp)Cl(3)] (3), where H(2)pda is pyridine-2,6-dicarboxylic acid, tpy is 2,2':6,2'-terpyridine and bbp is 2,6-bis(benzimidazolyl)pyridine, have been isolated and studied as functional models for the intradiol-cleaving catechol dioxygenase enzymes. Mixed ligand complexes of H(2)pda with the bidentate ligands 2,2'-bipyridine (bpy) and 1,10-phenanthroline (phen) have been also prepared and studied. All the complexes have been characterized using absorption spectral and electrochemical methods. The spectral changes in the catecholate adducts of the complexes generated in situ have been investigated. Upon interacting the complexes with catecholate anions a low energy catecholate to iron(III) charge transfer band appears, which is similar to that observed for enzyme-substrate complexes. All the complexes catalyze the oxidative intradiol cleavage of 3,5-di-tert-butylcatechol (H(2)dbc) in the presence of dioxygen. Interestingly, on replacing the pyridyl groups in 2 and the bulky benzimidazole groups in 3 by the carboxylate groups, the yields of the intradiol cleavage products of dioxygenation increases, 1 (50%)>2 (20%)>3 (10%). The higher intradiol yield for 1 has been ascribed to the meridional coordination of two carboxylate groups of pda(2-). In contrast to the trend in the intradiol cleavage yields, a tremendous decrease in the rate (200 times) is observed on replacing the two pyridyl moieties in 2 by two carboxylates as in 1 and a significant decrease in rate is observed on replacing the pyridyl moieties in 2 by strongly sigma-donating benzimidazole moieties as in 3. This is in conformity with the decrease in Lewis acidities of the iron(III) centers.     

Synthesis of redox derivatives of lysine and related peptides containing phenothiazine or tris(2,2'-bipyridine)ruthenium(II).

Boc-L-Lysine derivatives and lysine-containing peptides bearing the electron donor 10H-phenothiazine (PTZ) or the redox chromophore tris(2,2'-bipyridine)ruthenium(II) dication ([Rub3]2+, where b is 2,2'-bipyridine) have been synthesized and characterized. SeO2 oxidation (53% yield) of 4,4'-dimethyl-2,2'-bipyridine, Ag2O oxidation (85% yield) of the monoaldehyde, complexation (96% yield) of 4'-methyl-2,2'-bipyridine-4-carboxylic acid (m-OH) with Rub2Cl2, activation (81% yield) of the acid [Rub2m-OH]2+ (PF6-)2, and condensation (83% yield) of the succinimido ester [Rub2m-OSu]2+ (PF6-)2 with Boc-Lys furnished the protected redox-chromophore module [Boc-Lys(Rub2m)-OH]2+ (PF6-)2 in 29% overall yield over five steps. The first two steps constitute the first practical synthesis of the monocarboxylic acid m-OH (45% overall yield). Also prepared were m-OSu, Boc-Lys(m)-OH, Boc-Lys(m)-OCH3, and [Rub2m-NHCH3]2+ (PF6-)2. Activation (91% yield) of 3-(10H-phenothiazine-10)propanoic acid (PTZpn-OH) and condensation (92% yield) of the succinimido ester PTZpn-OSu with Boc-Lys furnished the protected electron-donor module Boc-Lys(PTZpn)-OH (84% overall yield). The latter was used in solid-phase syntheses of two redox tripeptides, CH3CO-Ala-Lys(PTZpn)-Ala-OH and [Rub2m-Ala-Lys(PTZpn)-Ala-OH]2+ (PF6-)2. The electrochemical properties of these redox amino acids and peptides were similar to those of PTZpn-OH, [Rub2m-OH]2+ (PF6-)2, or [Rub2m-NHCH3]2+ (PF6-)2. Lys(PTZpn), [Lys(Rub2m)]2+ (PF6-)2, and other redox modules may be useful for engineering light-harvesting proteins, photovoltaic cells, and other molecular electronic devices.     

Synthesis, characterization and DNA binding studies of two mixed ligand complexes of ruthenium(II)

Two mixed ligand complexes [Ru(bpy)(2)(DMHBT)]Cl(2)(1) and [Ru(phen)(2)(DMHBT)]Cl(2) (2) (where DMHBT is 11,13-dimethyl-13H-4,5,9,11,14-hexaaza-benzo[b]triphenylene-10,12-dione) have been synthesized and characterized by electrospray ionization (ESI) mass, (1)H-(1)H correlation spectroscopy (COSY), electronic spectroscopy, fluorescence spectroscopy and cyclic voltammetry. Spectroscopic titration and viscosity changes of calf thymus (CT)-DNA in the presence of incremental amount of complexes 1 and 2 clearly demonstrate that both these complexes bind intercalatively to DNA, with binding constant 2.87+/-0.20 x 10(4)M(-1) and 1.01+/-0.20 x 10(5)M(-1) for complexes 1 and 2, respectively. All the experimental evidences suggest that the ancillary ligand 2,2'-bipyridine (bpy) and 1,10-phenanthroline (phen) influences the intercalative binding of these complexes to DNA.     

The interaction of Rh(II) and Rh(III) with DNA

The interaction of Rh2(II)(acetate)4, cis-[Rh(III)(en)2Cl2] Cl (en = ethylenediamine) and [Rh(III) (NH3)5Cl]Cl2 with calf thymus DNA has been studied at various r values [formula; see text] and interaction times. Electronic spectra, melting and cooling curves and sedimentation data indicate no interaction of the acetate complex with DNA, except in the case of a high r value and long interaction time. The other two complexes have been found to interact with the phosphate groups, thus stabilizing the macromolecule.     

The macrocyclic effect and vasodilation response based on the photoinduced nitric oxide release from trans-[RuCl(tetraazamacrocycle)NO](2+)

Irradiation of trans-[RuCl(cyclam)(NO)](2+), cyclam is 1,4,8,11-tetraazacyclotetradecane, at pHs 1-7.4, with near UV light results in the release of NO and formation of trans-[Ru(III)Cl(OH)(cyclam)](+) with pH dependent quantum yields (from approximately 0.01 to 0.16 mol Einstein(-1)) lower than that for trans-[RuCl([15]aneN(4))(NO)](2+), [15]aneN(4) is 1,4,8,12-tetaazacyclopentadecane, (0.61 mol Einstein(-1)). After irradiation with 355 nm light, the trans-[RuCl([15]aneN(4))(NO)](2+) induces relaxation of the aortic ring, whereas the trans-[RuCl(cyclam)(NO)](2+) complex does not. The relaxation observed with trans-[RuCl([15]aneN(4))(NO)](2+) is consistent with a larger quantum yield of release of NO from this complex.     

Developing red-emissive ruthenium(II) complex-based luminescent probes for cellular imaging

Ruthenium(II) complexes have rich photophysical attributes, which enable novel design of responsive luminescence probes to selectively quantify biochemical analytes. In this work, we developed a systematic series of Ru(II)-bipyrindine complex derivatives, [Ru(bpy)(3-n)(DNP-bpy)(n)](PF(6))(2) (n = 1, 2, 3; bpy, 2,2'-bipyridine; DNP-bpy, 4-(4-(2,4-dinitrophenoxy)phenyl)-2,2'-bipyridine), as luminescent probes for highly selective and sensitive detection of thiophenol in aqueous solutions. The specific reaction between the probes and thiophenol triggers the cleavage of the electron acceptor group, 2,4-dinitrophenyl, eliminating the photoinduced electron transfer (PET) process, so that the luminescence of on-state complexes, [Ru(bpy)(3-n)(HP-bpy)(n)](2+) (n = 1, 2, 3; HP-bpy, 4-(4-hydroxyphenyl)-2,2'-bipyridine), is turned on. We found that the complex [Ru(bpy)(DNP-bpy)(2)](2+) remarkably enhanced the on-to-off contrast ratio compared to the other two (37.8 compared to 21 and 18.7). This reveals a new strategy to obtain the best Ru(II) complex luminescence probe via the most asymmetric structure. Moreover, we demonstrated the practical utility of the complex as a cell-membrane permeable probe for quantitative luminescence imaging of the dynamic intracellular process of thiophenol in living cells. The results suggest that the new probe could be a very useful tool for luminescence imaging analysis of the toxic thiophenol in intact cells.     

Synthesis and anti-amoebic activity of gold(I), ruthenium(II), and copper(II) complexes of metronidazole

A series of Au, Ru, and Cu complexes of metronidazole (= [1-(2-hydroxyethyl)-2-methyl-5-nitro-1H-imidazole; 1) were prepared as highly potent anti-amoebic drugs. The complexes [Au(PPh3)(1)]PF6 (2), [Ru(1)2(Cl)2(H2O)2] (3), and [Cu(1)2(mu-Cl)(H2O)]2Cl2 (4) were readily synthesized from [Au(PPh3)Cl], RuCl3 x 3 H2O, and CuCl2 x 2 H2O, respectively. All complexes were thoroughly characterized by IR, UV/VIS, 1H-NMR, FAB-MS, elemental and thermogravimetric analyses, and, in the case of 4, also by X-ray crystallography (Fig. 1). All complexes were evaluated in vitro as growth inhibitors of Entamoeba histolytica (HM1:IMSS strain). Their IC50 values were in the range of 0.10-0.51 microM (Table 2), which makes these drugs, especially the Cu(II) complex 4, considerably more potent than uncomplexed metronidazole (1; IC50 = 1.81 microM), the current standard drug for the worldwide treatment of amoebiasis.