Coordination of Thiosemicarbazones and Bis(thiosemicarbazones) to Bismuth(III) as a Strategy for the Design of Metal-Based Antibacterial Agents

Complexes [Bi(2Fo4Ph)Cl(2) ] (1), [Bi(2Ac4Ph)Cl(2) ] (2), [Bi(2Bz4Ph)Cl(2) ] (3), [Bi(H(2) Gy3DH)Cl(3) ] (4), [Bi(H(2) Gy4Et)(OH)(2) Cl] (5), and [Bi(H(2) Gy4Ph)Cl(3) ] (6) were prepared with pyridine-2-carbaldehyde 4-phenylthiosemicarbazone (H2Fo4Ph), 1-(pyridin-2-yl)ethanone 4-phenylthiosemicarbazone (H2Ac4Ph), phenyl(pyridin-2-yl)methanone 4-phenylthiosemicarbazone (H2Bz4Ph), as well as with glyoxaldehyde bis(thiosemicarbazone) (H(2) Gy4DH) and its 4-Et (H(2) Gy4Et) and 4-Ph (H(2) Gy4Ph) derivatives. The complexes exhibited antibacterial activities against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, and Pseudomonas aeruginosa. Coordination to Bi(III) proved to be an effective strategy to increase the antibacterial activity of the thiosemicarbazones and bis(thiosemicarbazones).     

Synthesis, structure and luminescence studies of heterometallic gold(I)-copper(I) and -silver(I) alkynyl clusters/aggregates.

A series of pentanuclear gold(I)-copper(I) and -silver(I) mixed-metal alkynyl complexes, [(n)Bu(4)N][Au(3)M(2)(C triple bond CC(6)H(4)R-p)(6)] [M = Cu, R = OMe, O(n)Bu, O(n)Hex, Me, Et; M = Ag, R = Et, O(n)Hex] have been synthesized. The complexes were found to be emissive both in the solid state and in fluid solutions. DFT calculations at the B3LYP level of theory were performed on [Au(3)M(2)(C triple bond CC(6)H(4)Me-p)(6)](-) (M = Cu, Ag) to provide an understanding on the electronic structure of the complexes.     

Gold(I) complexes with thiosemicarbazones: cytotoxicity against human tumor cell lines and inhibition of thioredoxin reductase activity

Complexes [Au(H2Ac4DH)Cl]?MeOH (1) [Au(H₂2Ac4Me)Cl]Cl (2) [Au(H₂2Ac4Ph)Cl]Cl?2H₂O (3) and [Au(H₂2Bz4Ph)Cl]Cl (4) were obtained with 2-acetylpyridine thiosemicarbazone (H2Ac4DH), its N(4)-methyl (H2Ac4Me) and N(4)-phenyl (H2Ac4Ph) derivatives, as well as with N(4)-phenyl 2-benzoylpyridine thiosemicarbazone (H2Bz4Ph). The compounds were cytotoxic to Jurkat (immortalized line of T lymphocyte), HL-60 (acute myeloid leukemia), MCF-7 (human breast adenocarcinoma) and HCT-116 (colorectal carcinoma) tumor cell lines. Jurkat and HL-60 cells were more sensitive than MCF-7 and HCT-116 cells. Upon coordinating to the gold(I) metal centers in complexes (2) and (4), the cytotoxic activity of the H2Ac4Me and H2Bz4Ph ligands increased against the HL-60 and Jurkat tumor cell lines. 2 was more active than auranofin against both leukemia cells. Most of the studied compounds were less toxic than auranofin to peripheral blood mononuclear cells (PBMC). All compounds induced DNA fragmentation in HL-60 and Jurkat cells indicating their pro-apoptotic potential. Complex (2) strongly inhibited the activity of thioredoxin reductase (TrxR), which suggests inhibition of TrxR to be part of its mechanism of action.     

Reactions of gold(III) complexes with serum albumin.

The reactions of a few representative gold(III) complexes -[Au(ethylenediamine)2]Cl3, [Au(diethylentriamine)Cl]Cl2, [Au(1,4,8,11-tetraazacyclotetradecane)](ClO4)2Cl, [Au(2,2',2'-terpyridine)Cl]Cl2, [Au(2,2'-bipyridine)(OH)2][PF6] and the organometallic compound [Au(6-(1,1-dimethylbenzyl)-2,2'-bipyridine-H)(OH)][PF6]- with BSA were investigated by the joint use of various spectroscopic methods and separation techniques. Weak metal-protein interactions were revealed for the [Au(ethylenediamine)2]3+ and [Au(1,4,8,11-tetraazacyclotetradecane)]3+ species, whereas progressive reduction of the gold(III) centre was observed in the cases of [Au(2,2'-bipyridine)(OH)2]+ and [Au(2,2',2'-terpyridine)Cl]2+. In contrast, tight metal-protein adducts are formed when BSA is reacted with either [Au(diethylentriamine)Cl]2+ and [Au(6-(1,1-dimethylbenzyl)-2,2'-bipyridine-H)(OH)]+. Notably, binding of the latter complex to serum albumin results in the appearance of characteristic CD bands in the visible spectrum. It is suggested that adduct formation for both of these gold(III) complexes occurs through coordination at the level of surface histidines. Stability of these gold(III) complexes/serum albumin adducts was tested under physiologically relevant conditions and found to be appreciable. Metal binding to the protein is tight; complete detachment of the metal from the protein has been achieved only after the addition of excess potassium cyanide. The implications of the present results for the pharmacological activity of these novel cytotoxic agents are discussed.     

Inhibition of lipoxygenase (LOX) and anticancer activity caused by gold(I) mixed ligands complexes of triphenylphosphine and thioamides

Four mixed ligand gold(I) complexes with the thioamides 2-mercapto-thiazolidine (mtzdH), 2-mercapto-benzothiazole (mbztH) and 5-chloro-2-mercapto-benzothiazole (ClmbztH) and triphenylphosphine (tpp) of formulae [Au(tpp)Cl] (1) [Au(tpp)(mtzd)] (2), [Au(tpp)(mbzt)] (3) and [Au(tpp)(Clmbzt)] (4), already known, were used to study their mechanism of inhibition activity towards the catalytic oxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX), kinetically and theoretically. The results are compared to those of cisplatin. In addition, the anticancer cell screening results against leimyosarcoma (LMS) cells have shown that 2-4 complexes were more active than cisplatin. The uptake of complexes in LMS cells were also studied with electrospray ionisation mass spectrometry spectroscopy.     

Complexes of dichloro[2-(dimethylaminomethyl)phenyl-C1,N]gold(III), [Au(damp-C1,N)Cl2], with formylferrocene thiosemicarbazones: synthesis, structure and cytotoxicity

Dichloro[2-(dimethylaminomethyl)phenyl- phenyl-C1,N]gold(III), [Au(damp-C1,N)Cl2], reacts with the formylferrocene thiosemicarbazones derived from 4-methyl-, 4-phenyl-, 4-ethyl- and 4,4-dimethyl-3-thiosemicarbazides, HFcTSC, to give complexes of general formula [Au(Hdamp-1C)Cl(FcTSC)]Cl. These complexes were isolated and characterized by elemental analysis, mass spectrometry and IR, 1H NMR and (13)C NMR spectroscopy. In some cases, cyclic voltammetric studies were carried out and these showed that the complexation of gold affects the redox behaviour of the ferrocene unit. The in vitro antitumor activity against the HeLa cell line was also determined for the more soluble complexes. The IC(50) values were found to be higher than that of cisplatin but the maximum antiproliferative activity was similar.     

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.     

Substrate and inhibitor specificities differ between human cytosolic and mitochondrial thioredoxin reductases: Implications for development of specific inhibitors

The cytosolic and mitochondrial thioredoxin reductases (TrxR1 and TrxR2) and thioredoxins (Trx1 and Trx2) are key components of the mammalian thioredoxin system, which is important for antioxidant defense and redox regulation of cell function. TrxR1 and TrxR2 are selenoproteins generally considered to have comparable properties, but to be functionally separated by their different compartments. To compare their properties we expressed recombinant human TrxR1 and TrxR2 and determined their substrate specificities and inhibition by metal compounds. TrxR2 preferred its endogenous substrate Trx2 over Trx1, whereas TrxR1 efficiently reduced both Trx1 and Trx2. TrxR2 displayed strikingly lower activity with dithionitrobenzoic acid (DTNB), lipoamide, and the quinone substrate juglone compared to TrxR1, and TrxR2 could not reduce lipoic acid. However, Sec-deficient two-amino-acid-truncated TrxR2 was almost as efficient as full-length TrxR2 in the reduction of DTNB. We found that the gold(I) compound auranofin efficiently inhibited both full-length TrxR1 and TrxR2 and truncated TrxR2. In contrast, some newly synthesized gold(I) compounds and cisplatin inhibited only full-length TrxR1 or TrxR2 and not truncated TrxR2. Surprisingly, one gold(I) compound, [Au(d2pype)(2)]Cl, was a better inhibitor of TrxR1, whereas another, [(iPr(2)Im)(2)Au]Cl, mainly inhibited TrxR2. These compounds also inhibited TrxR activity in the cytoplasm and mitochondria of cells, but their cytotoxicity was not always dependent on the proapoptotic proteins Bax and Bak. In conclusion, this study reveals significant differences between human TrxR1 and TrxR2 in substrate specificity and metal compound inhibition in vitro and in cells, which may be exploited for development of specific TrxR1- or TrxR2-targeting drugs.     

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.     

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.     

Inhibition of lipoxygenase (LOX) and anticancer activity caused by gold(I) mixed ligands complexes of triphenylphosphine and thioamides

Four mixed ligand gold(I) complexes with the thioamides 2-mercapto-thiazolidine (mtzdH), 2-mercapto-benzothiazole (mbztH) and 5-chloro-2-mercapto-benzothiazole (ClmbztH) and triphenylphosphine (tpp) of formulae [Au(tpp)Cl] (1) [Au(tpp)(mtzd)] (2), [Au(tpp)(mbzt)] (3) and [Au(tpp)(Clmbzt)] (4), already known, were used to study their mechanism of inhibition activity towards the catalytic oxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX), kinetically and theoretically. The results are compared to those of cisplatin. In addition, the anticancer cell screening results against leimyosarcoma (LMS) cells have shown that 2-4 complexes were more active than cisplatin. The uptake of complexes in LMS cells were also studied with electrospray ionisation mass spectrometry spectroscopy.     

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.     

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.     

Synthesis, crystal structure and antimicrobial activities of two isomeric gold(I) complexes with nitrogen-containing heterocycle and triphenylphosphine ligands, [Au(L)(PPh3)] (HL = pyrazole and imidazole)

Two isomeric gold(I)-triphenylphosphine complexes with nitrogen-containing heterocycles, [Au(L)(PPh3) (HL = pyrazole (1), imidazole (2)) were isolated as colorless cubic crystals for 1 and colorless plate crystals for 2, respectively. The crystal structures of 1 and 2 were determined by single-crystal X-ray diffraction. These complexes were also fully characterized by complete elemental analyses, thermogravimetric/differential thermal analyses (TG/DTA) and FT-IR in the solid state and by solution NMR (31P, 1H and 13C) spectroscopy and molecular weight measurements in acetone solution. These complexes consisted of a monomeric 2-coordinate AuNP core both in the solid state and in solution. The molecular structures of 1 and 2 were compared with those of related gold(I) complexes, [Au(1,2,3-triz)(PPh3)] (3, Htriz = triazole), [Au(1,2,4-triz)(PPh3)]2 (4) as a dimer through a gold(I)-gold(I) bond in the solid state, and [Au(tetz)(PPh3)] (5, Htetz = tetrazole). Selective and effective antimicrobial activities against two gram-positive bacteria (B. subtilis, S. aureus) and modest activities against one yeast (C. albicans) found in these gold(I) complexes 1-4 are noteworthy, in contrast to poor activities observed in the corresponding silver(I) complexes.     

Aurophilic interaction in gold(I) thiosaccharinates: Synthesis, characterization, crystal structures and DFT theoretical study

The reaction of gold with thiosaccharin ligand and additional phosphorous coligands is studied. Four new Au(I) complexes with thiosaccharinate as coordinating counteranion: [Au(tsac)(PPh₃)], [Au₂(tsac)₂(dppm)]·EtOH, Au₂(tsac)₂(dppe)·EtOH, and Au(tsac)(Htsac)₂·0.25 EtOH (tsac: thiosaccharinate, C₆H₄C(S)NSO₂⁻, dppm: bis(diphenylphosphino)methane, dppe: bis(diphenylphosphino)ethane) were synthesized and characterized by means of spectroscopic techniques (IR, UV-Vis, and ¹H, ¹³C and ¹³P NMR). The crystal structure of two of them, [Au(tsac)(PPh₃)] and [Au₂(tsac)₂(dppm)]·EtOH, were solved applying single crystal X-ray diffraction and studied using the density functional theory (DFT) formalism. In the latter, the aurophilic interaction between the two gold centers was analyzed and theoretically confirmed.     

Crystal structure and nuclease activity of mono(1,10-phenanthroline) copper complex

The hydroxo-bridged dinuclear copper (II)/phen complex [Cu(2)(phen)(2)(OH)(2)(H(2)O)(2)][Cu(2)(phen)(2)(OH)(2)Cl(2)]Cl(2).6H(2)O (phen=1,10-phenanthroline) has been prepared and characterized by single crystal X-ray diffraction. The coordinated area of the complex shows two distorted [CuN(2)O(2)O(w)] and [CuN(2)O(2)Cl] square-pyramidal and one strictly planar configuration CuO(2)Cu involving two O atoms of hydroxo-bridged, Cu(2+) cations, N atoms of two phen ligands and disorder solvate water and chlorine anions. In the presence of H(2)O(2), the complex of mono(1,10-phenanthroline)copper exhibits higher activity as a nuclease than bis(1,10-phenanthroline)copper.     

N,N-bis(2-mercaptoethyl)methylamine: a new coligand for Tc-99m labeling of hydrazinonicotinamide peptides

Hydrazinonicotinamide (HYNIC) forms stable coordination complexes with Tc-99m when reacted with Tc(V)oxo species such as Tc-mannitol or other Tc-polyhydric complexes. However, radio-HPLC of [Tc-For-MLFK-HYNIC] labeled via Tc-polyhydric ligands demonstrated multiple radiochemical species each with unique biodistribution patterns. This is likely due to the fact that Tc can bind to the hydrazino moiety, as well as polyhydric ligands, in a variety of coordination geometries. Tridentate ligands, such as bis(mercaptoethyl)methylamine (NS2), may constrain the possible coordination geometries and improve overall stability. To investigate this, we synthesized NS2, converted the [Tc-mannitol-For-MLFK-HYNIC] to the corresponding NS2-containing complex [Tc-NS2-For-MLFK-HYNIC], and compared its infection imaging and biodistribution properties with [Tc-mannitol-For-MLFK-HYNIC]. Conversion to the NS2 complex was confirmed by HPLC which showed a single unique hydrophobic species with retention time greater than the [Tc-mannitol-For-MLFK-HYNIC] complex. Imaging experiments with both preparations were performed in rabbits with E. coli infections in the left thigh. Tissue radioactivity measurements demonstrated that compared to Tc-mannitol-peptide, accumulation of Tc-NS2-peptide was lower in blood, heart, and normal muscle and higher in spleen, infected muscle, and pus (p < 0.01). These results indicate that the Tc-NS2-peptide complex is chemically more homogeneous and exhibits improved infection localization and biodistribution properties. In an effort to model the interactions of the metal-HYNIC core with NS2 and related ligand types, the reactions of [ReCl3(NNC5H4NH)(NHNC5H4N)] and [99TcCl3(NNC5H4NH)(NHNC5H4N)], effective structural analogues for the [M(NNC5H4NH(x))2] core, with NS2, C5H3N-2,6-(CH2SH)2, O(CH2CH2SH)2, and S(CH2CH2SH)2 were investigated and the compounds [M[CH3N(CH2CH2S)2](NNC5H4N)(NHNC5H4N] (M = 99Tc (5a), Re (5b)), [Re[C5H3N-2,6-(CH2S)2](NNC5H4N)(NHNC5H4N)].CH2Cl2.0.5MeOH (7), [Re[SCH2CH2)2O] (NNC5H4N)(NHNC5H4N)] (8), and [Re[(SCH2CH2)2S](NNC5H4NH)(NHNC5H4N)]Cl (9) were isolated. Similarly, the reaction of [ReCl3(NNC5H4NH)(NHNC5H4N)] with the bidentate ligands pyridine-2-methanethiol and 3-(trimethlysilyl)pyridine-2-thiol led to the isolation of [ReCl(C5H4N-2-CH2S) (NNC5H4N)(NHNC5H4N)] (10) and [Re(2-SC5H3N-3-SiMe3)2 (NNC5H4N)(NHNC5H4N)] (11), respectively, while reaction with N-methylimidazole-2-thiol yielded the binuclear complex [Re(OH)Cl(SC3H2N2CH3)2(NNC5H4N)2 (NHNC5H4N)2] (12). The analogous metal-(HYNIC-OH) precursor, [ReCl3[NNC5H3NH(CO2R)] [NHNC5H3N(CO2R)]] (R = H, 13a; R = CH3, 13b) has been prepared and coupled to lysine to provide [RCl3[NNC5H3NH(CONHCH2CH2CH2CH2CH(NH2)CO2H)] [NHNC5H3NH(CONHCH2CH2CH2CH2CH(NH2)CO2H)]].2HCl (14.2HCl), while the reaction of the methyl ester 13b with 2-mercaptopyridine yields [Re(2-SC5H4N)2[NNC5H3N(CO2Me)][NHNC5H3N(CO2Me)]] (15). While the chemical studies confirm the robustness of the M-HYNIC core (M = Tc, Re) and its persistence in ligand substitution reactions at adjacent coordination sites of the metal, the isolation of oligomeric structures and the insolubility of the peptide conjugates of 13, 14, and 15 underscore the difficulty of characterizing these materials on the macroscopic scale, an observation relevant to the persistent concerns with reagent purity and identity on the tracer level.     

Reactions of the Tridentate and Tetradentate Amine Ligands di-(2-picolyl)(N-ethyl)amine and 2,5-Bis-(2-pyridylmethyl)-2,5 diazohexane with Technetium Nitrosyl Complexes

The reaction of the Tc(II) nitrosyl complex (Bu₄N)[Tc(NO)Cl₄] with di-(2-picolyl)(NEt)amine in methanol yields the neutral complex [Tc(NO)Cl(py-N(Et)-py)]. The reaction of the Tc(I) nitrosyl complex [Tc(NO)Cl₂(HOMe)(PPh₃)₂] with this tridentate ligand yields cationic [Tc(NO)Cl(py-N(Et)-py)(PPh₃)]Cl. These two complexes have been structurally characterized. The reaction of [Tc(NO)Cl₂(HOMe)(PPh₃)₂] with the tetradentate ligand 1,4-bis-(2-pyridylmethyl)-1,4-diazobutane yields a mixture of products including cationic [Tc(NO)Cl(py-NH-NH-py)]Cl and cationic [Tc(NO)Cl(PPh₃)(py-NH-NH∼py)]Cl, with a pyridyl terminus left dangling.     

Au(2)(micro-G)(micro-dmpe)].(KBr)(0.75) 2H(2)O, a cyclic dinuclear gold(I) complex with an N3,N9-bridging coordination mode of guanine and aurophilic interactions: synthesis, X-ray crystal structure and luminescence properties (dmpe=1,2-bis(dimethylphosphino)ethane and G=guaninato dianion)

The digold complex [Au(2)(micro-G)(micro-dmpe)](KBr)(0.75) x 2H(2)O (dmpe=1,2-bis(dimethylphosphino)ethane (1)) has been prepared by nucleophilic attack of the guaninate dianion on the gold(I) atoms of [(AuBr)(2)(micro-dmpe)] and has been characterised by X-ray crystallography and spectroscopic studies. The structure of 1 consists of dinuclear nine-membered ring molecules, K(+) cations, Br(-) anions and water molecules, all of them involved in either weak K....O or hydrogen bonding interactions. Within the cyclic dinuclear molecules, gold(I) atoms are bridged on one side by the diphosphine ligand and on the other side by a doubly deprotonated guaninate anion coordinated through neighbouring N3 and N9 nitrogen atoms, with gold(I)....gold(I) interactions of 3.030(2) A. This is the first X-ray example showing an N3,N9-bridging mode for guanine. There are two types of K(+) cations in the structure, K1 and K2. The former interacts with water molecules to form a unique [K(H(2)O)(3)(micro-H(2)O)(2)K(H(2)O)(3)](2+) dipotassium unit whereas K2 interact with the O6 atom of the guaninate ligands and oxygen atoms of the dipotassium unit leading to a chain running along the c-axis. Each chain is interdigitated with four neighbouring ones to give rise to an intricate network in which Br1, Br2 and [K(H(2)O)(3)(micro-H(2)O)(2)K(H(2)O)(3)](2+) fit snugly into cavities defined by digold molecules. Complex 1 luminescence at room temperature and 77 K in the solid state with excitation maxima at 385 nm and emission maxima at 451.8 and 448.7 nm, respectively. The emission spectrum of a saturated solution of 1 in DMSO (dimethyl sulfoxide) shows the maximum at about 440 nm.     

Synthesis, characterization and biological activity of copper complexes with pyridoxal thiosemicarbazone derivatives. X-ray crystal structure of three dimeric complexes

A dimeric copper complex of the unsubstituted pyridoxal thiosemicarbazone (H(2)L), [[Cu(HL)(OH(2))](2)]Cl(2).2H(2)O, previously tested on Friend murine cell lines has been recently resynthesized to evaluate its behavior on different murine and human leukemic cell lines and has been compared, in vitro and in vivo, with its monomeric counterpart [Cu(H(2)L)(OH(2))Cl]Cl. On TS/A murine adenocarcinoma cell line in vitro, both compounds significantly inhibit cell proliferation at micromolar concentrations, although the dimeric compound is more active. Despite this cytotoxicity they lack in vivo activity on TLX5 lymphoma. The unsubstituted dimeric [[Cu(HL)(OH(2))](2)]Cl(2).2H(2)O induces apoptosis on CEM and U937 human cell lines, with IC(50) concentrations of 1.2 x 10(-5) and 6.7 x 10(-6) M, respectively, but it is inactive on K562. Moreover, it alters significantly the cell cycle of U937 and CEM lines and decreases the telomerase activity of U937. To verify if other dimeric copper complexes show relevant biological activity new complexes with N-substituted pyridoxal thiosemicarbazones have been synthesized and characterized using spectroscopic techniques. Three of them, namely [Cu(Me(2)-HL)Cl](2).6H(2)O (Me(2)-H(2)L=pyridoxal N1,N1-dimethylthiosemicarbazone) (1), [Cu(MeMe-HL)Cl](2)Cl(2).4H(2)O (MeMe-HL=pyridoxal N1,N2-dimethylthiosemicarbazone) (2), [Cu(Et-H(2)L)Cl](2)Cl(2).2H(2)O (Et-H(2)L=pyridoxal N1-ethylthiosemicarbazone) (3), were also characterized by X-ray diffractometry. These complexes are dimeric and all three present a square pyramidal coordinative geometry with the ligand showing an SNO tridentate behavior. Their biological activities have been tested in vitro on U937, CEM and K562 cell lines to ascertain their effectiveness in comparison to the corresponding unsubstituted complex [[Cu(HL)(OH(2))](2)]Cl(2).2H(2)O. Compound 1 shows weak proliferation inhibition on all three cell lines, but it does not induce apoptosis and it does not inhibit telomerase activity, compound 2 is not effective at low concentration and is toxic at higher doses; compound 3 inhibits CEM cell growth better than complex 1 but it does not exert any other biological effect.