Metallacages with 2,6-dipicolinoylbis(N,N-dialkylthioureas) as novel platforms in nuclear medicine for 68Ga, 177Lu and 198Au.

BACKGROUND: Heterometallic gold metallacages are of great interest for the incorporation of several cations. Especially in nuclear medicine, those metallacages can serve as a platform for radionuclides relevant for imaging or therapy (e.g. 68Ga or 177Lu). Moreover, the radionuclide 198Au is an attractive beta emitter, for potential application in nuclear medicine. Here, we aim to synthesize a new set of gold metallacages and to study their ability to coordinate to 68Ga, 177Lu and 198Au. RESULTS: New heterometallic gold metallacages of composition [M{Au(Lmorph-κS)}3] (M = La3+, Tb3+, Lu3+ or Y3+) and [Ga{Au(Lmorph-κS)}2]NO3 have been synthesized from 2,6-dipicolinoylbis(N,N-morpholinylthiourea) (H2Lmorph) with [AuCl(THT)] and the target M3+ metal ions in yields ranging from 33 (Lu) to 62% (Tb). The characterization of the compounds bases on ESI-MS, 1H NMR, IR, EA and single-crystal X-ray diffraction techniques (all except the Ga derivative). Selected gold cages derived from H2Lmorph were compared to previously reported gold cages that were derived from 2,6-dipicolinoylbis(N,N-diethylthiourea) (H2Ldiethyl). The tested metallacages show similar IC50 values close to that of auranofin in four different cancer cell lines (MCF-7, PC-3, U383, U343), e.g. 4.5 ± 0.7 µM for [Ga{Au(Ldiethyl)}2]NO3 on PC-3. The radiolabeling experiments thereof show high radiochemical purities with 68Ga and 198Au and low radiochemical purity with 177Lu. CONCLUSIONS: The results indicate that these gold metallacages could serve as a novel platform for inclusion of different (radio)nuclides with potential theranostic applications in nuclear medicine.

Solvents and Ligands Matter: Structurally Variable Palladium and Nickel Clusters Assembled by Tridentate Selenium- and Tellurium-Containing Schiff Bases.

Structurally variable organochalcogen clusters containing palladium(II) and nickel(II) ions were assembled starting from the salicylidene-substituted dichalcogenides (Y-C6H4-N═CH-C6H4-OH)2 ({HLY}2, where Y = Se or Te), and palladium or nickel acetate. The tetrameric palladium clusters contain reduced chalcogenolato ligands {Y-C6H4-N═CH-C6H4-O)}2- ({L'Y}2-, where Y = Se or Te), while the initially formed trimeric nickel clusters contain the intact, coordinated dichalcogenides. The palladium clusters have a general formula of [Pd4(L'Y)4] and represent the first examples of palladium complexes where both a gyrobifastigial and a pseudocubane arrangement of the central Pd4Y4 unit could be established with the same ligand, only depending on the solvents used for crystallization. Reduced density gradient (RDG) considerations based on density functional theory calculations suggest that the commonly referred to stabilizing chalcogen-palladium or palladium-palladium interactions for the two geometric arrangements are weak van der Waals contacts resulting from the contact of two nonbinding lone pairs. In the case of the pseudocubane arrangement, a repulsive steric effect, which is indicated by RDG analysis, is clearly supported by the cuplike distortions detected in the solid-state structure of the compound. In contrast to the reactions with palladium acetate, where the dichalcogenides were cleaved, during similar reactions with nickel acetate, the dichalcogenides remained intact and trimeric clusters of the composition [Ni-µ2-κ2-(Ni{κ5-LY}2)2-µ2-(OAc)2] (Y = Se, Te) were formed. Air oxidation and hydrolysis of [Ni-µ2-κ2-(Ni{κ5-LTe}2)2-µ2-(OAc)2] gave a rare example of a hexanuclear nickel cluster of the composition [Ni2-κ5-(Ni4-κ6-µ6-{(L'Te2O3)(L'TeO2)2}2)-µ2-(H2O)2], which is composed of a well-defined framework consisting of tellurinic anhydride and tellurinate units, which proves the comparably higher oxidation sensitivity of the trinickel dichalcogenide complexes. Electron spray ionization mass spectrometry spectra of both the palladium and nickel clusters indicate that they show fluctional behavior with varying nuclearity in solution and can adopt multiple charge states especially because of the noninnocence of the chalcogen-based ligands. The complexes were fully characterized by spectroscopic methods, elemental analyses, and X-ray diffraction.

Organometallic Gold(III) Complex [Au(Hdamp)(L14)]+ (L1 = SNS-Donating Thiosemicarbazone) as a Candidate to New Formulations against Chagas Disease.

Chagas disease remains a serious public health concern with unsatisfactory treatment outcomes due to strain-specific drug resistance and various side effects. To identify new therapeutic drugs against Trypanosoma cruzi, we evaluated both the in vitro and in vivo activity of the organometallic gold(III) complex [Au(III)(Hdamp)(L14)]Cl (L1 = SNS-donating thiosemicarbazone), henceforth denoted 4-Cl. Our results demonstrated that 4-Cl was more effective than benznidazole (Bz) in eliminating both the extracellular trypomastigote and intracellular amastigote forms of the parasite without cytotoxic effects on mammalian cells. In in vivo assays, 4-Cl in PBS solution loses the protonation and becomes the 4-neutral. 4-Neutral reduced parasitaemia and tissue parasitism in addition to protecting the liver and heart from tissue damage at 2.8 mg/kg/day. All these changes resulted in the survival of 100% of the mice treated with the gold complex during the acute phase. Analyzing the surviving animals of the acute infection, the parasite load after 150 days of infection was equivalent to those treated with the standard dose of Bz without demonstrating the hepatotoxicity of the latter. In addition, we identified a modulation of interferon gamma (IFN-γ) levels that may be targeting the disease's positive outcome. To the best of our knowledge, this is the first gold organometallic study that shows promise in an in vivo experimental model against Chagas disease.

Iron(III) Metallacryptand and Metallacryptate Assemblies Derived from Aroylbis(N,N-diethylthioureas).

The reaction of isophthaloylbis(N,N-diethylthiourea), H2L1, with FeCl3·6H2O gives the dinuclear tris-complex [Fe2(L1)3] (5), possessing a cryptand-like structure. A similar reaction with the ligand 2,6-dipicolinoylbis(N,N-diethylthiourea), H2L2, however, results in the formation of the anionic, mononuclear Fe(III) complex [Fe(L2)2]- (6), which could be isolated as its "Tl+ salt" by the subsequent addition of Tl(NO3). A tighter view to the solid state structure of the obtained product, however, characterizes compound 6 as a one-dimensional coordination polymer, in which four-coordinate Tl+ ions connect the {[Fe(L2)2]-} units to infinite chains. When Fe3+ ions and Tl+ ions are added to H2L2 simultaneously in a one-pot reaction, a different product is obtained: a cationic trinuclear complex of the composition {M⊂[Fe2(L2)3]}+. It has been isolated as a PF6- salt and represents a {2}-metallacryptate with a nine-coordinate Tl+ ion in the central void. Structurally related products of the compositions {M⊂[Fe2(L2)3]}(PF6) (M = Na+, K+, Rb+) (8(PF6)) could be isolated from analogous reactions with alkaline salts instead of Tl(NO3). {2}-Metallacryptates with larger central voids were synthesized with the ether-spaced aroylbis(N,N-diethylthiourea) H2L3. The compounds {M⊂[Fe2(L3)3]}(PF6) (M = K+, Rb+, Tl+ or Cs+) (9(PF6)) were prepared by a similar protocol like those with H2L2 with the simultaneous addition of the metal ions to a solution of H2L3. Due to the larger spacer between the aroylthiourea units, the coordination number of the central M+ ions is 12 by six carbonyl and six ether oxygen atoms. All products were characterized by elemental analysis, IR spectroscopy, and X-ray structure analysis. Cyclic voltammetric studies were carried out with the three representative complexes [Fe2(L1)3], {K⊂[Fe2(L2)3]}(PF6), and {K⊂[Fe2(L3)3]}(PF6). The obtained voltammograms indicate the dependence of the redox properties of the oligonuclear systems on the conjugation in the organic backbones of the ligands.

Gold(III) complexes in medicinal chemistry.

A number of gold(III) compounds has been designed with the objective of overcoming the disadvantages associated with the platinum-based drugs for cancer treatment. Compounds of a remarkable structural manifold show significant antiproliferative effects in vitro against a number of cancer cells, including cisplatin resistant ones. The target of most of them is, unlike that of cisplatin, not the DNA. Although the mechanisms of action displayed by the gold compounds in biological media are still under investigation, many studies show evidence that the cellular targets are mitochondria-based. Recent advances in gold(III) medicinal chemistry also recommend such compounds for other pharmacological applications such as the treatment of viral or parasitic diseases. The radioactive isotopes (198)Au and (199)Au present potential in radiotherapy.

Synthesis, characterization, and in vitro antiproliferative activity of [salophene]platinum(II) complexes.

A series of methoxy- and fluorine-substituted [salophene]platinum(II) complexes (salophene=N,N'-bis(salicylidene)-1,2-phenylenediamine) were synthesized and characterized by (1) H NMR spectroscopy and mass spectrometry. The structure was confirmed on the example of [5-OCH3 -salophene]platinum(II) (4-Pt) by crystal structure analysis. The cytotoxicity of all complexes against MCF-7 cells showed strong dependence on the kind of substituent and its position on the salicylidene moiety, whereas 1-Pt (H), 3-Pt (4-OCH3 ), and 6-Pt (3-F) exhibited high antiproliferative effects (IC50 <2 µM). Drug lipophilicity and cellular accumulation were analyzed in an attempt to explain the differences in antitumor potency. To gain insight into their mode of action, DNA interaction studies were performed, in which compounds such as 1-Pt acted as non-DNA-binding platinum anticancer drugs, as neither intercalation nor DNA covalent binding were detected.

Synthesis and biological evaluation of radio and dye labeled amino functionalized dendritic polyglycerol sulfates as multivalent anti-inflammatory compounds.

Herein we describe a platform technology for the synthesis and characterization of partially aminated, (35)S-labeled, dendritic polyglycerol sulfate (dPG(35)S amine) and fluorescent dPGS indocarbocyanine (ICC) dye conjugates. These polymer conjugates, based on a biocompatible dendritic polyglycerol scaffold, exhibit a high affinity to inflamed tissue in vivo and represent promising candidates for therapeutic and diagnostic applications. By utilizing a one-step sequential copolymerization approach, dendritic polyglycerol (Mn ≈ 4.5 kDa) containing 9.4% N-phthalimide protected amine functionalities was prepared on a large scale. Sulfation and simultaneous radio labeling with (35)SO3 pyridine complex, followed by cleavage of the N-phthalimide protecting groups, yielded dPG(35)S amine as a beta emitting, inflammation specific probe with free amino functionalities for conjugation. Furthermore, efficient labeling procedures with ICC via iminothiolane modification and subsequent "Michael" addition of the maleimide functionalized ICC dye, as well as by amide formation via NHS derivatized ICC on a dPGS amine scaffold, are described. The dPGS-ICC conjugates were investigated with respect to their photophysical properties, and both the radiolabeled and fluorescent compounds were comparatively visualized in histological tissue sections (radio detection and fluorescence microscopy) of animals treated with dPGS. Furthermore, cellular uptake of dPGS-ICC was found in endothelial cord blood (HUVEC) and the epithelial lung cells (A549). The presented synthetic routes allow a reproducible, controlled synthesis of dPGS amine on kilogram scale applying a one-pot batch reaction process. dPGS amine can be used for analysis via radioactivity or fluorescence, thereby creating a new platform for inflammation specific, multimodal imaging purposes using other attachable probes or contrast agents.

Rhenium mixed-ligand complexes with S,N,S-tridentate thiosemicarbazone/thiosemicarbazide ligands.

Rhenium(V) complexes containing tridentate thiosemicarbazones/thiosemicarbazides (H2L1) derived from N-[N',N'-dialkylamino(thiocarbonyl)]benzimidoyl chlorides with 4,4-dialkylthiosemicarbazides have been synthesized by ligand-exchange reactions starting from [ReOCl(L1)]. The chlorido ligand of [ReOCl(L1)] (4) is readily replaced and reactions with ammonium thiocyanate or potassium cyanide give [ReO(NCS)(L1)] (6) and [ReO(CN)(L1)] (7), respectively. The reaction of (NBu4)[ReOCl4] with H2L1 and two equivalents of ammonium thiocyanate, however, gives in a one-pot reaction [ReO(NCS)2(HL1)] (8), in which the pro-ligand H2L1 is only singly deprotonated. An oxo-bridged, dimeric nitridorhenium(V) compound of the composition [{ReN(HL1)}2O] (11) is obtained from a reaction of (NBu4)[ReOCl4], H2L1 and sodium azide. The six-coordinate complexes [ReO(L1)(Ph2btu)] (12), where HPh2btu is N,N-diphenyl-N'-benzoylthiourea, can be obtained by treatment of [ReOCl(L1)] with HPh2btu in the presence of NEt3. Studies of the antiproliferative effects of the [ReOX(L1)] system (X = Cl−, NCS− or CN−) on breast cancer cells show that the lability of a monodentate ligand seems to play a key role in the cytotoxic activity of the metal complexes, while the substitution of this ligand by the chelating ligand Ph2btu− completely terminates the cytotoxicity.

Synthesis, characterization and in vitro antitumour activity of a series of novel platinum(II) complexes bearing Schiff base ligands.

A series was neutral platinum(II) complexes bearing OCH(3)- or F-substituted 3,4-bis(4-fluorophenyl)-1,6-bis(2-hydroxyphenyl)-2,5-diazahexa-1,5-dienes (diarylsalenes) were synthesized and tested for in vitro antitumour activity. The growth inhibitory effects depended on the configuration and the substitution pattern of the salicylidene moiety. The lead compound [meso-3,4-bis(4-fluorophenyl)-1,6-bis(2-hydroxyphenyl)-2,5-diazahexa-1,5-diene]platinum(II) (1-Pt) reduced the cell growth of MCF-7 (IC(50) = 7.6 µM) and MDA-MB 231 cells (IC(50) = 10.0 µM), but was inactive against HT-29 cells at the used concentration range (IC(50) > 20 µM). The change of the configuration (meso → d,l) at the 1,2-diimino-1,2-diarylethane bridge and methoxy substitution led to completely inactive compounds, while fluorine substituents increased the antiproliferative effects depending on their position (3-F < 5-F < 4-F < 6-F). Complex 10-Pt (6-F: IC(50)(MCF-7) = 1.5 µM, IC(50)(MDA-MB 231) = 1.3 µM, IC(50) (HT-29) = 2.6 µM) was as active as cisplatin (IC(50)(MCF-7) = 1.6 µM, IC(50)(MDA-MB 231) = 1.5 µM, IC(50)(HT-29) = 4.1 µM).

Synthesis, characterization, and in vitro studies of bis[1,3-diethyl-4,5-diarylimidazol-2-ylidene]gold(I/III) complexes.

Cationic bis[1,3-diethyl-4,5-diarylimidazol-2-ylidene]gold(I) complexes with 4-OCH(3) or 4-F substituents in the aromatic rings and Br(-) (3a,b) or BF(4)(-) (7a,b) counterions were synthesized, characterized, and investigated for tumor growth inhibitory properties in vitro. Analogous to auranofin, the N-heterocyclic carbenes (NHCs) were also combined with a phosphine ligand (triphenylphosphine, 4a,b) and 2',3',4',6'-tetra-O-acetyl-ß-D-glucopyranosyl-1-thiolate (5a,b). The growth inhibitory effect against MCF-7, MDA-MB 231, and HT-29 cells, which is more than 10-fold higher than that of cisplatin or 5-FU, was independent of the oxidation state (Au(III), 6a,b) and the anionic counterion. Bis[1,3-diethyl-4,5-bis(4-fluorophenyl)imidazol-2-ylidene]gold(I) bromide 3b as the most cytotoxic compound reduced the growth of MCF-7 cells with IC(50) = 0.10 µM (cisplatin, 1.6 µM; 5-FU, 4.7 µM). The thioredoxin reductase (TrxR), the estrogen receptor (ER), and the cyclooxygenase (COX) enzymes, which have to be considered as possible targets based on the drug design, can be excluded from being involved in the mode of action.

Neutral gold complexes with tridentate SNS thiosemicarbazide ligands.

Na[AuCl(4)]·2H(2)O reacts with tridentate thiosemicarbazide ligands, H(2)L1, derived from N-[N',N'-dialkylamino(thiocarbonyl)]benzimidoyl chloride and thiosemicarbazides under formation of air-stable, green [AuCl(L1)] complexes. The organic ligands coordinate in a planar SNS coordination mode. Small amounts of gold(I) complexes of the composition [AuCl(L3)] are formed as side-products, where L3 is an S-bonded 5-diethylamino-3-phenyl-1-thiocarbamoyl-1,2,4-triazole. The formation of the triazole L3 can be explained by the oxidation of H(2)L1 to an intermediate thiatriazine L2 by Au(3+), followed by a desulfurization reaction with ring contraction. The chloro ligands in the [AuCl(L1)] complexes can readily be replaced by other monoanionic ligands such as SCN(-) or CN(-) giving [Au(SCN)(L1)] or [Au(CN)(L1)] complexes. The complexes described in this paper represent the first examples of fully characterized neutral Gold(III) thiosemicarbazone complexes. All the [AuCl(L1)] compounds present a remarkable cell growth inhibition against human MCF-7 breast cancer cells. However, systematic variation of the alkyl groups in the N(4)-position of the thiosemicarbazone building blocks as well as the replacement of the chloride by thiocyanate ligands do not considerably influence the biological activity. On the other hand, the reduction of Au(III) to Au(I) leads to a considerable decrease of the cytotoxicity.

NHC gold halide complexes derived from 4,5-diarylimidazoles: synthesis, structural analysis, and pharmacological investigations as potential antitumor agents.

A series of novel neutral NHC gold halide complexes derived from 4,5-diarylimidazoles were synthesized, characterized, and analyzed for biological effects. High growth inhibitory effects in MCF-7 and MDA-MB 231 breast cancer as well as HT-29 colon cancer cell lines depended on the presence of the C4,C5-standing aromatic rings. Methoxy groups at these rings did not change the growth inhibitory properties, while F-substituents in the ortho-position (5d) increased the activity in MCF-7 and MDA-MB 231 cells. The substituents at the nitrogen atoms and the oxidation state of the metal play a subordinate role. The most active bromo[1,3-diethyl-4,5-bis(2-fluorophenyl)-1,3-dihydro-2H-imidazol-2-ylidene]gold(I) (5d) was distinctly more active than cisplatin. All complexes caused thioredoxin reductase (TrxR) inhibition (EC50=374-1505 nM) distinctly lower than auranofin (EC50=18.6 nM) excluding this enzyme as main target. Because of the low nuclear content, a participation of DNA interaction on the mode of action is very unlikely. The missing ER binding and the missing correlation of growth inhibition and inactivation of COX enzymes exclude these targets, too.

Synthesis and biological studies of silver N-heterocyclic carbene complexes derived from 4,5-diarylimidazole.

A novel class of silver N-heterocyclic carbene complexes (5a-f) were synthesized in high yield by reacting silver(I) oxide with 4,5-diarylimidazolium halides (4a-f). The complexes were characterized using NMR and IR spectroscopy. The structure was confirmed on the example of bromo[1,3-diethyl-4,5-bis(4-fluorophenyl)imidazol-2-ylidene]silver(I) (5c) by crystal structure analysis. The X-ray structure indicated a three-dimensional coordination polymer with a repeating unit consisting of a C(carben)-Ag(2)-Br(2)-C(carben) cluster. Pharmacological investigations revealed that all silver complexes possessed growth inhibitory effects against breast cancer (MCF-7 and MDA-MB-231) as well as colon carcinoma (HT-29) cells. The most active compound 5c was slightly less active against MCF-7 cells, more active against MDA-MB-231 cells and comparable active as cisplatin against HT-29 cells. Further pharmacological investigations were performed with selected compounds on estrogen receptor (ER) binding, DNA intercalation, cyclooxygenase (COX) inhibition and antibacterial activity. The complexes were only marginally active at the DNA, ER and the COX enzymes, so these targets can be excluded to be involved in the mode of action. However, the growth of bacteria was significantly inhibited by 5c and 5f and opens a new application of this complex type.

Synthesis, structural characterization, and biological evaluation of oxorhenium(V) complexes with a novel type of thiosemicarbazones derived from N-[N',N'-dialkylamino(thiocarbonyl)]benzimidoyl chlorides.

Reactions of N-[N',N'-diethylamino(thiocarbonyl)]benzimidoyl chloride with 4,4-dialkylthiosemicarbazides give a novel class of thiosemicarbazides/thiosemicarbazones, H(2)L, which causes a remarkable reduction of cell growth in in vitro experiments. These strong antiproliferative effects are also observed for oxorhenium(V) complexes of the general composition [ReOCl(L)], which are formed by reactions of the potentially tridentate ligands with (NBu(4))[ReOCl(4)]. A systematic substitution of the alkyl groups in the thiosemicarbazone building blocks of the ligands do not significantly influence the biological activity of the metal complexes, while the replacement of the chloro ligand by a PPh(3) ligand (by the replacement of the oxo unit by a nitrido ligand) completely terminated the cytotoxicity of the metal complexes.

Organometallic [Re(CO)3]+ and [Re(CO)2(NO)]2+ labeled substrates for human thymidine kinase 1.

Thymidine was functionalized at position N3 with a tridentate iminodiacetic acid chelating system and a potentially tetradentate mercaptoethyliminodiacetic acid chelating system. Spacers of different lengths (ethyl and butyl) were introduced between the chelators and thymidine. The derivatives were labeled with the [Re(CO)(2)(NO)](2+) and [Re(CO)(3)](+) cores to give isostructural complexes with different overall charges. All complexes were analyzed by NMR, MS, and IR, and in addition, the X-ray structure of a [Re(CO)(2)(NO)](2+) labeled thymidine derivative functionalized at the N3 position was solved. The ligands incorporating the potentially tetradentate mercaptoethyliminodiacetic acid chelating system coordinated tridentately through iminodiacetic acid to both the [Re(CO)(2)(NO)](2+) core and the [Re(CO)(3)](+) core. This was surprising given that the reaction of [NEt(4)][Re(CO)(2)(NO)Br(3)] with the model ligand ethylmercaptoethyliminodiacetic acid led to dissociation of a carbonyl ligand and formation of a monocarbonyl-mononitrosyl complex, as confirmed by X-ray structure analysis. All of the organometallic thymidine derivatives were substrates for human thymidine kinase 1, a key enzyme in (cancer) cell proliferation. Neutral [Re(CO)(2)(NO)](2+) labeled thymidine derivatives revealed substrate activity ranging from 24 to 40%, and the structurally analogous anionic [Re(CO)(3)](+) labeled thymidine derivatives from 20 to 38% compared with the natural substrate thymidine.

A click approach to structurally diverse conjugates containing a central di-1,2,3-triazole metal chelate.

The selective and efficient synthesis of novel tridentate metal chelating systems containing two 1,4-disubstituted 1,2,3-triazole heterocycles obtained via the copper(I)-catalyzed cycloaddition of alkynes and azides (click reaction) is described. The constructs are shown to be efficient ligand systems for the chelation of fac-[M(CO)(3)(H(2)O)(3)](+) (M=(99m)Tc, Re) yielding well- defined and stable complexes. The organometallic (99m)Tc conjugates are suitable for application as diagnostic radiotracers for single photon emission computed tomography (SPECT) as demonstrated in vivo with a fragment of the tumor-targeting bombesin peptide functionalized with a di-1,2,3-triazole chelator and radiolabeled with [(99m)Tc(CO)(3)](+). Starting from readily available dialkyne precursors, the central chelating systems are formed as the conjugates are assembled by click reaction with azide-functionalized entities. Depending on the nature of the azide substrates employed (e.g. lipophilic or hydrophilic residues) pharmacologically relevant characteristics of the final metal conjugate such as hydrophilicity or overall charge can be readily modulated. The procedures described also enable the facile introduction of other probes into the metal conjugate, providing access to potential multimodal imaging agents.

Novel Cu(II) quinoxaline N1,N4-dioxide complexes as selective hypoxic cytotoxins.

As an effort to develop novel selective hypoxia-cytotoxins and to improve bioavailability and pharmacological and toxicological properties of quinoxaline N1,N4-dioxide derivatives (L1 = 3-amino-6(7)-chloroquinoxaline-2-carbonitrile N1,N4-dioxide, L2 = 3-amino-6(7)-bromoquinoxaline-2-carbonitrile N1,N4-dioxide and L3 = 3-amino-6(7)-methylquinoxaline-2-carbonitrile N1,N4-dioxide) and to get a synergism among metals and these type of bioreductive agents, L2 and three novel Cu(II) complexes of general formulae [Cu(II)(H2O)x(L - H)2], where L = L1 (x = 1), L2 (x = 0) or L3 (x = 2) were developed. L2 and complexes were synthesized and structurally characterized by elemental and thermal analyses, and FTIR, electronic, MS, NMR, and EPR spectroscopies. The new compounds were subjected to cytotoxic evaluation in V79 cells in hypoxic and aerobic conditions. The complexes showed excellent selective cytotoxicity in hypoxia, being their cytotoxicity similar to or higher than that of the ligands L1-L3. Besides, the copper complexes were so poorly cytotoxic in oxia as the free ligands. In addition, for the first time Cu(II)-quinoxaline complexes are reported as a family of hypoxic cytotoxins.

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.