The Enzymatic and Structural Basis for Inhibition of Echinococcus granulosus Thioredoxin Glutathione Reductase by Gold(I).

AIMS: New drugs are needed to treat flatworm infections that cause severe human diseases such as schistosomiasis. The unique flatworm enzyme thioredoxin glutathione reductase (TGR), structurally different from the human enzyme, is a key drug target. Structural studies of the flatworm Echinococcus granulosus TGR, free and complexed with AuI-MPO, a novel gold inhibitor, together with inhibition assays were performed. RESULTS: AuI-MPO is a potent TGR inhibitor that achieves 75% inhibition at a 1:1 TGR:Au ratio and efficiently kills E. granulosus in vitro. The structures revealed salient insights: (i) unique monomer-monomer interactions, (ii) distinct binding sites for thioredoxin and the glutaredoxin (Grx) domain, (iii) a single glutathione disulfide reduction site in the Grx domain, (iv) rotation of the Grx domain toward the Sec-containing redox active site, and (v) a single gold atom bound to Cys519 and Cys573 in the AuI-TGR complex. Structural modeling suggests that these residues are involved in the stabilization of the Sec-containing C-terminus. Consistently, Cys→Ser mutations in these residues decreased TGR activities. Mass spectroscopy confirmed these cysteines are the primary binding site. INNOVATION: The identification of a primary site for gold binding and the structural model provide a basis for gold compound optimization through scaffold adjustments. CONCLUSIONS: The structural study revealed that TGR functions are achieved not only through a mobile Sec-containing redox center but also by rotation of the Grx domain and distinct binding sites for Grx domain and thioredoxin. The conserved Cys519 and Cys573 residues targeted by gold assist catalysis through stabilization of the Sec-containing redox center. Antioxid. Redox Signal. 27, 1491-1504.

Expanding the family of heteroleptic oxidovanadium(IV) compounds with salicylaldehyde semicarbazones and polypyridyl ligands showing anti-Trypanosoma cruzi activity.

Searching for prospective vanadium-based drugs for the treatment of Chagas disease, a new series of heteroleptic [V(IV)O(L-2H)(NN)] compounds was developed by including the lipophilic 3,4,7,8-tetramethyl-1,10-phenanthroline (tmp) NN ligand and seven tridentate salicylaldehyde semicarbazone derivatives (L1-L7). The compounds were characterized in the solid state and in solution. EPR spectroscopy suggests that the NN ligand is bidentate bound through both nitrogen donor atoms in an axial-equatorial mode. The EPR and (51)V-NMR spectra of aerated solutions at room temperature indicate that the compounds are stable to hydrolysis and that no significant oxidation of V(IV) to V(V) takes place at least in 24h. The complexes are more active in vitro against Trypanosoma cruzi, the parasite responsible for Chagas disease, than the reference drug Nifurtimox and most of them are more active than previously reported [V(IV)O(L-2H)(NN)] complexes of other NN co-ligands. Selectivity towards the parasite was analyzed using J-774 murine macrophages as mammalian cell model. Due to both, high activity and high selectivity, L2, L4, L5 and L7 complexes could be considered new hits for further drug development. Lipophilicity probably plays a relevant role in the bioactivity of the new compounds. The [V(IV)O(L-2H)(NN)] compounds were designed aiming DNA as potential molecular target. Therefore, the novel L1-L7 tmp complexes were screened by computational modeling, comparing their DNA-binding features with those of previously reported [V(IV)O(L-2H)(NN)] compounds with different NN co-ligands. Whereas all the complexes interact well with DNA, with binding modes and strength tuned in different extents by the NN and semicarbazone co-ligands, molecular docking suggests that the observed anti-T. cruzi activity cannot be explained upon DNA intercalation as the sole mechanism of action.

Water-soluble ruthenium complexes bearing activity against protozoan parasites.

Parasitic illnesses are major causes of human disease and misery worldwide. Among them, both amebiasis and Chagas disease, caused by the protozoan parasites, Entamoeba histolytica and Trypanosoma cruzi, are responsible for thousands of annual deaths. The lack of safe and effective chemotherapy and/or the appearance of current drug resistance make the development of novel pharmacological tools for their treatment relevant. In this sense, within the framework of the medicinal inorganic chemistry, metal-based drugs appear to be a good alternative to find a pharmacological answer to parasitic diseases. In this work, novel ruthenium complexes [RuCl2(HL)(HPTA)2]Cl2 with HL=bioactive 5-nitrofuryl containing thiosemicarbazones and PTA=1,3,5-triaza-7-phosphaadamantane have been synthesized and fully characterized. PTA was included as co-ligand in order to modulate complexes aqueous solubility. In fact, obtained complexes were water soluble. Their activity against T. cruzi and E. histolytica was evaluated in vitro. [RuCl2(HL4)(HPTA)2]Cl2 complex, with HL4=N-phenyl-5-nitrofuryl-thiosemicarbazone, was the most active compound against both parasites. In particular, it showed an excellent activity against E. histolytica (half maximal inhibitory concentration (IC50)=5.2 µM), even higher than that of the reference drug metronidazole. In addition, this complex turns out to be selective for E. histolytica (selectivity index (SI)>38). The potential mechanism of antiparasitic action of the obtained ruthenium complexes could involve oxidative stress for both parasites. Additionally, complexes could interact with DNA as second potential target by an intercalative-like mode. Obtained results could be considered a contribution in the search for metal compounds that could be active against multiple parasites.

Homology modeling of T. cruzi and L. major NADH-dependent fumarate reductases: ligand docking, molecular dynamics validation, and insights on their binding modes.

Leishmania major and Trypanosoma cruzi are the main causes of leishmaniasis and Chagas disease, two endemic parasitosis identified as neglected diseases by the World Health Organization. Fumarate reductase (FR) is a central enzyme in the conversion of fumarate to succinate, an energy releasing path essential for the survival of these protozoans which is also absent in their mammalian hosts. FR can thus be considered as a good candidate for targeting specific inhibition by new drugs designed against L. major and T. cruzi. The lack of tertiary structures available for LmFR and TcFR has limited until now the possibility of performing structure-based drug design. Here we used homology modeling combined with enzyme-cofactor docking to propose tertiary structures for NADH-dependent LmFR and TcFR using an homologous X-ray crystallographic structure of flavine-adenine dinucleotide (FAD) dependent FR from Shewanella frigidimarina (PDB ID: 1QO8) as template. These models were refined and stabilized with/without substrate in the active site using classical molecular dynamics simulations under quasi-physiological conditions. Structural features relevant for understanding the mechanism of action of the enzyme were also analyzed, with special attention to the hydrogen bond network involving the cofactor and water molecules present at the binding sites. A small set of compounds previously synthesized and assayed for their inhibitory capacity against TcFR ([M(mpo)2] metal complexes with M=Pt(II), Pd(II) and V(IV)O and mpo=2-mercaptopyridine N-oxide) and LmFR (licochalcone A) were screened by protein-ligand docking using the NADH-LmFR and NADH-TcFR models here proposed and validated, gaining insight into their binding modes in each enzyme.

DNA as molecular target of analogous palladium and platinum anti-Trypanosoma cruzi compounds: a comparative study.

In the search for drugs with anti-trypanosome activity, we had previously synthesized two series of platinum and palladium analogous compounds of the formula [M(II)Cl(2)(HL)], where HL were bioactive 5-nitrofuryl or 5-nitroacroleine thiosemicarbazone derivatives. In this work, we thoroughly characterized [M(II)Cl(2)(HL)] complexes interaction with DNA by using different techniques: gel electrophoresis, DNA viscosity measurements, circular dichroism (CD) and atomic force microscopy (AFM). Electrophoresis results showed that all complexes induced a withdrawal of DNA superhelicity demonstrated by a decrease in electrophoretic mobility of supercoiled DNA form. This effect on migration was dependent on dose but also on the nature of both the metal and the ligand. In general, the effect produced by palladium complexes was significantly more intense than that observed for the corresponding platinum analogs. Differences between palladium and platinum complexes were also observed in CD experiments. While palladium complexes induce evident calf thymus (CT)-DNA profile changes compatible with B-DNA to Z-DNA conformational transition, no clear effect was observed for platinum ones. Additionally, AFM studies showed that changes in the shape of plasmid DNA, like supercoiling, kinks and thickness increase resulted more intense for the former. In addition, either Pd or Pt complexes increased the viscosity of CT DNA solutions in a concentration dependent manner. Although the nature of DNA interaction of both series of analogous palladium and platinum complexes seemed to be similar, an explanation for the observed differential intensity of the effect could be related to the known kinetic stability differences between palladium and platinum compounds.

Synthesis and characterization of a pyridine-2-thiol N-oxide gold(I) complex with potent antiproliferative effect against Trypanosoma cruzi and Leishmania sp. insight into its mechanism of action.

In the search for new therapeutic tools against parasitic diseases caused by the Kinetoplastids Leishmania spp. and Trypanosoma cruzi, a novel gold(I) triphenylphosphine complex with the bioactive coligand pyridine-2-thiol N-oxide (mpo) was synthesized and characterized by using analytical and conductometric measurements, electrospray ionization-mass spectrometry (ESI) and electronic, FTIR and (1)H and (31)P NMR spectroscopies. A dinuclear structure is suggested for the complex. At a 1 microM concentration the complex induced in vitro after 30 min a potent leishmanicidal effect (LD(50)) against promastigotes of Leishmania (L.) mexicana while on Leishmania (V.) braziliensis with the same concentration only a leishmanistatic effect (IC(75)) was observed 48 h after treatment. Similar differential susceptibilities were also found when testing the ligand mpo, but at a higher dose (5 microM). In addition, the compound showed growth inhibitory effect on Dm28c T. cruzi epimastigotes in culture (IC(50) 0.09 microM), being even more active than the anti-trypanosomal reference drug Nifurtimox (IC(50) 6 microM). DNA interaction studies showed that this biomolecule does not constitute a main target for the mpo complex currently tested. Instead, the significant potentiation of the antiproliferative effect against both Leishmania species and T. cruzi could be associated to the inhibition of NADH fumarate reductase, a kinetoplastid parasite-specific enzyme absent in the host. Furthermore, due to its low unspecific cytotoxicity on mammalian cells (J774 macrophages), the new gold complex showed a selective anti-parasite activity. It constitutes a promising new potent chemotherapeutic alternative to be evaluated in vivo in experimental models of leishmaniasis and Chagas disease.

Platinum-based complexes of bioactive 3-(5-nitrofuryl)acroleine thiosemicarbazones showing anti-Trypanosoma cruzi activity.

Eight new platinum(II) complexes with 3-(5-nitrofuryl)acroleine thiosemicarbazones showing anti-trypanosomal activity were synthesized, characterized and in vitro evaluated. Most of the complexes showed IC(50) values in the micromolar range against two different strains of Trypanosoma cruzi, causative agent of Chagas disease (American Trypanosomiasis). In addition, most of the newly developed complexes, together with the analogous platinum 5-nitrofuraldehyde containing thiosemicarbazones previously reported, resulted more active than the reference trypanocidal drug nifurtimox on the infective trypomastigote form of the parasite. Their capacity to produce free radicals that could lead to parasite death was evaluated by ESR experiments in the parasite and by respiration measurements. Compounds were tested for their DNA interaction ability. Results showed that some of the compounds could act as dual inhibitors in the parasite, through production of toxic free radicals and interaction with DNA. All the results were compared with those previously reported for the free ligands, the analogous palladium(II) compounds and the previously reported series of platinum(II) compounds.

Cytotoxic palladium complexes of bioreductive quinoxaline N1,N4-dioxide prodrugs.

Four new palladium(II) complexes with the formula Pd(L)(2), where L are quinoxaline-2-carbonitrile N(1),N(4)-dioxide derivatives, were synthesized as a contribution to the chemistry and pharmacology of metal compounds with this class of pharmacologically interesting bioreductive prodrugs. Compounds were characterized by elemental, conductometric and thermogravimetric analyses, fast atom bombardment mass spectrometry (FAB-MS) and electronic, Fourier transform infrared (FTIR) and (1)H-nuclear magnetic resonance spectroscopies. The complexes were subjected to cytotoxic evaluation on V79 cells in hypoxic and aerobic conditions. In addition, a preliminary study on interaction with plasmid DNA in normoxia was performed. Complexes showed different in vitro biological behavior depending on the nature of the substituent on the quinoxaline ring. Pd(L1)(2) and Pd(L2)(2), where L1 is 3-aminoquinoxaline-2-carbonitrile N(1),N(4)-dioxide and L2 is 3-amino-6(7)-methylquinoxaline-2-carbonitrile N(1),N(4)-dioxide, showed non selective cytotoxicity, being cytotoxic either in hypoxic or in aerobic conditions. On the other hand, Pd(L3)(2), where L3 is 3-amino-6(7)-chloroquinoxaline-2-carbonitrile N(1),N(4)-dioxide, resulted in vitro more potent cytotoxin in hypoxia (P=5.0 microM) than the corresponding free ligand (P=9.0 microM) and tirapazamine (P=30.0 microM), the first bioreductive cytotoxic drug introduced into clinical trials. In addition, it showed a very good selective cytotoxicity in hypoxic conditions, being non-cytotoxic in normoxia. Its hypoxic cytotoxicity relationship value, HCR, was of the same order than those of other hypoxia selective cytotoxins (i.e., Mitomycine C, Misonidazole and the N-oxide RB90740). Interaction of the complexes with plasmid DNA in normoxia showed dose dependent ability to relax the negative supercoiled forms via different mechanisms. Pd(L2)(2) introduced a scission event in supercoiled DNA yielding the circular relaxed form. Meanwhile, both Pd(L1)(2) and Pd(L3)(2) produced the loss of negative supercoils rendering a family of topoisomers with reduced electrophoretic mobility. Pd(L3)(2) showed a more marked effect than Pd(L1)(2). Indeed, for the highest doses assayed, Pd(L3)(2) was even able to introduce positive supercoils on the plasmid DNA.

Potent in vitro anti-Trypanosoma cruzi activity of pyridine-2-thiol N-oxide metal complexes having an inhibitory effect on parasite-specific fumarate reductase.

In the search for new therapeutic tools against Chagas disease (American trypanosomiasis) palladium and platinum complexes of the bioactive ligand pyridine-2-thiol N-oxide were exhaustively characterized and evaluated in vitro. Both complexes showed high in vitro growth inhibition activity (IC(50) values in the nanomolar range) against Trypanosoma cruzi, the causative agent of the disease. They were 39-115 times more active than the antitrypanosomal drug Nifurtimox. The palladium complex showed an approximately threefold enhancement of the activity compared with the parent compound. In addition, owing to their low unspecific cytotoxicity on mammalian cells, the complexes showed a highly selective antiparasite activity. To get an insight into the mechanism of action of these compounds, DNA, redox metabolism (intraparasite free-radical production) and two parasite-specific enzymes absent in the host, namely, trypanothione reductase and NADH-fumarate reductase, were evaluated as potential parasite targets. Additionally, the effect of metal coordination on the free radical scavenger capacity previously reported for the free ligand was studied. All the data strongly suggest that trypanocidal action of the complexes could mainly rely on the inhibition of the parasite-specific enzyme NADH-fumarate reductase.

Platinum(II) metal complexes as potential anti-Trypanosoma cruzi agents.

In the search for new therapeutic tools against Chagas' disease (American Trypanosomiasis) two series of new platinum(II) complexes with bioactive 5-nitrofuryl containing thiosemicarbazones as ligands were synthesized, characterized and in vitro evaluated. Most of the complexes showed IC50 values in the muM range against two different strains of Trypanosoma cruzi, causative agent of the disease, being as active as the anti-trypanosomal drug Nifurtimox. In particular, the coordination of L3 (4-ethyl-1-(5-nitrofurfurylidene)thiosemicarbazide) to Pt(II) forming [Pt(L3)2] lead to almost a five-fold activity increase in respect to the free ligand. Trying to get an insight into the trypanocidal mechanism of action of these compounds, DNA and redox metabolism (intra-parasite free radical production) were evaluated as potential parasite targets. Results suggest that the complexes could inhibit parasite growth through a dual mechanism of action involving production of toxic free radicals by bioreduction and DNA interaction.

ESR, electrochemical and reactivity studies of antitrypanosomal palladium thiosemicarbazone complexes.

Cyclic voltammetry (CV) and electron spin resonance (ESR) techniques were used in the investigation of novel palladium complexes with bioactive thiosemicarbazones derived from 5-nitrofurane or 5-nitrofurylacroleine. Sixteen palladium complexes grouped in two series of the formula [PdCl(2)HL] or [PdL(2)] were studied. ESR spectra of the free radicals obtained by electrolytic reduction were characterized and analyzed. The ESR spectra showed two different hyperfine patterns. The stoichiometry of the complexes does not seem to affect significantly the hyperfine constants however we observed great differences between 5-nitrofurane and 5-nitrofurylacroleine derivatives. The scavenger properties of this family of compounds were lower than Trolox.

Vibrational spectra of palladium 5-nitrofuryl thiosemicarbazone complexes: experimental and theoretical study.

The vibrational spectroscopic behavior of a series of 16 palladium(II) complexes with 8 bioactive nitrofuran containing thiosemicarbazones as ligands has been studied in the solid state. The IR and Raman spectra of these complexes and the free nitrofuran thiosemicarbazone ligands were recorded and analyzed. Experimental spectra were satisfactorily described by density functional theory (DFT) calculations. The combination of experimental and theoretical methods allowed us to perform the characterization of the main vibrations that show the mode of coordination of the thiosemicarbazone moiety to palladium even though these vibration bands are located in spectral regions showing a complicated pattern due to the presence of vibrations of the nitrofuran moiety and combination modes involving furan vibrations. A characteristic vibrational spectroscopic pattern has been defined for Pd(II) 5-nitrofuryl thiosemicarbazone complexes. This systematic knowledge may be useful for the analysis of the spectroscopic behavior of other coordination compounds holding the 5-nitrofuran thiosemicarbazone moiety.

DNA conformational changes and cleavage by ruthenium(II) nitrofurylsemicarbazone complexes.

Metal complexes that establish interactions with DNA are being studied not only because of their potential use as therapeutic agents but also as tools for biochemistry and molecular biology. Searching for drugs with anti-trypanosome activity, we previously synthesized a series of ruthenium mixed ligand dimethyl sulfoxide complexes of the type [Ru(II)Cl(2)(DMSO)(2)L], where L is 5-nitrofurylsemicarbazone derivatives and DMSO is dimethyl sulfoxide. Though they present the ability to bind DNA, no activity against parasites in cell culture was observed. Considering their potential application as molecular tools we further analyzed the interactions with DNA through an electrophoretic approach. Non covalent withdrawal of superhelicity and a rapid nicking activity upon covalent interaction was observed. Inhibition of both effects was observed in the presence of distamycin suggesting the involvement of the DNA minor groove in the interaction with the nitrofurylsemicarbazone ruthenium complexes. In addition cleavage inhibition by dimethyl sulfoxide suggests an oxidative mechanism of action.

Improving anti-trypanosomal activity of 3-aminoquinoxaline-2-carbonitrile N1,N4-dioxide derivatives by complexation with vanadium.

New vanadium complexes of the type [V(IV)O(L)(2)], where L are 3-aminoquinoxaline-2-carbonitrile N(1),N(4)-dioxide derivatives, were prepared as an effort to obtain new anti-trypanosomal agents improving the bioactivity of the free ligands. Complexation to vanadium of the quinoxaline ligands leads to excellent antiprotozoal activity, similar to that of the reference drugs nifurtimox and benznidazole and in all cases higher than that of the corresponding free ligands. In addition, it is for the first time that the V((IV))O-quinoxaline complexes are reported as a family of anti-Trypanosoma cruzi agents. Finally, the anti-trypanosomal activity of these vanadium complexes could be explained on the basis of their lipophilicity and the electronic characteristics of the quinoxaline substituents.

Novel antitrypanosomal agents based on palladium nitrofurylthiosemicarbazone complexes: DNA and redox metabolism as potential therapeutic targets.

In the search for new therapeutic tools against American Trypanosomiasis palladium complexes with bioactive nitrofuran-containing thiosemicarbazones as ligands were obtained. Sixteen novel palladium (II) complexes with the formulas [PdCl2(HL)] and [Pd(L)2] were synthesized, and the crystal structure of [Pd(5-nitrofuryl-3-acroleine thiosemicarbazone)2] x 3DMSO was solved by X-ray diffraction methods. Most complexes showed higher in vitro growth inhibition activity against Trypanosoma cruzi than the standard drug Nifurtimox. In most cases, the activity of the ligand was maintained or even increased as a result of palladium complexation. In addition, the complexes' mode of antitrypanosomal action was investigated. Although the complexes showed strong DNA binding, all data strongly suggest that the main trypanocidal mechanism of action is the production of oxidative stress as a result of their bioreduction and extensive redox cycling. Moreover, the complexes were found to be irreversible inhibitors of trypanothione reductase.

Selective hypoxia-cytotoxins based on vanadyl complexes with 3-aminoquinoxaline-2-carbonitrile-N1,N4-dioxide derivatives.

A new vanadyl complex with the formula VO(L1)2, where L1=3-amino-6(7)-chloroquinoxaline-2-carbonitrile N(1), N(4)-dioxide, has been synthesized and characterized by elemental analyses, conductometry, fast atom bombardment mass spectroscopy (FAB-MS) and electronic, Fourier transform infrared (FTIR), Raman, nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) spectroscopies. Results were compared with those previously reported for analogous vanadium complexes with other 3-aminoquinoxaline-2-carbonitrile N1,N4-dioxide derivatives as ligands. As an effort to develop novel metal-based selective hypoxia-cytotoxins and to improve bioavailability and pharmacological and toxicological properties of aminoquinoxaline carbonitrile N-dioxides bioreductive prodrugs, the new complex and VO(L)2 complexes, with L=3-amino-6(7)-bromoquinoxaline-2-carbonitrile N1,N4-dioxide (L2) and 3-amino-6(7)-methylquinoxaline-2-carbonitrile N1,N4-dioxide (L3), were subjected to cytotoxic evaluation in V79 cells in hypoxic and aerobic conditions. The complexes resulted in vitro more potent cytotoxins than the free ligands (i.e. potencies P(VO(L1)2)=3.0, P(L1)=9.0 microM) and Tirapazamine (P=30.0 microM) and showed excellent selective cytotoxicity in hypoxia, being no cytotoxic in oxia. In addition, the solubility in hydrophilic solvents resulted significantly higher for the vanadyl complexes than for the free ligands. These results could be indicative that complexation of the quinoxaline-2-carbonitrile N1,N4-dioxide derivatives with vanadium could improve their bioavailability. In addition, a new aspect of the series has been investigated. A detailed comparison of the electrochemical behavior of the free ligands and the complexes has been performed searching for a correlation between reduction potentials of the complexes and their activities and hypoxia selectivities.

Novel vanadyl complexes with quinoxaline N(1),N(4)-dioxide derivatives as potent in vitro insulin-mimetic compounds.

As a contribution to the development of novel vanadyl complexes with potential insulin-mimetic activity, three new oxovanadium(IV) complexes with the formula VO(L)(2), where L are 3-amino-quinoxaline-2-carbonitrile N(1),N(4)-dioxide derivatives, have been synthesized. Complexes have been characterized by elemental and thermal analyses, fast atom bombardment mass spectroscopy (FAB-MS), conductivity measurements and electronic, Fourier transform infrared (FTIR) and electron paramagnetic resonance (EPR) spectroscopies. The in vitro insulin-mimetic activity of the vanadyl complexes has been estimated by lipolysis inhibition tests, in which the inhibition of the release of free fatty acid from isolated rat adipocytes treated with epinephrine was determined. All the complexes showed inhibitory effects on free fatty acid release. [V(IV)O(3-amino-6(7)-bromoquinoxaline-2-carbonitrile N(1),N(4)-dioxide)(2)] exhibited higher in vitro insulin-mimetic activity than the very active bis(6-methylpicolinato)oxovanadium(IV), VO(6mpa)(2). This new vanadyl complex is expected to exhibit a higher blood glucose lowering activity than VO(6mpa)(2) in diabetic animals.

Palladium(II) complexes of 2-benzoylpyridine-derived thiosemicarbazones: spectral characterization, structural studies and cytotoxic activity.

Palladium(II) complexes of 2-benzoylpyridine thiosemicarbazone (H2Bz4DH) and its N4-methyl (H2Bz4M) and N4-phenyl (H2Bz4Ph) derivatives were obtained and fully characterized. [Pd(2Bz4DH)Cl] (1) crystallizes in the monoclinic space group P21/c with a=11.671(1), b=10.405(1), c=13.124(1), beta=115.60(1) degrees and Z=4; [Pd(2Bz4M)Cl] (2) in the monoclinic space group P21/c with a=9.695(1), b=15.044(1), c=10.718(1) A, beta=105.38(1) degrees and Z=4 and [Pd(2Bz4Ph)Cl] (3) in the triclinic space group P1 with a=9.389(1), b=13.629(1), c=15.218(1) A, alpha=70.25(1), beta=73.46(1), gamma=83.57(1) degrees and two independent molecules per asymmetric unit (Z=4). All complexes show a quite similar planar fourfold environment around palladium(II). A negatively charged organic molecule acts as a tridentate ligand and binds to the metal through the pyridine nitrogen, the imine nitrogen and the sulfur atom. A chloride ion occupies the fourth coordination site. The planar complexes stack nearly parallel to one another in the lattice conforming a layered crystal structure. The cytotoxic activity of the thiosemicarbazones and their metal complexes was tested against the MCF-7, TK-10 and UACC-62 human tumor cell lines. The ligands exhibit lower values of GI50 and LC50 than the complexes, H2Bz4Ph being the most active with GI50<0.003 microM; LC50=13.4 microM; GI50=9.3 microM, LC50=12.9 microM; GI50<0.003, LC50=13.8 microM in the MCF-7, TK-10 and UACC-62 cell lines, respectively. Among the complexes, [Pd(2Bz4Ph)Cl] (3) exhibited the lowest values of GI50 in the three studied cell lines.

Vanadium(V) complexes with salicylaldehyde semicarbazone derivatives bearing in vitro anti-tumor activity toward kidney tumor cells (TK-10): crystal structure of [VVO2(5-bromosalicylaldehyde semicarbazone)].

As a contribution to the development of novel vanadium complexes with pharmacologically interesting moieties, new dioxovanadium(V) semicarbazone complexes with the formula cis-VO(2)L, where L=5-bromosalicylaldehyde semicarbazone and 2-hydroxynaphtalen-1-carboxaldehyde semicarbazone have been synthesized and characterized by (1)H and (13)C NMR, Raman and FTIR spectroscopies. Results were compared with those previously reported for other three analogous complexes of this series. The five complexes were tested in three different human tumor cell lines for bioactivity as potential anti-tumor agents, showing selective cytotoxicity on TK-10 cell line. Results showed that structural modifications on the semicarbazone moiety could have a significant effect on the anti-tumor activity of the vanadium complexes. In addition, the electrochemical behavior of all the complexes was studied. No apparent correlation could be demonstrated between reduction potentials of the complexes and their anti-tumor activities. The molecular structure of the novel [V(V)O(2)(5-bromosalicylaldehyde semicarbazone)] complex was solved by X-ray diffraction methods. The vanadium atom shows a distorted square pyramidal coordination sphere. The (VO(2))(+) cation is coordinated to a nearly planar (L)(-) anion acting as a tridentate ligand through both oxygen and one nitrogen atoms.