New copper(II) and oxidovanadium(IV) complexes with a vitamin B6 Schiff base: mechanism of action and synergy studies on 2D and 3D human osteosarcoma cell models.

We report the synthesis, characterization and anticancer activity of a new Schiff base (H2L) derived from the condensation of pyridoxamine with pyridoxal and its novel copper(II) and oxidovanadium(IV) complexes: [Cu(HL)Cl] (1), [Cu(LH2)(phen)]Cl2 (2), [Cu(LH2)(amphen)]Cl2 (3), [VIVO(HL)Cl] (4), and [VIVO(LH2)(phen)]Cl2 (5), where phen is 1,10-phenanthroline and amphen is its 5-amino derivative. All compounds were characterized by analytical and spectroscopic techniques, namely FTIR, UV-vis and EPR spectroscopy. Their stability in aqueous media was evaluated, revealing that the presence of the phen co-ligand significantly increases the stability. The ternary Cu(II) complexes (2 and 3) impaired cell viability of osteosarcoma cells (MG-63) (IC50 values of 3.6 ± 0.6 and 7 ± 1.9 µM for 2 and 3), while 1 and the VIVO complexes did not show relevant anticancer activity. Complexes 2 and 3 are also more active than cisplatin (CDDP). Synergistic studies between 2 and sorafenib showed significant synergism on MG-63 cells for the following combinations: 2 (2.0 µM) + sorafenib (10.0 µM) and 2 (2.5 µM) + sorafenib (12.5 µM), whilst the combination of 2 and CDDP did not show synergy. Complex 2 interacts with DNA, inducing significant genotoxic effects on MG-63 cells from 1.0 to 2.5 µM and it increases the ROS levels 880% over basal. Moreover, 2 induces apoptosis at 1.0 and 2.0 µM, while its combination with sorafenib induces apoptosis and necrosis. Finally, compound 2 reduces the cell viability of MG-63 spheroids showing an IC50 value 7-fold lower than that of CDDP (8.5 ± 0.4 µM vs. 65 ± 6 µM). The combination of 2 and sorafenib also showed synergism on spheroids, suggesting that the combination of these drugs improves the anticancer effect against bone cancer cells.

Promising anticancer agents based on 8-hydroxyquinoline hydrazone copper(II) complexes.

We report the synthesis and characterization of a group of benzoylhydrazones (Ln) derived from 2-carbaldehyde-8-hydroxyquinoline and benzylhydrazides containing distinct para substituents (R = H, Cl, F, CH3, OCH3, OH and NH2, for L1-7, respectively; in L8 isonicotinohydrazide was used instead of benzylhydrazide). Cu(II) complexes were prepared by reaction of each benzoylhydrazone with Cu(II) acetate. All compounds were characterized by elemental analysis and mass spectrometry as well as by FTIR, UV-visible absorption, NMR or electron paramagnetic resonance spectroscopies. Complexes isolated in the solid state (1-8) are either formulated as [Cu(HL)acetate] (with L1 and L4) or as [Cu(Ln)]3 (n = 2, 3, 5, 6, 7 and 8). Single crystal X-ray diffraction studies were done for L5 and [Cu(L5)]3, confirming the trinuclear formulation of several complexes. Proton dissociation constants, lipophilicity and solubility were determined for all free ligands by UV-Vis spectrophotometry in 30% (v/v) DMSO/H2O. Formation constants were determined for [Cu(LH)], [Cu(L)] and [Cu(LH-1)] for L = L1, L5 and L6, and also [Cu(LH-2)] for L = L6, and binding modes are proposed, [Cu(L)] predominating at physiological pH. The redox properties of complexes formed with L1, L5 and L6 are investigated by cyclic voltammetry; the formal redox potentials fall in the range of +377 to +395 mV vs. NHE. The binding of the Cu(II)-complexes to bovine serum albumin was evaluated by fluorescence spectroscopy, showing moderate-to-strong interaction and suggesting formation of a ground state complex. The interaction of L1, L3, L5 and L7, and of the corresponding complexes with calf thymus DNA was evaluated by thermal denaturation. The antiproliferative activity of all compounds was evaluated in malignant melanoma (A-375) and lung (A-549) cancer cells. The complexes show higher activity than the corresponding free ligand, and most complexes are more active than cisplatin. Compounds 1, 3, 5, and 8 were selected for additional studies: while these complexes induce reactive oxygen species and double-strand breaks in both cancer cells, their ability to induce cell-death by apoptosis varies. Within the set of compounds tested, 8 emerges as the most promising one, presenting low IC50 values, and high induction of oxidative stress and DNA damage, which eventually lead to high rates of apoptosis.

Metal Coordination and Biological Screening of a Schiff Base Derived from 8-Hydroxyquinoline and Benzothiazole.

Designing new metallodrugs for anticancer therapy is a driving force in the scientific community. Aiming to contribute to this field, we hereby report the development of a Schiff base (H2L) derived from the condensation of 2-carbaldehyde-8-hydroxyquinoline with 2-hydrazinobenzothiazole and its complexation with transition metal ions. All compounds were characterised by analytical and spectroscopic techniques, which disclosed their structure: [Cu(HL)Cl], [Cu(HL)2], [Ni(HL)(acetate)], [Ni(HL)2], [Ru(HL)Cl(DMSO)], [VO(HL)2] and [Fe(HL)2Cl(H2O)]. Different binding modes were proposed, showing the ligand's coordination versatility. The ligand proton dissociation constants were determined, and the tested compounds showed high lipophilicity and light sensitivity. The stability of all complexes in aqueous media and their ability to bind to albumin were screened. Based on an antiproliferative in vitro screening, [Ni(HL)(acetate)] and [Ru(HL)Cl(DMSO)] were selected for further studies aiming to investigate their mechanisms of action and therapeutic potential towards colon cancer. The complexes displayed IC50 < 21 µM towards murine (CT-26) and human (HCT-116) colon cancer cell lines. Importantly, both complexes exhibited superior antiproliferative properties compared to the clinically approved 5-fluorouracil. [Ni(HL)(acetate)] induced cell cycle arrest in S phase in CT-26 cells. For [Ru(HL)Cl(DMSO)] this effect was observed in both colon cancer cell lines. Additionally, both compounds significantly inhibited cell migration particularly in the human colon cancer cell line, HCT-116. Overall, the therapeutic potential of both metal complexes was demonstrated.

Binding of VIV O2+ , VIV OL, VIV OL2 and VV O2 L Moieties to Proteins: X-ray/Theoretical Characterization and Biological Implications.

Vanadium compounds have frequently been proposed as therapeutics, but their application has been hampered by the lack of information on the different V-containing species that may form and how these interact with blood and cell proteins, and with enzymes. Herein, we report several resolved crystal structures of lysozyme with bound VIV O2+ and VIV OL2+ , where L=2,2'-bipyridine or 1,10-phenanthroline (phen), and of trypsin with VIV O(picolinato)2 and VV O2 (phen)+ moieties. Computational studies complete the refinement and shed light on the relevant role of hydrophobic interactions, hydrogen bonds, and microsolvation in stabilizating the structure. Noteworthy is that the trypsin-VV O2 (phen) and trypsin-VIV O(OH)(phen) adducts correspond to similar energies, thus suggesting a possible interconversion under physiological/biological conditions. The obtained data support the relevance of hydrolysis of VIV and VV complexes in the several types of binding established with proteins and the formation of different adducts that might contribute to their pharmacological action, and significantly widen our knowledge of vanadium-protein interactions.

Copper(II) and oxidovanadium(IV) complexes of chromone Schiff bases as potential anticancer agents.

We report the synthesis, characterization and biological screening of new chromone Schiff bases derived from the condensation of three 6-substituted-3-formyl-chromones with pyridoxal (HL1-3) and its Cu(II) complexes [Cu(L1-3)Cl], 1-3. For the 6-methyl derivative, HL2, the VIVO-complex [VO(L2)Cl] (5), as well as ternary Cu and VIVO complexes with 1,10-phenanthroline (phen), [Cu(L2)(phen)Cl] (4) and [VO(L2)(phen)Cl] (6), were also prepared and evaluated. Their stability in aqueous medium and radical scavenging activity toward DPPH are screened, with [Cu(L2)(phen)Cl] (4) showing hydrolytic stability and [VO(L2)(phen)Cl] (6) high radical scavenging activity. Spectroscopic studies establish bovine serum albumin (BSA), a model for HSA, as a potential reversible carrier of [Cu(L2)(phen)Cl] in blood with KBC ≈ 105 M-1. The cytotoxic activity of a group of compounds is evaluated against a panel of human cancer cell lines of different origin (ovary, cervix, brain and breast) and compared to normal cells. Our results indicate that Cu complexes are more cytotoxic than the ligands but not selective towards cancer cells. The most potent complexes (4 and 6) are further evaluated for their apoptotic potential, induction of reactive oxygen species (ROS) and genotoxicity. Both complexes efficiently triggered cell death through apoptosis as evaluated by DNA morphology and TUNEL assay, increased ROS formation as determined by DCFDA (2',7'-dichlorodihydrofluorescein diacetate) analysis, and induced genotoxic damage as visualized via COMET assay in all cancer cells under study. Therefore, 4 and 6 may be potential precursor anticancer molecules, yet they need to be targeted toward cancer cells.

New VIV, VIVO, VVO, and VVO2 Systems: Exploring their Interconversion in Solution, Protein Interactions, and Cytotoxicity.

The synthesis and characterization of one oxidoethoxidovanadium(V) [VVO(L1)(OEt)] (1) and two nonoxidovanadium(IV) complexes, [VIV(L2-3)2] (2 and 3), with aroylhydrazone ligands incorporating naphthalene moieties, are reported. The synthesized oxido and nonoxido vanadium complexes are characterized by various physicochemical techniques, and their molecular structures are solved by single crystal X-ray diffraction (SC-XRD). This revealed that in 1 the geometry around the vanadium atom corresponds to a distorted square pyramid, with a O4N coordination sphere, whereas that of the two nonoxido VIV complexes 2 and 3 corresponds to a distorted trigonal prismatic arrangement with a O4N2 coordination sphere around each "bare" vanadium center. In aqueous solution, the VVO moiety of 1 undergoes a change to VVO2 species, yielding [VVO2(L1)]- (1'), while the nonoxido VIV-compounds 2 and 3 are partly converted into their corresponding VIVO complexes, [VIVO(L2-3)(H2O)] (2' and 3'). Interaction of these VVO2, VIVO, and VIV systems with two model proteins, ubiquitin (Ub) and lysozyme (Lyz), is investigated through docking approaches, which suggest the potential binding sites: the interaction is covalent for species 2' and 3', with the binding to Glu16, Glu18, and Asp21 for Ub, and His15 for Lyz, and it is noncovalent for species 1', 2, and 3, with the surface residues of the proteins. The ligand precursors and complexes are also evaluated for their in vitro antiproliferative activity against ovarian (A2780) and prostate (PC3) human cancer cells and in normal fibroblasts (V79) to check the selectivity of the compounds for cancer cells.

Interaction with Blood Proteins of a Ruthenium(II) Nitrofuryl Semicarbazone Complex: Effect on the Antitumoral Activity.

The steady rise in the cancer burden and grim statistics set a vital need for new therapeutic solutions. Given their high efficiency, metallodrugs are quite appealing in cancer chemotherapy. This work examined the anticancer activity of an anti-trypanosomal ruthenium-based compound bearing the 5-nitrofuryl pharmacophore, [RuII(dmso)2(5-nitro-2-furaldehyde semicarbazone)] (abbreviated as RuNTF; dmso is the dimethyl sulfoxide ligand). The cytotoxicity of RuNTF was evaluated in vitro against ovarian adenocarcinoma, hormone-dependent breast adenocarcinoma, prostate carcinoma (grade IV) and V79 lung fibroblasts human cells. The activity of RuNTF was similar to the benchmark metallodrug cisplatin for the breast line and inactive against the prostate line and lung fibroblasts. Given the known role of serum protein binding in drug bioavailability and the distribution via blood plasma, this study assessed the interaction of RuNTF with human serum albumin (HSA) by circular dichroism (CD) and fluorescence spectroscopy. The fluorescence emission quenching from the HSA-Trp214 residue and the lifetime data upon RuNTF binding evidenced the formation of a 1:1 {RuNTF-albumin} adduct with log Ksv = (4.58 ± 0.01) and log KB = (4.55 ± 0.01). This is supported by CD data with an induced CD broad band observed at ~450 nm even after short incubation times. Importantly, the binding to either HSA or human apo-transferrin is beneficial to the cytotoxicity of the complex towards human cancer cells by enhancing the cytotoxic activity of RuNTF.

Exploring the cytotoxic activity of new phenanthroline salicylaldimine Zn(II) complexes.

Zinc(II) complexes bearing N-salicylideneglycinate (Sal-Gly) and 1,10-phenanthroline (phen) or phenanthroline derivatives [NN = 5-chloro-1,10-phenanthroline, 5-amine-1,10-phenanthroline (amphen), 4,7-diphenyl-1,10-phenanthroline (Bphen) and 5,6-epoxy-5,6-dihydro-1,10-phenanthroline] are synthesized. Complexes formulated as [Zn(NN)2(H2O)2]2+(NN = phen and amphen), are also prepared. The cytotoxicity of the compounds is evaluated towards a panel of human cancer cells: ovarian (A2780), breast (MCF7) and cervical (HeLa), as well as non-tumoral V79 fibroblasts. All compounds display higher cytotoxicity than cisplatin (IC50 = 22.5 ±â€¯5.0 µM) towards ovarian cells, showing IC50values in the low micromolar range. Overall, all compounds show higher selectivity for the A2780 cells than for the non-tumoral cells and higher selectivity indexes (IC50(V79)/IC50(A2780) than cisplatin. [Zn(Sal-Gly)(NN)(H2O)] complexes induce caspase-dependent apoptosis in A2780 cells, except [Zn(Sal-Gly)(Bphen)(H2O)], one of the most cytotoxic of the series. The cellular uptake in the ovarian cells analyzed by Inductively Coupled Plasma mass spectrometry indicates different Zn distribution profiles. Transmission electronic microscopy shows mitochondria alterations and apoptotic features consistent with caspase activation; cells incubated with [Zn(Sal-Gly)(amphen)(H2O)] present additional nuclear membrane alterations in agreement with significant association with the nucleus. The increase of reactive oxygen species and lipid peroxidation forms could be related to apoptosis induction. [Zn(NN)2(H2O)2]2+complexes have high ability to bind DNA through intercalation/groove binding, and circular dichroism data suggests that the main type of species that interact with DNA is [Zn(NN)]2+. Studies varying the % of fetal bovine serum (1-15%) in cell media show that albumin binding decreases the complex activity, indicating that distinct speciation of Zn- and phen-containing species in cell media may affect the cytotoxicity.

Vanadium ionic species from degradation of Ti-6Al-4V metallic implants: In vitro cytotoxicity and speciation evaluation.

Among the metallic materials used in biomedical industry, the most common choice for orthopedics and dental implants is titanium (Ti) and its alloys, mainly due to their superior corrosion and tribocorrosion resistance and biocompatibility. Under different conditions in vivo, such as different pH levels, composition of body fluid and mechanical loads, metallic materials may suffer from degradation, resulting in the release of undesired wear particles and ions. In particular, the Ti-6Al-4V system represents almost half of the production of Ti as a biomaterial and many concerns have been raised about titanium, aluminum and vanadium ions releasing. This work evaluates the cytotoxic effects of vanadium ionic species generated from Ti-6Al-4V surfaces regarding mouse pre-osteoblasts and fibroblasts. In our cell viability tests, we noticed a significant decrease in the fibroblasts' cell viability with vanadium concentrations (23 µM) close to those previously reported to be observed in vivo in patients with poor functioning of their medical devices based on Ti-6Al-4V (30 µM). Speciation modelling was carried-out, for the first time, to this system. Results of the modelling reveal that vanadates(V), namely H2VO4- and HVO42-, are the main species present in cell culture media. Otherwise, in synovial fluids of individuals with poorly functioning implants, wherein the concentration of vanadium may go up to ca. 30 µM, the tentative theoretical speciation data indicates a high occurrence probability for VV- and VIV-species bound to albumin and hyaluronic acid. In conclusion, even though relatively low concentrations of vanadium may be released from Ti-6Al-4V implants in vivo, the continuous contact with peri-implant cells for long periods of time may represent a potentially hazardous situation.

Synthesis, structure, solution behavior, reactivity and biological evaluation of oxidovanadium(iv/v) thiosemicarbazone complexes.

The synthesis and characterization of an oxidovanadium(iv) [VIVO(L)(acac)] (1) and of two dioxidovanadium(v) [VVO2(L')] (2) and [VVO2(L)] (2a) complexes of the Schiff base formed from the reaction of 4-(p-fluorophenyl) thiosemicarbazone with pyridine-2-aldehyde (HL) are described. The oxidovanadium(iv) species [VIVO(L)(acac)] (1) was synthesized by the reaction of VIVO(acac)2 with the thiosemicarbazone HL in refluxing ethanol. The recrystallization of [VIVO(L)(acac)] (1) in DMF, CH3CN or EtOH gave the same product i.e. the dioxidovanadium(v) complex [VVO2(L)] (2a); however, upon recrystallization of 1 in DMSO a distinct compound [VVO2(L')] (2) was formed, wherein the original ligand L- is transformed to a rearranged one, L'-. In the presence of DMSO the ligand in complex 1 is found to undergo methylation at the carbon centre attached to imine nitrogen (aldimine) and transformed to the corresponding VVO2-species through in situ reaction. The synthesized HL and the metal complexes were characterized by elemental analysis, IR, UV-Vis, NMR and EPR spectroscopy. The molecular structure of [VVO2(L')] (2) was determined by single crystal X-ray crystallography. The methylation of various other ligands and complexes prepared from different vanadium precursors under similar reaction conditions was also attempted and it was confirmed that the imine methylation observed is both ligand and metal precursor specific. Complexes 1 and 2 show in vitro insulin-like activity against insulin responsive L6 myoblast cells, higher than VIVO(acac)2, with complex 1 being more potent. In addition, the in vitro cytotoxicity studies of HL, and of complexes 1 and 2 against the MCF-7 and Vero cell lines were also done. The ligand is not cytotoxic and complex 2 is significantly more cytotoxic than 1. DAPI staining experiments indicate that an increase in the time of incubation and an increase of concentration of the complexes lead to the increase in cell death.

Photophysical properties and biological evaluation of a Zinc(II)-5-methyl-1H-pyrazole Schiff base complex.

A new ZnL2 complex containing two molecules of a tridentate Schiff base derived from 5-methyl-1H-pyrazole (HL) is synthesized and characterized. The photophysical properties of HL and ZnL2 are disclosed and supported by CAMB3LYP DFT/TDDFT calculations. It is shown that there is keto-tautomer stabilization upon excitation with an energetically accessible triplet state in HL, not present in ZnL2, this explaining the differences found in the emissions of the compounds. The intrinsic fluorescence of ZnL2 is used as probe for a detailed study of its binding to human serum albumin. The protein-complex association is thermodynamically favourable and it is shown by fluorescence quenching and time-resolved analysis that the fluorescence quenching involves a mixed mechanism with prevalence of static quenching, which corroborates adduct formation at site I, close to the Trp214 residue. The ability of ZnL2 to bind DNA was also evaluated, as well as its cytotoxic activity against MCF7 (breast), PC3 (prostate) cancer cells and hamster V79 fibroblasts. ZnL2 is a moderate DNA intercalator (Kapp = 3.9 × 104 M-1) and depicts a quite low IC50 value at 48 h against MCF7 cells (IC50 = 530 nM), but much higher for PC3 and V79 cells. The relevance of a more careful speciation evaluation of ZnL2 and other potential metal-based drugs in incubation media used in in vitro tests is highlighted.

Heteroleptic oxidovanadium(IV) complexes of 2-hydroxynaphtylaldimine and polypyridyl ligands against Trypanosoma cruzi and prostate cancer cells.

In Latin America Chagas disease is an endemic illness caused by the parasite Trypanosoma cruzi (T. cruzi), killing more people than any other parasitic disease. Current chemotherapies are old and inadequate, thus the development of efficient ones is urgently needed. Vanadium-based complexes have been shown to be a promising approach both against parasitic diseases and cancer and this study aims to achieve significant advances in the pursue of effective compounds. Heteroleptic vanadium complexes of Schiff bases and polypyridine compounds were prepared and their stability in solution evaluated by EPR (Electronic Paramagnetic Resonance) and NMR spectroscopy. Their in vitro activities were evaluated against T. cruzi and a set of cells lines representative of human cancer conditions, namely ovarian, breast and prostate cancer. In T. cruzi, most of the complexes depicted IC50 values in the low µM range, induced changes of mitochondrial membrane potential and apoptosis. In cancer cells, complexes showed good to moderate activity and in metastatic cells (prostate PC3), some complexes inhibited the migratory ability, this suggesting that they display antimetastatic potential. Interestingly, complex 5 seemed to have a dual effect being the most cytotoxic complex on all cancer cells and also the most active anti-T-cruzi compound of the series. Globally the complexes showed promising anticancer and anti T. cruzi activities and also displayed some characteristics indicating they are worth to be further explored as antimetastatic drugs.

New Cu(II) complexes with pyrazolyl derived Schiff base ligands: Synthesis and biological evaluation.

Since the discovery of cisplatin there has been a continuous pursuit for new metallodrugs showing higher efficacies and lower side effects. In this work, new copper(II) complexes (C1-C6) of Schiff bases derived from pyrazolyl were developed. Through condensation of 5-methyl-1H-pyrazole-3-carbohydrazide with different aromatic aldehydes - pyridoxal, salicylaldehyde, 3-methoxy-2-hydroxybenzaldehyde, 3-ethoxy-2-hydroxybenzaldehyde and 2-hydroxynaphthene-1-carbaldehyde - a set of new pyrazole based "ONO" tridentate Schiff bases were obtained in moderate to good yields - L1-L6, as well as their Cu(II)-complexes. All compounds were characterized by analytical techniques and their molecular formulae established. The antioxidant potential of all compounds was tested, yielding low activity in most cases, with the exception of L1 and C5. The Cu(II) complexes were tested for their aqueous stability, and for their interaction with biological molecules, namely DNA and HSA (human serum albumin), through fluorescence quenching experiments (and electrophoresis for DNA). With the exception of C3, all the synthesized complexes were able to interact with DNA and HSA. Their cytotoxic activity against two cancer cell lines (MCF7 - breast and PC3 - prostate) was also evaluated. Complexes C5 and C6, with larger aromatic systems, showed much higher cytotoxicity (in the low µM range), than C1-C4, as well as IC50 values much lower than cisplatin. For C6 the results suggest that the mechanisms of cell death do not seem to be mediated by apoptosis, through caspases 3/7 activation, but by involving membrane potential and imbalance in physiological elements such as P, K and Ca.

Evaluation of cellular uptake, cytotoxicity and cellular ultrastructural effects of heteroleptic oxidovanadium(IV) complexes of salicylaldimines and polypyridyl ligands.

Searching for prospective vanadium-based drugs for cancer treatment, a new series of structurally related [VIVO(L-2H)(NN)] compounds (1-8) was developed. They include a double deprotonated salicylaldimine Schiff base ligand (L-2H) and different NN-polypyridyl co-ligands having DNA intercalating capacity. Compounds were characterized in solid state and in solution. EPR spectroscopy suggests that the NN ligands act as bidentate and bind through both nitrogen donor atoms in an axial-equatorial mode. The cytotoxicity was evaluated in human tumoral cells (ovarian A2780, breast MCF7, prostate PC3). The cytotoxic activity was dependent on type of cell and incubation time. At 24h PC3 cells presented low sensitivity, but at 72h all complexes showed high cytotoxic activity in all cells. Human kidney HEK293 and ovarian cisplatin resistant A2780cisR cells were also included to evaluate selectivity towards cancer cells and potency to overcome cisplatin resistance, respectively. Most complexes showed no detectable interaction with plasmid DNA, except 2 and 7 which depicted low ability to induce single strand breaks in supercoiled DNA. Based on the overall cytotoxic profile, complexes with 2,2´-bipyridine and 1,10-phenanthroline ligands (1 and 2) were selected for further studies, which consisted on cellular distribution and ultrastructural analyses. In the A2780 cells both depicted different distribution profiles; the former accumulates mostly at the membrane and the latter in the cytoskeleton. Morphology of treated cells showed nuclear atypia and membrane alterations, more severe for 1. Complexes induce different cell death pathways, predominantly necrosis for 1 and apoptosis for 2. Complexes alternative mode of cell death motivates the possibility for further developments.

Strecker degradation of amino acids promoted by a camphor-derived sulfonamide.

A camphor-derived sulfonimine with a conjugated carbonyl group, oxoimine 1 (O2SNC10H13O), reacts with amino acids (glycine, L-alanine, L-phenylalanine, L-leucine) to form a compound O2SNC10H13NC10H14NSO2 (2) which was characterized by spectroscopic means (MS and NMR) and supported by DFT calculations. The product, a single diastereoisomer, contains two oxoimine units connected by a -N= bridge, and thus has a structural analogy to the colored product Ruhemann´s purple obtained by the ninhydrin reaction with amino acids. A plausible reaction mechanism that involves zwitterions, a Strecker degradation of an intermediate imine and water-catalyzed tautomerizations was developed by means of DFT calculations on potential transition states.

The effect of phosphate on the nuclease activity of vanadium compounds.

The nuclease activity of VO(acac)2 (1, acac = acetylacetone) and its derivatives VO(hd)2 (2, hd = 3,5-heptanedione), VO(Cl-acac)2 (3, Cl-acac = 3-chloro-2,4-pentanedione), VO(Et-acac)2 (4, Et-acac = 3-ethyl-2,4-pentanedione) and VO(Me-acac)2 (5, Me-acac = 3-methyl-2,4-pentanedione), is studied by agarose gel electrophoresis, UV-visible spectroscopy, cyclic and square wave voltammetry and (51)V NMR. The mechanism is shown to be oxidative and associated with the formation of reactive oxygen species (ROS). Hydrolytic cleavage of the phosphodiester bond is also promoted by 1, but at much slower rate which cannot compete with the oxidative mechanism. The generation of ROS is much higher in the presence of phosphate buffer when compared with organic buffers and this was attributed to the formation of a mixed-ligand complex containing phosphate, (V(IV)O)(V(V)O)(acac)2(HnPO4(n-3)), presenting a quasi-reversible voltammetric behavior. The formation of this species was further observed by Electrospray Ionization Mass Spectrometry (ESI-MS). Phosphate being an essential species in most biological media, the importance of the formation of mixed-ligand species in other vanadium systems is emphasized.

Oxidovanadium(IV) and dioxidovanadium(V) complexes of hydrazones of 2-benzoylpyridine and their catalytic applications.

Reactions between the tridentate ONN donor ligands, Hbzpy-tch () and Hbzpy-inh (), with [V(IV)O(acac)2] in dry methanol give two different types of complexes, [V(IV)O(acac)(bzpy-tch)] () and [V(IV)O(OMe)(bzpy-inh)] (), respectively. Irrespective of their nature in methanol upon aerial oxidation and precipitation both yield dinuclear [{V(V)O(bzpy-tch)}2(µ-O)2] () and [{V(V)O(bzpy-inh)}2(µ-O)2] (). Treatment of or in methanol with H2O2 yields the oxidomonoperoxidovanadium(v) complexes [{V(V)O(bzpy-tch)}2(µ-O2)2] () and [V(V)O(O2)(bzpy-inh)] (). Reactions of and with imidazolomethylpolystyrene cross-linked with 5% divinylbenzene (PS-im) in DMF give the polymer-supported PS-im[V(V)O2(bzpy-inh)] () and PS-im[V(V)O2(bzpy-tch)] (). The compounds are characterized by various spectroscopic techniques and compounds and were also analyzed by thermal, atomic force microscopy (AFM), field-emission scanning electron micrographs (FE-SEM) as well as energy dispersive X-ray (EDAX) studies. The molecular structures of and of [V(V)O(O2)(bzpy-inh)(H2O)]·0.5MeOH () were determined by single-crystal X-ray diffraction, confirming the µ-bis(O) and ONN binding mode in the dinuclear complexes and , as well as the side-on coordination of the peroxido ligand in and . The polymer-grafted compounds and were used for the catalytic oxidation of isoeugenol using aqueous H2O2 as an oxidant. The intermediate peroxido species, expected to be involved during catalytic action, were also generated from solutions of and studied by UV-Vis and (51)V NMR. The catalytic activity of the several systems was tested and the polymer-supported versions showed higher conversions than their neat counterparts. The polymer-supported complexes allow for recyclable catalytic systems, thus providing additional advantages over their homogeneous counterparts in terms of increased catalyst lifetime and easier separation from the reaction mixture.

Hydroxyquinoline derived vanadium(IV and V) and copper(II) complexes as potential anti-tuberculosis and anti-tumor agents.

Several mixed ligand vanadium and copper complexes were synthesized containing 8-hydroxyquinoline (8HQ) and a ligand such as picolinato (pic(-)), dipicolinato (dipic(2-)) or a Schiff base. The complexes were characterized by spectroscopic techniques and by single-crystal X-ray diffraction in the case of [V(V)O(L-pheolnaph-im)(5-Cl-8HQ)] and [V(V)O(OMe)(8HQ)2], which evidenced the distorted octahedral geometry of the complexes. The electronic absorption data showed the presence of strong ligand to metal charge transfer bands, significant solvent effects, and methoxido species in methanol, which was further confirmed by (51)V-NMR spectroscopy. The structures of [Cu(II)(dipic)(8HQ)]Na and [V(IV)O(pic)(8HQ)] were confirmed by EPR spectroscopy, showing only one species in solution. The biological activity of the compounds was assessed through the minimal inhibitory concentration (MIC) of the compounds against Mycobacterium tuberculosis (Mtb) and the cytotoxic activity against the cisplatin sensitive/resistant ovarian cells A2780/A2780cisR and the non-tumorigenic HEK cells (IC50 values). Almost all tested vanadium complexes were very active against Mtb and the MICs were comparable to, or better than, the MICs of drugs, such as streptomycin. The activity of the complexes against the A2780 cell line was dependent on incubation time presenting IC50 values in the 3-14 µM (at 48 h) range. In these conditions, the complexes were significantly (*P<0.05-**P<0.001) more active than cisplatin (22 µM), in the A2780 cells and even surpassing its activity in the cisplatin-resistant cells A2780cisR (2.4-8 µM vs. 75.4; **P<0.001). In the non-tumorigenic HEK cells poor selectivity toward cancer cells for most of the complexes was observed, as well as for cisplatin.

A new series of heteroleptic oxidovanadium(IV) compounds with phenanthroline-derived co-ligands: selective Trypanosoma cruzi growth inhibitors.

Searching for prospective metal-based drugs for the treatment of Chagas disease, a new series of ten mixed-ligand oxidovanadium(IV) complexes, [V(IV)O(L-2H)(NN)], where L is a tridentate salicylaldehyde semicarbazone derivative (L1-L5) and NN is either 5-amine-1,10-phenanthroline (aminophen) or 5,6-epoxy-5,6-dihydro-1,10-phenanthroline (epoxyphen), were synthesized. The compounds were characterized in the solid state and in solution. EPR spectroscopy suggests that the NN ligands act as bidentate through both nitrogen donor atoms in an axial-equatorial mode. The stability of the complexes in solution was investigated by EPR and (51)V-nuclear magnetic resonance spectroscopies. The complexes were evaluated in vitro for their activities against Trypanosoma cruzi (T. cruzi), the parasite responsible for the disease, and their selectivity was analyzed using J-774 murine macrophages, as a mammalian model. All the complexes are more active than both the reference drug Nifurtimox and the previously reported [V(IV)O(L-2H)(NN)] complexes. In general they are more active than the corresponding free NN ligands. Complexation led to highly increased selectivities towards the parasite. In addition, the lipophilicity of the compounds was determined and correlated with the observed activity in order to perform a QSAR (quantitative structure-activity relationship) study. A clear quadratic correlation is found. This study also confirms the influence of the structure of the co-ligand on the anti-T. cruzi effect. To get insight into the mechanism of action of the compounds, the changes in biochemical pathways promoted by two of the most active and most selective complexes are studied by analyzing a few of the parasite excreted metabolites by (1)H NMR spectroscopy. The combined information suggests that the mitochondrion could be a target for these complexes. Furthermore, DNA was preliminarily evaluated as a potential target by using atomic force microscopy (AFM), which showed that the complexes display an ability to interact with this biomolecule.

Vanadium complexes having [VO]2+, [VO]3+ and [VO2]+ cores with hydrazones of 2,6-diformyl-4-methylphenol: synthesis, characterization, reactivity, and catalytic potential.

The Schiff bases H3dfmp(L)2 obtained by the condensation of 2,6-diformyl-4-methylphenol and hydrazones [L = isonicotinoylhydrazide (inh), nicotinoylhydrazide (nah) and benzoylhydrazide (bhz)] are prepared and characterized. By reaction of [V(IV)O(acac)2] and the H3dfmp(L)2 in methanol the V(IV)O-complexes [V(IV)O{Hdfmp(inh)2}(H2O)] (1), [V(IV)O{Hdfmp(nah)2}(H2O)] (2) and [V(IV)O{Hdfmp(bhz)2}(H2O)] (3) were obtained. Upon their aerial oxidation in methanol [V(V)O(OMe)(MeOH){Hdfmp(inh)2}] (4), [V(V)O(OMe)(MeOH){Hdfmp(nah)2}] (5) and [V(V)O(OMe)(MeOH){Hdfmp(bhz)2}] (6) were isolated. In the presence of KOH, oxidation of 1-3 results in the formation of [V(V)O2{H2dfmp(inh)2}]n·5H2O (7), K[V(V)O2{Hdfmp(nah)2}] (8) and K[V(V)O2{Hdfmp(bhz)2}] (9). All compounds are characterized in the solid state and in solution, namely by spectroscopic techniques (IR, UV-Vis, EPR, (1)H, (13)C and (51)V NMR), and DFT is also used to calculate the V(IV) hyperfine coupling constants of V(IV)-compounds and (51)V NMR chemical shifts of several V(V)-species and assign them to those formed in solution. Single crystal X-ray analysis of [V(V)O(OMe)(MeOH){Hdfmp(bhz)2}] (6) and [V(V)O2{H2dfmp(inh)2}]n·5H2O (7) confirm the coordination of the ligand in the dianionic (ONO(2-)) enolate tautomeric form, one of the hydrazide moieties remaining non-coordinated. In the case of 7 the free N(pyridine) atom of the inh moiety coordinates to the other vanadium center yielding a polynuclear complex in the solid state. It is also demonstrated that the V(V)O2-complexes are catalyst precursors in the oxidative bromination of styrene by H2O2, therefore acting as functional models of vanadium dependent haloperoxidases. Plausible intermediates involved in the catalytic process are established by UV-Vis, (51)V NMR and DFT studies.