João Costa Pessoa

Vanadium compounds in medicine

Abstract Vanadium is a transition metal that, being ubiquitously distributed in soil, crude oil, water and air, also found roles in biological systems and is an essential element in most living beings. There are also several groups of organisms which accumulate vanadium, employing it in their biological processes. Vanadium being a biological relevant element, it is not surprising that many vanadium based therapeutic drugs have been proposed for the treatment of several types of diseases. Namely, vanadium compounds, in particular organic derivatives, have been proposed for the treatment of diabetes, of cancer and of diseases caused by parasites. In this work we review the medicinal applications proposed for vanadium compounds with particular emphasis on the more recent publications. In cells, partly due to the similarity of vanadate and phosphate, vanadium compounds activate numerous signaling pathways and transcription factors; this by itself potentiates application of vanadium-based therapeutics. Nevertheless, this non-specific bio-activity may also introduce several deleterious side effects as in addition, due to Fentons type reactions or of the reaction with atmospheric O2, VCs may also generate reactive oxygen species, thereby introducing oxidative stress with consequences presently not well evaluated, particularly for long-term administration of vanadium to humans. Notwithstanding, the potential of vanadium compounds to treat type 2 diabetes is still an open question and therapies using vanadium compounds for e.g. antitumor and anti-parasitic related diseases remain promising.

Vanadium polypyridyl compounds as potential antiparasitic and antitumoral agents: New achievements

In the search for new therapeutic tools against diseases produced by kinetoplastid parasites five vanadyl complexes, [V(IV)O(L-2H)(phen)], including 1,10-phenanthroline (phen) and tridentate salicylaldehyde semicarbazone derivatives as ligands have been synthesized and characterized in the solid state and in solution by using different techniques. EPR suggested a distorted octahedral geometry with the tridentate semicarbazone occupying three equatorial positions and phen coordinated in an equatorial/axial mode. The compounds were evaluated in vitro on epimastigotes of Trypanosoma cruzi, causative agent of Chagas disease, Leishmania panamensis and Leishmania chagasi and on tumor cells. The complexes showed higher in vitro anti-trypanosomal activities than the reference drug Nifurtimox (IC(50) values in the range 1.6-3.8 μM) and increased activities in respect to the free semicarbazone ligands. In vitro activity on promastigote and amastigote forms of Leishmania showed interesting results. The compounds [VO(L1-2H)(phen)] and [VO(L3-2H)(phen)], where L1 = 2-hydroxybenzaldehyde semicarbazone and L3 = 2-hydroxy-3-methoxybenzaldehyde semicarbazone, resulted active (IC(50) 2.74 and 2.75 μM, respectively, on promastigotes of L. panamensis; IC(50) 19.52 and 20.75 μM, respectively, on intracellular amastigotes of L. panamensis) and showed low toxicity on THP-1 mammalian cells (IC(50) 188.55 and 88.13 μM, respectively). In addition, the complexes showed cytotoxicity on human promyelocytic leukemia HL-60 cells with IC(50) values of the same order of magnitude as cisplatin. The interaction of the complexes with DNA was demonstrated by different techniques, suggesting that this biomolecule could be a potential target either in the parasites or in tumor cells.

Vanadium Diaminebis(phenolate) Complexes: Syntheses, Structures, and Reactivity in Sulfoxidation Catalysis

Vanadium diaminebis(phenolate) complexes of the general formulas [LVCl(THF)] (L = Me(2)NCH(2)CH(R)N(CH(2)-2-O-3,5-C(6)H(2)(t)Bu(2))(2), where R = H, Me) and [LV(O)X] [X = Cl; R = H (2), Me (3), O(i)Pr (4), (mu-O)V(O)L (5)] are described. All compounds display octahedral geometry and trans-O(Ph) coordination. For compounds 2, 3, and 5, only one isomer, presenting the V=O ligand trans to the tripodal nitrogen, was formed, while for 4, two isomers were observed by NMR in solution. The UV-vis and circular dichroism spectra of 2 and 3 display very intense charge-transfer transition bands from the phenolate donors to the vanadium, which are in agreement with the (51)V low-field shifts observed. All vanadium(V) complexes were tested as thioanisole sulfoxidation catalysts, revealing very high selectivity when H(2)O(2) was used as the oxidant. However, no enantioselectivity was observed even when enantiopure 3 was used as the catalyst precursor. (1)H and (51)V NMR studies were conducted for the reactions of 2 with aqueous solutions of H(2)O(2) in methanol-d(4) and in acetonitrile-d(3); 2 reacts with the solvents, leading to [LV(O)OMe], by replacement of Cl by MeO in methanol, and to a new vanadium aminebis(phenolate) complex, where the dimethylamine fragment of the original ligand L was replaced by CH(3)CN. In either case, (51)V NMR spectra suggest the formation of peroxovanadium species upon the addition of a H(2)O(2) solution. The subsequent addition of thioanisole to the methanol-d(4) solution leads to regeneration of the original complex.

Vanadium compounds as therapeutic agents: Some chemical and biochemical studies

The behaviour of three vanadium(V) systems, namely the pyridinone (V(V)-dmpp), the salicylaldehyde (V(V)-salDPA) and the pyrimidinone (V(V)-MHCPE) complexes, is studied in aqueous solutions, under aerobic and physiological conditions using (51)V NMR, EPR and UV-Visible (UV-Vis) spectroscopies. The speciations for the V(V)-dmpp and V(V)-salDPA have been previously reported. In this work, the system V(V)-MHCPE is studied by pH-potentiometry and (51)V NMR. The results indicate that, at pH ca. 7, the main species present are (V(V)O(2))L(2) and (V(V)O(2))LH(-1) (L=MHCPE(-)) and hydrolysis products, similar to those observed in aqueous solutions of V(V)-dmpp. The latter species is protonated as the pH decreases, originating (V(V)O(2))L and (V(V)O(2))LH. All the V(V)-species studied are stable in aqueous media with different compositions and at physiological pH, including the cell culture medium. The compounds were screened for their potential cytotoxic activity in two different cell lines. The toxic effects were found to be incubation time and concentration dependent and specific for each compound and type of cells. The HeLa tumor cells seem to be more sensitive to drug effects than the 3T3-L1 fibroblasts. According to the IC(50) values and the results on reversibility to drug effects, the V(V)-species resulting from the V(V)-MHCPE system show higher toxicity in the tumor cells than in non-tumor cells, which may indicate potential antitumor activity.

Vanadium-salen and -salan complexes: Characterization and application in oxygen-transfer reactions

Salen complexes are a versatile and standard system in oxidation catalysis. Their reduced derivatives, called salan, share their versatility but are still widely unexplored. We report the synthesis of a group of new vanadium-salen and -salan complexes, their characterization and application in the oxidation of simple organic molecules with H2O2. The ligands are derived from pyridoxal and chiral diamines (1,2-diaminocyclohexane and 1,2-diphenylethylenediamine) and were easily obtained in high yields. The VIV complexes were prepared and characterized in the solid state (Fourier transform infrared, FTIR, and magnetic properties) and in solution by spectroscopic techniques: UV–vis, circular dichroism (CD), electron paramagnetic resonance (EPR), and 51V NMR, which provide information on the coordination geometry. Single crystals suitable for X-ray diffraction studies were obtained from solutions containing the VIV-pyr(S,S-chan) complex: [VVO{pyr(S,S-chen)}]2(μ-O)2·2(CH3)2NCHO, where the ligand is the “half” Schiff base formed by pyridoxal and 1S,2S-diaminocyclohexane. The dinuclear species shows a OVV(μ-O)2VVO unit with tridentate ligands and two μ-oxo bridges. The VIV complexes of the salan-type ligands oxidize in organic solvents to a VV species, and the process was studied by spectroscopic techniques. The complexes were tested as catalysts in the oxidation of styrene, cyclohexene, and cumene with H2O2 as oxidant. Overall, the V-salan complexes show higher activity than the parent V-salen complexes and are an alternative ligand system for oxidation catalysis.

Interaction of vanadium(IV) with human serum apo-transferrin.

The interaction of V(IV)O-salts as well as of a few V(IV)O(carrier)n complexes with human serum transferrin (hTF) is studied focusing on the determination of the nature and stoichiometry of the binding of V(IV)O(2+) to hTF, as well as whether the conformation of hTF upon binding to V(IV)O(2+) or to its complexes is changed. Circular dichroism (CD) spectra measured for solutions containing V(IV)O(2+) and apo-hTF, and V(IV)O-maltol and apo-hTF, clearly indicate that hTF-V(IV)O-maltol ternary species form with a V(IV)O:maltol stoichiometry of 1:1. For V(IV)O salts and several V(IV)O(carrier)n complexes (carrier ligand=maltolato, dhp, picolinato and dipicolinato) (Hdhp=1,2-dimethyl-3-hydroxy-4-pyridinone) the maximum number of V(IV)O(2+) bound per mole of hTF is determined to be ~2 or lower in all cases. The binding of V(IV)O to apo-hTF most certainly involves several amino acid residues of the Fe-binding site, and as concluded by urea gel electrophoresis experiments, the formation of (V(IV)O)2hTF species may occur with the closing of the hTF conformation as is the case in (Fe(III))2hTF, which is an essential feature for the transferrin receptor recognition.

Evaluation of the binding of oxovanadium(IV) to human serum albumin

The understanding of the biotransformations of insulin mimetic vanadium complexes in human blood and its transport to target cells is an essential issue in the development of more effective drugs. We present the study of the interaction of oxovanadium(iv) with human serum albumin (HSA) by electron paramagnetic resonance (EPR), circular dichroism (CD) and visible absorption spectroscopy. Metal competition studies were done using Cu(II) and Zn(II) as metal probes. The results show that V(IV)O occupies two types of binding sites in albumin, which compete not only with each other, but also with hydrolysis of the metal ion. In one of the sites the resulting V(IV)O-HSA complex has a weak visible CD signal and its X-band EPR spectrum may be easily measured. This was assigned to amino acid side chains of the ATCUN site. The other binding site shows stronger signals in the CD in the visible range, but has a hardly measurable EPR signal; it is assigned to the multi metal binding site (MBS) of HSA. Studies with fatted and defatted albumin show the complexity of the system since conformational changes, induced by the binding of fatty acids, decrease the ability of V(IV)O to bind albumin. The possibility and importance of ternary complex formation between V(IV)O, HSA and several drug candidates - maltol (mal), picolinic acid (pic), 2-hydroxypyridine-N-oxide (hpno) and 1,2-dimethyl-3-hydroxy-4(1H)-pyridinone (dhp) was also evaluated. In the presence of maltol the CD and EPR spectra significantly change, indicating the formation of ternary VO-HSA-maltol complexes. Modeling studies with amino acids and peptides were used to propose binding modes. Based on quantitative RT EPR measurements and CD data, it was concluded that in the systems with mal, pic, hpno, and dhp (V(IV)OL(2))(n)(HSA) species form, where the maximum value for n is at least 6 (mal, pic). The degree of formation of the ternary species, corresponding to the reaction V(IV)OL(2) + HSA -->/<-- V(IV)OL(2)(HSA) is hpno > pic ≥ mal > dhp. (V(IV)OL)(n)(HSA) type complexes are detected exclusively with pic. Based on the spectroscopic studies we propose that in the (V(IV)OL(2))(n)(HSA) species the protein bounds to vanadium through the histidine side chains.

Copper(II) complexes with tridentate pyrazole-based ligands: synthesis, characterization, DNA cleavage activity and cytotoxicity.

Tridentate pyrazole-containing ligands of the Schiff base type, SalPz - HL(1), Cl(2)SalPz - HL(2) and I(2)SalPz - HL(3), were used to prepare a series of new Cu(II) complexes (CuSalPz - 1, CuCl(2)SalPz - 2 and CuI(2)SalPz - 3). These new complexes have been studied by different analytical techniques (electrospray ionization mass spectrometry (ESI-MS), elemental analysis, FT-IR and EPR). The spectroscopic properties of 1-3 are consistent with the formation of Cu(II) complexes coordinated by monoanionic and tridentate (N,N,O)-chelators, behaving as monomeric species in aqueous solution, as shown by EPR studies. Crystals of 2 and 3, obtained by slow concentration of methanolic solutions of the compounds, were also analyzed by X-ray diffraction analysis. The X-ray structural study has shown that 2 crystallized as a dinuclear compound, [Cu(2)(μ-Cl)(2)(Cl(2)SalPz)(2)], while the solid state structure determined for 3 is best described by monomeric units of [CuCl(I(2)SalPz)] displaying short Cu···Cl intermolecular contacts. The in vitro evaluation of 1-3 comprised the study of their DNA-cleaving ability using plasmid DNA and the assessment of their cytotoxic activity against several human cancer cell lines (PC-3 prostate, MCF-7 breast and A2780 and A2780cisR-ovary). The studies with plasmid DNA have shown that 2 and 3 induce extensive DNA cleavage in the presence of different additives. The cytotoxic activity of 2 and 3 is comparable to the one presented by cisplatin, with the exception of the A2780 cell line where cisplatin is more active. It has been found that the introduction of halogen substituents in the phenolate rings of the chelators enhanced the cytotoxicity of the respective Cu(II) complexes.

The systems VIVO2+-glutathione and related ligands: a potentiometric and spectroscopic study

Abstract. The equilibria in the system VIVO2+-glutathione in aqueous solution were studied in the pH range 2–11 by a combination of pH-potentiometry and spectroscopy (EPR, visible absorption and circular dichroism). The results of the various methods are consistent and the equilibrium model includes the species MLH3, MLH2, MLH, ML2H2, MLH–1, and MLH–2 and several hydrolysis products (where H4L denotes totally protonated glutathione); individual formation constants and spectra are given. ML2H2 is the predominant species at physiological pH. Plausible structures for each stoichiometry are discussed. The related VIVO2+ systems of S-methylglutathione and γ-L-glutamyl-L-cysteinyl ethyl ester were studied by means of the same spectroscopic techniques in order to support the established binding modes for the glutathione complexes. The importance of glutathione and oxidized glutathione in binding VIVO2+ in cells is assessed.

Polystyrene bound oxidovanadium(IV) and dioxidovanadium(V) complexes of histamine derived ligand for the oxidation of methyl phenyl sulfide, diphenyl sulfide and benzoin

Ligand Hsal-his (I) derived from salicylaldehyde and histamine has been covalently bound to chloromethylated polystyrene cross-linked with 5% divinylbenzene. Upon treatment with [VO(acac)(2)] in DMF, the polystyrene-bound ligand (abbreviated as PS-Hsal-his, II) gave the stable polystyrene-bound oxidovanadium(iv) complex PS-[V(IV)O(sal-his)(acac)] , which upon oxidation yielded the dioxidovanadium(v) PS-[V(V)O(2)(sal-his)] complex. The corresponding non polymer-bound complexes [V(IV)O(sal-his)(acac)] and [V(V)O(2)(sal-his)] have also been obtained. These complexes have been characterised by IR, electronic, (51)V NMR and EPR spectral studies, and thermal as well as scanning electron micrograph studies. Complexes and have been used as a catalyst for the oxidation of methyl phenyl sulfide, diphenyl sulfide and benzoin with 30% H(2)O(2) as oxidant. Under the optimised reaction conditions, a maximum of 93.8% conversion of methyl phenyl sulfide with 63.7% selectivity towards methyl phenyl sulfoxide and 36.3% towards methyl phenyl sulfone has been achieved in 2 h with 2 . Under similar conditions, diphenyl sulfide gave 83.4% conversion where selectivity of reaction products varied in the order: diphenyl sulfoxide (71.8%) > diphenyl sulfone (28.2%). A maximum of 91.2% conversion of benzoin has been achieved within 6 h, and the selectivities of reaction products are: methylbenzoate (37.0%) > benzil (30.5%) > benzaldehyde-dimethylacetal (22.5%) > benzoic acid (8.1%). The PS-bound complex, 1 exhibits very comparable catalytic potential. These polymer-anchored heterogeneous catalysts do not leach during catalytic action, are recyclable and show higher catalytic activity and turnover frequency than the corresponding non polymer-bound complexes. EPR and (51)V NMR spectroscopy was used to characterise methanolic solutions of 3 and 4 and to identify species formed upon addition of H(2)O(2) and/or acid and/or methyl phenyl sulfide.