Isabel Cavaco

Preparation and characterisation of new oxovanadium(IV) Schiff base complexes derived from amino acids and aromatic o-hydroxyaldehydes

Abstract A range of mostly new oxovanadium(IV) complexes is described. They contain coordinated Schiff bases, made from natural amino acids (glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, threonine, aspartic acid, and histidine) and salicylaldehyde or such derivatives as 3-, 4-, or 5-methoxy-salicylaldehyde. The coordination sphere is completed by simple ligands like water, 2,2′-bipyridyl or pyridine. The compounds are characterised and the nature of their coordination spheres shown by analysis, TLC, and by appropriate spectroscopy (EPR, IR, electronic and circular dichroism of solution and solids). In a few cases, magnetic properties are described to establish oxidation state. In several cases, the solubility of the compounds from racemic amino acids differs markedly from those containing the single enantiomer. The crystal and molecular structure of the related (and novel) compound with N-pyridoxylidene- d , l -isoleucinate, [VO(pyr- d , l -Ile)(bipy)]·H2O is described. It contains two diastereomers. Denoting the chiral vanadium centres as A or C, these are and [A(pyr- l -Ile)(bipy)] [C(pyr- d -Ile)(bipy)].

Oxovanadium(IV) complexes with aromatic aldehydes.

The synthesis, structure and spectroscopic properties of complexes with the formula [V(IV)O(dsal)2(H2O)], where Hdsal = salicylaldehyde, o-vanillin and 3-ethoxysalicylaldehyde, are presented. The crystal and molecular structures of [V(IV)O(o-van)2(H2O)] (1) (o-Hvan = o-vanillin = 3-methoxysalicylaldehyde) is studied by single-crystal X-ray diffraction. Each molecule exhibits an octahedral geometry with the two o-van ligands coordinated cis to the V(IV)O2+ group. 1 is the first example of a structurally characterized vanadium complex involving O(aldehyde) as the donor atom and this enables a comparison between the bonding characteristics and the contributions of O(aldehyde), O(amide), O(carboxylate) and O(ketone) (in acetylacetone) to the parallel hyperfine coupling constant in VOL2 complexes.

DNA cleavage activity of VIVO(acac)2 and derivatives

The DNA cleavage activity of several beta-diketonate vanadyl complexes is examined. Vanadyl acetylacetonate, V(IV)O(acac)(2), 1, shows a remarkable activity in degrading plasmid DNA in the absence of any activating agents, air and photoirradiation. The cleaving activity of several related complexes V(IV)O(hd)(2) (2, Hhd=3,5-heptanedione), V(IV)O(acac-NH(2))(2) (3, Hacac-NH(2)=acetoacetamide) and V(IV)O(acac-NMe(2))(2) (4, Hacac-NMe(2)=N,N-dimethylacetoacetamide) is also evaluated. It is shown that 2 exhibits an activity similar to 1, while 3 and 4 are much less efficient cleaving agents. The different activity of the complexes is related to their stability towards hydrolysis in aqueous solution, which follows the order 1 approximately 2>>3 approximately 4. The nature of the pH buffer was also found to be determinant in the nuclease activity of 1 and 2. In a phosphate buffered medium DNA cleavage by these agents is much more efficient than in tris, hepes, mes or mops buffers. The reaction seems to take place through a mixed mechanism, involving the formation of reactive oxygen species (ROS), namely OH radicals, and possibly also direct cleavage at phosphodiester linkages induced by the vanadium complexes.

Antioxidant, DNA cleavage, and cellular effects of silibinin and a new oxovanadium(IV)/silibinin complex

A new complex of the oxovanadium(IV) cation with the flavolignan silibinin has been synthesized and characterized. Vanadium compounds show interesting biological and pharmacological properties and some of them display antitumoral actions. Flavonoids are part of a larger group of antioxidant compounds called polyphenols which may inhibit the proliferation and growth of cancer cells. The antioxidant and antitumoral effects of silibinin and its oxovanadium(IV) complex were investigated. Silibinin acted as a very strong antioxidant and its complexation with oxovanadium(IV) improved this behavior. Besides, the generation of reactive oxygen species (ROS) by this compound was favored in tumoral (UMR106) cells and correlated with the deleterious behavior in the proliferation of this cell line. Conversely, silibinin did not exert any effect on the proliferation of normal osteoblasts (MC3T3E1). The cytotoxic action and ROS generation of the oxovanadium(IV) complex was more effective in tumoral cells. This behavior was not consistent with cleaving DNA of plasmid DNA pA1 because no significant cleaving activity was observed in both cases. These results suggest that the main deleterious mechanisms may take place through cytotoxic effects more than genotoxic actions. A comparison with our own findings on the behavior of other flavonoids and their vanadyl(IV) complex has also been performed.

Vanadium and cancer treatment: antitumoral mechanisms of three oxidovanadium(IV) complexes on a human osteosarcoma cell line.

We report herein the antitumor actions of three oxidovanadium(IV) complexes on MG-63 human osteosarcoma cell line. The three complexes: VO(oda), VO(oda)bipy and VO(oda)phen (oda=oxodiacetate), caused a concentration dependent inhibition of cell viability. The antiproliferative action of VO(oda)phen could be observed in the whole range of concentrations (at 2.5 μM), while VO(oda)bipy and VO(oda) showed a decrease of cell viability only at higher concentrations (at 50 and 75 μM, respectively) (p<0.01). Moreover, VO(oda)phen caused a decrease of lysosomal and mitochondrial activities at 2.5 μM, while VO(oda) and VO(oda)bipy affected neutral red uptake and mitochondrial metabolism at 50 μM (p<0.01). On the other hand, no DNA damage studied by the Comet assay could be observed in MG-63 cells treated with VO(oda) at 2.5-10 μM. Nevertheless, VO(oda)phen and VO(oda)bipy induced DNA damage at 2.5 and 10 μM, respectively (p<0.01). The generation of reactive oxygen species increased at 10 μM of VO(oda)phen and only at 100 μM of VO(oda) and VO(oda)bipy (p<0.01). Besides, VO(oda)phen and VO(oda)bipy triggered apoptosis as determined by externalization of the phosphatidylserine. The determination of DNA cleavage by agarose gel electrophoresis showed that the ability of VO(oda)(bipy) is similar to that of VO(oda), while VO(oda)(phen) showed the highest nuclease activity in this series. Overall, our results showed a good relationship between the bioactivity of the complexes and their structures since VO(oda)phen presented the most potent antitumor action in human osteosarcoma cells followed by VO(oda)bipy and then by VO(oda) according to the number of intercalating heterocyclic moieties.

Preparation and characterisation of new oxovanadium(IV) Schiff base complexes derived from salicylaldehyde and simple dipeptides

Abstract A range of mostly new oxovanadium(IV) complexes is described. They contain coordinated Schiff bases, made from simple dipeptides (glycylglycine, glycylsarcosine, l -alanylglycine, l -alanyl- l -alanine, d , l -alanyl- d , l -alanine and l -serylglycine), and salicylaldehyde. The compounds are characterised and the nature of their coordination spheres shown by analysis, TLC, by appropriate spectroscopy (EPR, IR, electronic and circular dichroism of solution and solids) and by magnetic susceptibility measurements. Serylglycine and threonylglycine are formed by reaction of VO(salGlyGly) with formaldehyde and acetaldehyde, respectively.

N-salicylideneamino-acidate complexes of oxovanadium(IV)—II. Synthesis, characterization and deamination of an n-salicylideneglycylglycinato complex

Abstract A vanadium(IV) complex VO(sal-glygly)(H 2 O) n ( 1 )(sal-glygly  N-salicylideneglycylglycinate; n = 1.5−3.0) has been isolated from relatively concentrated solutions containing oxovanadium(IV), glycylglycine and salicylaldehyde, and characterized by elemental analysis, thermal (TG and DSC), magnetic and spectroscopic techniques. From similar but dilute solutions the decavanadate, (NH 4 ) 4 (Na) 2 [V 10 O 28 ]·10H 2 O ( 2 ) was isolated after ageing: its structure has been determined by X-ray diffraction analysis. The NH 4 + cations were formed by deamination of the glycylglycine present in solution.

Oxovanadium(IV) and amino acids—VII. The system l-histidine+VO2+; a self-consistent potentiometric and spectroscopic study

Abstract The equilibria in the system l -histidine+VO 2+ in aqueous solution have been studied in the pH range 2–13 by a combination of pH potentiometry and spectroscopy (ESR, visible absorption and circular dichroism). The results of the various methods are made self-consistent, then rationalized assuming an equilibrium model including species (where HL denotes l -histidine): MLH 2 , MLH, MLH −2 , ML 2 H 4 , ML 2 H 3 , ML 2 H 2 , ML 2 H, ML 2 , ML 2 H −1 , M 2 L 2 H −4 and several products of hydrolysis; formation constants, absorption and circular dichroism spectra are given for each species. Plausible isomeric structures for each stoichiometry in solution are discussed.

Synthesis and structural characterization of a polyoxovanadate coordination complex [V4O8(CH3O)4(bipy)2] with a tetrametallate core

Abstract A vanadium(V) tetramer, [V4O8(CH3O)4(bipy)2] (1), has been isolated from a solution of [VIVP(sal-gly)(H2O)] (2) (sal-gly = N-salicylideneglycinate) and bipyridyl. Its structure has been determined by X-ray diffraction analysis. There is one molecule per unit cell and its centre lies at a crystallographic inversion centre. The vanadium atoms lies on the corners of a diamond-shaped planar unit and each of the two independent vanadium atoms V(1) and V(2) are octahedrally coordinated. The tetramer contains a V4O8 core, two μ3-OCH3, two CH3O− and two bipy ligands. The magnetic susceptibility was measured and data could be fitted to a χP = A + C/T function with A = 9.087 × 10−5 emu mol−1 and C = 1.809 × 10−3 emu K mol−1.

Electrochemical DNA sensor for detection of single nucleotide polymorphisms

Abstract In recent years there has been an increased interest in using biosensors for the recognition and monitoring of molecule interactions. DNA sensors and gene chips are particularly relevant for directly applying the information gathered from the genome projects. In this work electrochemical techniques are used to develop methodologies to detect DNA polymorphisms in human genes using cytochrome P450 3A4 (CYP3A4) as a model gene. CYP3A4*1B oligonucleotides were immobilized on the surface of a gold electrode and hybridized with fully complementary oligonucleotide sequences as well as with mismatched sequences corresponding to the CYP3A4*1A reference sequence. The methodology developed is based on double-stranded DNAs ability to transport charge along nucleotide stacking. The perturbation of the double helix pi-stack introduced by a mismatched nucleotide reduces electron flow and can be detected by measuring the attenuation of the charge transfer. The methodology developed could identify CYP3A4*1A homozygotes by the 5 μC charge attenuation observed when compared with DNA samples containing at least one CYP3A4*1B allele.