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- DNA cleavage activity of VIVO(acac)2 and derivativesPublication . Butenko, Nataliya; Tomaz, Ana Isabel; Nouri, Ofelia; Escribano, Esther; Moreno, Virtudes; Gama, Sofia; Ribeiro, Vera; Telo, João Paulo; Pessoa, João Costa; Cavaco, Isabel Maria Palma AntunesThe DNA cleavage activity of several b-diketonate vanadyl complexes is examined. Vanadyl acetylacetonate,VIVO(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 VIVO(hd)2(2, Hhd = 3,5-heptanedione), VIVO(acac-NH2)2 (3, Hacac-NH2 = acetoacetamide) and VIVO(acac-NMe2)2(4, Hacac-NMe2 = 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 2 3 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.
- New Cu(II) complexes with pyrazolyl derived schiff base ligands: synthesis and biological evaluationPublication . Ribeiro, Nadia; Roy, Somnath; Butenko, Nataliya; Cavaco, Isabel; Pinheiro, Teresa; Alho, Irina; Marques, Fernanda; Avecilla, Fernando; Pessoa, Joao Costa; Correia, IsabelSince 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-l-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 mu M 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.
- Cyto- and genotoxicity of a vanadyl(IV) complex with oxodiacetate in human colon adenocarcinoma (Caco-2) cells: potential use in cancer therapyPublication . Di Virgilio, Ana L.; Rivadeneira, Josefina; Muglia, Cecilia I.; Reigosa, Miguel A.; Butenko, Nataliya; Cavaco, Isabel Maria Palma Antunes; Etcheverry, Susana B.The complex of vanadyl(IV) cation with oxodiacetate, VO(oda) caused an inhibitory effect on the proliferation of the human colon adenocarcinoma cell line Caco-2 in the range of 25–100 lM (P\0.001). This inhibition was partially reversed by scavengers of free radicals. The difference in cell proliferation in the presence and the absence of scavengers was statistically significant in the range of 50–100 lM (P\0.05). VO(oda) altered lysosomal and mitochondria metabolisms (neutral red and MTT bioassays) in a dose–response manner from 10 lM(P\0.001). Morphological studies showed important transformations that correlated with the disassembly of actin filaments and a decrease in the number of cells in a dose response manner. Moreover, VO(oda) caused statistically significant genotoxic effects on Caco-2 cells in the low range of concentration (5–25 lM) (Comet assay). Increment in the oxidative stress and a decrease in the GSH level are the main cytotoxic mechanisms of VO(oda). These effects were partially reversed by scavengers of free radicals in the range of 50–100 lM (P\0.05). Besides, VO(oda) interacted with plasmidic DNA causing single and double strand cleavage, probably through the action of free radical species. Altogether, these results suggest that VO(oda) is a good candidate to be evaluated for alternative therapeutics in cancer treatment.
- Interaction of vanadium compounds with DNAPublication . Butenko, Nataliya; Cavaco, Isabel Maria Palma AntunesThe DNA cleavage activity of several vanadium complexes (VC) was studied. The focus was on vanadium acetylacetonate, VIVO(acac)2, 1, and several β-diketonate oxidovanadium(IV/V) derivatives: VIVO(hd)2 (2, hd = 3,5-heptanedione), VIVO(Cl-acac) 2, (3, Cl-acac = 3-chloro-2,4-pentanedione), VIVO(Et-acac)2 (4, Et-acac = 3-ethyl- 2,4- pentanedione) and VIVO(Me-acac)2 (5, Me-acac = 3-methyl-2,4-pentanedione), VV2O4(acac)2 (6), VVO2(acac)(phen) (7, phen = 1,10-phenanthroline) and VVO(OH)(OMe)(acac) (8). The nuclease activity of 28 additional vanadium, copper and nickel complexes was also analysed and compared. The experimental techniques involved digestion of plasmid DNA (pDNA) followed by agarose gel electrophoreses to evaluate nuclease efficiency. pDNA was prepared and purified to assure the absence of interference from EDTA (ethylenediaminetetraacetic acid) and Tris present in commercial pDNA. The stability of complexes in aqueous solutions was studied by UV/vis spectroscopy and electroanalytical techniques, cyclic (CV) and square wave voltammetry (SWV). The nature of DNA cleavage mechanisms was assayed using fluorescent probes and 1H and 51V NMR spectroscopy. VIVO(acac)2 was found to be efficient in cleaving pDNA. The extent of this pDNA cleavage is dependent on buffer media. In organic buffers (Tris, HEPES MOPS) no significant changes are observed, whereas in phosphate medium the nuclease activity is remarkable. The activity of the different complexes follows the order 3>1≥2>>4~5. The V(V) derivatives, 6-8, do not show any significant activity, except in the presence of an oxidant activating agent. CV results show that 1-3 have a quasi-reversible electrochemical behaviour, while of 4 and 5 have an irreversible one, similar to 6. The DNA cleavage by these complexes takes place through an oxidative mechanism. Complex 1 also cleaves DNA hydrolytically, however the reaction is too slow to compete with the radical mechanism. In conclusion, phosphate buffer potentiates the DNA cleavage by VIVO(acac)2 derivatives through a species which presents a quasi-reversible redox behaviour and facilitates the formation of ROS, probably a mixed V(IV)-V(V)-acac-phosphate complex.
- Antioxidant, DNA cleavage, and cellular effects of silibinin and a new oxovanadium(IV)/silibinin complexPublication . Naso, Luciana G.; Ferrer, Evelina G.; Butenko, Nataliya; Cavaco, Isabel Maria Palma Antunes; Lezama, Luis; Rojo, Teófilo; Etcheverry, Susana B.; Williams, Patricia A. M.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 andROSgeneration of the oxovanadium(IV) complex was more effective in tumoral cells. This behavior was not consistent with cleavingDNA 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.
- Formation and properties of sediments in constructed wetlands for treatment of domestic wastewaterPublication . Vergeles, Yuriy; Butenko, Nataliya; Ishchenko, Andriy; Stolberg, Felix; Hogland, Marika; Hogland, WilliamSediments formation and biogeochemical properties were studied in an experimental constructed wetland site in Ukraine (Bioplato) for treatment of domestic effluents. The wetland, with a capacity of 50m(3) d(-1) of wastewater, consists of vertical and horizontal filtrations units with fine gravel, middle and coarse sand, a subsurface flow unit with natural wetland soil applied, and a septic tank and sludge-drying field. Macrophytes, reed (Phragmites australis), cattail (Typha latifolia) and a number of sedge species (Carex spp.) were planted in the area and dominate the average cover of 85-90%. Treatment efficiency for BOD5 and suspended solids was 93-96%, for COD - 82%, for nutrients - 27-50%, and for pathogenic microorganisms 99.3-99.6%. Sludge was sampled at each unit followed by standard laboratory analyses of its main characteristics: total organic carbon (TOC), total nutrients (N, P), contents of trace elements, abundance of pathogenic microorganisms, and general toxicity. Results confirmed that the top layer of sludge from each unit of wetland could be used as a source of fertilizers for grain and leguminous crops.