Roberto W.A. Franco

Iron, copper, and manganese complexes with in vitro superoxide dismutase and/or catalase activities that keep Saccharomyces cerevisiae cells alive under severe oxidative stress

Due to their aerobic lifestyle, eukaryotic organisms have evolved different strategies to overcome oxidative stress. The recruitment of some specific metalloenzymes such as superoxide dismutases (SODs) and catalases (CATs) is of great importance for eliminating harmful reactive oxygen species (hydrogen peroxide and superoxide anion). Using the ligand HPClNOL {1-[bis(pyridin-2-ylmethyl)amino]-3-chloropropan-2-ol}, we have synthesized three coordination compounds containing iron(III), copper(II), and manganese(II) ions, which are also present in the active site of the above-noted metalloenzymes. These compounds were evaluated as SOD and CAT mimetics. The manganese and iron compounds showed both SOD and CAT activities, while copper showed only SOD activity. The copper and manganese in vitro SOD activities are very similar (IC50~0.4 μmol dm(-3)) and about 70-fold higher than those of iron. The manganese compound showed CAT activity higher than that of the iron species. Analyzing their capacity to protect Saccharomyces cerevisiae cells against oxidative stress (H2O2 and the O2(•-) radical), we observed that all compounds act as antioxidants, increasing the resistance of yeast cells mainly due to a reduction of lipid oxidation. Especially for the iron compound, the data indicate complete protection when wild-type cells were exposed to H2O2 or O2(•-) species. Interestingly, these compounds also compensate for both superoxide dismutase and catalase deficiencies; their antioxidant activity is metal ion dependent, in the order iron(III)>copper(II)>manganese(II). The protection mechanism employed by the complexes proved to be independent of the activation of transcription factors (such as Yap1, Hsf1, Msn2/Msn4) and protein synthesis. There is no direct relation between the in vitro and the in vivo antioxidant activities.

Induction of apoptosis in leukemia cell lines by new copper(II) complexes containing naphthyl groups via interaction with death receptors

The synthesis, physico-chemical characterization and cytotoxicity of four new ligands and their respective copper(II) complexes toward two human leukemia cell lines (THP-1 and U937) are reported (i.e. [(HL1)Cu(μ-Cl)2Cu(HL1)]Cl2·H2O (1), [(H2L2)Cu(μ-Cl)2Cu(H2L2)]Cl2·5H2O (2), [(HL3)Cu(μ-Cl)2Cu(HL3)]Cl2·4H2O (3), [(H2L4)Cu(μ-Cl)2Cu(H2L4)]Cl2·6H2O (4)). Ligands HL1 and HL3 contain two pyridines, amine and alcohol moieties with a naphthyl pendant unit yielding a N3O coordination metal environment. Ligands H2L2 and H2L4 have pyridine, phenol, amine and alcohol groups with a naphthyl pendant unit providing a N2O2 coordination metal environment. These compounds are likely to be dinuclear in the solid state but form mononuclear species in solution. The complexes have an antiproliferative effect against both leukemia cell lines; complex (2) exhibits higher activity than cisplatin against U937 (8.20 vs 16.25μmoldm(-3)) and a comparable one against THP-1. These human neoplastic cells are also more susceptible than peripheral blood mononuclear cells (PBMCs) toward the tested compounds. Using C57BL/6 mice an LD50 of 55mgkg(-1) was determined for complex (2), suggesting that this compound is almost four times less toxic than cisplatin (LD50=14.5mgkg(-1)). The mechanism of cell death promoted by ligand H2L2 and by complexes (2) and (4) was investigated by a range of techniques demonstrating that the apoptosis signal triggered at least by complex (2) starts from an extrinsic pathway involving the activation of caspases 4 and 8. This signal is amplified by mitochondria with the concomitant release of cytochrome c and the activation of caspase 9.

Spectroscopic characterization of the exopolysaccharide of Xanthomonas axonopodis pv. citri in Cu2+ resistance mechanism

We analyzed the role of exopolysaccharide in the Xanthomonas axonopodis pv. citri (Xac) Cu2+ resistance mechanism by Fourier transform infrared (FTIR), electron paramagnetic resonance (EPR) and nuclear magnetic resonance (NMR) spectroscopies. The FTIR data show that cells cultivated in the presence of 0.2 mmol L-1 of CuSO4 produce larger amounts of pyruvated exopolissacharide (EPS) than the ones cultivated in its absence. The EPR data indicate that the amount of Cu2+ decreases with cultivation time. The 13C-CPMAS NMR data also show the complexation of Cu2+ ions to the EPS. The results demonstrate that EPS plays an important role in Xac Cu2+ protection. Both capsular and slime EPS act as an initial protection mechanism, binding free Cu2+ ions, reducing their diffusion and their active transport to the cytoplasm. Cu2+ also induces the production of a highly pyruvated negative EPS, increasing its capture and binding capacity.

Iron complexes containing electrochemically active diazocycle-bis(di-tert-butyl-phenol) ligands

Quatro ligantes N, O-doadores contendo unidades centrais diazociclicas e grupos bis(di-terc-butilfenol) foram empregados na sintese de complexos de ferro(III), resultando em quatro complexos mononucleares e um binuclear. Os ligantes apresentados neste estudo diferem entre si na unidade diazociclica, sendo elas: piperazina (H2L1), diazepam/homopiperazina (H2L2), hexaidropirimidina (H2L3) ou hexaidropirimidin-5-ol (H3L4). As estruturas moleculares dos complexos [FeL2Cl], 2, e [Fe2(L4)(HL4)Cl], 4, foram elucidadas por difratometria de raios X de monocristal. Estudos eletroquimicos mostram que, alem de processos redox centrados no metal, os complexos apresentam processos redox atribuidos aos ligantes. Estudos coulometricos acoplados a espectroscopia eletronica no UV-Vis confirmam a formacao da especie radicalar para o complexo 2, enquanto dados de espectroscopia de ressonância paramagnetica eletronica (EPR) mostram a formacao do radical para os complexos 2, 4 e 5. De relevância e a observacao de que o ligante que sofre oxidacao em menor potencial eletroquimico e aquele cujo centro metalico apresenta a menor acidez de Lewis.

A new system for cyclohexane functionalization employing iron(III) catalysts and trichloroisocyanuric acid

Herein, dinuclear and mononuclear iron complexes were investigated as catalysts in the reaction of cyclohexane chlorination employing trichloroisocyanuric acid as oxidant. At 25 °C, the yields provided by both catalysts were similar (∼8%). However, at 50 °C, the mononuclear catalyst showed a better performance (34.4 ± 1.8%) than the binuclear catalyst (24.4 ± 1.0%).