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- Novel ruthenium methylcyclopentadienyl complex bearing a bipyridine perfluorinated ligand shows strong activity towards colorectal cancer cellsPublication . Teixeira, Ricardo G.; Brás, Ana Rita; Côrte-Real, Leonor; Tatikonda, Rajendhraprasad; Sanches, Anabela; Robalo, Maria Paula; Avecilla, Fernando; Moreira, Tiago; Garcia, M. Helena; Haukka, Matti; Preto, Ana; Valente, AndreiaThree new compounds have been synthesized and completely characterized by analytical and spectroscopic techniques. The new bipyridine-perfluorinated ligand L1 and the new organometallic complex [Ru(eta(5)-MeCp)(PPh3)(2)Cl] (Ru1) crystalize in the centrosymmetric triclinic space group P (1) over bar. Analysis of the phenotypic effects induced by both organometallic complexes Ru1 and [Ru(eta(5)-MeCp)(PPh3)(L1)] [CF3SO3] (Ru2), on human colorectal cancer cells (SW480 and RKO) survival, showed that Ru2 has a potent anti-proliferative activity, 4-6 times higher than cisplatin, and induce apoptosis in these cells. Data obtained in a noncancerous cell line derived from normal colon epithelial cells (NCM460) revealed an intrinsic selectivity of Ru2 for malignant cells at low concentrations, showing the high potential of this compound as a selective anticancer agent. (C) 2017 Elsevier Masson SAS. All rights reserved.
- Improvement of glycaemia and endothelial function by a new low-dose curcuminoid in an animal model of type 2 diabetesPublication . Oliveira, Sara; Alfredo, Tamaeh Monteiro-Alfredo; Tamaeh Monteiro; Henriques, Rita; Ribeiro; Seica, Raquel; Cruz, Maria Teresa; Cabral, C; Fernandes, Rosa; Piedade, Maria; Robalo, Maria Paula; Matafome, Paulo; Silva, SóniaCurcumin has been suggested as a promising treatment for metabolic diseases, but the high doses required limit its therapeutic use. In this study, a new curcuminoid is synthesised to increase curcumin anti-inflammatory and antioxidant potential and to achieve hypoglycaemic and protective vascular effects in type 2 diabetic rats in a lower dose. In vitro, the anti-inflammatory effect was determined through the Griess reaction, and the antioxidant activity through ABTS and TBARS assays. In vivo, Goto-Kakizaki rats were treated for 2 weeks with the equimolar dose of curcumin (40 mg/kg/day) or curcuminoid (52.4 mg/kg/day). Fasting glycaemia, insulin tolerance, plasma insulin, insulin signalling, serum FFA, endothelial function and several markers of oxidative stress were evaluated. Both compounds presented a significant anti-inflammatory effect. Moreover, the curcuminoid had a marked hypoglycaemic effect, accompanied by higher GLUT4 levels in adipose tissue. Both compounds increased NO-dependent vasorelaxation, but only the curcuminoid exacerbated the response to ascorbic acid, consistent with a higher decrease in vascular oxidative and nitrosative stress. SOD1 and GLO1 levels were increased in EAT and heart, respectively. Altogether, these data suggest that the curcuminoid developed here has more pronounced effects than curcumin in low doses, improving the oxidative stress, endothelial function and glycaemic profile in type 2 diabetes.
- Synthesis, structural characterization and leishmanicidal activity evaluation of ferrocenyl N-heterocyclic compoundsPublication . Quintal, Susana; Morais, Tânia S.; Matos, Cristina P.; Robalo, Maria Paula; Piedade, M. Fátima M.; Brito, Maria J. Villa de; Garcia, M. Helena; Marques, Mónica; Maia, Carla; Campino, Lenea; Madureira, JoãoNew ferrocenyl derivatives with the general formula FcC(O)L [Fc = (eta(5)-C5H5)Fe(eta(5)-C5H4)], where L is an aminoquinoline or hydroxyaminoquinoline, have been synthesized for evaluation of their leishmanicidal properties. The compounds were designed with ferrocene coupled to the quinolines by an amide or ester bridge. Ferrocenyl component is intended to act as quinoline carrier and ROS producer after in vivo oxidation to Fe(III), while decreasing normal cell cytotoxicity of coupled quinolines. The bridge was chosen based on its known ability to undergo hydrolysis by the protease/esterase rich media in phagolysosomes, the target of the intracellular form of leishmania parasites. The new compounds include N-(quinolin-3-yl)ferrocenamide (4), N-(quinolin-5-yl)ferrocenamide (5), N-(quinolin-6-yl)ferrocenamide (6), N-(2-methyl-quinolin-4-yl)ferrocenamide (7), N-(2-methylquinolin-6yl)ferrocenamide (8), N-(6-methoxy-quinolin-8-yl)ferrocenamide (9), 2-amino-quinolin-8-yl ferrocenoate (10) and 2-amino-quinolin-4-yl ferrocenoate (11). They were characterized by NMR, cyclic voltammetry, mass spectrometry, UV/vis, FT-IR and elemental analysis, which confirmed all the proposed molecular structures. Compounds 7 and 8 were also structurally characterized by single crystal X-ray diffraction. In 7, the 4-amino-2-methylquinoline moiety is perpendicular to the substituted cyclopentadienyl ring (Cp), while in 8 the 6-amino-2-methylquinoline component is coplanar to the substituted Cp. The new compounds (4-11), same as four other previously published (1-ferrocenoyl-1H-(2-aminobenzimidazole) (1), 1-ferrocenoyl-1H-benzimidazole (2), 1-ferrocenoyl-1H-imidazole (3) and N-(pyridin-4-yl)ferrocenamide (12)), were evaluated in vitro in cultures of a Leishmania infantum strain, isolated from a human visceral leishmaniasis case, to establish their leishmanicidal activity. The toxicity against the human caucasian histiocytic lymphoma U-937 cell line was analyzed for the same set of compounds. All of them show activity against promastigote forms of L. infantum parasites at relatively high concentration (64-269 mu M). Among the complexes that showed a better ratio between the toxic and the therapeutic dose, 3, 9 and 12 were selected for further studies in infected macrophages. Such compounds showed a very significant increase in their activity (17-23 times) giving very similar IC50 values (5.2-5.7 mu M). All three compounds gave significantly better therapeutic indexes (88.5, 12; 56.4, 3; 16.6, 9) than the control miltefosine (6.1).(2) (C) 2013 Elsevier B.V. All rights reserved.
- η6-(2-phenoxyethanol) ruthenium(II)-complexes of 2,2′-bipyridine and its derivatives: Solution speciation and kinetic behaviourPublication . Nogueira, Guilherme; Domotor, Orsolya; Pilon, Adhan; Robalo, Maria Paula; Avecilla, Fernando; Garcia, M. Helena; Enyedy, Eva Anna; Valente, AndreiaA novel family of Ru-II-arene compounds with the general formula of [Ru-II(eta(6)-(2-phenoxyethanol))(L) Cl](+) (L: 2,2'-bipyridine (bpy) (3), 4,4'-dimethyl-2,2'-bipyridine (4) and 4,4'-diyldimethanol-2,2'-bipyridine (5)) was synthesized and characterized by standard spectroscopic and analytical methods. Complex 3 was further studied by single-crystal X-ray diffraction analysis, showing a pseudo octahedral geometry and strong pi-pi lateral stacking interactions in the crystal packing. Effect of the substituents on the electrochemical properties and on the aqueous solution stability was monitored by cyclic voltammetry, UV-Vis and H-1 NMR spectroscopy. Complexes 3-5 presented multiple irreversible redox processes according to their cyclic voltammograms recorded in acetonitrile, and their Ru-II/Ru-III oxidation peaks were found at ca. +1.6 V. Hydrolysis of the binuclear [Ru-II(eta(6)-(2-phenoxyethanol))(mu(2)-Cl)Cl](2) precursor (1) resulted in binuclear hydroxido bridged species [(Ru-II(eta(6)-(2-phenoxyethanol)))(2)(mu-OH)(3)](+) and [(Ru-II(eta(6)-(2-phenoxyethanol)))(2)(mu-OH)(2)Z(2)] (Z = H2O/Cl-) in the presence of chloride ions in water. The hydrolytic behaviour of this Ru-II precursor is similar to that of the analogous species [Ru-II(eta(6)-p-cymene)(mu(2)-Cl)Cl](2) regarding the hydrolysis products and their stability constants. Formation of complexes 3 -5 by reaction of the Ru-II precursor with the (N, N) bidentate ligands was found to be relatively slow in aqueous solution. The complexation is complete already at pH 1 due to the formation of [Ru-II(eta(6)-(2-phenoxyethanol))(L)Z] complexes of significantly high stability in all cases, which are predominant species up to pH 6. However, besides the formation of the mixed hydroxido species [Ru-II(eta(6)-(2-phenoxyethanol))(L)(OH)] + at neutral and basic pH values, the slow oxidation of the RuII centre takes place as well leading to the partial loss of the arene moiety. The rate of these processes depends on the pH and its maximum was found at pH 8-9. Additionally the chlorido/aqua co-ligand exchange processes of the [Ru-II(eta(6)-(2-phenoxyethanol))(L)Cl](+) species were also monitored and only similar to 5% of the chlorido ligand was found to be replaced by water in 0.1 M chloride ion containing aqueous solutions at pH 5.
- A sustainable synthesis of asymmetric phenazines and phenoxazinones mediated by CotA-LaccasePublication . Sousa, Ana Catarina; Oliveira, Maria Conceição; Martins, Lígia O.; Robalo, Maria PaulaAn efficient and sustainable one-step procedure for the synthesis of new asymmetric phenazines and phenoxazinones from commercially available ortho-substituted diamines and ortho-substituted hydroxyamines is reported. In this study we have expanded the substrate scope of CotA-laccase-catalyzed aerobic oxidations through the use of aromatic amines presenting variable functional groups, including N-substitution, contributing to the rational synthesis of different heterocyclic scaffolds. The transformations proceed smoothly through a cascade of oxidative reactions to the benzoquinonediimine intermediates followed by nucleophilic addition, intramolecular cyclization and aromatization, all performed in mild conditions.
- A wide array of lignin-related phenolics are oxidized by an evolved bacterial dye-decolourising peroxidasePublication . Silva, Diogo; Sousa, Ana Catarina; Robalo, M.P.; Martins, Lígia O.Lignin is the second most abundant natural polymer next to cellulose and by far the largest renewable source of aromatic compounds on the planet. Dye-decolourising peroxidases (DyPs) are biocatalysts with immense potential in lignocellulose biorefineries to valorize emerging lignin building blocks for environmentally friendly chemicals and materials. This work investigates the catalytic potential of the engineered PpDyP variant 6E10 for the oxidation of 24 syringyl, guaiacyl and hydroxybenzene lignin-phenolic derivatives. Variant 6E10 exhibited up to 100-fold higher oxidation rates at pH 8 for all the tested phenolic substrates compared to the wild-type enzyme and other acidic DyPs described in the literature. The main products of reactions were dimeric isomers with molecular weights of (2 × MWsubstrate - 2 H). Their structure depends on the substitution pattern of the aromatic ring of substrates, i.e., of the coupling possibilities of the primarily formed radicals upon enzymatic oxidation. Among the dimers identified were syringaresinol, divanillin and diapocynin, important sources of structural scaffolds exploitable in medicinal chemistry, food additives and polymers.
- Recovering value from organic waste materials: Supercritical fluid extraction of oil from industrial grape seedsPublication . Coelho, Jose; Filipe, Rui; Robalo, Maria Paula; Stateva, Roumiana P.Supercritical extraction of oil from grape seed samples obtained from a Portuguese industry was carried out at temperatures from (313-333) K, pressures up to 40.0 MPa and different scCO(2) flow rates. The qualitative analysis of the crude oil was carried out by NMR. The fatty acids were analyzed by GC-Fid with reference to the parameters in Annex I to European Commission Regulation. The results show similar content of TAGs and DAGs both in the n-hexane and scCO(2) extraction methods, but the latter have higher PUPA and lower saturated fatty acids content. A dynamic model was used to simulate the extraction curves in gPROMS ModelBuilder. The grape seed oil was represented as either a one or a three component mixture of triacylglycerols, and the deviation between the experimental and calculated extraction yields was in the range (2-9) % for the first, and (4-11) % for the second case.
- New water-soluble Ruthenium(II) cytotoxic complex: biological activity and celular distributionPublication . Morais, Tânia S.; Santos, Filipa C.; Jorge, Tiago F.; Côrte-Real, Leonor; Madeira, Paulo J. Amorim; Marques, Fernanda; Robalo, Maria Paula; Matos, António; Santos, Isabel; Garcia, M. HelenaA novel water soluble organometallic compound, [RuCp(mTPPMSNa)(2,2'-bipy)][CF3SO3] (TM85, where Cp=eta(5)-cyclopentadienyl, mTPPMS = diphenylphosphane-benzene-3-sulfonate and 2,2'-bipy = 2,2'-bipyridine) is presented herein. Studies of interactions with relevant proteins were performed to understand the behavior and mode of action of this complex in the biological environment. Electrochemical and fluorescence studies showed that TM85 strongly binds to albumin. Studies carried out to study the formation of TM85 which adducts with ubiquitin and cytochrome c were performed by electrospray ionization mass spectrometry (ESI-MS). Antitumor activity was evaluated against a variety of human cancer cell lines, namely A2780, A2780cisR, MCF7, MDAMB231, HT29, PC3 and V79 non-tumorigenic cells and compared with the reference drug cisplatin. TM85 cytotoxic effect was reduced in the presence of endocytosis modulators at low temperatures, suggesting an energy-dependent mechanism consistent with endocytosis. Ultrastructural analysis by transmission electron microscopy (TEM) revealed that TM85 targets the endomembranar system disrupting the Golgi and also affects the mitochondria. Disruption of plasma membrane observed by flow cytometry could lead to cellular damage and cell death. On the whole, the biological activity evaluated herein combined with the water solubility property suggests that complex TM85 could be a promising anticancer agent. (C) 2013 Elsevier Inc. All rights reserved.
- Towards a sustainable production of biologically active building blocks from dye-rich wastewatersPublication . Fernandes, A.; Bonardo, L.; Royo, B.; Robalo, Maria Paula; Martins, L. O.Looking beyond the traditional economy of “take, make and dispose” we established a multi-step enzymatic system for an eco-friendly biological treatment of dye-rich wastewaters simultaneously producing commercially interesting compounds. The dyeing process is responsible for the release into the environment of about 2.8 × 105 tons of dyes and dyestuff each year. The major component of these wastewaters are azo (-N=N-) dyes, which are recalcitrant and hazardous molecules.
- Modelling the kinetics of supercritical CO2 extraction of biomassPublication . R. M. Filipe; Coelho, Jose; Robalo, Maria Paula; Cholakov, Georgi; Stateva, R. P.This work addresses the modelling and simulation of the kinetics of CO2 supercritical extraction of oils from biomass. Experimental and simulation results from different matrices and models are presented. gPROMS Model Builder is used to find solutions to three different models applied to study the extraction of three different volatile oils from aromatic plants (coriander, fennel and savoury), and from a bioresidue, industrial grape seeds. The supercritical extraction experiments performed at different temperature, pressure and flow rate conditions provide the data to the modelling studies and for model parameter estimation. The qualitative and quantitative agreement between the experimental and simulated extraction profiles in terms of yields was good for the cases investigated.