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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.
- 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.
- 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.
- Biological activity and cellular uptake of [Ru(eta(5)-C5H5)(PPh3)(Me(2)bpy)][CF3SO3] complexPublication . Morais, Tania S.; Santos, Filipa; Côrte-Real, Leonor; Marques, Fernanda; Robalo, Maria Paula; Paulo J. Amorim Madeira; Garcia, M. HelenaAnticancer activity of the new [Ru(eta(5)-C5H5)(PPh3)(Me(2)bpy)][CF3SO3] (Me(2)bpy = 4,4'-dimethyl-2,2'-bipyridine) complex was evaluated in vitro against several human cancer cell lines, namely A2780, A2780CisR, HT29, MCF7, MDAMB231 and PC3. Remarkably, the IC50 values, placed in the nanomolar and sub-micromolar range, largely exceeded the activity of cisplatin. Binding to human serum albumin, either HSA (human serum albumin) or HSA(faf) (fatty acid-free human serum albumin) does not affect the complex activity. Fluorescence studies revealed that the present ruthenium complex strongly quench the intrinsic fluorescence of albumin. Cell death by the [Ru(eta(5)-C5H5)(PPh3)(Me(2)bpy)][CF3SO3] complex was reduced in the presence of endocytosis modulators and at low temperature, suggesting an energy-dependent mechanism consistent with endocytosis. On the whole, the biological activity evaluated herein suggests that the complex could be a promising anticancer agent. (C) 2013 Elsevier Inc. All rights reserved.
- The key role of coligands in novel ruthenium(II)-cyclopentadienyl bipyridine derivatives: ranging from non-cytotoxic to highly cytotoxic compoundsPublication . Côrte-Real, Leonor; Robalo, Maria Paula; Marques, Fernanda; Nogueira, Guilherme; Avecilla, Fernando; Silva, Tiago J. L.; Santos, Filipa C.; Tomaz, A. Isabel; Garcia, M. Helena; Valente, AndreiaA new family of eight ruthenium(II)-cyclopentadienyl bipyridine derivatives, bearing nitrogen, sulfur, phosphorous and carbonyl sigma bonded coligands, has been synthesized. Compounds bearing nitrogen bonded coligands were found to be unstable in aqueous solution, while the others presented appropriate stabilities for the biologic assays and pursued for determination of IC50 values in ovarian (A2780) and breast (MCF7 and MDAMB231) human cancer cell lines. These studies were also carried out for the [5: HSA] and [6: HSA] adducts (HSA=human serum albumin) and a better performance was found for the first case. Spectroscopic, electrochemical studies by cyclic voltammetry and density functional theory calculations allowed us to get some understanding on the electronic flow directions within the molecules and to find a possible clue concerning the structural features of coligands that can activate bipyridyl ligands toward an increased cytotoxic effect. X-ray structure analysis of compound [Ru(η(5)-C5H5)(bipy)(PPh3)][PF6] (7; bipy=bipyridine) showed crystallization on C2/c space group with two enantiomers of the [Ru(η(5)-C5H5)(bipy)(PPh3)](+) cation complex in the racemic crystal packing.
- Methyl-cyclopentadienyl ruthenium compounds with 2,2 '-bipyridine derivatives display strong anticancer activity and multidrug resistance potentialPublication . Côrte-Real, Leonor; Gonçalves Teixeira, Ricardo; Girio, Patrícia; Comsa, Elisabeta; MORENO, Alexis; Nasr, Rachad; Baubichon-Cortay, Helene; Avecilla, Fernando; Marques, Fernanda; Robalo, Maria Paula; Mendes, Paulo; Prates Ramalho, João P.; Garcia; Falson, Pierre; Valente, AndreiaNew ruthenium methyl-cyclopentadienyl compounds bearing bipyridine derivatives with the general formula [Ru(eta(5)-MeCp)(PPh3)(4,4'-R-2,2'-bpy)](+) (Ru1, R = H; Ru2, R = CH3; and Ru3, R = CH2OH) have been synthesized and characterized by spectroscopic and analytical techniques. Ru1 crystallized in the monoclinic P2(1)/c, Ru2 in the triclinic P (1) over bar, and Ru3 in the monoclinic P2(1)/n space group. In all molecular structures, the ruthenium center adopts a "piano stool" distribution. Density functional theory calculations were performed for all complexes, and the results support spectroscopic data. Ru1 and Ru3 were poor substrates of the main multidrug resistance human pumps, ABCB1, ABCG2, ABCC1, and ABCC2, while Ru2 displayed inhibitory properties of ABCC1 and ABCC2 pumps. Importantly, all compounds displayed a very high cytotoxic profile for ovarian cancer cells (sensitive and resistant) that was much more pronounced than that observed with cisplatin, making them very promising anticancer agents.
- The key role of coligands in novel ruthenium(II)-cyclopentadienyl bipyridine derivatives: Ranging from non-cytotoxic to highly cytotoxic compoundsPublication . Côrte-Real, Leonor; Robalo, Maria Paula; Marques, Fernanda; Nogueira, Guilherme; Avecilla, Fernando; Silva, Tiago J.L.; Santos, Filipa C.; Tomaz, A. Isabel; Garcia, M. Helena; Valente, AndreiaA new family of eight ruthenium(II)-cyclopentadienyl bipyridine derivatives, bearing nitrogen, sulfur, phosphorous and carbonyl sigma bonded coligands, has been synthesized. Compounds bearing nitrogen bonded coligands were found to be unstable in aqueous solution, while the others presented appropriate stabilities for the biologic assays and pursued for determination of IC50 values in ovarian (A2780) and breast (MCF7 and MDAMB231) human cancer cell lines. These studies were also carried out for the [5: HSA] and [6: HSA] adducts (HSA = human serum albumin) and a better performance was found for the first case. Spectroscopic, electrochemical studies by cyclic voltammetry and density functional theory calculations allowed us to get some understanding on the electronic flow directions within the molecules and to find a possible clue concerning the structural features of coligands that can activate bipyridyl ligands toward an increased cytotoxic effect. X-ray structure analysis of compound [Ru(eta(5)-C5H5)(bipy)(PPh3)][PF6] (7; bipy = bipyridine) showed crystallization on C2/c space group with two enantiomers of the [Ru(eta(5)-C5H5)(bipy)(PPh3)](+) cation complex in the racemic crystal packing. (C) 2015 Elsevier Inc All rights reserved.
- New iron(II) cyclopentadienyl derivative complexes: synthesis and antitumor activity against human leucemia cancer cellsPublication . Valente, Andreia; Santos, Ana Margarida; Côrte-Real, Leonor; Robalo, Maria Paula; Moreno, Virtudes; Font-Bardia, Merce; Calvet, Teresa; Lorenzo, Julia; Garcia, M. HelenaA new family of "Fe-II(eta(5)-C5H5)" half sandwich compounds bearing a N-heteroaromatic ligand coordinated to the iron center by a nitrile functional group has been synthesized and fully characterized by NMR and UV-Vis spectroscopy. X-ray analysis of single crystal was achieved for complexes 1 and 3, which crystallized in the monoclinic P2(1)/c and monoclinic P2(1)/n space groups, respectively. Studies of interaction of these five new complexes with plasmid pBR322 DNA by atomic force microscopy showed very strong and different types of interaction. Antiproliferative tests were examined on human leukemia cancer cells (HL-60) using the MTT assay, and the IC50 values revealed excellent antiproliferative activity compared to cisplatin. (C) 2014 Elsevier B.V. All rights reserved.
- Synthesis and structural characterization of new Piano-stool Ruthenium(II) complexes bearing 1-Butylimidazole heteroaromatic ligandPublication . Morais, Tânia S.; Garcia, M. Helena; Robalo, Maria Paula; Piedade, M. F. M.; Duarte, M. Teresa; Brito, M. José Villa de; Madeira, Paulo J. AmorimNew cationic ruthenium(II) complexes with the formula [Ru(eta(5)-C5H5)(LL)(1-BuIm)] [Z], with (LL) = 2PPh(3) or DPPE, and Z = CF3SO3-, PF6-, BPh4-, have been synthesized and fully characterized. Spectroscopic and electrochemical studies revealed that the electronic properties of the coordinated 1-butylimidazole were clearly influenced by the nature of the phosphane coligands (LL) and also by the different counter ions. The solid state structures of the six complexes determined by X-ray crystallographic studies, confirmed the expected distorted three-legged piano stool structure. However the geometry of the 1-butylimidazole ligand was found considerably different in all six compounds, being governed by the stereochemistry of the mono and bidentate coligands (PPh3 or DPPE).