Navegando por Autor "Soares, Milena Botelho Pereira"
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Item Copper(II)/diiminic complexes based on 2-hydroxybenzophenones : DNA-and BSA-binding studies and antitumor activity against HCT116 and HepG2 tumor cells.(2023) Rodrigues, Júlia Helena Valadares; Carvalho, Alexandre Bizzotto de; Silva, Valdenizia Rodrigues; Santos, Luciano de Souza; Soares, Milena Botelho Pereira; Bezerra, Daniel Pereira; Oliveira, Katia Mara de; Correa, Rodrigo de SouzaHere, we report four new heteroleptic Cu(II) complexes with the formula [Cu(bipy)(2H4MeBz)]NO3 (1), [Cu (phen)(2H4MeBz)]NO3 (2), [Cu(bipy)(2H4OcBz)]NO3 (3) and [Cu(phen)(2H4OcBz)]NO3 (4), where the ligands are 2-hydroxy-4-methoxybenzophenone (2H4MeBz), 2-hydroxy-4-(octyloxy)benzophenone (2H4OcBz), 2,2′ - bipiridine (bipy) and 1,10-phenantroline (phen). All compounds present two bidentate ligands, a monoanionic 2- hydroxybenzophenone, forming a six-membered chelate ring and the diiminic ring forming a five-membered chelate ring, as well as one nitrate as counterion located at the axial position, as suggested by the crystal structure of complex 2. Complex/DNA interaction studies were also performed using spectroscopic titration (Kb close to 104 M− 1 ), viscosity, Hoechst 33258 competition, and circular dichroism, revealing a moderate interaction between them. Additionally, complexes 1–4 moderately interact with BSA (Bovine Serum Albumin). The compounds were evaluated against HCT116 (human colon carcinoma) and HepG2 (human hepatocellular carcinoma) cancer cells and against MRC-5 (human lung fibroblast), a noncancer cells. The cytotoxic results suggest that complexes 2 and 4 are more cytotoxic than 1 and 3, showing that the presence of phen ligand may play an important role in increasing the biological effect of the compounds.Item Cytotoxic potential of 14 Passiflora species against cancer cells.(2019) Amaral, Ricardo Guimarães; Gomes, Silvana Vieira Floresta; Luciano, Maria Claudia dos Santos; Pessoa, Claudia do Ó; Andrade, Luciana Nalone; Severino, Patrícia; Brandão, Geraldo Célio; Bomfim, Larissa Mendes; Soares, Milena Botelho Pereira; Bezerra, Daniel Pereira; David, Jorge Mauricio; Carvalho, Adriana AndradeThis work aimed to evaluate the cytotoxic potential against cancer cells of Passiflora genus plant species cultivated in Brazil and identify the mechanism of cytotoxicity induced by the most promising extract. Ethanolic extracts from the leaves of 14 Passiflora species were obtained by accelerated solvent extraction and in vitro cytotoxicity evaluated against cancer cell lines using MTT assay at a single concentration of 50 μg/ml. Additionally, the IC50 of the Passiflora alata (ELPA) leaf extracts was determined against both cancer (HCT-116, SF-295, OVACAR-8, and HL-60), and non-cancer cells (PBMC). The ELPA flavonoids were identified by HPLC-DAD and UHPLC-MS/MS. The morphological analyses, using light and fluorescence microscopy, and cell cycle and DNA fragmentation analysis, using flow cytometry, were evaluated to study the mechanism of cell death induced by ELPA in HL-60 cells. Among the Passiflora leaf extracts evaluated; ELPA stood out with high cytotoxic activity, followed by Passiflora capsularis and Passiflora quadrangularis with varying high and low cytotoxic activity. ELPA presented high cytotoxic potency in HL-60 (IC50 19.37 μg/ml), and without cytotoxicity against PBMC, suggesting selectivity for cancer cells. The cytotoxic activity of ELPA may well be linked to the presence of ten identified flavonoids. Cells treated with ELPA presented the hallmarks typical of apoptosis and necrosis, with cell cycle arrest in the G2/M phase. From among the studied species, ELPA presented greater cytotoxic activity, possibly a consequence of synergistic flavonoid action, which induces cell death by apoptosis and necrosis.Item Development and in vitro characterization of polymeric nanoparticles containing recombinant adrenomedullin-2 intended for therapeutic angiogenesis.(2019) Quadros, Helenita Costa; Santos, Laís de Macêdo Ferreira; Meira, Cássio Santana; Khouri, Mariana Ivo; Mattei, Bruno; Soares, Milena Botelho Pereira; Borges, William de Castro; Farias, Leonardo Paiva; Formiga, Fabio RochaCardiovascular diseases (CVD) are the leading cause of death worldwide. Growth factor therapy has emerged as novel therapeutic strategy under investigation for CVD. In this sense, adrenomedullin-2 (ADM-2) has been recently identified as a new angiogenic factor able to regulate the regional blood flow and cardiovascular function. However, the therapeutic value of ADM-2 is limited by its short biological half-life and low plasma stability. Poly (lactic-co-glycolic acid) (PLGA) micro- and nanoparticles have been investigated as growth factor delivery systems for cardiac repair. In this study, we aimed to develop PLGA nanoparticles containing ADM-2 intended for therapeutic angiogenesis. PLGA nanoparticles containing ADM-2 were prepared by a double emulsion modified method, resulting in 300 nm-sized stable particles with zeta potential around – 30 mV. Electron microscopy analysis by SEM and TEM revealed spherical particles with a smooth surface. High encapsulation efficiency was reached (ca.70%), as quantified by ELISA. ADM-2 associated to polymer nanoparticles was also determined by EDS elemental composition analysis, SDS-PAGE and LC-MS/MS for peptide identification. In vitro release assays showed the sustained release of ADM-2 from polymer nanoparticles for 21 days. Cell viability experiments were performed in J774 macrophages and H9c2 cardiomyocyte cells, about which PLGA nanoparticles loaded with ADM-2 did not cause toxicity in the range 0.01–1 mg/ml. Of note, encapsulated ADM-2 significantly induced cell proliferation in EA.hy926 endothelial cells, indicating the ADM-2 bioactivity was preserved after the encapsulation process. Collectively, these results demonstrate the feasibility of using PLGA nanoparticles as delivery systems for the angiogenic peptide ADM-2, which could represent a novel approach for therapeutic angiogenesis in CVD using growth factor therapy.Item In vitro and in vivo experimental models for drug screening and development for Chagas disease.(2010) Romanha, Alvaro José; Castro, Solange Lisboa de; Soeiro, Maria de Nazaré Correia; Vieira, Joseli Lannes; Ribeiro, Isabela; Silva, André Talvani Pedrosa da; Bourdin, Bernadette; Blum, Bethania; Olivieri, Bianca; Zani, Carlos Leomar; Spadafora, Carmenza; Chiari, Egler; Chatelain, Eric; Chaves, Gabriela; Calzada, José Eduardo; Bustamante, Juan Manuel; Freitas Junior, Lucio Holanda Godim de; Romero, Luz I.; Bahia, Maria Terezinha; Lotrowska, Michel; Soares, Milena Botelho Pereira; Andrade, Sonia Gumes; Lotrowska, Tanya; Degrave, Wim; Andrade, Zilton de AraújoChagas disease, a neglected illness, affects nearly 12-14 million people in endemic areas of Latin America. Al¬though the occurrence of acute cases sharply has declined due to Southern Cone Initiative efforts to control vector transmission, there still remain serious challenges, including the maintenance of sustainable public policies for Chagas disease control and the urgent need for better drugs to treat chagasic patients. Since the introduction of benznidazole and nifurtimox approximately 40 years ago, many natural and synthetic compounds have been as¬sayed against Trypanosoma cruzi, yet only a few compounds have advanced to clinical trials. This reflects, at least in part, the lack of consensus regarding appropriate in vitro and in vivo screening protocols as well as the lack of biomarkers for treating parasitaemia. The development of more effective drugs requires (i) the identification and validation of parasite targets, (ii) compounds to be screened against the targets or the whole parasite and (iii) a panel of minimum standardised procedures to advance leading compounds to clinical trials. This third aim was the topic of the workshop entitled Experimental Models in Drug Screening and Development for Chagas Disease, held in Rio de Janeiro, Brazil, on the 25th and 26th of November 2008 by the Fiocruz Program for Research and Technological Development on Chagas Disease and Drugs for Neglected Diseases Initiative. During the meeting, the minimum steps, requirements and decision gates for the determination of the efficacy of novel drugs for T. cruzi control were evaluated by interdisciplinary experts and an in vitro and in vivo flowchart was designed to serve as a general and standardised protocol for screening potential drugs for the treatment of Chagas disease.Item A novel platinum complex containing a piplartine derivative exhibits enhanced cytotoxicity, causes oxidative stress and triggers apoptotic cell death by ERK/p38 pathway in human acute promyelocytic leukemia HL-60 cells.(2019) Oliveira, Maiara de Souza; Barbosa, Marília Imaculada Frazão; Souza, Thiago Belarmino de; Moreira, Diogo Rodrigo de Magalhães; Martins, Felipe Terra; Villarreal, Wilmer; Machado, Rafael Pereira; Doriguetto, Antônio Carlos; Soares, Milena Botelho Pereira; Bezerra, Daniel PereiraPiplartine (piperlongumine) is a plant-derived compound found in some Piper species that became a novel potential antineoplastic agent. In the present study, we synthesized a novel platinum complex containing a piplartine derivative cis-[PtCl(PIP-OH)(PPh3)2]PF6 (where, PIP-OH = piplartine demethylated derivative; and PPh3 = triphenylphosphine) with enhanced cytotoxicity in different cancer cells, and investigated its apoptotic action in human promyelocytic leukemia HL-60 cells. The structure of PIP-OH ligand was characterized by X-ray crystallographic analysis and the resulting platinum complex was characterized by infrared, molar conductance measurements, elemental analysis and NMR experiments. We found that the complex is more potent than piplartine in a panel of cancer cell lines. Apoptotic cell morphology, increased internucleosomal DNA fragmentation, without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization and caspase-3 activation were observed in complex-treated HL-60 cells. Treatment with the complex also caused a marked increase in the production of reactive oxygen species (ROS), and the pretreatment with N-acetyl-L-cysteine, an antioxidant, reduced the complex-induced apoptosis, indicating activation of ROS-mediated apoptosis pathway. Important, pretreatment with a p38 MAPK inhibitor (PD 169316) and MEK inhibitor (U-0126), known to inhibit ERK1/2 activation, also prevented the complex-induced apoptosis. The complex did not induce DNA intercalation in cell-free DNA assays. In conclusion, the complex exhibits more potent cytotoxicity than piplartine in a panel of different cancer cells and triggers ROS/ERK/p38-mediated apoptosis in HL-60 cells.Item Nucleobase derivatives as building blocks to form Ru(II)-based complexes with high cytotoxicity.(2020) Carvalho, Diogo Emerson Leite de; Oliveira, Katia Mara de; Bomfim, Larissa Mendes; Soares, Milena Botelho Pereira; Bezerra, Daniel Pereira; Batista, Alzir Azevedo; Correa, Rodrigo de SouzaTwo new Ru(II)-based complexes containing 2-thiouracil derivatives, known as 2-thiouracil (2TU) and 6-methyl-2-thiouracil (6m2TU), were synthesized using cis,trans-[RuCl2(PPh3)2(bipy)] as a precursor. The obtained compounds with a general formula trans-[Ru(2TU)(PPh3)2(bipy)]PF6 (1) and trans-[Ru(6m2TU)(PPh3)2(bipy)]PF6 (2) were characterized by analytical techniques such as NMR, UV–vis, and IR spectroscopies, elementary analysis, mass spectrometry, and single-crystal X-ray diffraction. Moreover, the investigation of the complexes–DNA interaction were carried out using spectrophotometric titrations and showed that the complexes present a weak interaction with this biomolecule. The compounds were evaluated against HL-60, K-562, HepG2, and B16-F10 cancer cells and against noncancer cells (PBMCs). The results of the biological assay revealed that complex 2 is more promising than complex 1. Finally, the present study suggests that complexes 1 and 2 causes cell death by apoptosis, significantly increasing the percentage of apoptotic HL-60 cells, in which the compounds altered the cell cycle, reducing the cells in G1/G0, G2/M, and S phases.Item Ru(II) complexes containing uracil nucleobase analogs with cytotoxicity against tumor cells.(2019) Correa, Rodrigo de Souza; Bomfim, Larissa Mendes; Oliveira, Katia Mara de; Moreira, Diogo Rodrigo de Magalhães; Soares, Milena Botelho Pereira; Ellena, Javier Alcides; Bezerra, Daniel Pereira; Batista, Alzir AzevedoWe report on chemistry and cytotoxic studies of four new ruthenium (II) complexes containing uracil derivatives. All compounds are neutral, presenting the formula [Ru(PPh3)2(2TU)2] (1), [Ru(PPh3)2(6m2TU)2] (2), [Ru(dppb)(2TU)2] (3) and [Ru(dppb)(6m2TU)2] (4), where PPh3 = triphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane, 2TU = 2-thiouracil and 6m2TU = 6-methyl-2-thiouracil. They were characterized using NMR, UV–vis and IR spectroscopies, microanalytical analysis and mass spectrometry. Furthermore, the crystal structures of 1–4 were determined by single-crystal X-ray diffraction. The coordination of 2-thiouracil derivatives with ruthenium increases regions able to carry out hydrogen bonds with the biological targets, such as DNA. We evaluated the interaction of the complexes with DNA by UV/Vis spectrophotometric titration, and as a result, the values of DNA-binding constants are in the range of 0.8–1.8 × 104 M−1. Moreover, the interaction of the complexes with BSA was investigated. In vitro, activities against B16-F10 (mouse melanoma), HepG2 (human hepatocellular carcinoma), HL-60 (human promyelocytic leukemia) and K562 (human chronic myelocytic leukemia) and non-tumor cells: PBMC (human peripheral blood mononuclear cells activated with concanavalin A – human lymphoblast) were carried out. Cytotoxicity assays revealed that complexes (2) and (4) present biological activity against tumor cells comparable with oxaliplatin, the reference platinum drug, revealing that they are promising molecules for developing new antitumor compounds.Item Ru(II)-thymine complex causes cell growth inhibition and induction of caspase-mediated apoptosis in human promyelocytic leukemia HL-60 cells.(2018) Oliveira, Maiara de Souza; Santana, Adila Angélica Dantas de; Correa, Rodrigo de Souza; Soares, Milena Botelho Pereira; Batista, Alzir Azevedo; Bezerra, Daniel PereiraRuthenium-based compounds represent a class of potential antineoplastic drugs. Recently, we designed, synthesized, and identified the Ru(II)-thymine complex [Ru(PPh3)2(Thy)(bipy)]PF6 (where PPh = triphenylphosphine, Thy = thymine and bipy = 2,2′-bipyridine) as a potent cytotoxic agent with the ability to bind to DNA and human and bovine serum albumins. In this study, the underlying cytotoxic mechanism of the [Ru(PPh3)2(Thy)(bipy)]PF6 complex was assessed. This complex displayed potent cytotoxicity in different cancer cell lines; the morphology that is associated with apoptotic cell death, increased internucleosomal DNA fragmentation without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization, and caspase-3 activation were observed in human promyelocytic leukemia HL-60 cells that were treated with the complex. Moreover, pretreatment of HL-60 cells with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, partially reduced the apoptosis that was induced by the complex, indicating that the apoptotic cell death occurred through a caspase-mediated pathway. In conclusion, the [Ru(PPh3)2(Thy)(bipy)]PF6 complex displays potent cytotoxicity to different cancer cells and induces caspase-mediated apoptosis in HL-60 cells.Item Ru(II)-thymine complex causes DNA damage and apoptotic cell death in human colon carcinoma HCT116 cells mediated by JNK/ p38/ERK1/2 via a p53-independent signaling.(2019) Silva, Suellen Laila Rocha; Dias, Ingrid Rayssa Souza Baliza; Dias, Rosane Borges; Sales, Caroline Brandi Schlaepfer; Rocha, Clarissa Araújo Gurgel; Soares, Milena Botelho Pereira; Correa, Rodrigo de Souza; Batista, Alzir Azevedo; Bezerra, Daniel PereiraRu(II)-thymine complex [Ru(PPh3)2(Thy)(bipy)]PF6 (where PPh3 = triphenylphosphine, Thy = thyminate and bipy = 2,2′-bipyridine) is a potent cytotoxic agent with ability to bind to DNA, inducing caspase-mediated apoptosis in leukemia cells. In this study, we investigated the mechanism underlying the cell death induction by Ru(II)-thymine complex in human colon carcinoma HCT116 cells, as well as its effect in xenograft tumor model. The Ru(II)-thymine complex increased significantly the percentage of apoptotic HCT116 cells. Co-treatment with a JNK/SAPK inhibitor, p38 MAPK inhibitor and MEK inhibitor, which inhibit the activation of ERK1/2, caused a marked reduction of the percentage of complex-induced apoptotic cells. Moreover, the Ru(II)-thymine complex induced an increase in phospho-JNK2 (T183/Y185), phospho-p38α (T180/Y182) and phospho-ERK1 (T202/Y204) levels in HCT116 cells. Treatment with the Ru(II)-thymine complex increased significantly the phospho-histone H2AX (S139) expression, a DNA damage marker. The expression of phospho-p53 (S15) and MDM2 were not changed, and the co-treatment with a p53 inhibitor (cyclic pifithrin-α) did not reduce the complex-induced apoptosis in HCT116 cells, indicating that the Ru(II)-thymine complex induces DNA damage-mediated apoptosis by JNK/p38/ERK1/2 via a p53-independent signaling. The Ru(II)-thymine complex (1 and 2 mg/kg/day) also inhibited HCT116 cell growth in a xenograft model, reducing the tumor mass at 32.6–40.1%. Altogether, indicate that the Ru(II)-thymine complex is a promising anti-colon cancer drug candidate.Item Ru(II)–thyminate complexes : new metallodrug candidates against tumor cells.(2018) Correa, Rodrigo de Souza; Freire, Vitória; Barbosa, Marília Imaculada Frazão; Bezerra, Daniel Pereira; Bomfim, Larissa Mendes; Moreira, Diogo Rodrigo de Magalhães; Soares, Milena Botelho Pereira; Ellena, Javier Alcides; Batista, Alzir AzevedoHerein, we used thymine (HThy) as a ligand to form two new ruthenium(II) complexes with formula [Ru(PPh3)2(Thy)(bipy)]PF6 (1) and [Ru(Thy)(bipy)(dppb)]PF6 (2). The complexes were characterized by spectroscopic, spectrometric and X-ray crystallography analyses. Complexes 1 and 2 can interact with ctDNA presenting binding constants, Kb, of 0.4 and 1.2 × 103 M−1, respectively. Their cytotoxic activities towards tumor cell lines (B16-F10, HepG2, K562 and HL-60) and non-tumor cells (PBMCs) were evaluated using the Alamar blue assay. Complex 1 exhibits high cytotoxicity against tumor cells, showing IC50 values of 0.01 and 1.81 μM against the HL-60 and HepG2 cell lines, respectively. Therefore, compound 1 can be considered as a promising antitumor metallodrug.Item Ruthenium(II) complexes of 1,3-thiazolidine-2-thione : cytotoxicity against tumor cells and anti-Trypanosoma cruzi activity enhanced upon combination with benznidazole(2016) Correa, Rodrigo de Souza; Silva, Monize Martins da; Graminha, Angelica Ellen; Meira, Cássio Santana; Santos, Jamyle Andrade Ferreira dos; Moreira, Diogo Rodrigo de Magalhães; Soares, Milena Botelho Pereira; Poelhsitz, Gustavo Von; Castellano, Eduardo Ernesto; Bloch Junior, Carlos; Cominetti, Márcia Regina; Batista, Alzir AzevedoThree newmixed and mononuclear Ru(II) complexes containing 1,3-thiazolidine-2-thione (tzdtH) were synthesized and characterized by spectroscopic analysis, molar conductivity, cyclic voltammetry, high-resolution electrospray ionization mass spectra and X-ray diffraction. The complexes presented unique stereochemistry and the proposed formulae are: [Ru(tzdt)(bipy)(dppb)]PF6 (1), cis-[Ru(tzdt)2(PPh3)2] (2) and trans- [Ru(tzdt)(PPh3)2(bipy)]PF6 (3), where dppb = 1,4-bis(diphenylphosphino)butane and bipy= 2,2′-bipyridine. These complexes demonstrated strong cytotoxicity against cancer cell lines when compared to cisplatin. Specifically, complex 2 was the most potent cytotoxic agent against MCF-7 breast cells, while complexes 1 and 3 were more active in DU-145 prostate cells. Binding of complexes to ctDNA was determined by UV–vis titration and viscosity measurements and revealed binding constant (Kb) values in range of 1.0–4.9 × 103 M−1, which are characteristic of compounds possessing weak affinity to ctDNA. In addition, these complexes presented antiparasitic activity against Trypanosoma cruzi. Specifically, complex 3 demonstrated strong potency, moderate selectivity index and acted in synergism with the approved antiparasitic drug, benznidazole. Additionally, complex 3 caused parasite cell death through a necrotic process. In conclusion, we demonstrated that Ru(II) complexes have powerful pharmacological activity, while the metal-free tzdtH does not provoke the same outcome.Item Ruthenium(II) complexes with 6-methyl-2-thiouracil selectively reduce cell proliferation, cause DNA double-strand break and trigger caspase-mediated apoptosis through JNK/p38 pathways in human acute promyelocytic leukemia cells.(2019) Bomfim, Larissa Mendes; Araujo, Fênix Alexandra de; Dias, Rosane Borges; Sales, Caroline Brandi Schlaepfer; Rocha, Clarissa Araújo Gurgel; Correa, Rodrigo de Souza; Soares, Milena Botelho Pereira; Batista, Alzir Azevedo; Bezerra, Daniel PereiraRuthenium(II) complexes with 6-methyl-2-thiouracil cis-[Ru(6m2tu)2(PPh3)2] (1) and [Ru(6m2tu)2(dppb)] (2) (where PPh3 = triphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane; and 6m2tu = 6-methyl-2-thiouracil) are potent cytotoxic agents and able to bind DNA. The aim of this study was to evaluate in vitro cellular underlying mechanism and in vivo effectiveness of these ruthenium(II) complexes in human acute promyelocytic leukemia HL-60 cells. Both complexes displayed potent and selective cytotoxicity in myeloid leukemia cell lines, and were detected into HL-60 cells. Reduction of the cell proliferation and augmented phosphatidylserine externalization, caspase-3, -8 and -9 activation and loss of mitochondrial transmembrane potential were observed in HL-60 cells treated with both complexes. Cotreatment with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, reduced Ru(II) complexes-induced apoptosis. In addition, both metal complexes induced phosphorylation of histone H2AX (S139), JNK2 (T183/Y185) and p38α (T180/Y182), and cotreatment with JNK/SAPK and p38 MAPK inhibitors reduced complexes-induced apoptosis, indicating DNA double-strand break and activation of caspase-mediated apoptosis through JNK/p38 pathways. Complex 1 also reduced HL-60 cell growth in xenograft model. Overall, the outcome indicated the ruthenium(II) complexes with 6-methyl-2-thiouracil as a novel promising antileukemic drug candidates.Item A ruthenium-based 5-fluorouracil complex with enhanced cytotoxicity and apoptosis induction action in HCT116 cells.(2018) Silva, Valdenizia Rodrigues; Correa, Rodrigo de Souza; Santos, Luciano de Souza; Soares, Milena Botelho Pereira; Batista, Alzir Azevedo; Bezerra, Daniel PereiraCombination of multifunctionalities into one compound is a rational strategy in medicinal chemical design, and have often been used with metallodrug-based compounds. In the present study, we synthesized a novel ruthenium-based 5-fluorouracil complex [Ru(5-FU)(PPh3)2(bipy)]PF6 (PPh3 = triphenylphosphine; and bipy = 2,2′-bipyridine) with enhanced cytotoxicity in different cancer cells, and assessed its apoptosis induction action in human colon carcinoma HCT116 cells. The complex was characterized by infrared, cyclic voltammetry, molar conductance measurements, elemental analysis, NMR experiments and X-ray crystallographic analysis. In both 2D and 3D cell culture models, the complex presented cytotoxicity to cancer cells more potent than 5-FU. A typical morphology of apoptotic cell death, increased internucleosomal DNA fragmentation, without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization and caspase-3 activation were observed in complex-treated HCT116 cells. Moreover, the pre-treatment with Z-DEVD-FMK, a caspase-3 inhibitor, reduced the apoptosis induced by the complex, indicating cell death by apoptosis through caspase-dependent and mitochondrial intrinsic pathways. The complex failed to induce reactive oxygen species production and DNA intercalation. In conclusion, the novel complex displays enhanced cytotoxicity to different cancer cells, and is able to induce caspase-mediated apoptosis in HCT116 cells.Item Structural isomerism of Ru(II)-carbonyl complexes : synthesis, characterization and their antitrypanosomal activities.(2017) Barbosa, Marília Imaculada Frazão; Correa, Rodrigo de Souza; Bastos, Tanira Matutino; Pozzi, Lucas Vinícius dos Santos; Moreira, Diogo Rodrigo de Magalhães; Ellena, Javier Alcides; Doriguetto, Antônio Carlos; Silveira, Rafael Gomes da; Oliveira, Clayton Rodrigues de; Kuznetsov, Aleksey Evgenyevich; Malta, Valéria Rodrigues dos Santos; Soares, Milena Botelho Pereira; Batista, Alzir AzevedoNew complexes with the general formula [RuCl(CO)(dppb)(diimine)]PF6, [dppb = 1,4-bis(diphenylphosphino) butane; diimine = 2,20-bipyridine (bipy) or 1,10-phenanthroline (phen)], were prepared. Thus, the complexes ct-[RuCl(CO)(dppb)(bipy)]PF6 (1), ct-[RuCl(CO)(dppb)(phen)]PF6 (2), tc-[RuCl(CO)(dppb)(bipy)]PF6 (3), tc-[RuCl(CO)(dppb)(phen)]PF6 (4), cc-[RuCl(CO)(dppb)(bipy)]PF6 (5) and cc-[RuCl(CO)(dppb)(phen)]PF6 (6) were obtained and characterized. In this case, the first letter in the prefixes indicates the position of CO with respect to the chlorido ligand and the second one is related to the phosphorus atoms. The compositions of the complexes were confirmed by analytical techniques and an octahedral environment around the ruthenium was confirmed by single-crystal X-ray diffraction of the complexes ct-[RuCl(CO)(dppb)(bipy)]PF6 and cc-[RuCl(CO)(dppb)(phen)]PF6. The oxidation potentials of the complexes were determined by cyclic voltammetry and it was found that they vary according to the CO position in the complexes. In order to obtain information on the stability of the ct, tc and cc-[RuCl(CO)(dppb)(bipy)]PF6 (1), (3) and (5) isomers, computational studies were carried out, and they showed large differences between the HOMO/LUMO energies. As monitored by 13C NMR, the stability of the complexes with respect to CO displacement, for at least 72 h, in DMSO-d6 solution, is independent of the CO position in the complexes. Pharmacological evaluation of the complexes against the Trypanosoma cruzi parasite revealed the structure–activity relationships, showing that the presence and position of the CO ligand in the complexes are relevant for the antiparasitic activity of the compounds. The most active compound, the tc-[RuCl(CO)(dppb)(bipy)]PF6 isomer, presented potent antiparasitic activity, which was achieved by causing oxidative stress followed by parasite cell death through necrosis. Thus, the findings presented here demonstrate that the use of a carbonyl ligand provides stability and pharmacological properties to ruthenium/diphosphine/diimine complexes.