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Item Antitumor activity of Pd(II) complexes with N,S or O,S coordination modes of acylthiourea ligands.(2020) Plutín Stevens, Ana María; Ramos Cairo, Raúl; Mocelo, Raúl; Alvarez Hernández, Anislay; Castellano, Eduardo Ernesto; Cominetti, Márcia Regina; Oliveira, Katia Mara de; Oliveira, Tamires Donizeth de; Silva, Thales E. M.; Oliveira, Rodrigo Corrêa de; Batista, Alzir AzevedoSeven new complexes (1–7) of Pd(II) with N-alkyl- and N,N-dialkyl-N0 -acylthioureas were prepared and characterized by elemental analysis and spectroscopic techniques. The crystal structures of the coordination compounds [PdCl(PPh3)(5-cloropiridyl-N0 -benzoylthioureato-k2 N,S)] (2), cis-[Pd(PPh3)2 (N-morpholyn-N0 -benzoylthioureato-k2 O,S)]PF6 (4) and cis-[Pd(PPh3)2(N,N-diphenyl-N0 -thiophenylth ioureato-k2 O,S)]PF6 (7) were determined by X-ray crystallography. The present study reports on an inter esting contribution on the chemistry of Pd(II)/acylthiourea complexes, where the use of monosubstituted acylthiourea conducts to formation of neutral complexes with general formula [Pd(Cl)(PPh3) (acylthiourea)], with a N,S-coordination mode. On the other hand, cationic complexes with formula [Pd (PPh3)2(acylthiourea)]+ , with O,S bidentately coordinated to the metal, are obtained by using a disubsti tuted acylthiourea derivative. The antitumor activity of the N-alkyl- and N,N-dialkyl-N0 -acylthiourea ligands and their palladium (II) complexes with synthesized triphenylphosphine were evaluated against the growth of the DU-145 tumor cells (prostate cancer cells), (MDA-MB-231 (breast cancer cells), L929 (healthy mouse cells). The ligands are not cytotoxic, but the complexes showed good cytotoxicity against the tumor cells tested in this work, and were even better, when compared to the IC50 reported for the cis platin. The complexes showed better activity results in MDA-MB-231 tumor cells, than for the DU-145 tumor cells. Complexes 1 and 6 showed high cytotoxic activity at low micromolar concentrations (IC50 = 1.93 ± 0.45, 0.62 ± 0.08 lM) against MDA-MB-231 (human breast cancer cells). This result indicated that the binding of the ligands to the metal center increases their antitumor activity.Item cis-bis(N-benzoyl-N0 ,N0 -dibenzylthioureido) platinum(II) : synthesis, molecular structure and its interaction with human and bovine serum albumin.(2019) Correa, Rodrigo de Souza; Oliveira, Katia Mara de; Pérez, Hiram; Plutín Stevens, Ana María; Ramos Cairo, Raúl; Mocelo, Raúl; Castellano, Eduardo Ernesto; Batista, Alzir AzevedoIn this paper, the title compound was synthesized from N-benzoyl-N′,N′-dibenzylthiourea ligand and potassium tetrachloroplatinate(II), and its interaction with human (HSA) and bovine (BSA) serum albumin was evaluated. Also, the crystal structure was determined from single-crystal X‐ray diffraction, confirming that the platinum atom is coordinated with two chelated N-benzoyl-N′,N′-dibenzylthiourea ligands in a distorted square-planar geometry. In the solid state, Hirshfeld surface analysis emphasizes that the molecules are connected by non-classical C–H⋯C, C–H⋯S and H⋯H intermolecular contacts. These weak interactions can be mainly responsible due to complex-BSA and complex-HSA binding. The complex interacts differently with HSA and BSA such as observed by the binding constant, Kb, presenting values of around 105 M−1 and 104 M−1, respectively. Thermodynamic parameters (ΔG, ΔH and ΔS) suggest spontaneous interactions between complex and the proteins.Item Complexos heterolépticos de cobre (II) com 2-hidroxibenzofenonas e diiminas : síntese, caracterização e investigação de suas propriedades biológicas.(2022) Rodrigues, Júlia Helena Valadares; Correa, Rodrigo de Souza; Oliveira, Katia Mara de; Correa, Rodrigo de Souza; Oliveira, Katia Mara de; Teixeira, Leonardo César de Moraes; Rocha, Kelly Alessandra da SilvaNo presente trabalho obteve-se e caracterizou-se quatro novos complexos de cobre (II) identificados como [Cu(bipy)(2H4MeBz)]NO3 (1), [Cu(fen)(2H4MeBz)]NO3 (2), [Cu(bipy)(2H4OcBz)]NO3 (3) e [Cu(fen)(2H4OcBz)]NO3 (4), onde bipy é 2,2’-bipiridina, fen é 1,10-fenantrolina, 2H4MeBz significa 2-hidroxi-4-metoxibenzofenona e (2H4OcBz) presenta o ligante 2-hidroxi-4-(octiloxi)benzofenona. Os compostos foram sintetizados e caracterizados por meio de análise elementar, condutimetria, temperatura de decomposição, por técnicas espectroscópicas e espectrométricas, como espectroscopia de absorção na região do infravermelho e do ultravioleta e visível e espectrometria de massas, bem como por difração de raios X de monocristal, para o caso do complexo 2 via substituição do ligante nitrato (NO3 - ) pelo ligante perclorato (ClO4 - ). A atividade citotóxica dos complexos 1-4 foi investigada frente às linhagens celulares tumorais HCT116 (carcinoma de cólon humano) e HepG2 (carcinoma hepatocelular humano) e não tumoral MRC-5 (fibroblasto de pulmão humano). Os complexos foram citotóxicos frente a todas as linhagens celulares estudadas, apresentando valores de IC50 na faixa de 3,38μM – 64,9μM para as linhagens tumorais e para a linhagem celular não tumoral, MRC-5 os valores de IC50 variaram de 4,65 μM a 50,22 μM. Além disso o índice de seletividade para células tumorais variou de 0,77 a 1,42. Estes resultados indicam que complexos de cobre (II) 2 e 4 provaram ser mais citotóxicos que os demais complexos e foram mais seletivos para as células tumorais que a oxaliplatina. Interações dos complexos com macromoléculas [CT-DNA (DNA Calf-Thymus) e BSA (Albumina do soro bovino)] foram avaliadas para melhor compreender o mecanismo de ação dos complexos. Por fim, observou-se que os complexos contendo ligante 1,10-fenantrolina exibiram citotoxicidades mais promissoras que os complexos contendo 2,2’-bipiridina, podendo ser explorados com mais detalhes e estudos in vitro e in vivo.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 activity of Ru(II)/DPEPhos/N,S-mercapto complexes (DPEPhos = bis-[(2-diphenylphosphino)phenyl]ether).(2023) Grawe, Gregory Ferreira; Oliveira, Katia Mara de; Leite, Celisnolia Morais; Oliveira, Tamires Donizeth de; Costa, Analu Rocha; Moraes, Carlos André Ferreira; Araujo Neto, João Honorato de; Cominetti, Márcia Regina; Castellano, Eduardo Ernesto; Correa, Rodrigo de Souza; Machado, Sérgio de Paula; Batista, Alzir AzevedoWe report here on three new ruthenium(II) complexes, [Ru(DPEPhos)(mtz)(bipy)]PF6 (Ru1), [Ru(DPEPhos) (mmi)(bipy)]PF6 (Ru2) and [Ru(DPEPhos)(dmp)(bipy)]PF6 (Ru3). DPEPhos = bis-[(2-diphenylphosphino) phenyl]ether, mtz = 2-mercapto-2-thiazoline, mmi = 2-mercapto-1-methylimidazole, dmp = 4,6-diamino-2- mercaptopyrimidine and bipy = 2,2′ -bipyridine. The compounds were characterized by several spectroscopic techniques, and the molecular structure of Ru1 complex was determined by single-crystal X-ray diffraction. The cytotoxicity of Ru1 – Ru3 complexes were tested against the A549 (human lung) and the MDA-MB-231 (human breast) cancer cell lines and against MRC-5 (non-tumor lung) and MCF-10A (non-tumor breast) cell lines through the MTT assay. All three complexes are cytotoxic against the cell lines studied, with IC50 values lower than those found for the cisplatin. Among them, the Ru2 complex has shown the best selectivity against MDA-MB-231 cancer cell lines, with an IC50 value 12 times lower than that on MCF-10A. The complex Ru2 was capable to induce changes in MDA-MB-231 cells morphology, with loss of cellular adhesion, inhibited colony formation and induce an accumulation of cells at the sub-G1 phase, with an increase in S-phase and decrease of cells at G2 phase. Viscosity, electrochemical and Hoechst 33258 displacement experiments for Ru1 – Ru3 complexes with calf thymus DNA (CT-DNA) showed an electrostatic and groove binding mode of interaction. Additionally, the complexes interact with the protein Human Serum Albumin (HSA) by static mechanism. The negative values for ΔH and ΔS indicate that van der Waals forces and hydrogen bonding may occurs between the complexes and HSA. Therefore, this class of complexes are promising anticancer candidates and may be selected to further detailed studies.Item Exploring DNA-interaction and molecular structure of ruthenium/1,2-bis-(diphenylphosphino)ethane)-based complex.(2023) Campideli, Victor Cardoso; Montilla Suárez, Jerica Margely; Silva, Tiago Almeida; Sicupira, Dalila Chaves; Oliveira, Katia Mara de; Correa, Rodrigo de SouzaThe mixture of cis and trans-[RuCl2(dppe)2] (dppe: 1,2-bis-(diphenylphosphino)ethane) was prepared and the interaction with CT-DNA was evaluated by several methods, including UVvis DNA spectroscopic titration, viscosity, and electrochemical studies. Investigation suggests that [RuCl2(dppe)2] interacts moderately with CT-DNA. Interestingly, the cis- and trans-isomers interact differently with DNA, as proved by the square-wave voltammetry studies. Finally, the crystal structure of trans-[RuCl2(dppe)2]Cl was obtained from an electrochemical solution and studied in detail, which presents a distorted octahedral geometry and interatomic parameters different from those found in the trans- [RuCl2(dppe)2] complex. Crystal data for C52H48Cl4P4Ru: triclinic, space group P-1 (no. 2), a = 9.240(3) Å, b = 10.9290(18) Å, c = 11.993(3) Å, α = 78.707(11)°, β = 86.712(13)°, γ = 82.598(13)°, V = 1177.1(5) Å3, Z = 1, T = 293(2) K, μ(MoKα) = 0.732 mm-1, Dcalc = 1.467 g/cm3, 8434 reflections measured (6.934° ≤ 2Θ ≤ 51.986°), 4607 unique (Rint = 0.0973, Rsigma = 0.1171) which were used in all calculations. The final R1 was 0.0537 (I > 2σ(I)) and wR2 was 0.1347 (all data).Item "Half-sandwich"/RuII anticancer complexes containing triphenylphosphine and p-substituted benzoic acids.(2020) Araujo Neto, João Honorato de; Oliveira, Katia Mara de; Leite, Celisnolia Morais; Colina Vegas, Legna Andreina; Nóbrega, Joaquim de Araújo; Castellano, Eduardo Ernesto; Ellena, Javier Alcides; Correa, Rodrigo de Souza; Batista, Alzir AzevedoMononuclear and binuclear RuII/arene/triphenylphosphine complexes with p-substituted benzoic acid derivatives were prepared and characterized. These monocationic complexes of type [Ru(η6 -p-cymene)(PPh3)L] (L = benzoic acid (1), p-hydroxybenzoic acid (2), p-nitrobenzoic acid (3) and terephthalic acid (4)) were characterized using various techniques, such as nuclear magnetic resonance (NMR) and matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry, and the crystal structure of 1, 3 and 4 were determined by X-ray diffraction analysis. The cytotoxicity of the complexes was evaluated, in vitro, against tumorigenic [MDA-MB-231, MCF-7 (breast), A549 (lung) and DU-145 (prostate)] and non-tumorigenic [MCF-10A (breast), MRC-5 (lung) and PNT-2 (prostate)] cells. The binuclear complex (4) was inactive due to its low solubility. Complexes 1, 2 and 3 showed similar cytotoxicity, however, complex 1 presented better selectivity index against MDA-MB-231 than compounds 2 and 3. Cellular ruthenium absorption was explored by inductively coupled plasma mass spectrometry (ICP-MS) analyzing the whole cells and the culture medium. Complementary studies showed that complex 1 inhibited colony formation, induced morphology changes in cells and promoted cell cycle arrest in the Sub-G1 phase for the MDA-MB-231 cells.Item Lapachol and lawsone in the design of new ruthenium(II)-diphosphine complexes as promising anticancer metallodrugs.(2021) Oliveira, Katia Mara de; Araujo Neto, João Honorato de; Demidoff, Felipe Cerqueira; Schultz, Mario Sergio; Netto, Chaquip Daher; Cominetti, Márcia Regina; Correa, Rodrigo de Souza; Batista, Alzir AzevedoThe development of metal complexes containing natural products is a remarkable strategy to develop new anticancer candidates. Thus, we report here on the preparation of two new Ru(II)/diphosphine complexes containing Lapachol (Lap) and Lawsone (Law): (1) [Ru(Lap)(dppm)2]PF6 and (2) [Ru(Law)(dppm)2]PF6, where dppm = bis(diphenylphosphino)methane. The complexes were synthetized and fully characterized by elemental analyses, molar conductivity, UV-Vis, IR, 31P{1H}, 1H and 13C NMR, and the crystal structure of the complex (1) was determined by X-ray diffraction. Complexes (1) and (2) showed high in vitro cytotoxicity against four cancer cells (MDA-MB-231, MCF-7, A549 and DU-145), with IC50 values in the micromolar range (0.03 to 2.70 M). Importantly, complexes (1) and (2) were more active than the cisplatin, the drug used as a reference in the cytotoxic assays. Moreover, complex (1) showed high selectivity to triple-negative breast cancer cells (MDA-MB-231). Studies of the mechanism of action in MDA-MB-231 cancer cells showed that complex (1) inhibit cell migration, colony formation, and induces cell cycle arrest and apoptosis by activation of the mitochondrial pathway through the loss of mitochondrial membrane potential (m). Furthermore, the complex (1) induces ROS generation in MDA-MB-231 cells, which can cause DNA damage. Finally, complexes (1) and (2) interact with DNA by minor grooves and show a moderate interaction with BSA, with the involvement of hydrophobic interactions. Essentially, Ru(II)/diphosphine-naphthoquinone complexes have remarkable cytotoxic effects with high selectivity to triple-negative breast cancer (MDA-MB-231) and could be promising anticancer candidates for cancer treatment.Item A new monoclinic form of a Ru(II)/Fe(II) heterobimetallic complex : conformation, crystal packing and Hirshfeld surface.(2021) Teixeira, Tamara; Martir, Luiz Fernando Barbosa; Oliveira, Katia Mara de; Correa, Rodrigo de SouzaHerein, a new monoclinic form (C2/c), Form H-II, of the heterobimetallic cis-[RuCl2(dppf)(bipy)] complex was obtained and compared in terms of molecular conformation, as well as intra and intermolecular geometries with two orthorhombic forms (Pna21) previously reported, Form S and H-I. The crystal packing of Form H-II is based on weak intermolecular interactions that were explored by Hirshfeld surface and 2D-fingerprint plots analysis, revealing the presence of weak H…H, C…H, C…C and Cl…H contacts that stabilize the crystal structure. As can be seen, the Form H-II differs from hydrate form (Form H-I), according water molecule location and crystal self-assembly. This found emphasizes the versatility of the studied Ru(II)/Fe(II) heterobimetallic complex in the crystal engineering field.Item A new polymorph of six-coordinated bis(5,5′-dimethyl-2,2′-bipyridine) nitratocopper(II) nitrate and its DNA interactions.(2021) Gonçalves, Guilherme Resende; Carvalho, Alexandre Bizzotto de; Araujo Neto, João Honorato de; Oliveira, Katia Mara de; Correa, Rodrigo de SouzaHere, we present a new polymorph of the [Cu(5mebipy)(NO3)]NO3 complex (1, Form II), where 5mebipy means 5,5 -dimethyl-2,2 -bipyridine. The copper(II) complex 1 was characterized by spectroscopic techniques and single-crystal X-ray diffraction. The Form II presents a six-coordinated structure, meanwhile the Form I, previously reported, is five-coordinated with the nitrate ligand as monodentate. The molecular structures of both crystalline forms were compared based on intramolecular aspects using Kleywegt’s analysis and the intermolecular contacts evaluated by Hirshfeld surface studies. Moreover, the interaction of the complex [Cu(5mebipy)(NO3)]+ with CT-DNA was carried out using viscosity and spectrophotometric titrations, exhibiting a binding constant of 2.57 × 104 M − 1. This study contributes to explore the intra and intermolecular details of the new polymorph of the complex [Cu(5mebipy)(NO3)]NO3 and its capability to interacts with CT-DNA.Item New ruthenium complexes containing salicylic acid and derivatives induce triple-negative tumor cell death via the intrinsic apoptotic pathway.(2022) Graminha, Angelica Ellen; Popolin, Cecília; Araujo Neto, João Honorato de; Correa, Rodrigo de Souza; Oliveira, Katia Mara de; Godoy, Luani Rezende; Colina Vegas, Legna Andreina; Ellena, Javier Alcides; Batista, Alzir Azevedo; Cominetti, Márcia ReginaIn this work we present the synthesis and characterization of six new ruthenium compounds with general formulae [Ru(L)(dppb)(bipy)]PF6 and [Ru(L)(dppe)2]PF6 where L = salicylic acid (Sal), 4-aminosalicylic acid (AmSal) or 2,4-dihydroxybenzoic acid (DiSal), dppb = 1,4-bis(diphenylphosphino)butane, dppe = 1,2-bis (diphenylphosphino)ethane and bipy = 2,2′ -bipyridine. The complexes were characterized by elemental analysis, molar conductivity, cyclic voltammetry, NMR, UV–vis and IR spectroscopies, and two by X-ray crystallography. The 31P{1 H} NMR spectra of the complexes with the general formula [Ru(L)(dppe)2]PF6 showed that the phosphorus signals are solvent-dependent. Aprotic solvents, which form strong hydrogen bonds with the complexes, inhibit the free rotation of the salicylic acid-based, modifying the diphosphine cone angles, leading to distortion of the phosphorus signals in the NMR spectra. The cytotoxicity of the complexes was evaluated in MCF7, MDA-MB-231, SKBR3 human breast tumor cells, and MCF-10 non-tumor cell lines. The complexes with the structural formula [Ru(L)(dppe)2]PF6 were the most cytotoxic, and the complex [Ru(AmSal)(dppe)2]PF6 with L = 4-aminosalicylic acid ligand was the most selective for the MDA-MB-231 cell line. This complex interacts with the transferrin and induces apoptosis through the intrinsic pathway, as demonstrated by increased levels of proteins involved in apoptotic cell death.Item Novos complexos de Ru(II)/benzoato/bipiridina/difosfina : influência da variação do ligante difosfínico sobre suas atividades biológicas.(2022) Teixeira, Tamara; Correa, Rodrigo de Souza; Oliveira, Katia Mara de; Correa, Rodrigo de Souza; Bogado, André Luiz; Vieira, Camila GrossiComplexos de rutênio têm sido muito explorados no desenvolvimento de candidatos a novos metalofármacos. Propriedades promissoras atribuídas ao rutênio consideram sua capacidade e facilidade de atingir vários estados de oxidação em fluídos biológicos, assim como a habilidade de interagir com biomoléculas. Diante disso, o presente trabalho dedica-se a obtenção e caracterização de três novos complexos de rutênio contendo benzoato (AB), 2,2’-bipiridina (bipy) e diferentes ligantes difosfínicos, obtendo-se complexos de fórmula geral [Ru(AB)(bipy)(P-P)]PF6, onde P-P = 1,2’-bis(difenilfosfino)etano (dppe) [Complexo 1], 1,3’-bis(difenilfosfino)propano (dppp) [Complexo 2] e 1,2’-bis(difenilfosfino)ferroceno (dppf) [Complexo 3]. Os compostos sintetizados foram caracterizados por condutividade molar, análise elementar, ponto de fusão, voltametria cíclica e de pulso diferencial, espectroscopia de absorção na região do infravermelho e na região do UV-Vis, ressonância magnética nuclear (RMN) de 31P{1H}, 1H e 13C e por difração de raios X de monocristal no caso dos complexos 1 e 2. Ensaios de estabilidade em DMSO e meio de cultura sugerem que os complexos são estáveis nas condições utilizadas. Os complexos foram avaliados quanto à atividade citotóxica contra linhagens tumorais MDA-MB-231 (adenocarcinoma de mama triplo negativo), MCF-7 (adenocarcinoma de mama hormônio dependente), A549 (pulmão) e não tumorais MCF-10A (mama) e MRC-5 (pulmão). Resultados promissores foram obtidos comparados com os precursores, sendo que o complexo 3 foi o mais citotóxico. Por fim, visando a análise e estudo das propriedades biológicas dos complexos, estudos de interação com o DNA e com a albumina de soro bovino (BSA) foram realizados. Os resultados indicaram uma interação reversível com o DNA, provavelmente através de forças eletrostáticas. Os complexos 1 e 3 interagiram fracamente com a BSA e o complexo 2 interagiu fortemente com a BSA.Item Novos compostos diimínicos de cobre(II) com N,N-dibenzil-N′-benzoiltioureia, interações com biomoléculas e citotoxicidades.(2022) Gonçalves, Guilherme Resende; Correa, Rodrigo de Souza; Oliveira, Katia Mara de; Correa, Rodrigo de Souza; Guerra, Wendell; Peña, Wilmer José VillarealNo presente trabalho sintetizou-se e caracterizou-se quatro novos complexos metálicos de cobre(II) com a fórmula geral [Cu(N-N)(Th)(NO3)], onde N-N corresponde aos ligantes N- heterocíclicos 1,10-fenantrolina (fen), 2,2’-bipiridina (bipy), 4,7-difenil-1,10-fenantrolina (dpp) e 4,4-dimetil-2,2’-bipiridina (dmbp) e Th representa a aciltioureia N,N-dibenzil-N’- benzoiltiouréia. Os compostos obtidos foram caracterizados pelas técnicas de espectroscopia de absorção na região do infravermelho e do UV/visível, espectrometria de massas, condutividade molar, ponto de decomposição, análise elementar e difração de raios X. Posteriormente, as atividades citotóxicas dos complexos frente as células tumorais HCT116 (carcinoma de colón humano), HepG2 (carcinoma hepatocelular humano) e não tumoral MRC- 5 (fibroblasto de pulmão humano) foram investigadas. Os complexos apresentaram valores de IC50 promissores, variando de 0,3 μM à 9,0 μM. O composto [Cu(dpp)(Th)(NO3)] mostrou-se bastante citotóxico com valores de IC50 de 0,33 μM para a linhagem HCT116 e 0,54 μM para a linhagem HepG2 apresentando índices de seletividade de 1,78 e 1,09. Os compostos [Cu(fen)(Th)(NO3)], [Cu(bipy)(Th)(NO3)] e [Cu(dmbp)(Th)(NO3)] apresentaram valores de IC50 de 1,34 μM, 3,79 μM e 5,36 μM respectivamente para a linhagem celular HCT116 e 1,40 μM, 3,27 μM e 6,26 μM respectivamente para a linhagem celular HepG2. Além disso, estudos de interação com macromoléculas como o DNA e a Albumina de Soro Bovino (BSA), que podem atuar como possíveis alvos biológicos dos complexos, foram desenvolvidos. Os estudos mostraram que os compostos interagem de forma moderada com o DNA com constantes de interação da ordem de 103 e 104 M-1 . O composto [Cu(dpp)(Th)(NO3)] provavelmente está interagindo com o DNA via sulco menor e intercalação. Os outros compostos provavelmente interagem com o DNA majoritariamente por interação eletrostática e via sulco menor do DNA de forma mais fraca. Os complexos apresentaram interação moderada com a BSA indicando que o tipo de interação destes complexos com a BSA foi tanto por mecanismo dinâmico quanto mecanismo estático. O efeito das modificações estruturais nos compostos metálicos foi correlacionado com as propriedades biológicas dos mesmos, a fim de fazer uma relação entre a estrutura-atividade dos complexos, onde pôde-se perceber que ocorreu um aumento da atividade biológica com o aumento da extensão dos ligantes diimínicos.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)-based complexes with N-(acyl)-N′,N′-(disubstituted)thiourea ligands : synthesis, characterization, BSA- and DNA-binding studies of new cytotoxic agents against lung and prostate tumour cells.(2015) Correa, Rodrigo de Souza; Oliveira, Katia Mara de; Delolo, Fábio Godoy; Alvarez Hernández, Anislay; Mocelo, Raúl; Plutin, Ana M.; Cominetti, Márcia Regina; Castellano, Eduardo Ernesto; Batista, Alzir AzevedoFour ruthenium(II)-based complexeswith N-(acyl)-N′,N′-(disubstituted)thiourea derivatives (Th)were obtained. The compounds, with the general formula trans-[Ru(PPh3)2(Th)(bipy)]PF6, interact with bovine serum albumin (BSA) and DNA. BSA-binding constants, which were in the range of 3.3–6.5 × 104 M−1, and the thermodynamic parameters (ΔG, ΔH and ΔS), suggest spontaneous interactions with this protein by electrostatic forces due to the positive charge of the complexes. Also, binding constant by spectrophotometric DNA titration (Kb = 0.8–1.8 × 104 M−1) and viscosity studies indicate weak interactions between the complexes and DNA. Cytotoxicity assays against DU-145 (prostate cancer) and A549 (lung cancer) tumour cells revealed that the complexes are more active in tumour cells than in normal (L929) cells, and that they present high cytotoxicity (low IC50 values) compared with the reference metallodrug, cisplatin.Item Ru(II)-naphthoquinone complexes with high selectivity for triple negative breast cancer.(2020) Oliveira, Katia Mara de; Peterson, Erica J.; Carroccia, Murilo César; Cominetti, Márcia Regina; Deflon, Victor Marcelo; Farrell, Nicholas P.; Batista, Alzir Azevedo; Correa, Rodrigo de SouzaSix new ruthenium(II) complexes with lapachol (Lap) and lawsone (Law) with the general formula [Ru(L)(P– P)(bipy)]PF6, where L = Lap or Law, P–P = 1,2’-bis(diphenylphosphino)ethane (dppe), 1,4’-bis(diphenyl phosphino)butane (dppb), 1,1’-bis(diphenylphosphino)ferrocene (dppf) and bipy = 2,2’-bipyridine, were synthesized, fully characterized by elemental analysis, molar conductivity, NMR, cyclic voltammetry, UV vis, IR spectroscopies and three of them by X-ray crystallography. All six complexes were active against breast (MCF-7 and MDA-MB-231) and prostate (DU-145) cancer cell lines with lower IC50 values than cis platin. Complex [Ru(Lap)(dppe)(bipy)]PF6 (1a) showed significant selectivity for MDA-MB-231, a model of triple-negative breast cancer (TNBC), as compared to the “normal-like” human breast epithelial cell line, MCF-10A. Complex (1a) inhibited TNBC colony formation and induced loss of cellular adhesion. Furthermore, the complex (1a) induced mitochondrial dysfunction and generation of ROS, as is involved in the apoptotic cell death pathway. Preferential cellular uptake of complex (1a) was observed in MDA-MB-231 cells compared to MCF-10A cells, consistent with the observed selectivity for tumorigenic vs. non-tumorigenic cells. Taken together, these results indicate that ruthenium complexes containing lapachol and lawsone as ligands are promising candidates as chemotherapeutic agents.Item Ru(II)/diclofenac-based complexes : DNA, BSA interaction and their anticancer evaluation against lung and breast tumor cells.(2020) Oliveira, Katia Mara de; Peterson, Erica J.; Carroccia, Murilo César; Cominetti, Márcia Regina; Deflon, Victor Marcelo; Farrell, Nicholas P.; Batista, Alzir Azevedo; Correa, Rodrigo de SouzaSix new ruthenium(II) complexes with lapachol (Lap) and lawsone (Law) with the general formula [Ru(L)(P– P)(bipy)]PF6, where L = Lap or Law, P–P = 1,2’-bis(diphenylphosphino)ethane (dppe), 1,4’-bis(diphenyl phosphino)butane (dppb), 1,1’-bis(diphenylphosphino)ferrocene (dppf) and bipy = 2,2’-bipyridine, were synthesized, fully characterized by elemental analysis, molar conductivity, NMR, cyclic voltammetry, UV vis, IR spectroscopies and three of them by X-ray crystallography. All six complexes were active against breast (MCF-7 and MDA-MB-231) and prostate (DU-145) cancer cell lines with lower IC50 values than cis platin. Complex [Ru(Lap)(dppe)(bipy)]PF6 (1a) showed significant selectivity for MDA-MB-231, a model of triple-negative breast cancer (TNBC), as compared to the “normal-like” human breast epithelial cell line, MCF-10A. Complex (1a) inhibited TNBC colony formation and induced loss of cellular adhesion. Furthermore, the complex (1a) induced mitochondrial dysfunction and generation of ROS, as is involved in the apoptotic cell death pathway. Preferential cellular uptake of complex (1a) was observed in MDA-MB-231 cells compared to MCF-10A cells, consistent with the observed selectivity for tumorigenic vs. non-tumorigenic cells. Taken together, these results indicate that ruthenium complexes containing lapachol and lawsone as ligands are promising candidates as chemotherapeutic agents.Item Ruthenium complexes show promise when submitted to toxicological safety tests using alternative methodologies.(2021) Teixeira, Thallita Monteiro; Arraes, Isabela Gasparini; Abreu, Davi Carvalho; Oliveira, Katia Mara de; Correa, Rodrigo de Souza; Batista, Alzir Azevedo; Braunbeck, Thomas; Lacerda, Elisângela de Paula SilveiraThe number of cancer cases continues to increase worldwide, and unfortunately the main systemic treatments available have numerous of side effects. Ruthenium complexes have shown to be promising chemotherapeutic agents, since they present low toxicity and are more selective for tumor tissues. We report the synthesis, characterization and biological properties of two new ruthenium (II) complexes containing Lapachol and Lawsone as ligands: (1) [Ru(Law)(dppb)(phen)]PF6 and (2) [Ru(Lap)(dppb)(- phen)]PF6, where Law ¼ Lawsone, Lap ¼ Lapachol, dppb ¼ 1,4-bis(diphenylphosphine)butane and phen ¼ 1,10-phenanthroline. The ability of the complexes (1) and (2) to interact with CT-DNA (Calf Thymus) was investigated, and the results indicate that the complexes have shown a weak interaction with this macromolecule. Complexes (1) and (2) showed a moderate interaction with BSA, via a spontaneous process with the involvement of van der Waals and hydrogen bond interactions. Both complexes were tested against human lung cancer cell lines, chronic human myeloid leukemia, murine melanoma and human cervical and non-tumoral murine fibroblast adenocarcinoma, human lung fibroblasts and monkey kidney epithelia. The potential for cytotoxicity was tested out using the MTT assay and the neutral red test, to calculate inhibitory concentrations (IC50) and selectivity indices (IS). Both complexes showed a higher selectivity index of 1.17 and 10.91, respectively, for the HeLa tumor line. Studies of toxicological evaluation, using the micronucleus test and the comet assay against non-tumor cells, as well as an assessment of the potential for acute toxicity and neurotoxicity in zebrafish (Danio rerio). In the in vitro micronucleus test, complex (1) showed the least genotoxic potential, and in the in vitro comet assay both compounds had revealed a genotoxic potential at 0.5 and 1.0 mg L1 , with no difference between 24 h and 48 h exposure times. In the acute toxicity tests on zebrafish embryos, complex (1) showed sublethal effects such as decreased blood circulation and heartbeat rate, which were less pronounced than with complex (2). In contrast to complex 2, which caused lethality even before 48h, complex (1) did not cause the death of the embryos at concentrations up to (2.0 mg L1 ). Complex (2) also lead to a delay in the embryo. Cell based in vitro methods thus proved able to provide specific toxicological data, allowing a significant reduction in \animal experimentation. Given that in vitro tests cannot completely replace animal tests, the use of less advanced developmental stages such as zebrafish embryos, which - at least in the European Union - are not regarded protected, could be shown to be an excellent alternative for testing with, e.g., mammals.Item Ruthenium(II)/triphenylphosphine complexes : an effective way to improve the cytotoxicity of lapachol.(2017) Oliveira, Katia Mara de; Correa, Rodrigo de Souza; Barbosa, Marília Imaculada Frazão; Ellena, Javier Alcides; Cominetti, Márcia Regina; Batista, Alzir AzevedoThis study reports on the synthesis of a new ruthenium(II) complex, cis-[Ru(PPh3)2(lap)2] (1) with two molecules of the natural product known as lapachol [lap = (2-hydroxy-3-(3-methyl-2-buthenyl)-1,4- naphthoquinone)] coordinated as bidentated by oxygen atoms and two monodentate PPh3 (triphenylphosphine) in a cis configuration. This neutral complex was characterized by spectroscopic analysis, single-crystal X-ray diffraction, elemental analysis, molar conductivity and cyclic voltammetry. In this study, ruthenium complex trans-[Ru(lap)(PPh3)2(phen)]PF6 (2) was used for comparison purposes. The interaction of ruthenium complexes (1) and (2) with CT-DNA was evaluated by UV–Vis and circular dichroism and it was observed that the complexes interact weakly with the CT-DNA. The fluorescence measurements suggest that complex (1) shows stronger interaction with HSA and BSA proteins compared to complex (2). Cytotoxicity assays against A549 (lung cancer), MDA-MB-231 (breast cancer) and V79 (non-tumoral lung) revealed that complex (2) is more active (lower IC50 values) than complex (1) and the cisplatin, used as a reference.