DSpace Repository :: Browsing by Author "Batista, Alzir Azevedo"

Browsing by Author "Batista, Alzir Azevedo"

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Anti-mycobacterium tuberculosis and cytotoxicity activities of Ruthenium(II)/ bipyridine/diphosphine/pyrimidine-2-thiolate complexes : the role of the non- coordinated N-atom.
(2016) Benedicto, Augusto Vieira Lima; Correa, Rodrigo de Souza; Graminha, Angelica Ellen; Kuznetsov, Aleksey Evgenyevich; Ellena, Javier Alcides; Pavan, Fernando Rogério; Leite, Clarice Queico Fujimura; Batista, Alzir Azevedo
The [Ru(Spym)(bipy)(P–P)]PF6, [Spym = pyrimidine-2-thiolate anion; P–P = 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane and 1,1’-bis(diphenylphosphino)ferrocene] complexes were synthesized and characterized by spectroscopic, electrochemical and elemental analysis, and by X-ray crystallography. The minimal inhibitory concentration (MIC) of the compounds against Mycobacterium tuberculosis and the complex concentration causing 50% tumor cell growth inhibition (IC50) against breast cancer cells, MDA-MB-231, were determined. All three compounds gave promising values in both tests. It is interesting to mention that all three complexes display MICs against Mycobacterium tuberculosis showing higher activity than cycloserine, a second line drug used in the treatment of the illness. The complexes interact weakly with the DNA.
Antiparasitic activity and ultrastructural alterations provoked by organoruthenium complexes against Leishmania amazonensis.
(2019) Vegas, Legna Andreina Colina; Godinho, Joseane Lima Prado; Coutinho, Thallita; Correa, Rodrigo de Souza; Souza, Wanderley de; Rodrigues, Juliany Cola Fernandes; Batista, Alzir Azevedo; Navarro Acosta, Maribel Coromoto
Four new organoruthenium complexes with formula [RuCl(η6-p-cymene)(μ-FCZ)]2[Cl]2 (1), [RuCl(FCZ)(η6-p-cymene)(PPh3)]PF6 (2), [RuCl(CTZ)(η6-p-cymene)(PPh3)]PF6 (3) and [RuCl(KTZ)(η6-p-cymene)(PPh3)]PF6 (4) (where FCZ: 2-(2,4-difluorophenyl)-1,3-di(1H-1,2,4-triazol-1-yl)-2-propanol, CTZ: 1-[(2-chlorophenyl)-diphenylmethyl-1H-imidazole] and KTZ: cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine) were synthesized, characterized and evaluated as potential inhibitors for Leishmania amazonensis growth by widely reported methods. Complexes 3 and 4 displayed effective IC50 activities against Leishmania amazonensis promastigotes and intracellular amastigotes in the range of nanomolar concentration. Scanning and transmission electron microscopy analysis of Leishmania amazonensis promastigotes after treatment with 300 or 500 nM of complexes 3 and 4 for 48 h showed morphological alterations in the cell surface, a shortening of the flagellum, loss of mitochondrial matrix, disorganization of the kDNA and abnormal chromatin condensation. Thus, our strategy of incorporating a ruthenium atom into the structure of clinical drugs to improve their efficacy continues to demonstrate suitability for metallodrug discovery purposes.
Antitumor activity of Pd(II) complexes with N,S or O,S coordination modes of acylthiourea ligands.
(2020) Stevens, Ana María Plutín; 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 Azevedo
Seven 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.
Antitumor and anti-Mycobacterium tuberculosis agents based on cationic ruthenium complexes with amino acids.
(2017) Santos, Edjane Rocha dos; Correa, Rodrigo de Souza; Cunha, Lucas Vinícius Pozzi da; Graminha, Angelica Ellen; Araujo, Heloisa Sobreiro Selistre de; Pavan, Fernando Rogério; Batista, Alzir Azevedo
Six new complexes of Ru(II)/phenanthroline/1,4-bis(diphenylphosphino)butane containing amino acids (Glycine, L-Alanine, L-Valine, L-Tyrosine, L-Methionine or L-Tryptophan) were synthesized and characterized by IR, 31P{1H}, 13C and 1H NMR spectroscopies and cyclic voltammetry experiments. These data suggest the presence of diastereoisomers, except for the complex with glycine, amino acid that does not exhibit chiral carbon. The compounds are active against the MDA-MB-231 tumor cells and against Mycobacterium tuberculosis. The cationic ruthenium complexes with amino acids, reported here, show similar cytotoxicity against the MDA-MB-231 tumor cells. When compared with analogs complexes containing 2,20-bipyridine as ligands, instead of 1,10-phenatroline, the new complexes studied here are, in general, roughly twice more active than the 2,20-bipyridine ones and their IC50 values comparable with the cisplatin. In addition, low MICs values were obtained against Mycobacterium tuberculosis compared with the reference drugs, cycloserine and ethambutol.
Characterization and screening of tight binding inhibitors of xanthine oxidase : an on-flow assay.
(2015) Rodrigues, Marili Villa Nova; Correa, Rodrigo de Souza; Vanzolini, Kenia Lourenço; Santos, Diogenes Santiago; Batista, Alzir Azevedo; Cass, Quezia Bezerra
Xanthine oxidase (XO) is an enzyme in the purine salvage pathway that catalyzes the oxidation of hypoxanthine to xanthine with subsequent production of uric acid from the xanthine oxidation, and it has been considered an important target of newly developed inhibitors. Based on the advantages of using immobilized capillary enzyme reactors (ICERs) in a 2D LC system as a tool for screening new enzymatic ligands, this work validated an XO-ICER using allopurinol as a positive control. Despite the complex interaction between XO and allopurinol due its tight binding nature, it was possible to recognize the inhibitory kinetics parameters through Morrison's equation. The tight binding nature of inhibition was established by varying the IC50 values according to the substrate concentration. The kinetic inhibitory profile of allopurinol was used to validate the XO-ICER. Then, the XO-ICER was used to screen specific ruthenium derivatives. The selected compound, 4CBALO, an allopurinol ruthenium derivative, exhibited 100% inhibition at 200 mM compared to 86% inhibition from allopurinol at the same concentration. The inhibitory effect on the immobilized XO was reversible after the elution of the compound, with immediate recovery of the ICER activity. Additionally, 4CBALO behaved as a selective and competitive tight binder of xanthine oxidase with a true Ki value of 0.29 mM, which was obtained from the Morrison equation. This report describes the first on-flow characterization of tight binders of xanthine oxidase
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; Stevens, Ana María Plutín; Ramos Cairo, Raúl; Mocelo, Raúl; Castellano, Eduardo Ernesto; Batista, Alzir Azevedo
In 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.
Copper(I)−Phosphine polypyridyl complexes : synthesis, characterization, DNA/HSA binding study, and antiproliferative activity.
(2017) Villarreal, Wilmer; Vegas, Legna Andreina Colina; Visbal, Gonzalo; Corona, Oscar; Correa, Rodrigo de Souza; Ellena, Javier Alcides; Cominetti, Márcia Regina; Batista, Alzir Azevedo; Navarro Acosta, Maribel Coromoto
A series of copper(I)−phosphine polypyridyl complexes have been investigated as potential antitumor agents. The complexes [Cu(PPh3)2dpq]NO3 (2), [Cu(PPh3)2dppz]NO3 (3), [Cu(PPh3)2dppa]NO3 (4), and [Cu(PPh3)2dppme]NO3 (5) were synthesized by the reaction of [Cu(PPh3)2NO3] with the respective planar ligand under mild conditions. These copper complexes were fully characterized by elemental analysis, molar conductivity, FAB-MS, and NMR, UV−vis, and IR spectroscopies. Interactions between these copper(I)−phosphine polypyridyl complexes and DNA have been investigated using various spectroscopic techniques and analytical methods, such as UV−vis titrations, thermal denaturation, circular dichroism, viscosity measurements, gel electrophoresis, and competitive fluorescent intercalator displacement assays. The results of our studies suggest that these copper(I) complexes interact with DNA in an intercalative way. Furthermore, their high protein binding affinities toward human serum albumin were determined by fluorescence studies. Additionally, cytotoxicity analyses of all complexes against several tumor cell lines (human breast, MCF-7; human lung, A549; and human prostate, DU-145) and nontumor cell lines (Chinese hamster lung, V79-4; and human lung, MRC-5) were performed. The results revealed that copper(I)− phosphine polypyridyl complexes are more cytotoxic than the corresponding planar ligand and also showed to be more active than cisplatin. A good correlation was observed between the cytostatic activity and lipophilicity of the copper(I) complexes studied here.
Cytotoxic activity and structural features of Ru(II)/phosphine/amino acid complexes.
(2018) Santos, Edjane Rocha dos; Graminha, Angelica Ellen; Schultz, Mario Sergio; Correia, Isabel; Araujo, Heloisa Sobreiro Selistre de; Correa, Rodrigo de Souza; Ellena, Javier Alcides; Lacerda, Elisângela de Paula Silveira; Pessoa, João Costa; Batista, Alzir Azevedo
Thirteen new ruthenium amino acid complexes were synthesized and characterized. They were obtained by the reaction of α-amino acids (AA) with [RuCl2(P-P)(N-N)], where P-P = 1,4-bis(diphenylphosphino)butane (dppb) or 1,3-bis(diphenylphosphino)propane (dppp) and N-N = 4,4′-dimethyl-2,2′-bipyridine (4′-Mebipy), 5,5′-dimethyl-2,2′-bipyridine (5′-Mebipy) or 4,4′-Methoxy-2-2′-bipyridine (4′-MeObipy). This afforded a family of complexes formulated as [Ru(AA-H)(P-P)(N-N)]PF6, where AA = glycine (Gly), L-alanine (Ala), L-valine (Val), L-tyrosine (Tyr), L-tryptophan (Trp), L-histidine (His) and L-methionine (Met). All compounds were characterized by elemental analysis, spectroscopic and electrochemical techniques. The [Ru(AA-H)(P-P)(N-N)]PF6 complexes are octahedral (the AA-H ligand binding involves N-amine and O-carboxylate), diamagnetic (low-spin d6, S = 0) and present bands due to electronic transitions in the visible region. 1H, 13C{1H} and 31P{1H} NMR spectra of the complexes indicate the presence of C2 symmetry, and the identification of diastereoisomers. In vitro cytotoxicity assays of the compounds and cisplatin were carried out using MDA-MB-231 (human breast) tumor cell line and a non-tumor breast cell line (MCF-10A). Most complexes present promising results with IC50 values comparable with the reference drug cisplatin and high selectivity indexes were found for the complexes containing L-Trp. The binding of two Ru-precursors of the type [RuCl2(dppb)(NN)] (N-N = 4′-MeObipy or 4′-Mebipy) to the blood transporter protein human serum albumin (HSA) was evaluated by fluorescence and circular dichroism spectroscopy. Both complexes bind HSA, probably in the hydrophobic pocket near Trp214, and the Ru-complex containing 4′-MeObipy shows higher affinity for HSA than the 4′-Mebipy one.
Esterification of the free carboxylic group from the lutidinic acid ligand as a tool to improve the cytotoxicity of Ru(II) complexes.
(2019) Araujo Neto, João Honorato de; Vegas, Legna Andreina Colina; Correa, Rodrigo de Souza; Macedo, Adriana Pereira Mundim Guedes; Miyata, Marcelo; Pavan, Fernando Rogério; Ellena, Javier Alcides; Batista, Alzir Azevedo
In this study, we report on the selective esterification of the carboxyl group in a coordinated ligand based on the Fischer reaction. The new [Ru(N–O)(bipy)(dppb)]PF6 complex 1 was used as a precursor to obtain the ester derivative [Ru(N–Oet)(bipy)(dppb)]PF6 (2), and in order to establish the influence of either the free carboxyl group or the ethoxycarbonyl group on biological properties, the [Ru(pic)(bipy)(dppb)]PF6 complex (3) was synthesized for comparison (dppb = 1,4-bis(diphenylphosphino)butane, bipy = 2,2′-bipyridine, N–O = mono-deprotonated 2,4-pyridinedicarboxylic acid, N–Oet = 4-ethoxycarbonyl-2-pyridinecarboxylic acid). All three complexes interact weakly with human serum albumin (HSA) with Kb values ranging from 101–104 M−1, suggesting a spontaneous interaction with this protein by electrostatic (1–2) or van der Waals interactions (3). Moreover, complex/DNA-binding experiments indicate that complexes 2 and 3 interact weakly with DNA, while no interaction is observed between complex 1 and DNA, probably due to the repulsion involving the free carboxylate group/DNA-phosphate. Anti-Mycobacterium tuberculosis (MTB) activity and cytotoxicity assays against one normal cell line V79 (hamster fibroblast) and three human cancer cell lines A549 (lung), MCF7 and MDA-MB-231 (breast) revealed that complexes 2 and 3 exhibit good activity against MTB and tumor cells, presenting high cytotoxicity (low IC50). On the other hand, complex 1 is practically inactive. Therefore, the best biological results found for complex 2 can be attributed to its esterification, improving the lipophilicity and cellular uptake, in order to facilitate its passive permeation through the tumor cell membranes allowing for cell death, as well as DNA and HSA interactions, when compared with complex 1.
Facile synthesis and characterization of symmetric N-[(Phenylcarbonyl) carbamothioyl]benzamide thiourea : experimental and theoretical investigations.
(2018) Silveira, Rafael Gomes da; Catão, Anderson José Lopes; Cunha, Beatriz Nogueira da; Almeida, Fernando; Diniz, Luan Farinelli; Clavijo, Juan Carlos Tenorio; Ellena, Javier Alcides; Kuznetsov, Aleksey Evgenyevich; Batista, Alzir Azevedo; Alcântara, Edésio
A thiourea derivative, N-[(phenylcarbonyl)carbamothioyl]benzamide, was synthesized and characterized by elemental analysis, thermal analysis, spectroscopic methods (Fourier transform infrared (FTIR), UV-Vis, Raman, matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF), tandem mass spectrometry (MS/MS) and nuclear magnetic resonance (NMR)) and quantum-chemical calculations. The synthetic route was simple and efficient, conducted just by one-step and no purification step was needed. The compound crystallizes in a non-centrosymmetric orthorhombic crystal system with a P21 21 21 space group, with a= 5.06220(10) Å, b= 11.8623(3) Å, c= 21.9682(8) Å. The molecular conformation of the solid is stabilized by the N-H···O intramolecular hydrogen bond, which was present in the X-ray structure and was also found in the optimized geometry. The theoretical analysis showed that this strong interaction remains even when molecules are solvated, i.e., the rotation barrier and the hydrogen bond strength are greater than the solvent stabilization energy. In addition to this hydrogen bond effect, the relative position of phenyl groups has a certain influence on the chemical behavior of this thiourea and probably for other phenylthioureas.
"Half-sandwich"/RuII anticancer complexes containing triphenylphosphine and p-substituted benzoic acids.
(2020) Araujo Neto, João Honorato de; Oliveira, Katia Mara de; Leite, Celisnolia M.; Colina Vegas, Legna Andreina; Nóbrega, Joaquim de Araújo; Castellano, Eduardo Ernesto; Ellena, Javier Alcides; Correa, Rodrigo de Souza; Batista, Alzir Azevedo
Mononuclear 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.
Influence of gold nanoparticles applied to catalytic hydrogenation of acetophenone with cationic complexes containing ruthenium.
(2016) Souza, Lanarck Cristina Moro; Santos, Thiago A.; Prado, Cássio Roberto Arantes do; Lima, Benedicto Augusto Vieira; Correa, Rodrigo de Souza; Batista, Alzir Azevedo; Otubo, Larissa; Ellena, Javier Alcides; Ueno, Leonardo Tsuyoshi; Dinelli, Luís Rogério; Bogado, André Luiz
Herein the catalytic activity of cationic ruthenium(II) complexes [Ru]+ is described in the presence of gold nanoparticles (AuNPsn ) in the transfer hydrogenation of acetophenone, to produce phenylethanol. The catalytic activity of the complexes, with a general formula cis-[RuCl(CH3OH)(P–P)(N–N)]+ or cis- [RuCl(CH3OH)(P)2(N–N)]+ {where: P ¼ triphenylphosphine (PPh3); P–P ¼ 1,1-bis(diphenylphosphino) methane (dppm); 1,2-bis(diphenylphosphino)ethane (dppe); 1,3-bis(diphenylphosphino)propane (dppp), 1,4-bis(diphenylphosphino)butane (dppb); N–N ¼ 2,20-bipyridine; 4,40-dimethyl-2,20-bipyridine} was investigated in the presence of AuNPsn . The interaction between [Ru]+ and AuNPsn citrate capped is an electrostatic interaction, by a self-assembly processes, to produce a supramolecular species, labeled as [Ru]+/AuNPsn . This non-covalent interaction has no effect over the chemical and physical chemical parameters of the complexes, which provides a good point of comparison in the presence and absence of AuNPsn . The AuNPsn alone have no catalytic activity in the transfer hydrogenation of acetophenone within 24 h of reaction. However, the AuNPsn have improved the catalytic activity of the complexes that have biphosphines with tensioned or large bite angle, while for the complexes that have biphosphines with a strong chelate effect a decrease in the catalytic activity was observed. The evidence is supported by experimental values of the yields of the hydrogenated product and DFT calculations of the “RuP–P” intermediates. Suitable crystals of cis-[RuCl2(dppe)(bipy)], cis-[RuCl2(dppp)(bipy)] and cis- [RuCl(CH3OH)(dppb)(bipy)](PF6) were obtained and the X-ray structures are presented here.
Inhibition of human DNA topoisomerase IB by nonmutagenic ruthenium(ii)-based compounds with antitumoral activity.
(2016) Camargo, Mariana Santoro de; Silva, Monize Martins da; Correa, Rodrigo de Souza; Vieira, Sara Dourado; Castelli, Silvia; D’Anessa, Ilda; Grandis, Rone De; Varanda, Eliana Aparecida; Deflon, Victor Marcelo; Desideri, Alessandro; Batista, Alzir Azevedo
Herein we synthesized two new ruthenium(II) compounds [Ru(pySH)(bipy)(dppb)]PF6 (1) and [Ru(HSpym)(bipy)- (dppb)]PF6 (2) that are analogs to an antitumor agent recently described, [Ru(SpymMe2)(bipy)(dppb)]PF6 (3), where [(Spy) = 2-mercaptopyridine anion; (Spym) = 2-mercaptopyrimidine anion and (SpymMe2) = 4,6-dimethyl-2-mercaptopyrimidine anion]. In vitro cell culture experiments revealed significant antiproliferative activity for 1–3 against HepG2 and MDA-MB-231 tumor cells, higher than the standard anticancer drugs doxorubicin and cisplatin. No mutagenicity is detected when compounds are evaluated by cytokinesis-blocked micronucleus cytome and Ames test in the presence and absence of S9 metabolic activation from rat liver. Interaction studies show that compounds 1–3 can bind to DNA through electrostatic interactions and to albumin through hydrophobic interactions. The three compounds are able to inhibit the DNA supercoiled relaxation mediated by human topoisomerase IB (Top1). Compound 3 is the most efficient Top1 inhibitor and the inhibitory effect is enhanced upon pre-incubation with the enzyme. Analysis of different steps of Top1 catalytic cycle indicates that 3 inhibits the cleavage reaction impeding the binding of the enzyme to DNA and slows down the religation reaction. Molecular docking shows that 3 preferentially binds closer to the residues of the active site when Top1 is free and lies on the DNA groove downstream of the cleavage site in the Top1–DNA complex. Thus, 3 can be considered in further studies for a possible use as an anticancer agent.
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 Azevedo
The 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.
New heteroleptic RuII/diphosphine complexes with cytotoxicity against human breast and murine ascitic sarcoma 180 tumor cells.
(2020) Lima, Benedicto Augusto Vieira; Correa, Rodrigo de Souza; Graminha, Angelica Ellen; Varela Júnior, Jaldyr de Jesus Gomes; Silva, Albérico B. F. da; Ellena, Javier Alcides; Silva, Thales E. M.; Batista, Alzir Azevedo
The preparation, characterization, theoretical calculations and biological application of four RuII complexes with 2-picolinate (pic), 2,2’-bipyridine (bipy) and P-P as ligands [P-P = 1,1-bis(diphenylphosphino)methane (dppm-1), 1,2-bis(diphenylphosphino)ethane (dppe-2), 1,3-bis(diphenylphosphino)propane (dppp-3) or 1,1’-bis(diphenylphosphino)ferrocene (dppf-4)], is here presented. The complexes 1-4, with general formula [Ru(pic)(P-P)(bipy)]PF6, were characterized by elemental analysis and by infrared (IR), UV-Vis, nuclear magnetic resonance (NMR 1 H and 13P{1 H}) spectroscopies, cyclic voltammetry and X-ray crystallography technique. Additionally, preliminary in vitro tests against human breast (MDA-MB-231) and murine ascitic sarcoma 180 (S180) tumor cell lines were carried out, and compared with cisplatin, a reference drug. The drug concentration at which 50% of the cells are viable relative to the control (IC50) values found for complexes 1, 2, 3 and 4 against MDA-MB-231 tumor cells were around 14.6, 7.6, 3.3 and 0.4 μM, respectively, while against S180 tumor cells these complexes showed IC50 values of 71.9, 31.3, 11.2 and 3.5 μM, respectively. Therefore, the complexes were more active against MDA-MB-231 than S180.
Non-mutagenic Ru(II) complexes : cytotoxicity, topoisomerase IB inhibition, DNA and HSA binding.
(2019) Silva, Monize Martins da; Camargo, Mariana Santoro de; Correa, Rodrigo de Souza; Castelli, Silvia; Grandis, Rone De; Takarada, Jéssica Emi; Varanda, Eliana Aparecida; Castellano, Eduardo Ernesto; Deflon, Victor Marcelo; Cominetti, Márcia Regina; Desideri, Alessandro; Batista, Alzir Azevedo
Herein we discuss five ruthenium(II) complexes with good cytotoxicity against cancer cells. These complexes are named [Ru(tzdt)(bipy)(dppb)]PF6 (1), [Ru(mmi)(bipy)(dppb)]PF6 (2), [Ru(dmp)(bipy)(dppb)]PF6 (3), [Ru(mpca)(bipy)(dppb)]PF6 (4) and [Ru(2mq)(bipy)(dppb)]PF6 (5), where tzdt = 1,3-thiazolidine-2-thione, mmi = mercapto-1-methyl-imidazole, dmp = 4,6-diamino-2-mercaptopyrimidine, mpca = 6-mercaptopyridine-3-carboxylic acid, 2mq = 2-mercapto-4(3H)-quinazolinone, bipy = 2,2′-bipyridine and dppb = 1,4-bis(diphenylphosphino)butane. In vitro cell culture experiments revealed significant cytotoxic activity for 1–5 against MDA-MB-231, MCF-7, A549, DU-145 and HepG2 tumor cells, higher than that for the standard anticancer drug cisplatin. Compound/DNA interaction studies were carried out showing that 1–5 interact with DNA by electrostatic force of attraction or by hydrogen bonding. Moreover, the complexes interact, moderately and spontaneously, with human serum albumin (HSA) through the hydrophobic region. The five complexes are able to inhibit the DNA supercoiled relaxation mediated by human topoisomerase IB (TopIB), and complex 1 is found to be the most efficient TopIB inhibitor among the five compounds. The inhibitory effect and analysis of different steps of the TopIB catalytic cycle indicate that complex 1 inhibits the cleavage reaction impeding the binding of the enzyme to DNA and has no effect on the religation step. Complexes 1, 2 and 3 did not show mutagenic activity when they were evaluated by the cytokinesis-block micronucleus cytome assay in HepG2 cells and the Ames test in the presence and absence of mouse liver S9 metabolic activation. Therefore, it is necessary to perform further in-depth analysis of the therapeutic potential of these promising ruthenium complexes as anticancer drugs.
A novel ruthenium(II) gallic acid complex disrupts the actin cytoskeleton and inhibits migration, invasion and adhesion of triple negative breast tumor cells.
(2021) Graminha, Angelica Ellen; Araujo Neto, João Honorato de; Correa, Rodrigo de Souza; Cominetti, Márcia Regina; Menezes, Antônio Carlos Severo; Batista, Alzir Azevedo
This work describes the synthesis of three new ruthenium(II) complexes with gallic acid and derivatives of the general formula [Ru(L)(dppb)(bipy)]PF6, where L = gallate (GAC), benzoate (BAC), and esterified-gallate (EGA), bipy = 2,2’-bipyridine and dppb = 1,4-bis(diphenylphosphino)butane. The complexes were characterized by elemental analysis, molar conductivity, NMR, cyclic voltammetry, UV-vis and IR spectroscopy, and two of them by X-ray crystallography. Cell viability assays show promising results, indicating higher cytotoxicity of the complexes in MDA-MB-231 cells, a triple-negative breast cancer (TNBC) cell line, compared with the hormone-dependent MCF-7 cell line. Studies in vitro with the MDA-MB-231 cell line showed that only Ru(BAC) and Ru(GAC) interacted with BSA. Besides that, the Ru(GAC) complex, which has a polyphenolic acid, interacted in an apo-Tf structure and function dependent manner and it was able to inhibit the formation of reactive oxygen species. Ru(GAC) was able to cause damage to the cellular cytoskeleton leading to inhibition of some cellular processes of TNBC cells, such as invasion, migration, and adhesion.
Nucleobase derivatives as building blocks to form Ru(II)-based complexes with high cytotoxicity.
(2020) Carvalho, Diogo Émerson Leite de; Oliveira, Katia Mara de; Bomfim, Larissa Mendes; Soares, Milena Botelho Pereira; Bezerra, Daniel Pereira; Batista, Alzir Azevedo; Correa, Rodrigo de Souza
Two 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.
Polypyridyl ruthenium complexes : novel DNA-intercalating agents against human breast tumor.
(2017) Reis, João Paulo Barolli; Correa, Rodrigo de Souza; Miranda, Fabio da Silva; Ribeiro, Juliana Uema; Bloch Junior, Carlos; Ellena, Javier Alcides; Moreno, Virtudes; Cominetti, Márcia Regina; Batista, Alzir Azevedo
This paper describes a new series of four DNA-intercalating agents with promising anticancer activities, based on ruthenium(II) with the planar ligand dpqQX (dpqQX = dipyrido[3,2-a:2',3'-c]quinoxaline[2,3-b]quinoxaline). The complexes identified as trans-[RuCl2(dppb)(dpqQX)], cis-[RuCl2(dppb)(dpqQX)], ct-[RuCl(CO)(dppb)(dpqQX)]PF6 and ct-[RuCl2(PPh3)2(dpqQX)] (dppb = 1,4-bis(diphenylphosphine)butane and PPh3 = triphenylphosphine) were characterized by 31P{1H} nuclear magnetic resonance (NMR) and infrared spectroscopies, cyclic voltammetry, molar conductance measurements, elemental analysis, mass spectrometry and X-ray diffraction analysis for complex ct-[RuCl2(PPh3)2(dpqQX)]. Their in vitro cytotoxic activities against MDA-MB-213 and MCF-7 breast cancer cells were evaluated and compared with normal L-929 cells. Low drug concentration at which 50% of the cells are viable relative to the control (IC50) values were obtained for all four complexes compared with a reference metallodrug, cisplatin. In addition, DNA affinity studies from titrations, as well as the images obtained by atomic force microscopy (AFM) involving pBR322 plasmid DNA, suggest interactions between the metal complexes and the DNA macromolecule, in which they act as intercalating agents. The intercalation of the complexes with DNA was confirmed by viscosity measurements.
Reactive nitrogen/oxygen species production by nitro/nitrosyl supramolecular ruthenium porphyrin complexes.
(2017) Barbosa, Marília Imaculada Frazão; Gimenez Parra, Gustavo; Correa, Rodrigo de Souza; Sampaio, Renato Neiva; Magno, Lais Nogueira; Silva, Rodrigo Costa; Doriguetto, Antônio Carlos; Ellena, Javier Alcides; Barbosa Neto, Newton Martins; Batista, Alzir Azevedo; Gonçalves, Pablo José
This manuscript reports on new nitro/nitrosyl Ru-based complexes, which were synthesized with the purpose of using them as precursors to obtain supramolecular ruthenium porphyrin species ({TPyP[Ru (NO2)(5,50-Mebipy)2]4}(PF6)4) and ({TPyP[Ru(NO)(5,50-Mebipy)2]4}(PF6)12). The photochemical and photophysical properties of these porphyrin species were investigated. Results show that the complex containing nitrite is able to produce NO by homolytic O—NO cleavage (FPPh NO = 0.05) while the {TPyP[Ru (NO)(5,50-Mebipy)2]4}(PF6)12 does it by direct labilization (FPPh NO = 0.53) of the Ru NO bond. Furthermore, a triplet quantum yield of 0.09 and 0.27 was observed for complexes containing nitrite and nitric oxide, respectively. The reactive oxygen species quantum yield for the complex {TPyP[Ru(NO) (5,50-Mebipy)2]4}(PF6)12 (0.78) is consistent with the sum of quantum yields NO release (0.53) and triplet state (0.27), which suggests that both processes participate in the formation of the reactive species. Our results show that combining these characteristics, NO production and triplet states, on the same platform could induce a synergic effect, leading to a considerable improvement in the photodynamic action of these complexes.

Browsing by Author "Batista, Alzir Azevedo"

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