Browsing by Author "Castellano, Eduardo Ernesto"

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    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.
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    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.
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    "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.
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    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.
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    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 Azevedo
    Four 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.
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    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 Azevedo
    Three 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.
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    Synthesis and X-ray crystal structure of the [Ni(HDPE)2][NO3]2.2H2O.
    (1991) Levy, Noel Massinhan; Neves, Ademir; Franco, César Vitorio; Cota, André Barros; Castellano, Eduardo Ernesto; Mascarenhas, Yvone Primerano
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    Understanding the conformational changes and molecular structure of furoyl thioureas upon substitution.
    (2017) Ramos Cairo, Raúl; Stevens, Ana María Plutín; Oliveira, Tamires Donizeth de; Batista, Alzir Azevedo; Castellano, Eduardo Ernesto; Duque, Julio; Soria, Delia B.; Fantoni, Adolfo C.; Correa, Rodrigo de Souza; Erbene, Mauricio F.
    1-Acyl thioureas [R1C(O)NHC(S)NR2R3] are shown to display conformational flexibility depending on the degree of substitution at the nitrogen atom. The conformational landscape and structural features for two closely related thioureas having R1=2-furoyl have been studied. The un-substituted 2-furoyl thiourea (I) and its dimethyl analogue, i.e. 1-(2-furoyl)-3,3-dimethyl thiourea (II), have been synthesized and fully characterized by spectroscopic (FT-IR, 1H and 13C NMR) and elemental analysis. According to single crystal X-ray diffraction analysis, compounds I and II crystallize in the monoclinic space group P21/c. In the compound I, the trans–cis geometry of the almost planar thiourea unit is stabilized by intramolecular N\\H⋯O_C hydrogen bond between the H atom of the cis thioamide and the carbonyl O atom. In compound II, however, the acyl thiourea group is non-planar, in good agreement with the potential energy curve computed at the B3LYP/6-31+G(d,p) level of approximation. Centrosymmetric dimers generated by intermolecular N\\H⋯S_C hydrogen bond forming R2 2 (8) motif are present in the crystals. Intermolecular interactions have been rationalized in terms of topological partitions of the electron distributions and Hirshfeld surface analysis, which showed the occurrence of S⋯H, O⋯H and H⋯H contacts that display an important role to crystal packing stabilization of both thiourea derivatives.