Publications by authors named "Angélica E Graminha"

13 Publications

  • Page 1 of 1

A novel ruthenium(ii) gallic acid complex disrupts the actin cytoskeleton and inhibits migration, invasion and adhesion of triple negative breast tumor cells.

Dalton Trans 2021 Jan 11;50(1):323-335. Epub 2020 Dec 11.

Departamento de Química, Universidade Federal de São Carlos - UFSCar, Rodovia Washington Luís Km 235, CP 676, 13561-901, São Carlos, SP, Brazil.

This work describes the synthesis of three new ruthenium(ii) complexes with gallic acid and derivatives of the general formula [Ru(L)(dppb)(bipy)]PF, 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.
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http://dx.doi.org/10.1039/d0dt03490hDOI Listing
January 2021

Evaluation of the biological potential of ruthenium(II) complexes with cinnamic acid.

J Inorg Biochem 2020 05 14;206:111021. Epub 2020 Feb 14.

Departamento de Química, Universidade Federal de São Carlos, CEP 13565-905 São Carlos, SP, Brazil. Electronic address:

In this work, we present the synthesis and characterization of five new ruthenium compounds with general formula [Ru(L)(dppb)(bipy)]PF, where L = cinnamic acid derivatives, dppb = 1,4-bis(diphenylphosphino)butane and bipy = 2,2'-bipyridine. The cytotoxicity of the complexes was evaluated against human breast tumor cells from the lines MCF-7, MDA-MB-231 and in human (MCF-10A) or mouse (L929) non-tumor cells. Complexes Ru(L)(dppb)(bipy)]PF (4) (L = 4-hydroxycinnamic acid) and [Ru(L)(dppb)(bipy)]PF (5) (L = 3,4-dihydroxycinnamic acid) were the most selective, presenting the highest values of selectivity indexes besides inhibited some processes related to tumor progression in vitro, such as invasion, migration, and adhesion in the MDA-MB-231 cell line. In addition, the complexes 4 and 5 were able to interact with Bovine Serum Albumin (BSA) and complex 5 showed antioxidant activity.
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http://dx.doi.org/10.1016/j.jinorgbio.2020.111021DOI Listing
May 2020

Transport of the Ruthenium Complex [Ru(GA)(dppe)]PF into Triple-Negative Breast Cancer Cells Is Facilitated by Transferrin Receptors.

Mol Pharm 2019 03 25;16(3):1167-1183. Epub 2019 Jan 25.

Campus of Exact Sciences and Technology (CCET) , State University of Goiás , CEP 75132-903 Anápolis , GO , Brazil.

The triple-negative breast cancer subtype (TNBC) is highly aggressive and metastatic and corresponds to 15-20% of diagnosed cases. TNBC treatment is hampered, because these cells usually do not respond to hormonal therapy, and they develop resistance to chemotherapeutic drugs. On the other hand, the severe side effects of cisplatin represent an obstacle for its clinical use. Ruthenium (Ru)-based complexes have emerged as promising antitumor and antimetastatic substitutes for cisplatin. In this study, we demonstrated the effects of a Ru/biphosphine complex, containing gallic acid (GA) as a ligand, [Ru(GA)(dppe)]PF, hereafter called Ru(GA), on a TNBC cell line, and compared them to the effects in a nontumor breast cell line. Ru(GA) complex presented selective cytotoxicity against TNBC over nontumor cells, inhibited its migration and invasion, and induced apoptosis. These effects were associated with the increased amount of transferrin receptors (TfR) on tumor cells, compared to nontumor ones. Silencing of TfR decreased Ru(GA) effects on TNBC cells, demonstrating that these receptors were at least partially responsible for Ru(GA) delivery into tumor cells. The Ru(GA) compound must be further studied in different in vivo assays in order to investigate its antitumor properties and its toxicity in complex biological systems.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b01154DOI Listing
March 2019

Cytotoxic activity and structural features of Ru(II)/phosphine/amino acid complexes.

J Inorg Biochem 2018 05 23;182:48-60. Epub 2017 Dec 23.

Departamento de Química, Universidade Federal de São Carlos, C.P. 676, CEP 13565-905 São Carlos, (SP), Brazil.

Thirteen new ruthenium amino acid complexes were synthesized and characterized. They were obtained by the reaction of α-amino acids (AA) with [RuCl(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)]PF, 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)]PF complexes are octahedral (the AA-H ligand binding involves N-amine and O-carboxylate), diamagnetic (low-spin d, S=0) and present bands due to electronic transitions in the visible region. H, C{H} and P{H} NMR spectra of the complexes indicate the presence of C 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 IC 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 [RuCl(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.
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http://dx.doi.org/10.1016/j.jinorgbio.2017.12.010DOI Listing
May 2018

Cytotoxicity and anti-tumor effects of new ruthenium complexes on triple negative breast cancer cells.

PLoS One 2017 12;12(9):e0183275. Epub 2017 Sep 12.

Departmento de Gerontologia, Universidade Federal de São Carlos, São Carlos, São Paulo, Brazil.

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype. The high rate of metastasis associated to the fact that these cells frequently display multidrug resistance, make the treatment of metastatic disease difficult. Development of antitumor metal-based drugs was started with the discovery of cisplatin, however, the severe side effects represent a limitation for its clinical use. Ruthenium (Ru) complexes with different ligands have been successfully studied as prospective antitumor drugs. In this work, we demonstrated the activity of a series of biphosphine bipyridine Ru complexes (1) [Ru(SO4)(dppb)(bipy)], (2) [Ru(CO3)(dppb)(bipy)], (3) [Ru(C2O4)(dppb)(bipy)] and (4) [Ru(CH3CO2)(dppb)(bipy)]PF6 [where dppb = 1,4-bis(diphenylphosphino)butane and bipy = 2,2'-bipyridine], on proliferation of TNBC (MDA-MB-231), estrogen-dependent breast tumor cells (MCF-7) and a non-tumor breast cell line (MCF-10A). Complex (4) was most effective among the complexes and was selected to be further investigated on effects on tumor cell adhesion, migration, invasion and in apoptosis. Moreover, DNA and HSA binding properties of this complex were also investigated. Results show that complex (4) was more efficient inhibiting proliferation of MDA-MB-231 cells over non-tumor cells. In addition, complex (4) was able to inhibit MDA-MB231 cells adhesion, migration and invasion and to induce apoptosis and inhibit MMP-9 secretion in TNBC cells. Complex (4) should be further investigated in vivo in order to stablish its potential to improve breast cancer treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183275PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595280PMC
October 2017

Synthesis, Characterization, Cytotoxic Activity, and Interactions with CT-DNA and BSA of Cationic Ruthenium(II) Complexes Containing Dppm and Quinoline Carboxylates.

Bioinorg Chem Appl 2017 26;2017:2562780. Epub 2017 Jul 26.

Instituto de Química, Universidade Federal de Uberlândia, 38400-902 Uberlândia, MG, Brazil.

The complexes -[Ru(quin)(dppm)]PF and -[Ru(kynu)(dppm)]PF (quin = quinaldate; kynu = kynurenate; dppm = (diphenylphosphino)methane) were prepared and characterized by elemental analysis, electronic, FTIR, H, and P{H} NMR spectroscopies. Characterization data were consistent with a arrangement for the dppm ligands and a bidentate coordination through carboxylate oxygens of the quin and kynu anions. These complexes were not able to intercalate CT-DNA as shown by circular dichroism spectroscopy. On the other hand, bovine serum albumin (BSA) binding constants and thermodynamic parameters suggest spontaneous interactions with this protein by hydrogen bonds and van der Waals forces. Cytotoxicity assays were carried out on a panel of human cancer cell lines including HepG2, MCF-7, and MO59J and one normal cell line GM07492A. In general, the new ruthenium(II) complexes displayed a moderate to high cytotoxicity in all the assayed cell lines with IC ranging from 10.1 to 36 M and were more cytotoxic than the precursor -[RuCl(dppm)]. The -[Ru(quin)(dppm)]PF were two to three times more active than the reference metallodrug cisplatin in the MCF-7 and MO59J cell lines.
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http://dx.doi.org/10.1155/2017/2562780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549488PMC
July 2017

Ruthenium(II) complexes of 1,3-thiazolidine-2-thione: Cytotoxicity against tumor cells and anti-Trypanosoma cruzi activity enhanced upon combination with benznidazole.

J Inorg Biochem 2016 Mar 2;156:153-63. Epub 2016 Jan 2.

Departamento de Química, Universidade Federal de São Carlos, CP 676, CEP 13565-905 São Carlos, SP, Brazil. Electronic address:

Three new mixed 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 1.0-4.9×10(3)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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http://dx.doi.org/10.1016/j.jinorgbio.2015.12.024DOI Listing
March 2016

Cytotoxicity of Ru(II) piano-stool complexes with chloroquine and chelating ligands against breast and lung tumor cells: Interactions with DNA and BSA.

J Inorg Biochem 2015 Dec 23;153:150-161. Epub 2015 Jul 23.

Departamento de Química, Universidade Federal de São Carlos - UFSCar, CEP 13565-905 São Carlos, SP, Brazil. Electronic address:

The synthesis and spectroscopic characterization of nine π-arene piano-stool ruthenium (II) complexes with aromatic dinitrogen chelating ligands or containing chloroquine (CQ), are described in this study: [Ru(η(6)-C10H14)(phen)Cl]PF6 (1), [Ru(η(6)-C10H14)(dphphen)Cl]PF6 (2), [Ru(η(6)-C10H14)(bipy)Cl]PF6 (3), [Ru(η(6)-C10H14)(dmebipy)Cl]PF6 (4) and [Ru(η(6)-C10H14)(bdutbipy)Cl]PF6 (5), [Ru(η(6)-C10H14)(phen)CQ](PF6)2 (6), [Ru(η(6)-C10H14)(dphphen)CQ](PF6)2 (7), [Ru(η(6)-C10H14)(bipy)CQ](PF6)2 (8), [Ru(η(6)-C10H14)(dmebipy)CQ](PF6)2 (9): [1,10-phenanthroline (phen), 4,7-diphenyl-1,10-phenanthroline (dphphen), 2,2'-bipyridine (bipy), 5,5'-dimethyl-2,2'-bipyridine (dmebipy), and 4,4'-di-t-butyl-2,2'-bipyridine (dbutbipy)]. The solid state structures of five ruthenium complexes (1-5) were determined by X-ray crystallography. Electrochemical experiments were performed by cyclic voltammetry to estimate the redox potential of the Ru(II)/Ru(III) couple in each case. Their interactions with DNA and BSA, and activity against four cell lines (L929, A549, MDA-MB-231 and MCF-7) were evaluated. Compounds 2, 6 through 9, interact with DNA which was comparable to the one observed for free chloroquine. The results of fluorescence titration revealed that these complexes strongly quenched the intrinsic fluorescence of BSA following a static quenching procedure. Binding constants (Kb) and the number of binding sites (n~1) were calculated using modified Stern-Volmer equations. The thermodynamic parameters ΔG at different temperatures were calculated and subsequently the values of ΔH and ΔS were also calculated, which revealed that hydrophobic and electrostatic interactions play a major role in the BSA-complex association. The MTT assay results indicated that complexes 2, 5 and 7 showed cytostatic effects at appreciably lower concentrations than those needed for cisplatin, chloroquine and doxorubicin.
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http://dx.doi.org/10.1016/j.jinorgbio.2015.07.016DOI Listing
December 2015

Cis-[RuCl(BzCN)(N-N)(P-P)]PF6 complexes: Synthesis and in vitro antitumor activity: (BzCN=benzonitrile; N-N=2,2'-bipyridine; 1,10-phenanthroline; P-P=1,4-bis(diphenylphosphino) butane, 1,2-bis(diphenylphosphino)ethane, or 1,1'-(diphenylphosphino)ferrocene).

J Inorg Biochem 2015 Aug 31;149:91-101. Epub 2015 Mar 31.

Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás - UFG, Goiânia, GO CEP 74001-970, Brazil. Electronic address:

The motivation to use ruthenium complexes in cancer treatment has led our research group to synthesize complexes with this metal and test them against several types of tumor cells, yielding promising results. In this paper the results of biological tests, assessed by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, were carried out on the complexes cis-[RuCl(BzCN)(bipy)(dppe)]PF6 (1), cis-[RuCl(BzCN)(bipy)(dppb)]PF6 (2), cis-[RuCl(BzCN)(bipy)(dppf)]PF6 (3) and cis-[RuCl(BzCN)(phen)(dppb)]PF6 (4) which are described [BzCN = b enzonitrile; bipy = 2,2'-bipyridine; phen = 1,10-phenanthroline; dppe = 1,2-bis(diphenylphosphino) ethane; dppb = 1,4-bis-(diphenylphosphino)butane; dppf = 1,1'-bis(diphenylphosphino)ferrocene]. The present study is focused on the cytotoxic activity of complexes (1)-(4) against four tumor cell lines and on the apoptosis and changes in the cell cycle and gene expression observed in the sarcoma 180 (S180) tumor cell line treated with complex (1). The results demonstrated that this complex inhibits S180 cell growth, with an IC50 of 17.02 ± 8.21 μM, while exhibiting lower cytotoxicity (IC50 = 53.73 ± 5.71 μM) towards lymphocytes (normal cells). Flow cytometry revealed that the complex inhibits the growth of tumor cells by inducing apoptosis as evidenced by an increase in the proportion of cells positive for annexin V staining and G0/G1 phase cell-cycle arrest. Further investigation showed that complex (1) induces a drop in the mitochondrial membrane potential and provokes a decrease in Bcl-2 protein expression and increase in caspase 3 activation, while the increased activation of caspase 8 caused a decrease in the gene expression in caspases 3 and 9. Increases in Tp53 and Bax expressions were also observed.
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http://dx.doi.org/10.1016/j.jinorgbio.2015.03.011DOI Listing
August 2015

On the cytotoxic activity of Pd(II) complexes of N,N-disubstituted-N'-acyl thioureas.

J Inorg Biochem 2014 May 8;134:76-82. Epub 2014 Feb 8.

Departamento de Química, Universidade Federal de São Carlos, São Carlos, SP, Brazil. Electronic address:

The rational design of anticancer drugs is one of the most promising strategies for increasing their cytotoxicity and for minimizing their toxicity. Manipulation of the structure of ligands or of complexes represents a strategy for which is possible to modify the potential mechanism of their action against the cancer cells. Here we present the cytotoxicity of some new palladium complexes and our intention is to show the importance of non-coordinated atoms of the ligands in the cytotoxicity of the complexes. New complexes of palladium (II), with general formulae [Pd(PPh3)2(L)]PF6 or [PdCl(PPh3)(L)], where L=N,N-disubstituted-N'-acyl thioureas, were synthesized and characterized by elemental analysis, molar conductivity, melting points, IR, NMR((1)H, (13)C and (31)P{(1)H}) spectroscopy. The spectroscopic data are consistent with the complexes containing an O, S chelated ligand. The structures of complexes with N,N-dimethyl-N'-benzoylthiourea, N,N-diphenyl-N'-benzoylthiourea, N,N-diethyl-N'-furoylthiourea, and N,N-diphenyl-N'-furoylthiourea were determined by X-ray crystallography, confirming the coordination of the ligands with the metal through sulfur and oxygen atoms, forming distorted square-planar structures. The N,N-disubstituted-N'-acyl thioureas and their complexes were screened with respect to their antitumor cytotoxicity against DU-145 (human prostate cancer cells), MDA-MB-231 (human breast cancer cells) and their toxicity against the L929 cell line (health cell line from mouse).
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http://dx.doi.org/10.1016/j.jinorgbio.2014.01.022DOI Listing
May 2014

Weak C-H···Cl-Pd interactions toward conformational polymorphism in trans-dichloridobis(triphenylphosphane)palladium(II).

Acta Crystallogr C 2011 Sep 26;67(Pt 9):m304-6. Epub 2011 Aug 26.

Departamento de Química, Universidade Federal de São Carlos-UFSCar, Rodovia Washington Luiz, KM 235 CP 676, CEP 13561-901, São Carlos-SP, Brazil.

A new triclinic polymorph of the title compound, [PdCl(2)(C(18)H(15)P)(2)], has two independent molecules in the unit cell, with the Pd atoms located on inversion centres. One molecule has an eclipsed conformation, whereas the second molecule adopts a gauche conformation. The molecules with a gauche conformation are involved in weak intermolecular C-H···Cl-Pd interactions with symmetry-related molecules. It is suggested that C-H···Cl-Pd interactions are mainly responsible for the existence of conformational differences, which contribute to the polymorph formation. In the crystal, there are layers of eclipsed and gauche molecules separated by normal van der Waals interactions.
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http://dx.doi.org/10.1107/S0108270111033051DOI Listing
September 2011

Ruthenium(II) complexes containing 2-pyridineformamide- and 2-benzoylpyridine-derived thiosemicarbazones and PPh3: NMR and electrochemical studies of cis-trans-isomerization.

Spectrochim Acta A Mol Biomol Spectrosc 2008 Apr 17;69(4):1277-82. Epub 2007 Jul 17.

Departamento de Química, Universidade Federal de São Carlos, 1365-905 São Carlos, Brazil.

[RuCl(L)(PPh(3))(2)] complexes with 2-benzoylpyridine- and 2-pyridineformamide-derived thiosemicarbazones (HL) were obtained and fully characterized. The complexes form cis-trans isomers. The cis isomer is disfavored by the sterical effect of two bulky groups close to each other whereas the trans isomer is disfavored by the electronic effect of competition of two phosphorous for pi-bonding d orbitals of the metal. Our results suggest that, although both factors may be operating simultaneously, in CH(2)Cl(2) solution the balance of these counterpoising effects favors the formation of the trans isomer.
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http://dx.doi.org/10.1016/j.saa.2007.07.005DOI Listing
April 2008

Ruthenium(II) complexes of 2-benzoylpyridine-derived thiosemicarbazones with cytotoxic activity against human tumor cell lines.

Spectrochim Acta A Mol Biomol Spectrosc 2008 Apr 9;69(4):1073-6. Epub 2007 Jun 9.

Departamento de Química, Universidade Federal de São Carlos, 1365-905 São Carlos, Brazil.

Reaction of [RuCl(3)(dppb)H(2)O] (dppb=1,4 bis(diphenylphospine)butane) with 2-benzoylpyridine thiosemicarbazone (H2Bz4DH) and its N(4)-methyl (H2Bz4M) and N(4)-phehyl (H2Bz4Ph) derivatives gave [RuCl(dppb)(H2Bz4DH)]Cl (1), [RuCl(dppb)(H2Bz4M)]Cl (2) and [RuCl(dppb)(H2Bz4Ph)]Cl (3). The cytotoxic activity of the studied compounds was tested against the MCF-7, TK-10 and UACC-62 human tumor cell lines. The precursor [RuCl(3)(dppb)H(2)O] exhibits cytocidal activity against the tree cell lines. H2BzDH, H2Bz4M, and [RuCl(dppb)(H2Bz4M)]Cl (2) show a selective cytocidal effect against the UACC-62 cell line which makes them the most promising compounds.
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http://dx.doi.org/10.1016/j.saa.2007.06.005DOI Listing
April 2008