RESUMO
We describe the synthesis, physicochemical characterization, and in vitro antitumor assays of four novel analogous ruthenium(II) complexes with general formula cis-[RuII(N-L)(P-P)2]PF6, where P-P = bis(diphenylphosphine)methane (dppm, in complexes 1 and 2) or bis(diphenylphosphine)ethane (dppe, in complexes 3 and 4) and N-L = 5,6-diphenyl-4,5-dihydro-2H-[1,2,4]triazine-3-thione (Btsc, in complexes 1 and 3) or 5,6-diphenyltriazine-3-one (Bsc, in complexes 2 and 4). The data were consistent with cis arrangement of the biphosphine ligands. For the Btsc and Bsc ligands, the data pointed to monoanionic bidentate coordination to ruthenium(II) through N,S and N,O, respectively. Single-crystal X-ray diffraction showed that complex 1 crystallized in the monoclinic system, space group P21/c. Determination of the cytotoxicity profiles of complexes 1-4 gave SI values ranging from 1.19 to 3.50 against the human lung adenocarcinoma cell line A549 and the non-tumor lung cell line MRC-5. Although the molecular docking studies suggested that the interaction between DNA and complex 4 was energetically favorable, the experimental results showed that they interacted weakly. Overall, our results demonstrated that these novel ruthenium(II) complexes have interesting in vitro antitumor potential and this study may contribute to further studies in medicinal inorganic chemistry.
Assuntos
Antineoplásicos , Complexos de Coordenação , Neoplasias Pulmonares , Rutênio , Semicarbazonas , Humanos , Complexos de Coordenação/química , Rutênio/farmacologia , Rutênio/química , Linhagem Celular Tumoral , Ligantes , Simulação de Acoplamento Molecular , Semicarbazonas/farmacologia , Antineoplásicos/química , Apoptose , Neoplasias Pulmonares/tratamento farmacológico , Movimento Celular , PulmãoRESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Ácido Gálico/farmacologia , Piridinas/farmacologia , Rutênio/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Citoesqueleto de Actina/efeitos dos fármacos , Animais , Apoproteínas/metabolismo , Compostos de Bifenilo/química , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Ácido Gálico/química , Humanos , Camundongos , Picratos/química , Piridinas/química , Rutênio/química , Soroalbumina Bovina/metabolismo , Transferrina/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Rutênio/farmacologia , Antineoplásicos/química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Cristalografia por Raios X , DNA/química , DNA/metabolismo , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Rutênio/química , Rutênio/toxicidade , Neoplasias de Mama Triplo Negativas , Ensaio Tumoral de Célula-TroncoRESUMO
The complexes cis-[Ru(quin)(dppm)2]PF6 and cis-[Ru(kynu)(dppm)2]PF6 (quin = quinaldate; kynu = kynurenate; dppm = bis(diphenylphosphino)methane) were prepared and characterized by elemental analysis, electronic, FTIR, 1H, and 31P{1H} NMR spectroscopies. Characterization data were consistent with a cis 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 IC50 ranging from 10.1 to 36 µM and were more cytotoxic than the precursor cis-[RuCl2(dppm)2]. The cis-[Ru(quin)(dppm)2]PF6 were two to three times more active than the reference metallodrug cisplatin in the MCF-7 and MO59J cell lines.
RESUMO
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.
Assuntos
Antineoplásicos/síntese química , Complexos de Coordenação/síntese química , Rutênio/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Humanos , CamundongosRESUMO
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.
Assuntos
Compostos Organometálicos/química , Paládio/química , Cristalografia por Raios X , Ligação de Hidrogênio , Conformação Molecular , Estrutura MolecularRESUMO
[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.
Assuntos
Eletroquímica/métodos , Formamidas/química , Compostos Organometálicos/química , Fosfinas/química , Piridinas/química , Rutênio/química , Tiossemicarbazonas/química , Isomerismo , Espectroscopia de Ressonância Magnética , Espectrofotometria InfravermelhoRESUMO
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.