Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 84
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
ACS Appl Mater Interfaces ; 11(37): 33650-33658, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31448891

RESUMO

Spectral computed tomography (CT) imaging as a novel imaging technique shows promising prospects in the accurate diagnosis of various diseases. However, clinically iodinated contrast agents suffer from poor signal-to-noise ratio, and emerging heavy-metal-based CT contrast agents arouse great biosafety concern. Herein, we show the fabrication of rhenium sulfide (ReS2) nanoparticles, a clinic radiotherapy sensitizer, as a biosafe spectral CT contrast agent for the gastrointestinal tract imaging and tumor theranostics in vivo by teaching old drugs new tricks. The ReS2 nanoparticles were fabricated in a one-pot facile method at room temperature, and exhibited sub-10 nm size, favorable monodispersity, admirable aqueous solubility, and strong X-ray attenuation capability. More importantly, the proposed nanoparticles possess an outstanding spectral CT imaging ability and undoubted biosafety as a clinic therapeutic agent. Besides, the ReS2 nanoparticles possess appealing photothermal performance due to their intense near-infrared absorption. The proposed nano-agent not only guarantees obvious contrast enhancement in gastrointestinal tract spectral CT imaging in vivo, but also allows effective CT imaging-guided tumor photothermal therapy. The proposed "teaching old drugs new tricks" strategy shortens the time and cuts the cost required for clinical application of nano-agents based on existing clinical toxicology testing and trial results, and lays down a low-cost, time-saving, and energy-saving method for the development of multifunctional nano-agents toward clinical applications.


Assuntos
Meios de Contraste , Trato Gastrointestinal/diagnóstico por imagem , Hipertermia Induzida , Nanopartículas , Neoplasias , Fototerapia , Rênio , Sulfetos , Nanomedicina Teranóstica , Tomografia Computadorizada por Raios X , Animais , Linhagem Celular Tumoral , Meios de Contraste/química , Meios de Contraste/farmacocinética , Meios de Contraste/farmacologia , Camundongos , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Rênio/química , Rênio/farmacocinética , Rênio/farmacologia , Sulfetos/química , Sulfetos/farmacocinética , Sulfetos/farmacologia
2.
Inorg Chem ; 58(15): 10129-10138, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31310108

RESUMO

A series of 16 "3 + 2" mixed-ligand complexes of the general composition [ReO(L1)(L2)] (H2L1a-H2L1d = tridentate thiosemicarbazones having a phenyl group with 4-H, 4-F, 3,5-di-F, and 4-CF3 substituents; HL2a-HL2d = bidentate N,N-diethyl-N'-benzoylthioureas with 4-H, 4-F, 3,5-di-F, and 4-CF3 substituents at the benzoyl groups) have been synthesized and characterized by spectroscopic methods and X-ray diffraction. Irrespective of the individual fluorine substitution, the complexes are stable and possess the same general structure. Some systematic electronic effects of the fluorine-substitution patterns of the ligands have been found on the 13C NMR chemical shifts of the N-C═N carbon atoms of the {L1}2- and the C═O carbon atoms of the {L2}- ligands. Antiparasitic properties of the rhenium complexes have been tested against epimastigotes and trypomastigotes forms of two Trypanosoma cruzi strains and the amastigotes form of one of them. The results of this study indicate that the activity of the rhenium complexes can clearly be modulated by fluorine substitution of their ligands. Some of the fluorinated compounds show a high activity against epimastigotes and trypomastigotes forms of the parasites. Reactions between (NBu4)[TcOCl4] and two representatives of the fluorinated ligands (H2L1b, 4-F-substituted, and H2L1c, 4-CF3-substituted) form stable complexes of the composition [TcOCl(L1b)] and [TcOCl(L1c)]. Subsequent reactions of these products with HL2b (4-F-substituted) give the corresponding [TcO(L1)(L2)] mixed-ligand complexes. Also, the technetium compounds are stable as solids and in solutions and have structures corresponding to those of their rhenium analogues.


Assuntos
Complexos de Coordenação/farmacologia , Halogenação , Rênio/farmacologia , Tiossemicarbazonas/farmacologia , Tioureia/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Haplorrinos , Ligantes , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Rênio/química , Tiossemicarbazonas/química , Tioureia/química , Tripanossomicidas/síntese química , Tripanossomicidas/química
3.
Lett Appl Microbiol ; 69(3): 168-174, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30929272

RESUMO

Antimicrobial resistance presents major global concerns to patient health. In this study, metal ions of molybdenum, rhenium, yttrium and thallium were tested against bacteria in planktonic and biofilm form using one strain of Klebsiella pneumoniae and Acinetobacter baumannii. The antimicrobial efficacy of the metal ions was evaluated against the planktonic bacterial strains using minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations, whilst the efficacy of the metal ions against biofilms was tested using a crystal violet biofilm assay. Live Dead staining was used to visualize the antimicrobial activity elicited by the metal ions on the bacterial cell. The results showed that higher concentrations of the metals were required to inhibit the growth of biofilms (72·9 mg l-1 to 416·7 mg l-1 ), in comparison to their planktonic counterparts. MICs of the metal ions (<46·9 mg l-1 ) (planktonic cells) did not affect biofilm formation. Overall, rhenium and yttrium were effective antimicrobial agents. Molybdenum demonstrated the greatest level of biotoxicity. When taking into account these results and the known toxicity of thallium, it is possible that rhenium or yttrium ions could be developed as effective biocidal formulations in order to prevent transmission in healthcare environments. SIGNIFICANCE AND IMPACT OF THE STUDY: The metal ions, molybdenum, rhenium, thallium and yttrium were tested against both Klebsiella pneumoniae and Acinetobacter baumannii in planktonic and biofilm forms. This research demonstrated that all the metal ions may be effective antimicrobial agents. However, molybdenum induced high levels of cytotoxicity, whilst, there was no significant difference in the toxicity of the other metal ions tested. When considering the results for the antimicrobial efficacy and biotoxicity of the metal ions, in conjunction with the known toxicity of thallium in certain chemical compositions, it was concluded that overall rhenium or yttrium ions may be effective antimicrobial agents, one potential application may be utilizing these metal ions in hospital surface cleaning formulations.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacologia , Klebsiella pneumoniae/efeitos dos fármacos , Molibdênio/farmacologia , Rênio/farmacologia , Tálio/farmacologia , Ítrio/farmacologia , Biofilmes/efeitos dos fármacos , Farmacorresistência Bacteriana/fisiologia , Humanos , Testes de Sensibilidade Microbiana , Plâncton/efeitos dos fármacos
4.
J Enzyme Inhib Med Chem ; 34(1): 773-782, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30843736

RESUMO

In this work, two bidentate 2-pyridyl-1,2,3-triazole ligands (3a and 3b) containing a 4-substituted benzenesulfonamide pharmacophore prepared by classical click chemistry procedures, as well as their corresponding rhenium complexes, 4a and 4b of general formula [ReCl(CO)3(L)] (L = 3a or 3b) were prepared and fully characterised by spectroscopic methods (IR, NMR, MS, UV-Vis), elemental analysis, X-ray diffraction, and theoretical studies using DFT and TD-DFT methods. In particular, we showed that, in the solid state, the pyridine and the triazole rings of 3b adopted an uncommon cis configuration which stems from intermolecular hydrogen bonds. Preliminary assays demonstrated a promising nanomolar inhibitory activity against carbonic anhydrase isoform IX for both ligands and complexes with a strong affinity Ki of 2.8 nM for ligand 3a. More interestingly, complex 4b exhibited a pronounced selectivity against hCA IX over the off-targets hCA I and hCA II which makes this compound a promising potential anticancer drug candidate.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Teoria da Densidade Funcional , Antígenos de Neoplasias/metabolismo , Monóxido de Carbono/química , Monóxido de Carbono/farmacologia , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Modelos Moleculares , Estrutura Molecular , Rênio/química , Rênio/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Triazóis/química , Triazóis/farmacologia
5.
Inorg Chem ; 58(6): 3895-3909, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30793900

RESUMO

Combinatorial synthesis can be applied for developing a library of compounds that can be rapidly screened for biological activity. Here, we report the application of microwave-assisted combinatorial chemistry for the synthesis of 80 rhenium(I) tricarbonyl complexes bearing diimine ligands. This library was evaluated for anticancer activity in three different cancer cell lines, enabling the identification of three lead compounds with cancer cell growth-inhibitory activities of less than 10 µM. These three lead structures, Re-9B, Re-9C, and Re-9D, were synthesized independently and fully characterized by NMR spectroscopy, mass spectrometry, elemental analysis, and X-ray crystallography. The most potent of these three complexes, Re-9D, was further explored to understand its mechanism of action. Complex Re-9D is equally effective in both wild-type and cisplatin-resistant A2780 ovarian cancer cells, indicating that it circumvents cisplatin resistance. This compound was also shown to possess promising activity against ovarian cancer tumor spheroids. Additionally, flow cytometry showed that Re-9D does not induce cell cycle arrest or flipping of phosphatidylserine to the outer cell membrane. Analysis of the morphological changes of cancer cells treated with Re-9D revealed that this compound gives rise to rapid plasma membrane rupture. Collectively, these data suggest that Re-9D induces necrosis in cancer cells. To assess the in vivo biodistribution and stability of this compound, a radioactive 99mTc analogue of Re-9D, 99mTc-9D(H2O), was synthesized and administered to naïve BALB/c mice. Results of these studies indicate that 99mTc-9D(H2O) exhibits high metabolic stability and a distinct biodistribution profile. This research demonstrates that combinatorial synthesis is an effective approach for the development of new rhenium anticancer agents with advantageous biological properties.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Necrose/induzido quimicamente , Rênio/química , Rênio/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Química Combinatória/métodos , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacocinética , Cristalografia por Raios X , Resistencia a Medicamentos Antineoplásicos , Feminino , Células HeLa , Humanos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Rênio/farmacocinética , Distribuição Tecidual
6.
Future Med Chem ; 11(2): 119-135, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30644327

RESUMO

Despite improvements in the 5-year survival rate to over 80% in cancers, such as Hodgkin lymphoma and testicular cancer, more aggressive tumors including pancreatic and brain cancer still have extremely low survival rates. The establishment of chemoresistance, responsible for the reduction in treatment efficiency and cancer relapse, is one possible explanation for this setback. Metal-based compounds, a class of anticancer drugs, are largely used in the treatment of cancer. Herein, we will review the use of metal-based small molecules in chemotherapy, focusing on recent studies, and we will discuss how new nonplatinum-based agents are prompting scientists to increase drug specificity to overcome chemoresistance in cancer cells.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Metais/química , Metais/farmacologia , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Animais , Antineoplásicos/uso terapêutico , Carboplatina/química , Carboplatina/farmacologia , Carboplatina/uso terapêutico , Cisplatino/química , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Cobre/química , Cobre/farmacologia , Cobre/uso terapêutico , Descoberta de Drogas , Ouro/química , Ouro/farmacologia , Ouro/uso terapêutico , Humanos , Irídio/química , Irídio/farmacologia , Irídio/uso terapêutico , Ferro/química , Ferro/farmacologia , Ferro/uso terapêutico , Metais/uso terapêutico , Neoplasias/tratamento farmacológico , Compostos Organometálicos/uso terapêutico , Rênio/química , Rênio/farmacologia , Rênio/uso terapêutico , Ródio/química , Ródio/farmacologia , Ródio/uso terapêutico , Rutênio/química , Rutênio/farmacologia , Rutênio/uso terapêutico
7.
Bioorg Med Chem ; 27(3): 492-501, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30594453

RESUMO

The somatostatin receptor subtype 2 (SSTR2) is often highly expressed on neuroendocrine tumors (NETs), making it a popular in vivo target for diagnostic and therapeutic approaches aimed toward management of NETs. In this work, an antagonist peptide (sst2-ANT) with high affinity for SSTR2 was modified at the N-terminus with a novel [N,S,O] bifunctional chelator (2) designed for tridentate chelation of rhenium(I) and technetium(I) tricarbonyl cores, [Re(CO)3]+ and [99mTc][Tc(CO)3]+. The chelator-peptide conjugation was performed via a Cu(I)-assisted click reaction of the alkyne-bearing chelator (2) with an azide-functionalized sst2-ANT peptide (3), to yield NSO-sst2-ANT (4). Two synthetic methods were used to prepare Re-4 at the macroscopic scale, which differed based on the relative timing of the click conjugation to the [Re(CO)3]+ complexation by 2. The resulting products demonstrated the expected molecular mass and nanomolar in vitro SSTR2 affinity (IC50 values under 30 nM, AR42J cells, [125I]iodo-Tyr11-somatostatin-14 radioligand standard). However, a difference in their HPLC retention times suggested a difference in metal coordination modes, which was attributed to a competing N-triazole donor ligand formed during click conjugation. Surprisingly, the radiotracer scale reaction of [99mTc][Tc(OH2)3(CO)3]+ (99mTc; t½â€¯= 6 h, 141 keV γ) with 4 formed a third product, distinct from the Re analogues, making this one of the unusual cases in which Re and Tc chemistries are not well matched. Nevertheless, the [99mTc]Tc-4 product demonstrated excellent in vitro stability to challenges by cysteine and histidine (≥98% intact through 24 h), along with 75% stability in mouse serum through 4 h. In vivo biodistribution and microSPECT/CT imaging studies performed in AR42J tumor-bearing mice revealed improved clearance of this radiotracer in comparison to a similar [99mTc][Tc(CO)3]-labeled sst2-ANT derivative previously studied. Yet despite having adequate tumor uptake at 1 h (4.9% ID/g), tumor uptake was not blocked by co-administration of a receptor-saturating dose of SS-14. Aimed toward realignment of the Re and Tc product structures, future efforts should include distancing the alkyne group from the intended donor atoms of the chelator, to reduce the coordination options available to the [M(CO)3]+ core (M = Re, 99mTc) by disfavoring involvement of the N-triazole.


Assuntos
Quelantes/farmacologia , Compostos Organometálicos/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Rênio/farmacologia , Tecnécio/farmacologia , Animais , Linhagem Celular Tumoral , Quelantes/síntese química , Quelantes/química , Relação Dose-Resposta a Droga , Feminino , Camundongos , Camundongos Endogâmicos ICR , Camundongos SCID , Estrutura Molecular , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/metabolismo , Imagem Óptica , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Ratos , Receptores de Somatostatina/metabolismo , Rênio/química , Relação Estrutura-Atividade , Tecnécio/química , Distribuição Tecidual
8.
Environ Toxicol Pharmacol ; 63: 127-134, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30223109

RESUMO

188Re-magnetoferritin nanoparticles (NPs) provide an attractive platform for localized radiation therapy due to their magnetic targeting capability while enhancing contrast in magnetic resonans imaging (MRI) signals. In this study, cellular uptake, in vitro cytotoxicity, apoptotic potential of a non-radioactive isotope of rhenium in the form of 187Re-magnetoferritin NPs were evaluated in both human normal mammary epithelial and breast metastatic adenocarcinoma cell lines. The results showed that, NP administration into the cells is through receptor mediated endocytosis and cancer cells displayed significantly higher uptake and cytotoxicity compared to normal cells. IC50 values of nanoparticles were calculated as 0.96 mg/mL for cancer and 1.73 mg/mL for normal cells. Annexin V/ Propidium Iodide (PI) staining also showed that, NPs induced higher apoptotic rates in cancer cells compared to normal cells. Gene expression analyses confirming the results showed that, pro-apoptotic PUMA and BAX genes were significantly up-regulated while anti-apoptotic BCL-2 and SURVIVIN genes were down-regulated in cancer cells compared to normal cells. Overall, these in vitro results suggest that, 187Re-magnetoferritin NPs have a promising potential for cancer therapy and can be used for imaging and diagnostic purposes for breast cancer at concentrations lower than 0.96 mg/mL. At concentrations above 1 mg/mL, NPs induce apoptosis which can also be used for cancer treatments.


Assuntos
Apoferritinas/química , Proteínas Reguladoras de Apoptose/genética , Neoplasias da Mama/genética , Ferro/química , Óxidos/química , Radioisótopos/farmacologia , Rênio/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Endocitose , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Nanopartículas de Magnetita/química , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Radioisótopos/química , Rênio/química , Survivina/genética , Proteína X Associada a bcl-2/genética
9.
Eur J Med Chem ; 157: 773-781, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30142613

RESUMO

A series of mono- and multinuclear [2 + 1] Re(I) tricarbonyl complexes were synthesised and evaluated as antiproliferative agents against the epithelial carcinoma (A431), colon carcinoma (DLD-1) and ovarian cancer (A2780) tumour cell lines and a healthy fibroblast (BJ) cell line. The compounds have moderate to good activity against the tumour cell lines, with the trinuclear and tetranuclear complexes showing selective cytotoxicity towards the tumour cell lines. The Re(I) complexes were found to influence programmed cell death mechanisms in vitro. They were able to inhibit the soluble form of the Fas receptor in malignant cells, allowing the Fas domain to receive the apoptotic signal through an extrinsic pathway. The complexes augmented the pro-apoptotic Bax-α concentrations, with the tetranuclear complex more superior at modulating the Bax-α molecular target in all tested cell lines, which influenced its cell growth inhibitory activity. The tetranuclear complex has the best activity against all tumour cell lines.


Assuntos
Antineoplásicos/farmacologia , Compostos Organometálicos/farmacologia , Rênio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Rênio/química , Relação Estrutura-Atividade
10.
Biometals ; 31(4): 517-525, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29574625

RESUMO

Tumorigenic cell lines are more susceptible to [Re6Se8I6]3- cluster-induced death than normal cells, becoming a novel candidate for cancer treatment. Still, the feasibility of using this type of molecules in human patients remains unclear and further pharmacokinetics analysis is needed. Using coupled plasma optical emission spectroscopy, we determined the Re-cluster tissue content in injected mice, as a biodistribution measurement. Our results show that the Re-cluster successfully reaches different tissues, accumulating mainly in heart and liver. In order to dissect the mechanism underlying cluster biodistribution, we used three different experimental approaches. First, we evaluate the degree of lipophilicity by determining the octanol/water partition coefficient. The cluster mostly remained in the octanol fraction, with a coefficient of 1.86 ± 0.02, which indicates it could potentially cross cell membranes. Then, we measured the biological membrane penetration through a parallel artificial membrane permeability assays (PAMPA) assay. The Re-cluster crosses the artificial membrane, with a coefficient of 122 nm/s that is considered highly permeable. To evaluate a potential application of the Re-cluster in central nervous system (CNS) tumors, we analyzed the cluster's brain penetration by exposing cultured blood-brain-barrier (BBB) cells to increasing concentrations of the cluster. The Re-cluster effectively penetrates the BBB, reaching nearly 30% of the brain side after 24 h. Thus, our results indicate that the Re-cluster penetrates biological membranes reaching different target organs-most probably due to its lipophilic properties-becoming a promising anti-cancer drug with high potential for CNS cancer's diagnosis and treatment.


Assuntos
Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Complexos de Coordenação/farmacologia , Rênio/farmacologia , Transporte Biológico/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Humanos , Selênio/farmacologia , Distribuição Tecidual/efeitos dos fármacos
11.
Inorg Chem ; 57(3): 1311-1331, 2018 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-29323880

RESUMO

Fifteen water-soluble rhenium compounds of the general formula [Re(CO)3(NN)(PR3)]+, where NN is a diimine ligand and PR3 is 1,3,5-triaza-7-phosphaadamantane (PTA), tris(hydroxymethyl)phosphine (THP), or 1,4-diacetyl-1,3,7-triaza-5-phosphabicylco[3.3.1]nonane (DAPTA), were synthesized and characterized by multinuclear NMR spectroscopy, IR spectroscopy, and X-ray crystallography. The complexes bearing the THP and DAPTA ligands exhibit triplet-based luminescence in air-equilibrated aqueous solutions with quantum yields ranging from 3.4 to 11.5%. Furthermore, the THP and DAPTA complexes undergo photosubstitution of a CO ligand upon irradiation with 365 nm light with quantum yields ranging from 1.1 to 5.5% and sensitize the formation of 1O2 with quantum yields as high as 70%. In contrast, all of the complexes bearing the PTA ligand are nonemissive and do not undergo photosubstitution upon irradiation with 365 nm light. These compounds were evaluated as photoactivated anticancer agents in human cervical (HeLa), ovarian (A2780), and cisplatin-resistant ovarian (A2780CP70) cancer cell lines. All of the complexes bearing THP and DAPTA exhibited a cytotoxic response upon irradiation with minimal toxicity in the absence of light. Notably, the complex with DAPTA and 1,10-phenanthroline gave rise to an IC50 value of 6 µM in HeLa cells upon irradiation, rendering it the most phototoxic compound in this library. The nature of the photoinduced cytotoxicity of this compound was explored in further detail. These data indicate that the phototoxic response may result from the release of both CO and the rhenium-containing photoproduct, as well as the production of 1O2.


Assuntos
Antineoplásicos/farmacologia , Ácidos Carboxílicos/farmacologia , Complexos de Coordenação/farmacologia , Fosfinas/farmacologia , Rênio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Ácidos Carboxílicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Fosfinas/química , Processos Fotoquímicos , Rênio/química , Solubilidade , Relação Estrutura-Atividade , Água/química
12.
Mol Cell Biochem ; 441(1-2): 151-163, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28913709

RESUMO

Cisplatin and other metal-based drugs often display side effects and tumor resistance after prolonged use. Because rhenium-based anticancer complexes are often less toxic, a novel series of organorhenium complexes were synthesized of the types: XRe(CO)3Z (X = α-diimines and Z = p-toluenesulfonate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, picolinate, nicotinate, aspirinate, naproxenate, flufenamate, ibuprofenate, mefenamate, tolfenamate, N-acetyl-tryptophanate), and their biological properties were examined. Specifically, in hormone-dependent MCF-7 and hormone-independent triple-negative MDA-MB-231 breast cancer cells, the p-toluenesulfonato, 1-naphthalenesulfonato, 2-naphthalenesulfonato, picolinato, nicotinato, acetylsalicylato, flufenamato, ibuprofenato, mefenamato, and N-acetyl-tryptophanato complexes were found to be far more potent than conventional drug cisplatin. DNA-binding studies were performed in each case via UV-Vis titrations, cyclic voltammetry, gel electrophoresis, and viscosity, which suggest DNA partial intercalation interaction, and the structure-activity relationship studies suggest that the anticancer activities increase with the increasing lipophilicities of the compounds, roughly consistent with their DNA-binding activities.


Assuntos
Antineoplásicos , Complexos de Coordenação , Compostos Organometálicos , Rênio , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Feminino , Humanos , Células MCF-7 , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Rênio/química , Rênio/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
13.
Inorg Chem ; 56(24): 15159-15170, 2017 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-29172469

RESUMO

Hetero-bimetallic and -trimetallic complexes were synthesized by the combination of different metallic fragments, a luminescent Re(I) species, and a bioactive Au(I) derivative. A ditopic P,N-donor ligand (L) was used as linker between both metals, affording six new bipyridine (bipy) Re(I)/Au(I) hetero-metallic complexes of the type fac-[Re(bipy)(CO)3(LAuCl)]+ (4-6) and [(fac-[Re(bipy)(CO)3(L)])2Au]3+ (7-9) after a thorough synthetic procedure. Their emission is associated with a triplet metal-to-ligand charge transfer (Re(dπ) → bipy(π*)) transition and red-shifted in polar solvents with lifetimes in the range of nanoseconds and quantum yield values up to 12.5%. Cytotoxicity values in A549 cells of hetero-trimetallic species are almost twice that for the hetero-bimetallic (ca. 37 vs 69 µM, respectively), being the L-Au fragment the source of the antiproliferative activity. Species 7 and 8 showed similar behavior by fluorescence microscopy, with a nonuniform cytoplasmatic distribution, a clear accumulation in single spots at the edge of the inner cell membrane as well as in areas within the nucleus. Preliminary studies suggest the DNA as one of the targets and passive diffusion as the entrance pathway.


Assuntos
2,2'-Dipiridil/química , Antineoplásicos/química , Complexos de Coordenação/química , Ouro/química , Substâncias Luminescentes/química , Rênio/química , 2,2'-Dipiridil/farmacocinética , 2,2'-Dipiridil/farmacologia , Células A549 , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/farmacocinética , Complexos de Coordenação/farmacologia , Ouro/farmacocinética , Ouro/farmacologia , Humanos , Ligantes , Luminescência , Substâncias Luminescentes/farmacocinética , Substâncias Luminescentes/farmacologia , Neoplasias/tratamento farmacológico , Imagem Óptica , Rênio/farmacocinética , Rênio/farmacologia
14.
J Am Chem Soc ; 139(40): 14302-14314, 2017 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-28948792

RESUMO

Seven rhenium(I) complexes of the general formula fac-[Re(CO)3(NN)(OH2)]+ where NN = 2,2'-bipyridine (8), 4,4'-dimethyl-2,2'-bipyridine (9), 4,4'-dimethoxy-2,2'-bipyridine (10), dimethyl 2,2'-bipyridine-4,4'-dicarboxylate (11), 1,10-phenanthroline (12), 2,9-dimethyl-1,10-phenanthroline (13), or 4,7-diphenyl-1,10-phenanthroline (14), were synthesized and characterized by 1H NMR spectroscopy, IR spectroscopy, mass spectrometry, and X-ray crystallography. With the exception of 11, all complexes exhibited 50% growth inhibitory concentration (IC50) values that were less than 20 µM in HeLa cells, indicating that these compounds represent a new potential class of anticancer agents. Complexes 9, 10, and 13 were as effective in cisplatin-resistant cells as wild-type cells, signifying that they circumvent cisplatin resistance. The mechanism of action of the most potent complex, 13, was explored further by leveraging its intrinsic luminescence properties to determine its intracellular localization. These studies indicated that 13 induces cytoplasmic vacuolization that is lysosomal in nature. Additional in vitro assays indicated that 13 induces cell death without causing an increase in intracellular reactive oxygen species or depolarization of the mitochondrial membrane potential. Further studies revealed that the mode of cell death does not fall into one of the canonical categories such as apoptosis, necrosis, paraptosis, and autophagy, suggesting that a novel mode of action may be operative for this class of rhenium compounds. The in vivo biodistribution and metabolism of complex 13 and its 99mTc analogue 13* were also evaluated in naïve mice. Complexes 13 and 13* exhibited comparable biodistribution profiles with both hepatic and renal excretion. High-performance liquid chromatography inductively coupled plasma mass-spectrometry (HPLC-ICP-MS) analysis of mouse blood plasma and urine postadministration showed considerable metabolic stability of 13, rendering this potent complex suitable for in vivo applications. These studies have shown the biological properties of this class of compounds and demonstrated their potential as promising theranostic anticancer agents that can circumvent cisplatin resistance.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Neoplasias/tratamento farmacológico , Rênio/química , Rênio/farmacologia , Animais , Antineoplásicos/farmacocinética , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/farmacocinética , Cristalografia por Raios X , Células HeLa , Humanos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Neoplasias/metabolismo , Neoplasias/patologia , Espécies Reativas de Oxigênio/metabolismo , Rênio/farmacocinética , Distribuição Tecidual
15.
J Inorg Biochem ; 170: 125-133, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28237731

RESUMO

American Trypanosomiasis is a chronic infection discovered and described in 1909 by the Brazilian scientist Carlos Chagas. It is caused by the protozoan parasite Trypanosoma cruzi. Although it affects about 10million people in Latin America, the current chemotherapy is still inadequate. The discovery of new drugs is urgently needed. Our group is focused on the development of prospective metal-based drugs mainly based on bioactive ligands and pharmacologically interesting metal ions. In this work three new rhenium(I) tricarbonyl compounds fac-[ReI(CO)3Br(HL)] where HL=5-nitrofuryl containing thiosemicarbazones were synthesized and fully characterized in solution and in the solid state. The in vitro evaluation of the compounds on T. cruzi trypomastigotes (Dm28c strain) showed that the Re(I) compounds are 8 to 15 times more active than the reference drug Nifurtimox and show a 4 to 17 fold increase in activity in respect to the free (HL) ligands. Obtained compounds also show good selectivity indexes (IC50 endothelial cells Ea.hy926/IC50 T. cruzi (Dm28c tripomastigotes)). 1H NMR and MS studies, performed with time, showed that the fac-[Re(CO)3Br(HL)] species convert into the dimers [Re2(CO)6(L)2] in solution. Crystal structure of [ReI2(CO)6(L2)2], the product of complexes' dimerization, was solved. Related to the mechanism of action, the studied compounds do not generate radical oxygen species in the parasite (as 5-nitrofuryl derived thiosemicarbazones do) probably due to the unfavorable nitro reduction potential of the generated dimeric species. On the contrary, the compounds produce a decrease of the oxygen consumption rate of the parasites, maybe inhibiting their mitochondrial respiration.


Assuntos
Complexos de Coordenação , Rênio , Tiossemicarbazonas , Tripanossomicidas , Trypanosoma cruzi/crescimento & desenvolvimento , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Rênio/química , Rênio/farmacologia , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/química , Tripanossomicidas/farmacologia
16.
Molecules ; 21(10)2016 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-27706035

RESUMO

The malignant behaviors of solid tumors such as growth, infiltration and metastasis are mainly nourished by tumor neovascularization. Thus, anti-angiogenic therapy is key to controlling tumor progression. Bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) antibody, plus chemotherapy or biological therapy can prolong survival for cancer patients, but treatment-related mortality is a concern. To improve inhibitory effect and decrease side-effects on non-small-cell lung cancer (NSCLC), we used Re-188, which is a ß emitting radionuclide, directly labeled with bevacizumab for radioimmunotherapy in a human A549 tumor model. Cytotoxic assay data showed that, after 188ReO4- or 188Re-bevacizumab at different concentration for 4 and 24 h, a time- and radioactivity does-dependent reduction in cell viability occurred. Also, an apoptosis assay conformed great apoptosis in the 188Re-bevacizumab group compared with controls and other treatment groups. In vivo, tumor volumes in the 188Re-bevacizumab (11.1 MBq/mice) group were not reduced but growth was delayed compared with other groups. Thus, 188Re-bevacizumab enhanced the therapeutic effect of bevacizumab, suggesting a potential therapeutic strategy for NSCLC treatment.


Assuntos
Bevacizumab/farmacologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Radioisótopos/farmacologia , Rênio/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia
17.
Oncotarget ; 7(40): 65782-65796, 2016 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-27588466

RESUMO

Human head and neck squamous cell carcinoma (HNSCC) is usually treated by surgical resection with adjuvant radio-chemotherapy. In this study, we examined whether the radiopharmaceutical 188Re-liposome could suppress the growth of HNSCC followed by an investigation of molecular mechanisms. The orthotopic HNSCC tumor model was established by human hypopharyngeal FaDu carcinoma cells harboring multiple reporter genes. The drug targeting and therapeutic efficacy of 188Re-liposome were examined using in vivo imaging, bio-distribution, pharmacokinetics, and dosimetry. The results showed that 188Re-liposome significantly accumulated in the tumor lesion compared to free 188Re. The circulation time and tumor targeting of 188Re-liposome were also longer than that of free 188Re in tumor-bearing mice. The tumor growth was suppressed by 188Re-liposome up to three weeks using a single dose treatment. Subsequently, microarray analysis followed by Ingenuity Pathway Analysis (IPA) showed that tumor suppressor let-7 microRNA could be an upstream regulator induced by 188Re-liposome to regulate downstream genes. Additionally, inhibition of let-7i could reduce the effects of 188Re-liposome on suppression of tumor growth, suggesting that let-7 family was involved in 188Re-liposome mediated suppression of tumor growth in vivo. Our data suggest that 188Re-liposome could be a novel strategy for targeting HNSCC partially via induction of let-7 microRNA.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Lipossomos , MicroRNAs/genética , Nanopartículas/química , Radioisótopos/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Rênio/farmacologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/administração & dosagem , Radioisótopos/química , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Rênio/química , Rênio/farmacocinética , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Biometals ; 29(4): 743-9, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27460450

RESUMO

Trypanosoma cruzi (T. cruzi) is the parasite that causes Chagas disease. Nifurtimox is the most used drug against the T. cruzi, this drug increases intermediaries nitro group, being mainly responsible for the high toxicity component, for this reason it is important to study new organic compounds and thus improve therapeutic strategies against Chagas disease. The electronic effects of ferrocenyl and cyrhetrenyl fragments were investigated by DFT calculation. A close correlation was found between HOMO-LUMO gap of nitro radical NO 2 (-) with the experimental reduction potential found for nitro group and IC50 of two forms the T. cruzi (epimastigote and trypomastigote). The IC50 on human hepatoma cells is higher for both compounds compared to IC50 demonstrated in the two forms the T. cruzi, and additionally show reactive oxygen species release. The information obtained in this paper could generate two new drugs with anti-T. cruzi activity, but additional studies are needed.


Assuntos
Compostos Ferrosos/farmacologia , Compostos Organometálicos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Rênio/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Compostos Ferrosos/química , Células Hep G2 , Humanos , Compostos Organometálicos/química , Testes de Sensibilidade Parasitária , Rênio/química , Tripanossomicidas/química , Trypanosoma cruzi/metabolismo
19.
Chemistry ; 22(23): 7800-9, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27106876

RESUMO

Elucidation of relationship among chemical structure, cellular uptake, localization, and biological activity of anticancer metal complexes is important for the understanding of their mechanisms of action. Organometallic rhenium(I) tricarbonyl compounds have emerged as potential multifunctional anticancer drug candidates that can integrate therapeutic and imaging capabilities in a single molecule. Herein, two mononuclear phosphorescent rhenium(I) complexes (Re1 and Re2), along with their corresponding dinuclear complexes (Re3 and Re4), were designed and synthesized as potent anticancer agents. The subcellular accumulation of Re1-Re4 was conveniently analyzed by confocal microscopy in situ in live cells by utilizing their intrinsic phosphorescence. We found that increased lipophilicity of the bidentate ligands could enhance their cellular uptake, leading to improved anticancer efficacy. The dinuclear complexes were more potent than the mononuclear counterparts. The molecular anticancer mechanisms of action evoked by Re3 and Re4 were explored in detail. Re3 with a lower lipophilicity localizes to lysosomes and induces caspase-independent apoptosis, whereas Re4 with higher lipophilicity specially accumulates in mitochondria and induces caspase-independent paraptosis in cancer cells. Our study demonstrates that subcellular localization is crucial for the anticancer mechanisms of these phosphorescent rhenium(I) complexes.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Rênio/química , Rênio/farmacologia , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Caspases/genética , Caspases/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Compostos Organometálicos/farmacocinética , Espécies Reativas de Oxigênio/metabolismo , Rênio/farmacocinética , Transcriptoma/efeitos dos fármacos
20.
Angew Chem Int Ed Engl ; 55(8): 2792-5, 2016 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-26799241

RESUMO

Doxorubicin, a well-established chemotherapeutic agent, is known to accumulate in the cell nucleus. By using ICP-MS, we show that the conjugation of two small organometallic rhenium complexes to this structural motif results in a significant redirection of the conjugates from the nucleus to the mitochondria. Despite this relocation, the two bioconjugates display excellent toxicity toward HeLa cells. In addition, we carried out a preliminarily investigation of aspects of cytotoxicity and present evidence that the conjugates disrupt the mitochondrial membrane potential, are strong inhibitors of human Topoisomerase II, and induce apoptosis. Such derivatives may enhance the therapeutic index of the aggressive parent drug and overcome drug resistance by influencing nuclear and mitochondrial homeostasis.


Assuntos
Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/farmacocinética , Mitocôndrias/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Rênio/farmacologia , Células HeLa , Humanos , Microscopia de Fluorescência , Rênio/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA