RESUMO
Rhenium complexes show great promise as anticancer drug candidates. Specifically, compounds with a Re(CO)3(NN)(py)+ core in their architecture have shown cytotoxicity equal to or greater than that of well-established anticancer drugs based on platinum or organic molecules. This study aimed to evaluate how the strength of the interaction between rhenium(I) tricarbonyl complexes fac-[Re(CO)3(NN)(py)]+, NN = 1,10-phenanthroline (phen), dipyrido[3,2-f:2',3'-h]quinoxaline (dpq) or dipyrido[3,2-a:2'3'-c]phenazine (dppz) and biomolecules (protein, lipid and DNA) impacted the corresponding cytotoxic effect in cells. Results showed that fac-[Re(CO)3(dppz)(py)]+ has higher Log Po/w and binding constant (Kb) with biomolecules (protein, lipid and DNA) compared to complexes of fac-[Re(CO)3(phen)(py)]+ and fac-[Re(CO)3(dpq)(py)]+. As consequence, fac-[Re(CO)3(dppz)(py)]+ exhibited the highest cytotoxicity (IC50 = 8.5 µM for HeLa cells) for fac-[Re(CO)3(dppz)(py)]+ among the studied compounds (IC50 > 15 µM). This highest cytotoxicity of fac-[Re(CO)3(dppz)(py)]+ are probably related to its lipophilicity, higher permeation of the lipid bilayers of cells, and a more potent interaction of the dppz ligand with biomolecules (protein and DNA). Our findings open novel avenues for rational drug design and highlight the importance of considering the chemical structures of rhenium complexes that strongly interact with biomolecules (proteins, lipids, and DNA).
Assuntos
Antineoplásicos , Complexos de Coordenação , DNA , Rênio , Rênio/química , Humanos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , DNA/química , DNA/metabolismo , Fenantrolinas/química , Fenantrolinas/farmacologia , Quinoxalinas/química , Quinoxalinas/farmacologia , Fenazinas/química , Fenazinas/farmacologia , Linhagem Celular Tumoral , Células HeLaRESUMO
We report on interactions of different types of DNA molecules including double-stranded and plasmid DNA as well as polynucleotides (poly[dGdC]2 and poly[dAdT]2) with fac-[ReI(CO)3(pterin)(H2O)] (or Reptr) complex. The interaction was characterized spectroscopically and changes in the plasmid structure were verified by both electrophoresis and AFM microscopy. For comparative reasons, two others related tricarbonyl rhenium(I) complexes, fac-[(4,4'-bpy)ReI(CO)3(dppz)]+ (or Redppz) and fac-[(CF3SO3)ReI(CO)3(2,2'-bpy)] (or Rebpy) were also studied to further explore the influence of the different co-ligands on the interaction and DNA (photo)damage. Data reported herein suggests that DNA molecules can be structurally modified either by direct interaction with Re(I) complexes in their ground states inducing DNA relaxation, and/or through photoinduced cross-linking processes. The chemical nature of the co-ligands modulates the extent of the damage observed.
Assuntos
Pterinas , Rênio , Rênio/química , DNA/química , Plasmídeos , LigantesRESUMO
Reactivity of new tetrahedral rhenium cluster complexes with pnictogenide inner ligands µ3-As3-, µ3-Sb3-, and µ3-Bi3- has been investigated in reactions with aqueous H2O2. It has been found that the oxidation of clusters [{Re4As3Q}(CN)12]7- (Q = S or Se) led to the formation of stable clusters with µ3-(AsO)3- ligands. Under the same conditions, the oxidation of [{Re4As2S2}(CN)12]6- cluster led to substitution of µ3-As3- ligands to µ3-O2-. The resulting cluster [{Re4O2S2}(CN)12]4- easily undergoes further oxidation, and even at room temperature, a unique {Re4} to {Re3} rearrangement occurs with the formation of the new triangular cluster [{Re3(µ3-S)(µ-O)2(µ-SO2)}(CN)9]5-. Upon heating, this process proceeds faster and the triangular cluster can be isolated as individual compounds. Cluster anions [{Re4SbSe3}(CN)12]5- and [{Re4BiS3}(CN)12]5- reacted with H2O2, yielding clusters containing µ3-O2- ligands, namely, [{Re4OSe3}(CN)12]4- and [{Re4OS3}(CN)12]4-. This indicates that oxidized forms of µ3-Sb3- and µ3-Bi3- ligands can be easily substituted.
Assuntos
Rênio , Ligantes , Estrutura Molecular , Modelos Moleculares , Peróxido de HidrogênioRESUMO
Five newly synthetized fac-Re(I) tricarbonyl compounds were explored as prospective antitrypanosomal agents. The biological activity of the whole series was evaluated preliminarily against the epimastigote form of Trypanosoma cruzi. All compounds showed activity against epimastigotes with IC50 values in the low micromolar range. The most active compound [fac-Re(I)(CO)3(tmp)(CTZ)](PF6), with CTZ = clotrimazole and tmp = 3,4,7,8-tetramethyl-1,10-phenantroline, showed good selectivity towards the parasites and thus was selected to carry out further metallomic studies. For this task, a newly bioanalytical method based on microwave plasma atomic emission spectrometry (MP-AES) was developed and validated. The accuracy of the method was ensured by testing a certified reference material. Results of rhenium elemental analysis by MP-AES agreed with the proposed formula of the studied compounds, contributing to the overall validation of the method, which was then applied to evaluate the percentage of rhenium uptaken by the parasites and the association of the compounds with parasite biomacromolecules. Metallomics results showed low total rhenium percentage uptaken by parasites (â¼1.2%) and preferential accumulation in the soluble proteins fraction (â¼82.8%). Thus, the method based on MP-AES turned out to be an economical and green alternative for metallomics studies involving potential rhenium metallodrugs. Moreover, a comparison against rhenium determination by electrothermal atomic absorption spectrometry (ET-AAS) was included.
Assuntos
Rênio , Micro-Ondas , Plasma , Estudos Prospectivos , Rênio/química , Espectrofotometria Atômica/métodosRESUMO
In the present study, the photophysical properties and preliminary time-dependent density functional theory (TD-DFT) data of new rhenium(i) polypyridyl compounds, fac-[Re(L)(Am2phen)(CO)3]0/+, where Am2phen = 4,7-diamine-1,10-phenanthroline and L = Cl and ethyl isonicotinate (et-isonic), provided new insights into excited-state deactivation through an unusual inversion between two metal-to-ligand charge-transfer excited states. In addition, their cellular uptake using breast cancer (MCF-7) and melanoma (SkMel-147 and SkMel-29) cell lines and bioactivity were investigated and their cell-killing mechanism and protein expression were also studied. Preliminary TD-DFT results showed that both compounds exhibited a strong and broad absorption band around 300-400 nm which corresponds to a combination of ILAm2phen and MLCTReâAm2phen transitions, and a strong contribution of charge transfer transition MLCTReâet-isonic for fac-[Re(et-isonic)(Am2phen)(CO)3]+ is also observed. In contrast to typical Re(i) polypyridyl complexes, the substitution of Cl with the et-isonic ligand showed a bathochromic shift of the emission maxima, relatively low emission quantum yield and fast lifetime. Photophysical investigation of the fac-[ReCl(et-isonic)2(CO)3] compound provided meaningful information on the excited state manifold of the fac-[Re(L)(Am2phen)(CO)3]0/+ complexes. As shown in the absorption profile, a remarkable inversion of the lowest-lying excited state takes place from the usually observed MLCTReâAm2phen to the unusual MLCTReâet-isonic. The lipophilicity of the positive-complex was higher than that of the non-charge compound and the same trend for the activity against cells was observed, in the absence of light. In addition, flow cytometry and Western Blot analyses showed an overexpression of pro-caspase-9, suggesting a caspase proteolytic cascade through an intrinsic-pathway apoptosis mechanism. The photophysical properties of these compounds reported herein provide new fundamental insights into the understanding of substituent groups on polypyridyl ligands which are relevant to practical development.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Luminescência , Fenantrolinas/química , Rênio/química , Antineoplásicos/química , Caspase 9/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Complexos de Coordenação/química , Ativação Enzimática/efeitos dos fármacos , Humanos , Células MCF-7RESUMO
In this research, we report a simple hydrothermal synthesis to prepare rhenium (Re)- doped MoS2 flower-like microspheres and the tuning of their structural, electronic, and electrocatalytic properties by modulating the insertion of Re. The obtained compounds were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS). Structural, morphological, and chemical analyses confirmed the synthesis of poorly crystalline Re-doped MoS2 flower-like microspheres composed of few stacked layers. They exhibit enhanced hydrogen evolution reaction (HER) performance with low overpotential of 210 mV at current density of 10 mA/cm2, with a small Tafel slope of 78 mV/dec. The enhanced catalytic HER performance can be ascribed to activation of MoS2 basal planes and by reduction in charge transfer resistance during HER upon doping.
Assuntos
Dissulfetos/química , Hidrogênio/química , Microesferas , Molibdênio/química , Rênio/química , Catálise , Técnicas de Química Sintética , Eletroquímica , Cinética , Análise Espectral , Difração de Raios XRESUMO
BACKGROUND: In patients with hemophilia, radionuclide synoviorthesis, or the intra-articular injection of a radionuclide to decrease the synovial hypertrophy tissue, aims to decrease or avoid hemarthrosis. AIM: To evaluate the effectiveness of radionuclide synoviorthesis in hemophilia. MATERIAL AND METHODS: Observational retrospective study of the evolution of 107 male patients aged 3 to 54 years who were subjected to radionuclide synoviorthesis between 2007 and 2015. RESULTS: Of 164 treated joints, in 65% treatment was successful, (defined as zero to two hemarthroses and absence of synovitis during the follow up period), in 17% it was partially successful (defined as two or less hemarthroses, but persistence of the synovitis) and failed in 18% of the procedures. No important complications were recorded. CONCLUSIONS: Radionuclide synoviorthesis has an overall 82% success rate, is minimally invasive, can be used at any age and is inexpensive We recommend its implementation in Chilean hemophilia treatment centers.
Assuntos
Hemartrose/terapia , Hemofilia A/terapia , Radioisótopos/administração & dosagem , Rênio/uso terapêutico , Sinovite/terapia , Radioisótopos de Ítrio/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Hemartrose/diagnóstico por imagem , Hemartrose/fisiopatologia , Hemofilia A/fisiopatologia , Humanos , Injeções Intra-Articulares , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sinovite/diagnóstico por imagem , Sinovite/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Background: In patients with hemophilia, radionuclide synoviorthesis, or the intra-articular injection of a radionuclide to decrease the synovial hypertrophy tissue, aims to decrease or avoid hemarthrosis. Aim: To evaluate the effectiveness of radionuclide synoviorthesis in hemophilia. Material and Methods: Observational retrospective study of the evolution of 107 male patients aged 3 to 54 years who were subjected to radionuclide synoviorthesis between 2007 and 2015. Results: Of 164 treated joints, in 65% treatment was successful, (defined as zero to two hemarthroses and absence of synovitis during the follow up period), in 17% it was partially successful (defined as two or less hemarthroses, but persistence of the synovitis) and failed in 18% of the procedures. No important complications were recorded. Conclusions: Radionuclide synoviorthesis has an overall 82% success rate, is minimally invasive, can be used at any age and is inexpensive We recommend its implementation in Chilean hemophilia treatment centers.
Assuntos
Humanos , Masculino , Pré-Escolar , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Radioisótopos/administração & dosagem , Rênio/uso terapêutico , Sinovite/terapia , Radioisótopos de Ítrio/uso terapêutico , Hemartrose/terapia , Hemofilia A/terapia , Sinovite/fisiopatologia , Sinovite/diagnóstico por imagem , Fatores de Tempo , Reprodutibilidade dos Testes , Estudos Retrospectivos , Resultado do Tratamento , Hemartrose/fisiopatologia , Hemartrose/diagnóstico por imagem , Hemofilia A/fisiopatologia , Injeções Intra-ArticularesRESUMO
PURPOSE: To study the rhenium-188 labeling of polyamidoamine (PAMAM) generation 4 (G4) dendrimer and its evaluation on biodistribution and chromosomal aberrations in melanoma cells induced by ionizing radiation as potential treatment agent. MATERIALS AND METHODS: Dendrimers were first conjugated with Suc-HYNIC (succinimidyl 6-hydrazinopyridine-3-carboxylic acid hydrochloride). Dendrimer-HYNIC was then incubated with 188ReO4-. Biodistribution was performed administrating 188Re-dendrimer to normal (NM) or melanoma-bearing mice (MBM). Chromosome aberration test was conducted in order to measure treatment capacity of 188Re-dendrimer in melanoma cells. RESULTS: Radiolabeling yield of dendrimer was approx. 70%. Biodistribution studies in NM showed blood clearance with hepatic and renal depuration. MBM showed a similar pattern of biodistribution with tumor uptake of 6% of injected dose. Aberrant metaphases quantified in control cells were 7%, increasing to 29.5% in cells treated with 15µCi (0.555 MBq) of 188Re-dendrimer for 24 h. CONCLUSIONS: 188Re-dendrimer can produce double-stranded breaks in DNA induced by ionizing radiation in melanoma cells in vitro.
Assuntos
Aberrações Cromossômicas/efeitos da radiação , Dendrímeros/química , Melanoma Experimental/radioterapia , Radioisótopos/toxicidade , Rênio/toxicidade , Animais , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla , Marcação por Isótopo , Melanoma Experimental/genética , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Radioisótopos/farmacocinética , Rênio/farmacocinética , Distribuição TecidualRESUMO
ReI -polypyridyl complexes have interesting and distinctive photochemical and photosensitizing properties. This work describes the capability to induce (or photoinduce) DNA damage of three ReI -complexes with a naturally occurring alkaloid called norharmane (nHo) as ligand: [Re(CO)3 (nHo)(L)]CF3 SO3 where L=2,2'-bipyridine (ReBpy), phenanthroline (RePhen) or dipyrido[3,2-a:2',3'-c]phenazine (ReDppz). The interaction of the complexes with DNA was investigated by steady-state and time-resolved spectroscopy. Data show that the mode and strength of interaction depend on the chemical structure of the bidentate ligand. The complexes show a major static contribution to the overall interaction, giving rise to the formation of noncovalent adducts with DNA, and the particular trend observed was RePhen>ReDppz>ReBpy. Photo-oxidation at the purine bases represents the major DNA damaging mechanism. RePhen also induces single-strand breaks in a yield similar to that of base damage, suggesting an additional photosensitizing pathway. We also performed the Ames test to evaluate the cytotoxic and mutagenic properties of both non-irradiated and photoexcited complexes. RePhen, but not the other complexes, turned out to be both toxic and phototoxic for the bacteria.