RESUMEN
INTRODUCTION: With the aim of repositioning commercially available drugs for the inhibition of the anti-apoptotic myeloid cell leukemia protein, Mcl-1, implied in various cancers, five molecules, highlighted from a published theoretical screening, were selected to experimentally validate their affinity toward Mcl-1. RESULTS: A detailed NMR study revealed that only two of the five tested drugs, Torsemide and Deferasirox, interacted with Mcl-1. NMR data analysis allowed the complete characterization of the binding mode of both drugs to Mcl-1, including the estimation of their affinity for Mcl-1. Biological assays evidenced that the biological activity of Torsemide was lower as compared to the Deferasirox, which was able to efficiently and selectively inhibit the anti-apoptotic activity of Mcl-1. Finally, docking and molecular dynamics led to a 3D model for the Deferasirox:Mcl-1 complex and revealed the positioning of the drug in the Mcl-1 P2/P3 pockets as well as almost all synthetic Mcl-1 inhibitors. Interestingly, contrary to known synthetic Mcl-1 inhibitors which interact through Arg263, Deferasirox, establishes a salt bridge with Lys234. CONCLUSION: Deferasirox could be a potential candidate for drug repositioning as Mcl-1 inhibitor.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/efectos de los fármacos , Deferasirox/farmacología , Reposicionamiento de Medicamentos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Deferasirox/química , Lenalidomida/química , Lenalidomida/farmacología , Espectroscopía de Resonancia Magnética , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Oxcarbazepina/química , Oxcarbazepina/farmacología , Risperidona/química , Risperidona/farmacología , Torasemida/química , Torasemida/farmacologíaRESUMEN
We report here strategic functionalization of the FDA approved chelator deferasirox (1) in an effort to produce organelle-targeting iron chelators with enhanced activity against A549 lung cancer cells. Derivative 8 was found to have improved antiproliferative activity relative to 1. Fluorescent cell imaging revealed that compound 8 preferentially localises within the lysosome.
Asunto(s)
Antineoplásicos/farmacología , Deferasirox/farmacología , Quelantes del Hierro/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Orgánulos/química , Células A549 , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Deferasirox/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Quelantes del Hierro/química , Neoplasias Pulmonares/diagnóstico por imagen , Lisosomas/química , Microscopía Confocal , Estructura Molecular , Imagen ÓpticaRESUMEN
In the current study, the synthesis of a theranostic platform composed of superparamagnetic iron oxide nanoparticles (SPION)-deferasirox conjugates targeted with AS1411 DNA aptamer was reported. In this regard, SPION was amine-functionalized by (3-aminopropyl)trimethoxysilane (ATPMS), and then deferasirox was covalently conjugated onto its surface. Finally, to provide guided drug delivery to cancerous tissue, AS1411 aptamer was conjugated to the complex of SPION-deferasirox. The cellular toxicity assay on CHO, C-26 and AGS cell lines verified higher cellular toxicity of targeted complex in comparison with non-targeted one. The evaluation of in vivo tumor growth inhibitory effect in C26 tumor-bearing mice illustrated that the aptamer-targeted complex significantly enhanced the therapeutic outcome in comparison with both non-targeted complex and free drug. The diagnostic capability of the prepared platform was also evaluated implementing C26-tumor-bearing mice. Obtained data confirmed higher tumor accumulation and higher tumor residence time for targeted complex through MRI imaging due to the existence of SPION as a contrast agent in the core of the prepared complex. The prepared multimodal theranostic system provides a safe and effective platform for fighting against cancer.
Asunto(s)
Antineoplásicos/uso terapéutico , Medios de Contraste/uso terapéutico , Deferasirox/uso terapéutico , Quelantes del Hierro/uso terapéutico , Nanopartículas de Magnetita/uso terapéutico , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/síntesis química , Aptámeros de Nucleótidos/química , Células CHO , Línea Celular Tumoral , Medios de Contraste/síntesis química , Cricetulus , Deferasirox/química , Femenino , Humanos , Ácidos Nucleicos Inmovilizados/química , Ácidos Nucleicos Inmovilizados/uso terapéutico , Quelantes del Hierro/síntesis química , Estimación de Kaplan-Meier , Imagen por Resonancia Magnética , Nanopartículas de Magnetita/química , Ratones Endogámicos BALB C , Medicina de Precisión , Propilaminas/química , Silanos/químicaRESUMEN
Deferasirox (DFX) is an oral iron-chelating agent and classified into class II of the Biopharmaceutics Classification System. Low bioavailability of the drug due to insufficient solubility in physiological fluids is the main drawback of DFX. The idea of the current study was to explore the potential of solid dispersion (SD) as an effective method to improve the dissolution rate of DFX in pellets. The SDs were made by the solvent evaporation technique using polyethylene glycol 4000 (PEG 4000) and polyvinylpyrrolidone K25 with different drug-to-carrier ratios. Then, the dispersion was milled and mixed with other components and the mixture layered on sugar-based cores by pan coating technique. The pellets were evaluated in terms of size distribution, morphology (SEM), and dissolution behaviour. Drug-polymer interactions were studied using differential scanning calorimetry (DSC), X-ray diffraction study (XRD), and Fourier transformation infrared (FTIR) spectroscopy. The pellets coated with SD showed a remarkable rise in the solubility of DFX than that of free drug-loaded pellets. The dispersion with PVP K25 showed a faster dissolution rate as compared to other mixtures. The DSC and XRD analysis indicated that the drug was in the amorphous state when dispersed in the polymer. The FTIR studies demonstrated any ruled out interaction between drug and polymer. The SEM showed smoothness on the surface of the pellets. It is resolved that the SD method considerably enriched the dissolution rate of DFX in pellets, which can also be utilized for other poorly water-soluble drugs.
Asunto(s)
Deferasirox , Rastreo Diferencial de Calorimetría , Química Farmacéutica , Deferasirox/química , Deferasirox/farmacocinética , Composición de Medicamentos , Implantes de Medicamentos/química , Implantes de Medicamentos/farmacocinética , Solubilidad , Difracción de Rayos XRESUMEN
The development and malignancy of cancer cells are closely related to the changes of the epigenome. In this work, a mitochondria-targeted rhenium(I) complex (DFX-Re3), integrating the clinical iron chelating agent deferasirox (DFX), has been designed. By relocating iron to the mitochondria and changing the key metabolic species related to epigenetic modifications, DFX-Re3 can elevate the methylation levels of histone, DNA, and RNA. As a consequence, DFX-Re3 affects the events related to apoptosis, RNA polymerases, and T-cell receptor signaling pathways. Finally, it is shown that DFX-Re3 induces immunogenic apoptotic cell death and exhibits potent antitumor activity in vivo. This study provides a new approach for the design of novel epigenetic drugs that can recode the cancer epigenome by intervening in mitochondrial metabolism and iron homeostasis.
Asunto(s)
Complejos de Coordinación/química , Hierro/metabolismo , Mitocondrias/metabolismo , Renio/química , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Complejos de Coordinación/farmacología , Complejos de Coordinación/uso terapéutico , Deferasirox/química , Evaluación Preclínica de Medicamentos , Epigenómica , Histonas/metabolismo , Humanos , Quelantes del Hierro/química , Metilación/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , ARN Polimerasa II/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
A series of new deferasirox derivatives were synthesized through the reaction of monosubstituted hydrazides with 2-(2-hydroxyphenyl)-4H-benzo[e][1,3]oxazin-4-one. For the first time, deferasirox and some of its derivatives were evaluated for their inâ vitro inhibitory activity against Jack bean urease. The potencies of the members of this class of compounds are higher than that of acetohydroxamic acid. Two compounds, bearing tetrazole and hydrazine derivatives (bioisoester of carboxylate group), represented the most potent urease inhibitory activity with IC50 values of 1.268 and 3.254â µm, respectively. In silico docking studies were performed to delineate possible binding modes of the compounds with the enzyme, urease. Docking analysis suggests that the synthesized compounds were anchored well in the catalytic site and extending to the entrance of binding pocket and thus restrict the mobility of the flap by interacting with its crucial amino acid residues, CME592 and His593. The overall results of urease inhibition have shown that these target compounds can be further optimized and developed as a lead skeleton for the discovery of novel urease inhibitors.
Asunto(s)
Deferasirox/farmacología , Inhibidores Enzimáticos/farmacología , Simulación del Acoplamiento Molecular , Triazoles/farmacología , Canavalia/enzimología , Deferasirox/síntesis química , Deferasirox/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Estructura Molecular , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/química , Ureasa/antagonistas & inhibidores , Ureasa/metabolismoRESUMEN
In this work, a new pH-responsive nanocarrier based on mesoporous silica nanoparticle which was functionalized by polyamidoamine dendrimer with sugar conjugation was designed for targetable and controllable delivery of deferasirox to cancer cells. To obtain the optimum conditions for the preparation of drug-loaded nanocarrier, the response surface method was employed. The effect of drug/silica ratio, temperature, and operation time on loading efficiency of deferasirox was evaluated, and high loading content achieved under optimized condition. The in vitro drug release studies at different pHs proved the pH-sensitivity of the nanocarrier. Due to the open state of dendritic structure in acidic pH, the maximum release observed at pHâ¯4.5 (lysosomal pH). In the presence of the sugar decorated carrier, cytotoxicity of retinoblastoma cell line Y79 was enhanced which confirmed that tumor cell uptake was improved. These results suggested that this nanocarrier has the potential for treatment of cancer.