RESUMEN
Aldehyde dehydrogenase-1a1 (ALDH1a1), the enzyme responsible for the oxidation of retinal into retinoic acid, represents a key therapeutic target for the treatment of debilitating disorders such as cancer, obesity, and inflammation. Drugs that can inhibit ALDH1a1 include disulfiram, an FDA-approved drug to treat chronic alcoholism. Disulfiram, by carbamylation of the catalytic cysteines, irreversibly inhibits ALDH1a1 and ALDH2. The latter is the isozyme responsible for important physiological processes such as the second stage of alcohol metabolism. Given the fact that ALDH1a1 has a larger substrate tunnel than that in ALDH2, replacing disulfiram ethyl groups with larger motifs will yield selective ALDH1a1 inhibitors. We report herein the synthesis of new inhibitors of ALDH1a1 where (hetero)aromatic rings were introduced into the structure of disulfiram. Most of the developed compounds retained the anti-ALDH1a1 activity of disulfiram; however, they were completely devoid of inhibitory activity against ALDH2.
Asunto(s)
Inhibidores del Acetaldehído Deshidrogenasa/química , Inhibidores del Acetaldehído Deshidrogenasa/farmacología , Familia de Aldehído Deshidrogenasa 1/antagonistas & inhibidores , Disulfiram/química , Disulfiram/farmacología , Retinal-Deshidrogenasa/antagonistas & inhibidores , Inhibidores del Acetaldehído Deshidrogenasa/síntesis química , Inhibidores del Acetaldehído Deshidrogenasa/metabolismo , Familia de Aldehído Deshidrogenasa 1/química , Familia de Aldehído Deshidrogenasa 1/metabolismo , Aldehído Deshidrogenasa Mitocondrial/antagonistas & inhibidores , Aldehído Deshidrogenasa Mitocondrial/química , Aldehído Deshidrogenasa Mitocondrial/metabolismo , Disulfiram/análogos & derivados , Disulfiram/síntesis química , Humanos , Simulación del Acoplamiento Molecular , Proteínas Recombinantes/metabolismo , Retinal-Deshidrogenasa/química , Retinal-Deshidrogenasa/metabolismoRESUMEN
Disulfiram is an FDA-approved drug used to treat chronic alcoholism. This drug works by blocking the second step of ethanol metabolism by inhibiting aldehyde dehydrogenase-2 (ALDH2), the enzyme responsible for acetaldehyde oxidation into acetic acid. This leads to the accumulation of acetaldehyde in the blood following alcohol ingestion and to highly unpleasant symptoms known as acetaldehyde syndrome. Disulfiram also inhibits ALDH1a1, another member of the aldehyde dehydrogenases that catalyzes the oxidation of retinal into retinoic acid. ALDH1a1 represents a key therapeutic target for the treatment of important diseases such as cancer and obesity. The substrate tunnel is larger in ALDH1a1 than in ALDH2; therefore. Thus, replacing disulfiram ethyl groups with larger groups will yield selective ALDH1a1 inhibitors. In this work, we successfully synthesized derivative 2b, in which two ethyl groups were replaced by two para fluorobenzyl groups. The 2b derivative showed a comparable activity to disulfiram against ALDH1a1; however, it was completely devoid of inhibitory activity against ALDH2.
Asunto(s)
Inhibidores del Acetaldehído Deshidrogenasa/química , Disuasivos de Alcohol/química , Familia de Aldehído Deshidrogenasa 1/antagonistas & inhibidores , Disulfiram/análogos & derivados , Retinal-Deshidrogenasa/antagonistas & inhibidores , Inhibidores del Acetaldehído Deshidrogenasa/síntesis química , Disuasivos de Alcohol/síntesis química , Familia de Aldehído Deshidrogenasa 1/química , Aldehído Deshidrogenasa Mitocondrial/antagonistas & inhibidores , Aldehído Deshidrogenasa Mitocondrial/química , Disulfiram/síntesis química , Pruebas de Enzimas , Humanos , Retinal-Deshidrogenasa/química , Especificidad por SustratoRESUMEN
[Thiocarbonyl-11C]disulfiram ([11C]DSF) was synthesized via iodine oxidation of [11C]diethylcarbamodithioic acid ([11C]DETC), which was prepared from [11C]carbon disulfide and diethylamine. The decay-corrected isolated radiochemical yield (RCY) of [11C]DSF was greatly affected by the addition of unlabeled carbon disulfide. In the presence of carbon disulfide, the RCY was increased up to 22% with low molar activity (Am, 0.27 GBq/µmol). On the other hand, [11C]DSF was obtained in 0.4% RCY with a high Am value (95 GBq/µmol) in the absence of carbon disulfide. The radiochemical purity of [11C]DSF was always >98%. The first PET study on [11C]DSF was performed in mice. A high uptake of radioactivity was observed in the liver, kidneys, and gallbladder. The uptake level and distribution pattern in mice were not significantly affected by the Am value of the [11C]DSF sample used. In vivo metabolite analysis showed the rapid decomposition of [11C]DSF in mouse plasma.
Asunto(s)
Radioisótopos de Carbono/química , Disulfiram/síntesis química , Tomografía de Emisión de Positrones/métodos , Radiofármacos/síntesis química , Animales , Disulfuro de Carbono/química , Complejos de Coordinación/química , Dietilaminas/química , Disulfiram/metabolismo , Ditiocarba/química , Vesícula Biliar/metabolismo , Yodo/química , Riñón/metabolismo , Ligandos , Hígado/metabolismo , Ratones , Oxidación-Reducción , Radiofármacos/metabolismo , Distribución TisularRESUMEN
PURPOSE: This work aims to create a novel Cu2+ liposome with excellent loading stability and develop synergistic effect with disulfiram (DSF) for the treatment of tumor. METHODS: Copper oleate was incorporated into the liposome membrane via alcohol injection method in this work. In vitro release test was applied to evaluate the release profile of the liposomes. Pharmacokinetic studies were performed in rats and the antitumor efficacy was assessed in mice bearing hepatoma xenografts. RESULTS: The copper oleate liposome (Cu(OI)2-L) was formulated and the loading efficiency were more than 85%. TEM images confirmed that the Cu(OI)2-L had a spherical morphology with an average diameter of 100 nm. Cu(OI)2-L displayed a biphasic release profile, with >70% retained drug over 8 h incubation in PBS at pH 7.4. Pharmacokinetic studies demonstrated that Cu(OI)2-L had a prolonged circulation time and increased AUC when compared to the injection of copper oleate solution. The antitumor efficacy test demonstrated an enhanced tumor inhibition rate with the treatment of Cu(OI)2-L and DSF nanoparticles, indicating an improved synergistic antitumor effect. CONCLUSIONS: The Cu(OI)2-L was suitable to be employed in combination with disulfiram for tumor treatment and can also open up opportunities for targeted delivery of copper.
Asunto(s)
Antineoplásicos/síntesis química , Protocolos de Quimioterapia Combinada Antineoplásica/síntesis química , Cobre/química , Disulfiram/síntesis química , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Ácido Oléico/síntesis química , Animales , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Ehrlich/tratamiento farmacológico , Carcinoma de Ehrlich/patología , Cobre/administración & dosificación , Disulfiram/administración & dosificación , Sinergismo Farmacológico , Neoplasias Hepáticas Experimentales/patología , Masculino , Ratones , Ácido Oléico/administración & dosificación , Polietilenglicoles/administración & dosificación , Polietilenglicoles/síntesis química , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacos , Carga Tumoral/fisiología , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Sixteen disulfides derived from disulfiram (Antabuse™) were evaluated as antibacterial agents. Derivatives with hydrocarbon chains of seven and eight carbons in length exhibited antibacterial activity against Gram-positive Staphylococcus, Streptococcus, Enterococcus, Bacillus, and Listeria spp. A comparison of the cytotoxicity and microsomal stability with disulfiram further revealed that the eight carbon chain analog was of lower toxicity to human hepatocytes and has a longer metabolic half-life. In the final analysis, this investigation concluded that the S-octylthio derivative is a more effective growth inhibitor of Gram-positive bacteria than disulfiram and exhibits more favorable cytotoxic and metabolic parameters over disulfiram.
Asunto(s)
Antibacterianos/farmacología , Disulfiram/análogos & derivados , Disulfiram/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/toxicidad , Ciprofloxacina/farmacología , Disulfiram/síntesis química , Disulfiram/toxicidad , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Semivida , Células Hep G2 , Humanos , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/efectos de los fármacos , Estructura Molecular , Ratas , Vancomicina/farmacologíaRESUMEN
Despite the fact that chemotherapy has been widely used in the clinical treatment of breast cancer, the toxicity of chemotherapeutics to normal tissues cannot be ignored due to the low specificity. Therefore, due to the non-negligible toxicity of chemotherapeutic agents to normal tissues, tumor microenvironment (TME)-responsive cancer therapy has attracted a great deal of attention. Here, we report a TME-responsive theranostic nanoagent MnOx@PAA@HKUST-1-DSF@BSA fabricated via a layer-by-layer synthesis method. Once endocytosed by tumor cells, the nanoagent can be degraded into Mn2+ for magnetic resonance imaging and Cu2+ for Fenton-like reaction and chelating with released disulfiram in situ, achieving enhanced chemotherapy. Both in vitro and in vivo experiments demonstrate that the TME-targeted nanoagent can efficiently kill tumor cells. This work provides an alternative option for effective imaging and treatment of breast cancer without collateral damage to normal tissues.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Disulfiram/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Disulfiram/síntesis química , Disulfiram/química , Humanos , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Ratones , Tamaño de la Partícula , Nanomedicina Teranóstica , Microambiente Tumoral/efectos de los fármacosRESUMEN
Disulfiram (DSF) is an inhibitor of P-glycoprotein (Pgp), the main obstacle limiting the success of doxorubicin (DOX), but it has poor solubility and stability. With the aim to overcome these limitations we prepared liposomes coencapsulating DSF and DOX (LipoDSF-DOX). Liposome stability, drugs release profile, effects on DOX cytotoxicity, Pgp activity and expression in breast cancer cells were evaluated. We observed that LipoDSF-DOX with a 1:3 weight ratio, with DSF in lipid bilayer and DOX in aqueous core, released DSF faster than DOX. LipoDSF-DOX increased DOX intracellular accumulation and cytotoxicity in Pgp-expressing breast cancer cells, with an efficacy superior to the mixture of free DSF and DOX, thanks to a differential kinetics of release of DSF and DOX when carried by liposomes. The mechanism of the increased DOX retention relied on the DSF-induced sulfhydraton of Pgp and followed by its ubiquitination. These events reduced Pgp expression and catalytic activity in LipoDSF-DOX-treated cells. Our results show that LipoDSF-DOX effectively reversed DOX resistance in Pgp-expressing breast cancer cells, exploiting the temporally different kinetics of release of DSF and DOX, optimized to decrease expression and activity of Pgp.
Asunto(s)
Neoplasias de la Mama/metabolismo , Disulfiram/metabolismo , Doxorrubicina/metabolismo , Portadores de Fármacos/metabolismo , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Disulfiram/administración & dosificación , Disulfiram/síntesis química , Doxorrubicina/administración & dosificación , Doxorrubicina/síntesis química , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/síntesis química , Resistencia a Múltiples Medicamentos/fisiología , Resistencia a Antineoplásicos/fisiología , Femenino , Humanos , Liposomas , Células MCF-7 , Tamaño de la PartículaRESUMEN
Cervical cancer is the third most prevalent cancer in women and disproportionately affects those in low resource settings due to limited programs for screening and prevention. In the developed world treatment for the disease in the non-metastasised state usually takes the form of surgical intervention and/or radiotherapy. In the developing world such techniques are less widely available. This paper describes the development of an intravaginal ring for the localised delivery of a chemotherapeutic drug to the cervix that has the potential to reduce the need for surgical intervention and will also provide a novel anti-cancer therapy for women in low resource settings. Disulfiram has demonstrated antineoplastic action against prostate, breast and lung cancer. Both PEVA and silicone elastomer were investigated for suitability as materials in the manufacture of DSF eluting intravaginal rings. DSF inhibited the curing process of the silicone elastomer, therefore PEVA was chosen as the material to manufacture the DSF-loaded vaginal rings. The vaginal rings had an excellent content uniformity while the DSF remained stable throughout the manufacturing process. Furthermore, the rings provided diffusion controlled release of DSF at levels well in excess of the IC50 value for the HeLa cervical cancer cell line.
Asunto(s)
Dispositivos Anticonceptivos Femeninos , Disulfiram/síntesis química , Portadores de Fármacos/síntesis química , Neoplasias del Cuello Uterino/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Dispositivos Anticonceptivos Femeninos/tendencias , Disulfiram/administración & dosificación , Disulfiram/metabolismo , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/metabolismo , Femenino , Humanos , Resultado del Tratamiento , Neoplasias del Cuello Uterino/metabolismoRESUMEN
The zinc-ejecting aldehyde dehydrogenase (ALDH) inhibitory drug disulfiram (DSF) was found to be a breast cancer-associated protein 2 (BCA2) inhibitor with potent antitumor activity. We herein describe our work in the synthesis and evaluation of new series of zinc-affinic molecules to explore the structural requirements for selective BCA2-inhibitory antitumor activity. An N(C=S)S-S motif was found to be required, based on selective activity in BCA2-expressing breast cancer cell lines and against recombinant BCA2 protein. Notably, the DSF analogs (3a and 3c) and dithio(peroxo)thioate compounds (5d and 5f) were found to have potent activity (submicromolar IC(50)) in BCA2 positive MCF-7 and T47D cells but were inactive (IC(50) > 10 microM) in BCA2 negative MDA-MB-231 breast cancer cells and the normal breast epithelial cell line MCF10A. Testing in the isogenic BCA2 +ve MDA-MB-231/ER cell line restored antitumor activity for compounds that were inactive in the BCA2 -ve MDA-MB-231 cell line. In contrast, structurally related dithiocarbamates and benzisothiazolones (lacking the disulfide bond) were all inactive. Compounds 5d and 5f were additionally found to lack ALDH-inhibitory activity, suggestive of selective E3 ligase-inhibitory activity and worthy of further development.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/enzimología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Aldehído Deshidrogenasa/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Disulfiram/síntesis química , Disulfiram/química , Disulfiram/farmacología , Disulfiram/uso terapéutico , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/uso terapéutico , Estabilidad de Enzimas , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Relación Estructura-Actividad , Especificidad por Sustrato , Ubiquitina-Proteína Ligasas/química , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación/efectos de los fármacos , Zinc/metabolismoRESUMEN
The effect of some close structural analogues of disulfiram on the activity of the cytoplasmic and mitochondrial aldehyde dehydrogenases of sheep liver was studied. Several thiuram disulphides are equally potent inhibitors of the cytoplasmic enzyme, but in all cases the mitochondrial enzyme is much less strongly affected. Tetramethylthiuram monosulphide decreases the activity of the cytoplasmic enzyme in a process apparently involving a covalent interaction.