RESUMO
Although Alzheimer's disease (AD) was first described over a century ago, it remains the leading cause of age-related dementia. Innumerable changes have been linked to the pathology of AD; however, there remains much discord regarding which might be the initial cause of the disease. The "amyloid cascade hypothesis" proposes that the amyloid ß (Aß) peptide is central to disease pathology, which is supported by elevated Aß levels in the brain before the development of symptoms and correlations of amyloid burden with cognitive impairment. The "metals hypothesis" proposes a role for metal ions such as iron, copper, and zinc in the pathology of AD, which is supported by the accumulation of these metals within amyloid plaques in the brain. Metals have been shown to induce aggregation of Aß, and metal ion chelators have been shown to reverse this reaction in vitro. 8-Hydroxyquinoline-based chelators showed early promise as anti-Alzheimer's drugs. Both 5-chloro-7-iodo-8-hydroxyquinoline (CQ) and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline (PBT2) underwent unsuccessful clinical trials for the treatment of AD. To gain insight into the mechanism of action of 8HQs, we have investigated the potential interaction of CQ, PBT2, and 5,7-dibromo-8-hydroxyquinoline (B2Q) with Cu(II)-bound Aß(1-42) using X-ray absorption spectroscopy (XAS), high energy resolution fluorescence detected (HERFD) XAS, and electron paramagnetic resonance (EPR). By XAS, we found CQ and B2Q sequestered â¼83% of the Cu(II) from Aß(1-42), whereas PBT2 sequestered only â¼59% of the Cu(II) from Aß(1-42), suggesting that CQ and B2Q have a higher relative Cu(II) affinity than PBT2. From our EPR, it became clear that PBT2 sequestered Cu(II) from a heterogeneous mixture of Cu(II)Aß(1-42) species in solution, leaving a single Cu(II)Aß(1-42) species. It follows that the Cu(II) site in this Cu(II)Aß(1-42) species is inaccessible to PBT2 and may be less solvent-exposed than in other Cu(II)Aß(1-42) species. We found no evidence to suggest that these 8HQs form ternary complexes with Cu(II)Aß(1-42).
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Clioquinol , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/química , Quelantes/farmacologia , Quelantes/uso terapêutico , Clioquinol/análogos & derivados , Clioquinol/química , Cobre/química , Humanos , Íons , Metais , Oxiquinolina/química , Oxiquinolina/farmacologia , Fragmentos de Peptídeos , Solventes , ZincoRESUMO
Diabetes mellitus is a chronic metabolic disorder with increasing prevalence and long-term complications. The aim of this study was to identify α-glucosidase inhibitory compounds with potential anti-hyperglycemic activity. For this purpose, a series of new clioquinol derivatives 2a-11a was synthesized, and characterized by various spectroscopic techniques. The enzyme inhibitory activities of the resulting derivatives were assessed using an in-vitro mechanism-based assay. All the tested compounds 2a-11a of the series showed a significant α-glucosidase inhibition with IC50 values 43.86-325.81 µM, as compared to the standard drug acarbose 1C50: 875.75 ± 2.08 µM. Among them, compounds 4a, 5a, 10a, and 11a showed IC50 values of 105.51 ± 2.41, 119.24 ± 2.37, 99.15 ± 2.06, and 43.86 ± 2.71 µM, respectively. Kinetic study of the active analogues showed competitive, non-competitive, and mixed-type inhibitions. Furthermore, the molecular docking study was performed to elucidate the binding interactions of most active analogues with the various sites of α-glucosidase enzyme. The results indicate that these compounds have the potential to be further studied as new anti-diabetic agents.
Assuntos
Clioquinol/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/farmacologia , Simulação de Acoplamento Molecular , alfa-Glucosidases/metabolismo , Células Cultivadas , Clioquinol/síntese química , Clioquinol/química , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Cinética , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Metastable and rarely reported GO warped tetragonal phase t-lanthanum vanadate nanocomposites (GO@LaVO4-NCs) are reported for the sensitive electrochemical determination of antifungal drug Clioquinol (CQ). The hydrothermal method was adopted for synthesis of GO@LaVO4-NCs. The electrochemical performance of CQ was examined using cyclic voltammetry (CV) and differential plus voltammetry (DPV) at GO@LaVO4-NCs modified glassy carbon electrode (GCE). The electrocatalytic oxidation of CQ at the GO@LaVO4-NCs/GCE shows the highest anodic peak current at a potential of +0.51 V vs. Ag/AgCl. The proposed sensor provides excellent sensitivity of 4.1894 µA µM-1 cm-2, a very low detection limit (LOD) of 2.44 nM, and a wide range of 25 nM to 438.52 µM towards CQ detection. Finally, the detection of CQ in biological media was successfully done using the GO@LaVO4-NCs/GCE and possesses recoveries of 94.67-98.0%.
Assuntos
Antifúngicos/análise , Antiprotozoários/análise , Clioquinol/análise , Técnicas Eletroquímicas/métodos , Nanocompostos/química , Antifúngicos/sangue , Antifúngicos/química , Antifúngicos/urina , Antiprotozoários/sangue , Antiprotozoários/química , Antiprotozoários/urina , Clioquinol/sangue , Clioquinol/química , Clioquinol/urina , Grafite/química , Humanos , Lantânio/química , Limite de Detecção , Oxirredução , Reprodutibilidade dos Testes , Vanadatos/químicaRESUMO
PBT2 (5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline) is a small Cu(II)-binding drug that has been investigated in the treatment of neurodegenerative diseases, namely, Alzheimer's disease (AD). PBT2 is thought to be highly effective at crossing the blood-brain barrier and has been proposed to exert anti-Alzheimer's effects through the modulation of metal ion concentrations in the brain, specifically the sequestration of Cu(II) from amyloid plaques. However, despite promising initial results in animal models and in clinical trials where PBT2 was shown to improve cognitive function, larger-scale clinical trials did not find PBT2 to have a significant effect on the amyloid plaque burden compared with controls. We propose that the results of these clinical trials likely point to a more complex mechanism of action for PBT2 other than simple Cu(II) sequestration. To this end, herein we have investigated the solution chemistry of Cu(II) coordination by PBT2 primarily using X-ray absorption spectroscopy (XAS), high-energy-resolution fluorescence-detected XAS, and electron paramagnetic resonance. We propose that a novel bis-PBT2 Cu(II) complex with asymmetric coordination may coexist in solution with a symmetric four-coordinate Cu(II)-bis-PBT2 complex distorted from coplanarity. Additionally, PBT2 is a more flexible ligand than other 8HQs because it can act as both a bidentate and a tridentate ligand as well as coordinate Cu(II) in both 1:1 and 2:1 PBT2/Cu(II) complexes.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Quelantes/uso terapêutico , Clioquinol/análogos & derivados , Complexos de Coordenação/uso terapêutico , Cobre/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Deficiências na Proteostase/tratamento farmacológico , Animais , Quelantes/síntese química , Quelantes/química , Clioquinol/química , Clioquinol/uso terapêutico , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cobre/química , Teoria da Densidade Funcional , Humanos , Ligantes , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Espectroscopia por Absorção de Raios XRESUMO
A clioquinol (ICHQ)-containing Pluronic® F127 polymeric micelle system (ICHQ/Mic) was recently shown to be effective against Leishmania amazonensis infection in a murine model. In the present study, ICHQ/Mic was tested against L. infantum infection. BALB/c mice (n = 12 per group) were infected with L. infantum stationary promastigotes through subcutaneous injection and, 45 days after challenge, received saline or were treated via the subcutaneous route with empty micelles, ICHQ or ICHQ/Mic. In addition, animals were treated with miltefosine by the oral route, as a drug control. Half of the animals were euthanized 1 and 15 days after treatment, aiming to evaluate two endpoints after therapy, when parasitological and immunological parameters were investigated. Results showed that the treatment using miltefosine, ICHQ or ICHQ/Mic induced significantly higher anti-parasite IFN-γ, IL-12, GM-CSF, nitrite and IgG2a isotype antibody levels, which were associated with low IL-4 and IL-10 production. In addition, a higher frequency of IFN-γ and TNF-α-producing CD4+ and CD8+ T-cells was found in these animals. The parasite load was evaluated in distinct organs, and results showed that the treatment using miltefosine, ICHQ or ICHQ/Mic induced significant reductions in organic parasitism in the treated and infected mice. A comparison between the treatments suggested that ICHQ/Mic was the most effective in inducing a highly polarized Th1-type response, as well as reducing the parasite load in significant levels in the treated and infected animals. Data obtained 15 days after treatment suggested maintenance of the immunological and parasitological responses. In conclusion, ICHQ/Mic could be considered in future studies for the treatment of visceral leishmaniasis.
TITLE: Un système à micelles polymériques Pluronic® F127 contenant du clioquinol est efficace pour le traitement de la leishmaniose viscérale dans un modèle murin. ABSTRACT: Un système à micelles polymériques Pluronic® F127 (ICHQ/Mic) contenant du clioquinol (ICHQ) s'est récemment révélé efficace contre l'infection à Leishmania amazonensis dans un modèle murin. Dans la présente étude, l'ICHQ/Mic a été testé contre l'infection à L. infantum. Les souris BALB/c (n = 12 par groupe) ont été infectées par des promastigotes stationnaires de L. infantum par injection sous-cutanée et ont reçu 45 jours après l'épreuve une solution saline ou ont été traitées par voie sous-cutanée avec des micelles vides, ICHQ ou ICHQ/Mic. De plus, les animaux ont été traités avec de la miltefosine par voie orale, comme contrôle médicamenteux. La moitié des animaux ont été euthanasiés 1 et 15 jours après le traitement, dans le but de mesurer deux critères d'évaluation après la thérapie, lorsque les paramètres parasitologiques et immunologiques ont été étudiés. Les résultats ont montré que le traitement par miltefosine, ICHQ ou ICHQ/Mic induisait des niveaux d'anticorps anti-parasite IFN-γ, IL-12, GM-CSF, nitrite et IgG2a significativement plus élevés, associés à de faibles productions d'IL-4 et IL-10. De plus, une fréquence plus élevée de cellules T CD4+ et CD8+ produisant de l'IFN-γ and TNF-α a été trouvée chez ces animaux. La charge parasitaire a été évaluée dans des organes distincts et les résultats ont montré que le traitement utilisant la miltefosine, ICHQ ou ICHQ/Mic induisait des réductions significatives du parasitisme des organes chez les souris traitées et infectées. Une comparaison entre les traitements a suggéré qu'ICHQ/Mic était le plus efficace pour induire une réponse de type Th1 polarisée, ainsi que pour réduire la charge parasitaire à des niveaux significatifs chez les animaux traités et infectés. Les données obtenues 15 jours après le traitement suggèrent le maintien des réponses immunologiques et parasitologiques. En conclusion, ICHQ/Mic pourrait être envisagé dans de futures études pour le traitement contre la leishmaniose viscérale.
Assuntos
Clioquinol/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Micelas , Poloxâmero/química , Animais , Anticorpos Antiprotozoários/sangue , Clioquinol/química , Citocinas/imunologia , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Feminino , Leishmania infantum , Camundongos , Camundongos Endogâmicos BALB C , Carga Parasitária , Poloxâmero/uso terapêutico , Células Th1/imunologiaRESUMO
A series of novel flurbiprofen-clioquinol hybrids were designed and synthesized as multifunctional agents for Alzheimer's disease therapy, and their potential was evaluated through various biological experiments. In vitro studies showed that most target compounds exhibited significant ability to inhibit self- and Cu2+-induced ß-amyloid aggregation. Furthermore, some target compounds, especially 7i and 7r, also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activity and appropriate BBB permeability. These biological activities indicated that the representative compound 7i and 7r might be promising multifunctional agents for AD treatment.
Assuntos
Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/química , Clioquinol/química , Flurbiprofeno/química , Peptídeos beta-Amiloides/metabolismo , Descoberta de Drogas , Humanos , Ligantes , Membranas Artificiais , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
A turn on-off fluorometric assay for clioquinol (CQ) is described here. It is based on modulation of the fluorescence of sulfur quantum dots (SQDs; best measured at excitation/emission wavelengths of 360/426 nm) by using the Zn2+-CQ affinity pair. Although the fluorescence enhancement effect of Zn2+ on SQDs was not obvious, a good quenching modulation effect was observed in the presence of CQ. This resulted in a linear analytical range that is increased by two orders of magnitude (from 0.024 µM to 0.24 µM, and 0.62 µM to 30 µM), with a detection limit (3 s) of 0.015 µM. The selectivity of the method is also improved. Graphical abstractSchematic illustration of the turn on-off fluorometric assay for for clioquinol (CQ) based on Zn2+-modulated sulfur quantum dots (SQDs).
Assuntos
Antifúngicos/análise , Antifúngicos/química , Clioquinol/análise , Clioquinol/química , Pontos Quânticos/química , Enxofre/química , Zinco/química , Limite de Detecção , Espectrometria de FluorescênciaRESUMO
Previously, we designed, synthesized, and evaluated a series of quinolone-benzofuran derivatives as multitargeted anti-Alzheimer's disease (anti-AD) compounds, and we discovered that WBQ5187 possesses superior anti-AD bioactivity. In this work, we investigated the pharmacokinetics of this new molecule, as well as its therapeutic efficacy in restoring cognition and neuropathology, in the APP/PS1 mouse model of AD. Pharmacokinetic analyses demonstrated that WBQ5187 possessed rational oral bioavailability, metabolic stability, and excellent blood-brain barrier (BBB) permeability. Pharmacodynamics studies indicated that a 12-week treatment with the lead compound at doses of 40 mg/kg or higher significantly enhanced the learning and memory performance of the APP/PS1 transgenic mice, and the effect was more potent than that of clioquinol (CQ). Furthermore, WBQ5187 notably reduced cerebral ß-amyloid pathology, gliosis, and neuronal cell loss and increased the levels of cAMP in the hippocampus of these mice. The surrogate measures of emesis indicated that WBQ5187 had no effect at its cognitive effective doses. Overall, our results demonstrated that this compound markedly improves cognitive and spatial memory functions in AD mice and represents a promising pharmaceutical agent with potential for the treatment of AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Benzofuranos/uso terapêutico , Química Encefálica/efeitos dos fármacos , Clioquinol/análogos & derivados , Fármacos Neuroprotetores/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêutico , Resorcinóis/uso terapêutico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Anestésicos Gerais/toxicidade , Animais , Benzofuranos/química , Benzofuranos/farmacocinética , Disponibilidade Biológica , Barreira Hematoencefálica , Clioquinol/química , Clioquinol/farmacocinética , Clioquinol/uso terapêutico , AMP Cíclico/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Gliose/tratamento farmacológico , Gliose/prevenção & controle , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Náusea/induzido quimicamente , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacocinética , Inibidores da Fosfodiesterase 4/toxicidade , Resorcinóis/química , Resorcinóis/farmacocinética , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Vômito/induzido quimicamenteRESUMO
Clioquinol has recently been proposed for the treatment of Alzheimer's disease. It is able to diminish ß-amyloid protein aggregation and to restore cognition of Alzheimer's mice. However, its therapeutic benefits for Alzheimer's disease in human remain controversy and need further confirmation. Herein, we have explored the interaction mechanism of clioquinol toward bovine serum albumin (BSA) by means of multi-spectroscopic and docking simulation approaches. Clioquinol interacts with BSA by a combined mechanism of static and dynamic processes. Application of the Hill's equation to fluorescence quenching experiment revealed that the binding constant of the BSA-clioquinol complex is extremely high at 108â¯M-1 level. Competitive displacement and docking analysis consistently suggested that there are the multiple binding modes of clioquinol toward BSA. Competitive binding study showed that clioquinol shares the binding sites with ibuprofen and digitoxin on albumin, referring to be site II and site III binding compounds. Besides, partial binding in site I was also observed. Docking simulation confirmed that clioquinol favors to bind in site I, site II, site III, fatty acid binding site 5, and the protein cleft between subdomain IB and IIIB of the BSA. Due to its small size and electric dipole property, clioquinol may easily fit in multiple pockets of the BSA. Our finding suggests the potential role of BSA as a clioquinol carrier in the vascular system. Nonetheless, clioquinol-induced BSA aggregation has been observed by the three-dimensional fluorescence technique. This phenomenon may not only impair the BSA, but may also affect other endogenous proteins, which eventually causes adverse effects to human. Therefore, the redesigned or modified molecular structure of clioquinol may reduce its toxicity and improve its bioavailability.
Assuntos
Clioquinol/metabolismo , Soroalbumina Bovina/metabolismo , Animais , Sítios de Ligação , Bovinos , Clioquinol/química , Simulação de Acoplamento Molecular , Agregados Proteicos/efeitos dos fármacos , Ligação Proteica , Soroalbumina Bovina/química , TermodinâmicaRESUMO
PURPOSE: Candida biofilm infections are frequently linked to the use of biomaterials and are of clinical significance because they are commonly resistant to antifungals. Clioquinol is an antiseptic drug and is effective against multidrug-resistant Candida. We investigated the effect of clioquinol and two other 8-hydroxyquinoline derivatives on Candida biofilm. METHODOLOGY: The ability to inhibit biofilm formation, inhibit preformed biofilm and remove established biofilms was evaluated using in vitro assays on microtitre plates. The action of clioquinol on biofilm in intrauterine devices (IUDs) was also investigated, describing the first protocol to quantify the inhibitory action of compounds on biofilms formed on IUDs. RESULTS: Clioquinol was found to be the most effective 8-hydroxyquinoline derivative among those tested. It prevented more than 90â% of biofilm formation, which can be attributed to blockade of hyphal development. Clioquinol also reduced the metabolic activity of sessile Candida but the susceptibility was lower compared to planktonic cells (0.031-0.5 µg ml-1 required to inhibit 50â% planktonic cells and 4-16 µg ml-1 to inhibit 50â% preformed biofilms). On the other hand, almost complete removal of biofilms was not achieved for the majority of the isolates. Candida spp. also showed the ability to form biofilm on copper IUD; clioquinol eradicated 80-100â% of these biofilms. CONCLUSION: Our results indicate a potential application in terms of biomaterials for 8-hydroxyquinoline derivatives. Clioquinol could be used as a coating to prevent morphological switching and thus prevent biofilm formation. Furthermore, clioquinol may have future applications in the treatment of Candida infections linked to the use of IUDs.
Assuntos
Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Candida/efeitos dos fármacos , Candidíase/prevenção & controle , Clioquinol/farmacologia , Oxiquinolina/farmacologia , Antifúngicos/química , Antifúngicos/uso terapêutico , Candida/fisiologia , Candidíase/tratamento farmacológico , Candidíase/etiologia , Candidíase/microbiologia , Clioquinol/análogos & derivados , Clioquinol/química , Clioquinol/uso terapêutico , Cobre , Feminino , Humanos , Dispositivos Intrauterinos/efeitos adversos , Dispositivos Intrauterinos/microbiologia , Testes de Sensibilidade Microbiana , Oxiquinolina/análogos & derivados , Oxiquinolina/químicaRESUMO
Clioquinol (CQ) is an FDA-approved topical antifungal agent known to kill cancer cells. This facilitated the initiation of clinical trials in patients with refractory hematologic malignancies. These repurposing efforts were not successful; this was likely due to low intracellular levels of the drug owing to poor absorption and rapid metabolism upon oral administration. CQ forms a sparingly soluble copper complex (Cu(CQ)2) that exhibits enhanced anticancer activity in some cell lines. We have utilized a novel method to synthesize Cu(CQ)2 inside liposomes, an approach that maintains the complex suspended in solution and in a format suitable for intravenous administration. The complex was prepared inside 100-nm liposomes composed of 1,2-distearoyl-sn-glycero-3-phosphocholine/cholesterol (55:45). The therapeutic activity of the resultant formulation was evaluated in two subcutaneous tumor models (glioblastoma and ovarian cancers) but was not active. We also assessed the ability of the Cu(CQ)2 formulation to increase copper delivery to cancer cells in vitro and its potential to be used in combination with disulfiram (DSF). The results suggested that addition of Cu(CQ)2 enhanced cellular copper levels and the activity of DSF in vitro; however, this combination did not result in a statistically significant reduction in tumor growth in vivo. These studies demonstrate that a Cu(CQ)2 formulation suitable for intravenous use can be prepared, but this formulation used alone or in combination with DSF was not efficacious. The methods described are suitable for development formulations of other analogues of 8-hydroxyquinoline which could prove to be more potent.
Assuntos
Antifúngicos/administração & dosagem , Antineoplásicos/administração & dosagem , Clioquinol/administração & dosagem , Cobre/administração & dosagem , Administração Intravenosa , Animais , Antifúngicos/química , Antifúngicos/farmacocinética , Antifúngicos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Colesterol/química , Clioquinol/química , Clioquinol/farmacocinética , Clioquinol/uso terapêutico , Cobre/química , Cobre/farmacocinética , Cobre/uso terapêutico , Dissulfiram/administração & dosagem , Dissulfiram/química , Dissulfiram/uso terapêutico , Quimioterapia Combinada , Humanos , Lipossomos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fosfatidilcolinas/química , Carga Tumoral/efeitos dos fármacosRESUMO
To administer cancer drugs with improved convenience to patients and to enhance the bioavailability of cancer drugs for oral cancer therapy, this study prepared gellan gum/glucosamine/clioquinol (GG/GS/CQ) film as the oral cancer treatment patch. GG/GS/CQ film fabricated through the EDC-mediated coupling reactions (GG/GS/CQ/EDC film). The film of the physicochemical properties and drug release kinetics were studied. The effectiveness of GG/GS/CQ/EDC film as oral cancer treatment patch were evaluated with the animal model. The results confirmed that CQ can be incorporated via EDC-mediated covalent conjugation to gellan gum/glucosamine. Mechanical testing revealed that the maximum tensile strength and elongation percentage at break were 1.91kgf/mm2 and 5.01% for GG/GS/CQ/EDC film. After a drug release experiment lasting 45days, 86.8% of CQ was released from GG/GS/CQ/EDC film. The Huguchi model fit the GG/GS/CQ/EDC drug release data with high correlation coefficients (R2=0.9994, respectively). The effect of the CQ dose on oral cancer cells (OC-2) was tested, and the IC50 of CQ alone and CQ with 10µM CuCl2 were 9.59 and 2.22µM, respectively. The animal testing indicated that GG/GS/CQ/EDC film was decreased epidermal growth factor receptor (EGFR) expression and suppress tumor progression. These findings provide insights into a possible use for GG/GS/CQ/EDC film for oral ca in clinical practice. The GG/GS/CQ/EDC film is suitable as the dressing for use in the treatment of early-stage cancer or as wound care after surgery in late-stage of oral cancer treatment.
Assuntos
Antineoplásicos/química , Clioquinol/química , Portadores de Fármacos/química , Glucosamina/química , Polissacarídeos Bacterianos/química , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Carbodi-Imidas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Clioquinol/uso terapêutico , Clioquinol/toxicidade , Cobre/química , Cobre/toxicidade , Cricetinae , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Receptores ErbB/metabolismo , Humanos , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/patologia , Espectroscopia de Infravermelho com Transformada de Fourier , Resistência à TraçãoAssuntos
Acetiltransferases/antagonistas & inibidores , Amicacina/farmacologia , Antibacterianos/farmacologia , Clioquinol/química , Clioquinol/farmacologia , Farmacorresistência Bacteriana/genética , Zinco/química , Zinco/farmacologia , Acetiltransferases/metabolismo , Acinetobacter baumannii/efeitos dos fármacos , Antineoplásicos/farmacologia , Ionóforos , Testes de Sensibilidade Microbiana , Doenças Neurodegenerativas/tratamento farmacológicoRESUMO
Vanadium compounds were studied in recent years by considering them as a representative of a new class of non-platinum metal anticancer drugs. However, a few challenges still remain in the discovery of new molecular targets of these new metallodrugs. Studies on cell signaling pathways related to vanadium compounds have scarcely been reported and so far this information is highly critical for identifying novel targets that play a key role in the antitumor actions of vanadium complexes. This research deals with the alterations in the intracellular signaling pathways promoted by an oxovanadium(iv) complex with the clioquinol (5-chloro-7-iodo-8-quinolinol), VO(CQ)2, on a human osteosarcoma cell line (MG-63). Herein are reported, for the first time, the antitumor properties of VO(CQ)2 and the relative abundance of 224 proteins (which are involved in most of the common intracellular pathways) to identify novel targets of the studied complex. Besides, full-length human recombinant AKT1 kinase was produced by using an IVTT system to evaluate the variation of relative tyrosin-phosphorylation levels caused by this compound. The results of the differential protein expression levels reveal several up-regulated proteins such as CASP3, CASP6, CASP7, CASP10, CASP11, Bcl-x, DAPK and down-regulated ones, such as PKB/AKT, DIABLO, among others. Moreover, cell signaling pathways involved in several altered pathways related to the PKC and AP2 family have been identified in both treatments (2.5 and 10 µM) suggesting the crucial antitumoral role of VO(CQ)2. Finally, it has been demonstrated that this compound (10 µM, 6 h) triggers a decrease of 2-fold in in situ AKT1 expression.
Assuntos
Antineoplásicos/farmacologia , Clioquinol/farmacologia , Osteossarcoma/patologia , Transdução de Sinais/efeitos dos fármacos , Compostos de Vanádio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Clioquinol/síntese química , Clioquinol/química , Perfilação da Expressão Gênica , Humanos , Reprodutibilidade dos Testes , Compostos de Vanádio/síntese química , Compostos de Vanádio/químicaRESUMO
Amyloid ß (Aß) fibrils and amorphous aggregates are found in the brain of patients with Alzheimer's disease (AD), and are implicated in the etiology of AD. The metal imbalance is also among leading causes of AD, owing to the fact that Aß aggregation takes place in the synaptic cleft where Aß, Cu(II) and Fe(III) are found in abnormally high concentrations. Aß40 and Aß42 are the main components of plaques found in afflicted brains. Coordination of Cu(II) and Fe(III) ions to Aß peptides have been linked to Aß aggregation and production of reactive oxygen species, two key events in the development of AD pathology. Metal chelation was proposed as a therapy for AD on the basis that it might prevent Aß aggregation. In this work, we first examined the formation of Aß40 and Aß42 aggregates in the presence of metal ions, i.e. Fe(III) and Cu(II), which were detected by fluorescence spectroscopy and atomic force microscopy. Second, we studied the ability of the two chelators, ethylenediaminetetraacetic acid and 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol), to investigate their effect on the availability of these metal ions to interact with Aß and thereby their effect on Aß accumulation. Our findings show that Fe(III), but not Cu(II), promote aggregation of both Aß40 and Aß42. We also found that only clioquinol decreased significantly iron ion-induced aggregation of Aß42. The presence of ions and/or chelators also affected the morphology of Aß aggregates.
Assuntos
Peptídeos beta-Amiloides/química , Clioquinol/química , Cobre/química , Ácido Edético/química , Ferro/química , Fragmentos de Peptídeos/química , Cátions , Quelantes/química , Clioquinol/farmacologia , Ácido Edético/farmacologia , Humanos , Microscopia de Força Atômica , Agregados Proteicos/efeitos dos fármacos , SoluçõesRESUMO
The development of copper-drug complexes (CDCs) is hindered due to their very poor aqueous solubility. Diethyldithiocarbamate (DDC) is the primary metabolite of disulfiram, an approved drug for alcoholism that is being repurposed for cancer. The anticancer activity of DDC is dependent on complexation with copper to form copper bis-diethyldithiocarbamate (Cu(DDC)2), a highly insoluble complex that has not been possible to develop for indications requiring parenteral administration. We have resolved this issue by synthesizing Cu(DDC)2 inside liposomes. DDC crosses the liposomal lipid bilayer, reacting with the entrapped copper; a reaction that can be observed through a colour change as the solution goes from a light blue to dark brown. This method is successfully applied to other CDCs including the anti-parasitic drug clioquinol, the natural product quercetin and the novel targeted agent CX-5461. Our method provides a simple, transformative solution enabling, for the first time, the development of CDCs as viable candidate anticancer drugs; drugs that would represent a brand new class of therapeutics for cancer patients.
Assuntos
Antineoplásicos/síntese química , Cobre/química , Ditiocarb/química , Nanotecnologia , Neoplasias/patologia , Animais , Antineoplásicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Benzotiazóis/química , Benzotiazóis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Clioquinol/química , Clioquinol/farmacologia , Cobre/metabolismo , Ditiocarb/metabolismo , Feminino , Humanos , Lipossomos , Camundongos , Naftiridinas/química , Naftiridinas/farmacologia , Neoplasias/tratamento farmacológico , Quercetina/química , Quercetina/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Copper and zinc have been found to contribute to the burden of amyloid-ß (Aß) aggregations in neurodegenerative Alzheimer's disease (AD). Dysregulation of these metals leads to the generation of reactive oxygen species (ROS) and eventually results in oxidative damage and accumulation of the Aß peptide, which are the key elements of the disease. Aiming to pursue the discovery of new modulators for the disease, we here rationally focused on conjugating the core hydroxyquinoline of the metal-protein attenuating compound PBT2 and the N-methylanilide analogous moiety of the Aß imaging agent to build a new type of multi-target modulators of Aß aggregations. We found that the N,N-dimethylanilinyl imines 7a, 8a, and the corresponding amines 7b, 8b exerted efficient inhibition of Cu(2+) - or Zn(2+) -induced Aß aggregations and significant disassembly of metal-mediated Aß aggregated fibrils. Further, 7a and 7b also exhibited significant ROC scavenging effects compared to PBT2. The results suggested that 7a and 7b are promising lead compounds for the development of a new therapy for AD.
Assuntos
Peptídeos beta-Amiloides/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Hidroxiquinolinas/química , Hidroxiquinolinas/uso terapêutico , Agregação Patológica de Proteínas/tratamento farmacológico , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/ultraestrutura , Quelantes/síntese química , Quelantes/farmacologia , Quelantes/uso terapêutico , Clioquinol/análogos & derivados , Clioquinol/química , Clioquinol/farmacologia , Clioquinol/uso terapêutico , Cobre/efeitos adversos , Hidroxiquinolinas/síntese química , Hidroxiquinolinas/farmacologia , Relação Estrutura-Atividade , Zinco/efeitos adversosRESUMO
Metal ionophores are considered as potential anti-dementia agents, and some are currently undergoing clinical trials. Many metals are known to accumulate and distribute abnormally in the aging brain. Alterations in zinc metal homeostasis in the glutaminergic synapse could contribute to ageing and the pathophysiology of Alzheimer's disease (AD). The present study was designed to investigate the effect of metal ionophores on long term administration of zinc in D-galactose induced senescent mice. The ageing model was established by combined administration of zinc and D-galactose to mice for 6 weeks. A novel metal ionophore, PBT-2 was given daily to zinc-induced d-galactose senescent mice. The cognitive behaviour of mice was monitored using the Morris Water Maze. The anti-oxidant status and amyloidogenic activity in the ageing mouse was measured by determining mito-oxidative parameters and deposition of amyloid ß (Aß) in the brain. Systemic administration of both zinc and D-galactose significantly produced memory deficits, mito-oxidative damage, heightened acetylcholinesterase enzymatic activity and deposition of amyloid-ß. Treatment with PBT-2 significantly improved behavioural deficits, biochemical profiles, cellular damage, and curbed the deposition of APP in zinc-induced senescent mice. These findings suggest that PBT-2, acting as a metal protein attenuating compound, may be helpful in the prevention of AD or alleviation of ageing.
Assuntos
Envelhecimento , Clioquinol/análogos & derivados , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/prevenção & controle , Galactose/farmacologia , Sulfato de Zinco/farmacologia , Administração Oral , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/química , Animais , Clioquinol/administração & dosagem , Clioquinol/química , Clioquinol/farmacologia , Clioquinol/uso terapêutico , Transtornos Cognitivos/metabolismo , Relação Dose-Resposta a Droga , Galactose/administração & dosagem , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos , Sulfato de Zinco/administração & dosagemRESUMO
Recently, phosphodiesterase-9 (PDE9) inhibitors and biometal-chelators have received much attention as potential therapeutics for the treatment of Alzheimer's disease (AD). Here, we designed, synthesized, and evaluated a novel series of PDE9 inhibitors with the ability to chelate metal ions. The bioassay results showed that most of these molecules strongly inhibited PDE9 activity. Compound 16 showed an IC50 of 34 nM against PDE9 and more than 55-fold selectivity against other PDEs. In addition, this compound displayed remarkable metal-chelating capacity and a considerable ability to halt copper redox cycling. Notably, in comparison to the reference compound clioquinol, it inhibited metal-induced Aß(1-42) aggregation more effectively and promoted greater disassembly of the highly structured Aß fibrils generated through Cu(2+)-induced Aß aggregation. These activities of 16, together with its favorable blood-brain barrier permeability, suggest that 16 may be a promising compound for treatment of AD.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Quelantes/química , Fragmentos de Peptídeos/metabolismo , Inibidores de Fosfodiesterase/química , Pirazóis/química , Pirimidinonas/química , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Barreira Hematoencefálica/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quelantes/farmacologia , Quelantes/uso terapêutico , Clioquinol/química , Clioquinol/farmacologia , Cobre/química , Humanos , Microscopia Eletrônica de Transmissão , Simulação de Acoplamento Molecular , Fragmentos de Peptídeos/antagonistas & inibidores , Permeabilidade/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Estrutura Terciária de Proteína , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêuticoRESUMO
We discovered a small series of hit compounds that show multitargeting activities against key targets in Alzheimer's disease (AD). The compounds were designed by combining the structural features of the anti-AD drug donepezil with clioquinol, which is able to chelate redox-active metals, thus decreasing metal-driven oxidative phenomena and ß-amyloid (Aß)-mediated neurotoxicity. The majority of the new hybrid compounds selectively target human butyrylcholinesterase at micromolar concentrations and effectively inhibit Aß self-aggregation. In addition, compounds 5-chloro-7-((4-(2-methoxybenzyl)piperazin-1-yl)methyl)-8-hydroxyquinoline (1 b), 7-((4-(2-methoxybenzyl)piperazin-1-yl)methyl)-8-hydroxyquinoline (2 b), and 7-(((1-benzylpiperidin-4-yl)amino)methyl)-5-chloro-8-hydroxyquinoline (3 a) are able to chelate copper(II) and zinc(II) and exert antioxidant activity inâ vitro. Importantly, in the case of 2 b, the multitarget profile is accompanied by high predicted blood-brain barrier permeability, low cytotoxicity in T67 cells, and acceptable toxicity in HUVEC primary cells.