RESUMO
Ferroptosis is an iron-catalyzed, nonapoptotic form of regulated necrosis that has been implicated in the pathological cell death associated with various disorders including neurodegenerative diseases (e.g., Friedreich's ataxia (FRDA), Alzheimer's disease, and Parkinson's disease), stroke, and traumatic brain injury. Recently, we showed that lipophilic methylene blue (MB) and methylene violet (MV) analogues both promoted increased frataxin levels and mitochondrial biogenesis, in addition to their antioxidant activity in cultured FRDA cells. Presently, we report the synthesis of series of lipophilic phenothiazine analogues that potently inhibit ferroptosis. The most promising compounds (1b-5b) exhibited an improved protection compared to the parent phenothiazine against erastin- and RSL3-induced ferroptotic cell death. These analogues have equivalent or better potency than ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1), that are among the most potent inhibitors of this regulated cell death described so far. They represent novel lead compounds with therapeutic potential in relevant ferroptosis-driven disease models such as FRDA.
RESUMO
There has been little innovation in identifying novel insulin sensitizers. Metformin, developed in the 1920s, is still used first for most Type 2 diabetes patients. Mice with genetic reduction of p52Shc protein have improved insulin sensitivity and glucose tolerance. By high-throughput screening, idebenone was isolated as the first small molecule 'Shc Blocker'. Idebenone blocks p52Shc's access to Insulin Receptor to increase insulin sensitivity. In this work the avidity of 34 novel idebenone analogs and 3 metabolites to bind p52Shc, and to block the interaction of p52Shc with the Insulin receptor was tested. Our hypothesis was that if an idebenone analog bound and blocked p52Shc's access to insulin receptor better than idebenone, it should be a more effective insulin sensitizing agent than idebenone itself. Of 34 analogs tested, only 2 both bound p52Shc more tightly and/or blocked the p52Shc-Insulin Receptor interaction more effectively than idebenone. Of those 2 only idebenone analog #11 was a superior insulin sensitizer to idebenone. Also, the long-lasting insulin-sensitizing potency of idebenone in rodents over many hours had been puzzling, as the parent molecule degrades to metabolites within 1 h. We observed that two of the idebenone's three metabolites are insulin sensitizing almost as potently as idebenone itself, explaining the persistent insulin sensitization of this rapidly metabolized molecule. These results help to identify key SAR = structure-activity relationship requirements for more potent small molecule Shc inhibitors as Shc-targeted insulin sensitizers for type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor de Insulina/metabolismo , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/genética , Ubiquinona/análogos & derivados , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Insulina/metabolismo , Resistência à Insulina , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ubiquinona/química , Ubiquinona/farmacologiaRESUMO
DNA polymerase ß (Pol ß) repairs cellular DNA damage. When such damage is inflicted upon the DNA in tumor cells treated with DNA targeted antitumor agents, Pol ß thus diminishes their efficacy. Accordingly, this enzyme has long been a target for antitumor therapy. Although numerous inhibitors of the lyase activity of the enzyme have been reported, none has yet proven adequate for development as a therapeutic agent. In the present study, we developed a new strategy to identify lyase inhibitors that critically engage the lyase active site primary nucleophile Lys72 as part of the binding interface. This involves a parallel evaluation of the effect of the inhibitors on the wild-type DNA polymerase ß (Pol ß) and Pol ß modified with a lysine analogue at position 72. A model panel of five structurally diverse lyase inhibitors identified in our previous studies (only one of which has been published) with unknown modes of binding were used for testing, and one compound, cis-9,10-epoxyoctadecanoic acid, was found to have the desired characteristics. This finding was further corroborated by in silico docking, demonstrating that the predominant mode of binding of the inhibitor involves an important electrostatic interaction between the oxygen atom of the epoxy group and Nε of the main catalytic nucleophile, Lys72. The strategy, which is designed to identify compounds that engage certain structural elements of the target enzyme, could find broader application for identification of ligands with predetermined sites of binding.
Assuntos
DNA Polimerase beta/metabolismo , Ácidos Esteáricos/metabolismo , Sítios de Ligação , Domínio Catalítico , DNA Polimerase beta/antagonistas & inibidores , DNA Polimerase beta/genética , Humanos , Ligantes , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Ligação Proteica , Ácidos Esteáricos/químicaRESUMO
Mitochondrial dysfunction is associated with a wide range of human diseases, including neurodegenerative diseases, and is believed to cause or contribute to the etiology of these diseases. These disorders are frequently associated with increased levels of reactive oxygen species. One of the design strategies for therapeutic intervention involves the development of novel small molecules containing redox cores, which can scavenge reactive oxygen radicals and selectively block oxidative damage to the mitochondria. Presently, we describe recent research dealing with multifunctional radical quenchers as antioxidants able to scavenge reactive oxygen radicals. The review encompasses ubiquinone and tocopherol analogs, as well as novel pyri(mi)dinol derivatives, and their ability to function as protective agents in cellular models of mitochondrial diseases.
Assuntos
Antioxidantes/farmacologia , Mitocôndrias/efeitos dos fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antioxidantes/química , Humanos , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Bibliotecas de Moléculas Pequenas/químicaRESUMO
Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease that is linked to transcriptional repression of the nuclear FXN gene encoding the essential mitochondrial protein frataxin (FXN). Compounds that increase frataxin levels may enable effective therapeutic intervention for blunting disease progression. Recently, we showed that lipophilic methylene violet (MV) and methylene blue (MB) analogues both conferred benefit to cultured FRDA cells in several regards, including ROS suppression, maintenance of mitochondrial membrane potential and increased ATP production. Some of the MB analogues were also shown to promote increased frataxin levels and mitochondrial biogenesis. Presently, we report that two of the MV analogues studied previously (1 and 2) also increased frataxin levels and mitochondrial biogenesis significantly. Because the substitution pattern in the two series of compounds was not the same, we also prepared new MV derivatives having the same substitution pattern as the original MB derivatives studied to enable a more direct comparison. Two of the new MV compounds, 4b and 6b, exhibited enhanced antioxidant capability, increased frataxin levels and mitochondrial biogenesis, and improved aconitase activity. These encouraging findings demonstrated that the MV analogues had better overall activity with less cytotoxicity.
RESUMO
As part of an ongoing program to develop potential therapeutic agents for the treatment of the neurodegenerative disease Friedreich׳s ataxia (FRDA), we have prepared a number of lipophilic methylene blue analogues. Some of these compounds significantly increase mitochondrial biogenesis and frataxin levels in cultured Friedreich's ataxia cells [1]. This data article describes the chemical synthesis and full physicochemical characterization of the new analogues.
RESUMO
Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder resulting from reduced expression of the protein frataxin (FXN). Although its function is not fully understood, frataxin appears to help assemble iron sulfur clusters; these are critical for the function of many proteins, including those needed for mitochondrial energy production. Finding ways to increase FXN levels has been a major therapeutic strategy for this disease. Previously, we described a novel series of methylene violet analogues and their structural optimization as potential therapeutic agents for neurodegenerative and mitochondrial disorders. Presently, a series of methylene blue analogues has been synthesized and characterized for their in vitro biochemical and biological properties in cultured Friedreich's ataxia lymphocytes. Favorable methylene blue analogues were shown to increase frataxin levels and mitochondrial biogenesis, and to improve aconitase activity. The analogues were found to be good ROS scavengers, and able to protect cultured FRDA lymphocytes from oxidative stress resulting from inhibition of complex I and from glutathione depletion. The analogues also preserved mitochondrial membrane potential and augmented ATP production. Our results suggest that analogue 5, emerging from the initial structure of the parent compound methylene blue (MB), represents a promising lead structure and lacks the cytotoxicity associated with the parent compound MB.
Assuntos
Proteínas de Ligação ao Ferro/metabolismo , Azul de Metileno/análogos & derivados , Mitocôndrias/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Complexo I de Transporte de Elétrons/metabolismo , Ataxia de Friedreich/metabolismo , Ataxia de Friedreich/patologia , Glutationa/metabolismo , Humanos , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Azul de Metileno/farmacologia , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , FrataxinaRESUMO
INTRODUCTION: Our laboratories have demonstrated that accumulation of oligomeric amyloid ß (OAß) in neurons is an essential step leading to OAß-mediated mitochondrial dysfunction. METHODS: Alzheimer's disease (AD) and matching control hippocampal neurons, astrocytes, and microglia were isolated by laser-captured microdissection from the same subjects, followed by whole-transcriptome sequencing. Complementary in vitro work was performed in OAß-treated differentiated SH-SY5Y, followed by the use of a novel CoQ10 analogue for protection. This compound is believed to be effective both in suppressing reactive oxygen species and also functioning in mitochondrial electron transport. RESULTS: We report decreases in the same mitochondrial-encoded mRNAs in Alzheimer's disease laser-captured CA1 neurons and in OAß-treated SH-SY5Y cells, but not in laser-captured microglia and astrocytes. Pretreatment with a novel CoQ10 analogue, protects neuronal mitochondria from OAß-induced mitochondrial changes. DISCUSSION: Similarity of expression changes in neurons from Alzheimer's disease brain and neuronal cells treated with OAß, and the effect of a CoQ10 analogue on the latter, suggests a pretreatment option to prevent OAß toxicity, long before the damage is apparent.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Neurônios/metabolismo , RNA Mensageiro/metabolismo , RNA Mitocondrial/metabolismo , Idoso , Doença de Alzheimer/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Linhagem Celular Tumoral , Feminino , Hipocampo/metabolismo , Humanos , Técnicas In Vitro , Microdissecção e Captura a Laser , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microscopia Eletrônica de Transmissão , Neurônios/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mitocondrial/genética , Ubiquinona/análogos & derivados , Ubiquinona/farmacologiaRESUMO
In an effort to identify methylene blue analogues having improved antioxidant activity, a series of new methylene violet analogues have been designed and synthesized. The analogues were prepared following a synthetic route that is more efficient than the previously reported methods, both in terms of yield and purity of the final products. The route involves the Smiles rearrangement as one of the crucial steps. Smiles rearrangement of suitably substituted diphenyl sulfide intermediates afforded the corresponding phenothiazine analogues in high yields, which were subsequently converted to the final products. The methylene violet analogues were evaluated for their ability to preserve mitochondrial function in Friedreich's ataxia (FRDA) lymphocytes. The analogues were shown to be efficient ROS scavengers, and able to protect cultured FRDA lymphocytes from oxidative stress resulting from inhibition of complex I. The analogues also preserved mitochondrial membrane potential and augmented ATP production. The analogues were found to be better antioxidants than the parent compounds methylene blue and methylene violet.
Assuntos
Mitocôndrias/efeitos dos fármacos , Fenotiazinas/farmacologia , Trifosfato de Adenosina/biossíntese , Células Cultivadas , Humanos , Interações Hidrofóbicas e Hidrofílicas , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fenotiazinas/síntese química , Fenotiazinas/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
In a recent study, several new derivatives of antimycin A (AMA) were produced by means of a novel transacylation reaction, and these were shown to mediate selective toxicity toward cultured A549 human lung epithelial adenocarcinoma cells, as compared with WI-38 normal human lung fibroblasts. The purpose of our study was to investigate whether the analogues all expressed their cytotoxicity by the same mechanism. This was done by studying the effects of the compounds in several types of cell lines. In comparison with 2-O-methylantimycin, which acts at the locus of Bcl-2, none of the new derivatives exhibited a difference in cytotoxicity toward cells expressing different levels of Bcl-2. In cell lines that over- or underexpress estrogen or Her2 receptors, AMA analogue 2 exhibited Her2 receptor dependency at low concentration. Three compounds (1, 4, and 6) exhibited concentration-dependent increases in reactive oxygen species, with 6 being especially potent. Compounds 5 and 6 diminished mitochondrial membrane potential more potently than AMA, and 1 also displayed enhanced activity relative to 2-4. Interestingly, only 1 and AMA displayed strong inhibition of the respiratory chain, as measured by monitoring NADH (reduced nicotinamide adenine dinucleotide) oxidase. Because four of the analogues have positively charged substituents, two of these (4 and 6) were studied to see whether the observed effects were due to much higher level of accumulation within the mitochondria. Their presence in the mitochondria was not dramatically enhanced. Neither of the two presently characterized mechanisms of cell killing by AMA can fully account for the observed results.
Assuntos
Antimicina A/análogos & derivados , Citotoxinas/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Complexos Multienzimáticos/antagonistas & inibidores , NADH NADPH Oxirredutases/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Acilação , Animais , Antimicina A/química , Ácido Ascórbico/análogos & derivados , Ácido Ascórbico/farmacologia , Bovinos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citotoxinas/química , Fibroblastos/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genéticaRESUMO
Recently, we described the optimization of novel pyrimidinol-based antioxidants as potential therapeutic molecules for targeting mitochondrial diseases. That study focused on improving the potency and metabolic stability of pyrimidinol antioxidants. This led us to consider the possibility of altering the positions of the exocyclic alkoxy and alkylamino substituents on the pyrimidinol scaffold. Twelve new analogues were prepared and their biological activities were investigated. The metabolic stability of the prepared regioisomers was also assessed in vitro using bovine liver microsomes. Unexpectedly, the 2-alkoxy-4-alkylamino substituted pyrimidinol antioxidants were found to have properties in protecting mitochondrial function superior to the isomeric 4-alkoxy-2-alkylamino substituted pyrimidinols evaluated in all earlier studies. This observation suggests a possible mode of action involving the intermediacy of an ortho-iminoquinone, a species not previously associated with mitochondrial respiratory chain function.
Assuntos
Antioxidantes/farmacologia , Citoproteção/efeitos dos fármacos , Pirimidinas/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Bovinos , Espectrometria de Massas , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
INTRODUCTION: We have comprehensively described the expression profiles of mitochondrial DNA and nuclear DNA genes that encode subunits of the respiratory oxidative phosphorylation (OXPHOS) complexes (I-V) in the hippocampus from young controls, age matched, mild cognitively impaired (MCI), and Alzheimer's disease (AD) subjects. METHODS: Hippocampal tissues from 44 non-AD controls (NC), 10 amnestic MCI, and 18 AD cases were analyzed on Affymetrix Hg-U133 plus 2.0 arrays. RESULTS: The microarray data revealed significant down regulation in OXPHOS genes in AD, particularly those encoded in the nucleus. In contrast, there was up regulation of the same gene(s) in MCI subjects compared to AD and ND cases. No significant differences were observed in mtDNA genes identified in the array between AD, ND, and MCI subjects except one mt-ND6. DISCUSSION: Our findings suggest that restoration of the expression of nuclear-encoded OXPHOS genes in aging could be a viable strategy for blunting AD progression.
Assuntos
Envelhecimento/genética , Doença de Alzheimer/genética , Transtornos Cognitivos/genética , Mitocôndrias/genética , Fosforilação Oxidativa , Adulto , Idoso de 80 Anos ou mais , Autopsia , Feminino , Hipocampo , Humanos , Masculino , Análise de Sequência com Séries de OligonucleotídeosRESUMO
Previously we described a novel series of pyrimidinol antioxidants and their structural optimization as potential therapeutic agents for neurodegenerative and mitochondrial disorders. Our initial lead compound was a potent antioxidant in vitro, but was subsequently found to exhibit poor stability to oxidative metabolism. The current study focused on balancing potency with metabolic stability through structural modification, and involved modifications at positions 2 and 4 of the pyrimidinol redox core, likely sites of oxidative metabolism. Eight new analogues have been prepared and their ability to suppress lipid peroxidation and reactive oxygen species (ROS), and to preserve mitochondrial membrane potential (Δψm) and support ATP production, has been investigated. The metabolic stability of the prepared compounds was also assessed in vitro using bovine liver microsomes to obtain preliminary insight on this class of compounds. This study revealed the complexity of balancing reasonable metabolic stability with efficient antioxidant properties. While a few analogues appear promising, especially in terms of metabolic stability, a 4-isopropoxy derivative conserved the favorable biological activity and exhibited good metabolic stability. The favorable metabolic stability conferred by the combination of the azetidine and isopropoxy moieties in analogue 6 makes this compound an excellent candidate for further evaluation.
Assuntos
Trifosfato de Adenosina/biossíntese , Antioxidantes/farmacologia , Microssomos Hepáticos/química , Mitocôndrias/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Pirimidinas/farmacologia , Animais , Antioxidantes/química , Antioxidantes/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Substâncias Protetoras/química , Substâncias Protetoras/metabolismo , Pirimidinas/química , Pirimidinas/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , SuínosRESUMO
Nitroreductase (NTR) activities have been known for decades, studied extensively in bacteria and also in systems as diverse as yeast, trypanosomes, and hypoxic tumors. The putative bacterial origin of mitochondria prompted us to explore the possible existence of NTR activity within this organelle and to probe its behavior in a cellular context. Presently, by using a profluorescent near-infrared (NIR) dye, we characterize the nature of NTR activity localized in mammalian cell mitochondria. Further, we demonstrate that this mitochondrially localized enzymatic activity can be exploited both for selective NIR imaging of mitochondria and for mitochondrial targeting by activating a mitochondrial poison specifically within that organelle. This constitutes a new mechanism for mitochondrial imaging and targeting. These findings represent the first use of mitochondrial enzyme activity to unmask agents for mitochondrial fluorescent imaging and therapy, which may prove to be more broadly applicable.
Assuntos
Mitocôndrias/enzimologia , Nitrorredutases/metabolismo , Células A549 , Antimicina A/análogos & derivados , Antimicina A/química , Antimicina A/farmacologia , Escherichia coli/enzimologia , Corantes Fluorescentes/química , Humanos , Mitocôndrias/efeitos dos fármacos , Estrutura Molecular , Nitrorredutases/genética , Imagem Óptica , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
Acylation of 3-(N-formylamino)salicylic acids resulted in transacylation with loss of the formyl moiety. The reaction proceeds through a bis-N-acylated intermediate, which undergoes facile deformylation. This transacylation reaction has been employed for the site-specific functionalization of the mitochondrial poison antimycin A, affording several novel derivatives. The selective cytotoxicity of some of these derivatives toward cultured A549 human lung epithelial adenocarcinoma cells, in comparison with WI-38 normal human lung fibroblasts, illustrates one application of this transacylation reaction.
RESUMO
Alzheimer's disease is associated with metabolic deficits and reduced mitochondrial function, with the latter due to the effects of oligomeric amyloid beta peptide (AßO) on the respiratory chain. Recent evidence has demonstrated reduction of epigenetic markers, such as DNA methylation, in Alzheimer's disease. Here we demonstrate a link between metabolic and epigenetic deficits via reduction of mitochondrial function which alters the expression of mediators of epigenetic modifications. AßO-induced loss of mitochondrial function in differentiated neuronal cells was reversed using two novel antioxidants (1 and 2); both have been shown to mitigate the effects of reactive oxygen species (ROS), and compound 1 also restores adenosine triphosphate (ATP) levels. While both compounds were effective in reducing ROS, restoration of ATP levels was associated with a more robust response to AßO treatment. Our in vitro system recapitulates key aspects of data from Alzheimer's brain samples, the expression of epigenetic genes in which are also shown to be normalized by the novel analogues.
Assuntos
Peptídeos beta-Amiloides/toxicidade , Antioxidantes/farmacologia , Epigênese Genética/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/toxicidade , Trifosfato de Adenosina/metabolismo , Doença de Alzheimer/metabolismo , Antioxidantes/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Cromatina/efeitos dos fármacos , Cromatina/metabolismo , Epigênese Genética/fisiologia , Histona Acetiltransferases/efeitos dos fármacos , Histona Acetiltransferases/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/fisiologia , Mitocôndrias/fisiologia , Estrutura Molecular , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/fisiologia , Fármacos Neuroprotetores/química , Espécies Reativas de Oxigênio/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/patologia , Sinapses/fisiologia , Lobo Temporal/metabolismoRESUMO
As part of our ongoing efforts to identify compounds having potential utility in treating neurodegenerative and mitochondrial disorders, a series of pyridinol analogues have been prepared. The synthetic route employed for the preparation of the new analogues is different, and considerably more efficient, than that used in previously reported studies. The new route yields a pair of pyridinol regioisomers that can be readily separated and evaluated. Their ability to quench lipid peroxidation and reactive oxygen species (ROS), and to preserve mitochondrial membrane potential (Δψm) and support ATP synthesis is reported. The optimal side chain length was found to be 16 carbon atoms. The metabolic stability of those compounds having optimal biological activities was evaluated in vitro using bovine liver microsomes. The omission of any side chain hydroxyl group and introduction of an azetidine moiety at position 6 of the pyridinol redox core (8 and 9) increased their microsomal stability as compared to the exocyclic dimethylamino group. The favorable metabolic stability conferred by the azetidine moiety in compounds 8 and 9 makes these compounds excellent candidates for further evaluation.
Assuntos
Antioxidantes/farmacologia , Citoproteção/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Piridinas/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/química , Bovinos , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Doenças Mitocondriais/patologia , Estrutura Molecular , Doenças Neurodegenerativas/patologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Piridinas/síntese química , Piridinas/química , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
The effect of the alkyl side chain length of coenzyme Q10 on mitochondrial respiratory chain function has been investigated by the use of synthetic ubiquinone derivatives. Three analogues (3, 4 and 6) were identified that exhibited significantly improved effects on mitochondrial oxygen consumption and mitochondrial membrane potential, and also conferred significant cytoprotection on cultured mammalian cells in which glutathione had been depleted by treatment with diethyl maleate. The analogues also exhibited lesser inhibition of the electron transport chain than idebenone. The results obtained provide guidance for the design of CoQ10 analogues with improved activity compared to that of idebenone (1), the latter of which is undergoing evaluation in the clinic as a therapeutic agent.
Assuntos
Transporte de Elétrons/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Ubiquinona/análogos & derivados , Animais , Bovinos , Linhagem Celular , Linhagem Celular Tumoral , Citoproteção , Transporte de Elétrons/fisiologia , Humanos , Leucemia/metabolismo , Leucemia/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Células Ganglionares da Retina/citologia , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo , Relação Estrutura-Atividade , Ubiquinona/química , Ubiquinona/metabolismo , Ubiquinona/farmacologiaRESUMO
Two new aza analogues of the neuroprotective agent idebenone have been synthesized and characterized. Their antioxidant activity, and ability to augment ATP levels have been evaluated in several different cell lines having suboptimal mitochondrial function. Both compounds were found to be good ROS scavengers, and to protect the cells from oxidative stress induced by glutathione depletion. The compounds were more effective than idebenone in neurodegenerative disease cells. These novel pyrimidinol derivatives were also shown to augment ATP levels in coenzyme Q(10)-deficient human lymphocytes. The more lipophilic side chains attached to the pyrimidinol redox core in these compounds resulted in less inhibition of the electron transport chain and improved antioxidant activity.
Assuntos
Antioxidantes/química , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/química , Pirimidinas/química , Ubiquinona/análogos & derivados , Trifosfato de Adenosina/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/toxicidade , Bovinos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Glutationa/metabolismo , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Mitocôndrias/enzimologia , Complexos Multienzimáticos/antagonistas & inibidores , Complexos Multienzimáticos/metabolismo , NADH NADPH Oxirredutases/antagonistas & inibidores , NADH NADPH Oxirredutases/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/toxicidade , Pirimidinas/síntese química , Pirimidinas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Ubiquinona/síntese química , Ubiquinona/química , Ubiquinona/genética , Ubiquinona/metabolismo , Ubiquinona/toxicidadeRESUMO
The syntheses of a structurally simplified geldanamycin analogue 2 and two related compounds are described. Compound 2 conferred cytoprotection and quenched ROS and lipid peroxidation in a dose-dependent manner in Friedreich's ataxia (FRDA) lymphocytes at low micromolar concentrations. It also prevented ROS-induced damage of cellular lipid membranes and maintained the mitochondrial membrane potential of FRDA lymphocytes. In addition, 2 did not inhibit Hsp90 when tested at micromolar concentrations, exhibited no cytotoxicity, and afforded neuroprotection to differentiated SH-SY5Y cells under conditions of Aß-induced cell toxicity.