Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Med Chem ; 53(13): 4849-61, 2010 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-20527971

RESUMO

Our group has demonstrated that the amphiphilic character of alpha-phenyl-N-tert-butyl nitrone based agents is a key feature in determining their bioactivity and protection against oxidative toxicity. In this work, we report the synthesis of a new class of amphiphilic amide nitrones. Their hydroxyl radical scavenging activity and radical reducing potency were shown using ABTS competition and ABTS(+) reduction assays, respectively. Cyclic voltammetry was used to investigate their redox behavior, and the effects of the substitution of the PBN on the charge density of the nitronyl atoms, the electron affinity, and the ionization potential were computationally rationalized. The protective effects of amphiphilic amide nitrones in cell cultures exposed to oxidotoxins greatly exceeded those exerted by the parent compound PBN. They decreased electron and proton leakage as well as hydrogen peroxide formation in isolated rat brain mitochondria at nanomolar concentration. They also significantly enhanced mitochondrial membrane potential. Finally, dopamine-induced inhibition of complex I activity was antagonized by pretreatment with these agents. These findings indicate that amphiphilic amide nitrones are much more than just radical scavenging antioxidants but may act as a new class of bioenergetic agents directly on mitochondrial electron and proton transport.


Assuntos
Encéfalo/metabolismo , Mitocôndrias/metabolismo , Óxidos de Nitrogênio/química , Óxidos de Nitrogênio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Tensoativos/farmacologia , Animais , Benzotiazóis/química , Encéfalo/efeitos dos fármacos , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Peróxido de Hidrogênio/química , Espectroscopia de Ressonância Magnética , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Óxidos de Nitrogênio/síntese química , Rotação Ocular , Oxirredução , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray , Ácidos Sulfônicos/química , Tensoativos/síntese química , Tensoativos/química
2.
J Med Chem ; 50(17): 3976-9, 2007 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-17649989

RESUMO

A new series of hydrophilic, lipophilic, and amphiphilic alpha-phenyl-N-tert-butylnitrone (PBN) derivatives were synthesized to explore the relationship between their hydrophilic-lipophilic properties and antioxidant potency. Very potent protective effects of amphiphilic lactobionamide and tris(hydroxymethyl)aminomethane PBN derivatives were observed in mitochondrial preparations, in cell cultures, and in rotifers exposed to unspecific and mitochondria targeted oxidotoxins.


Assuntos
Antioxidantes/síntese química , Óxidos N-Cíclicos/química , Óxidos de Nitrogênio/síntese química , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Células Cultivadas , Dissacarídeos/síntese química , Dissacarídeos/química , Dissacarídeos/farmacologia , Desenho de Fármacos , Complexo I de Transporte de Elétrons/metabolismo , Técnicas In Vitro , Óxidos de Nitrogênio/química , Óxidos de Nitrogênio/farmacologia , Ratos , Rotíferos/efeitos dos fármacos , Relação Estrutura-Atividade , Partículas Submitocôndricas/efeitos dos fármacos , Partículas Submitocôndricas/metabolismo , Trometamina/análogos & derivados , Trometamina/síntese química , Trometamina/química , Trometamina/farmacologia
3.
Environ Toxicol ; 22(1): 33-43, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17295279

RESUMO

The quinalphos metabolite 2-hydroxyquinoxaline (HQO), previously shown to photocatalytically destroy antioxidant vitamins and biogenic amines in vitro, was tested for toxicity in several small aquatic organisms and for mutagenicity in Salmonella typhimurium. In the rotifer Philodina acuticornis, HQO caused the disappearance of large individuals and increased hydroperoxide concentration. The latter effect was not only observed in animals kept in a light/dark cycle, but also in constant darkness, indicating that HQO can assume a reactive state and/or form reactive intermediates under the influence of either light or redox-active metabolites, in particular, free radicals. Cell proliferation was inhibited in the ciliate Paramecium bursaria. In the dinoflagellate Lingulodinium polyedrum, which allows early detection of cellular stress on the basis of bioluminescence measurements, strong rises in light emission became apparent on the 2nd day of exposure to HQO and continued until cells died between 12 and 18 days of treatment. Oxidative damage of protein by HQO was demonstrated by measuring protein carbonyl in L. polyedrumin vivo as well as in light-exposed bovine serum albumin in vitro. In an Ames test of mutagenicity, HQO proved to be genotoxic in both light- and dark-exposed bacteria. HQO appears as a source of secondary quinalphos toxicity, which deserves further attention.


Assuntos
Proliferação de Células/efeitos dos fármacos , Dinoflagellida/efeitos dos fármacos , Compostos Organotiofosforados/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Paramecium/efeitos dos fármacos , Quinoxalinas/toxicidade , Salmonella typhimurium/efeitos dos fármacos , Animais , Dinoflagellida/genética , Dinoflagellida/crescimento & desenvolvimento , Inseticidas/metabolismo , Inseticidas/toxicidade , Luz , Medições Luminescentes , Testes de Mutagenicidade , Compostos Organotiofosforados/metabolismo , Oxirredução , Paramecium/genética , Paramecium/crescimento & desenvolvimento , Quinoxalinas/metabolismo , Salmonella typhimurium/genética , Salmonella typhimurium/crescimento & desenvolvimento , Fatores de Tempo
4.
J Med Chem ; 49(9): 2812-20, 2006 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-16640342

RESUMO

The use of classical antioxidants is limited by their low bioavailabilities, and therefore, high doses are usually required to display significant protective activity. In a recent article (J. Med. Chem. 2003, 46, 5230) we showed that the ability of the alpha-phenyl-N-tert-butylnitrone (PBN) to restore the viability of ATPase-deficient human skin fibroblasts was greatly enhanced by grafting it on a fluorinated amphiphilic carrier. With the aim of extending this concept to other antioxidants, we present here the design, the synthesis, and the physicochemical measurements of a new series of fluorinated amphiphilic antioxidant derivatives. The hydroxyl radical scavenging activity and the radical reducing potency of these newly designed compounds were respectively demonstrated in an ABTS competition and an ABTS(*+) reduction assay. We also showed that the protective effects of amphiphilic antioxidants derived from PBN, Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) or lipoic acid (5-[1,2]-dithiolan-3-ylpentanoic acid) in primary cortical mixed cell cultures exposed to oxidotoxins are greatly improved compared to their parent compounds in the following rank-order: (1) PBN, (2) Trolox, and (3) lipoic acid. In contrast, the protective activity of indole-3-propionic acid was slightly decreased by grafting it on the amphiphilic carrier. Similar observations were made in in vivo experiments using aquatic invertebrate microorganisms, called rotifers, which were exposed to lethal concentrations of nonselective (H(2)O(2)) and mitochondria-selective (doxorubicin) oxidotoxins. The conclusion of these studies is that fluorinated amphiphilic PBN, Trolox, and lipoic acid derivatives exhibit very potent protective activities in in vitro and in vivo experiments. The findings demonstrated herein therefore strongly suggest that the amphiphilic character enhances the bioavailability of the antioxidants and allows for a selective targeting of mitochondria.


Assuntos
Aminoácidos/química , Aminoácidos/farmacologia , Antioxidantes/química , Flúor/química , Substâncias Protetoras/síntese química , Substâncias Protetoras/farmacologia , Tensoativos/química , Aminoácidos/síntese química , Animais , Morte Celular/efeitos dos fármacos , Células Cultivadas , Fenômenos Químicos , Físico-Química , Doxorrubicina/toxicidade , Peróxido de Hidrogênio/farmacologia , Peróxido de Hidrogênio/toxicidade , Estrutura Molecular , Oxirredução , Substâncias Protetoras/química , Substâncias Protetoras/classificação , Tensoativos/síntese química , Tensoativos/classificação , Tensoativos/farmacologia
5.
J Neurochem ; 95(4): 962-73, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16135084

RESUMO

The search for effective treatments that prevent oxidative stress associated with premature ageing and neurodegenerative diseases is an important area of neurochemical research. As age- and disease-related oxidative stress is frequently associated with mitochondrial dysfunction, amphiphilic antioxidant agents of high stability and selectivity that target these organelles can provide on-site protection. Such an amphiphilic nitrone protected human neuroblastoma cells at low micromolar concentrations against oxidative damage and death induced by exposure to the beta-amyloid peptide, hydrogen peroxide and 3-hydroxykynurenine. Daily administration of the antioxidant at a concentration of only 5 mum significantly increased the lifespan of the individually cultured rotifer Philodina acuticornis odiosa Milne. This compound is unique in its exceptional anti-ageing efficacy, being one order of magnitude more potent than any other compound previously tested on rotifers. The nitrone protected these aquatic animals against the lethal toxicity of hydrogen peroxide and doxorubicin and greatly enhanced their survival when co-administered with these oxidotoxins. These findings indicate that amphiphilic antioxidants have a great potential as neuroprotective agents in preventing the death of cells and organisms exposed to enhanced oxidative stress and damage.


Assuntos
Dissacarídeos/uso terapêutico , Iminas/uso terapêutico , Expectativa de Vida , Doenças Mitocondriais/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Óxidos de Nitrogênio/uso terapêutico , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Peptídeos beta-Amiloides/toxicidade , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diagnóstico por Imagem/métodos , Dissacarídeos/síntese química , Dissacarídeos/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , Peróxido de Hidrogênio/toxicidade , Iminas/síntese química , Iminas/química , Doenças Mitocondriais/induzido quimicamente , Doenças Mitocondriais/mortalidade , Neuroblastoma , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Óxidos de Nitrogênio/síntese química , Óxidos de Nitrogênio/química , Estresse Oxidativo/efeitos dos fármacos , Rotíferos/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...