RESUMO
A series of hydroquinone monoalkyl ethers was synthesized and evaluated for anti lipid-peroxidation activity in rat liver microsomes. 4-Hexyloxy-2,3,6-trimethylphenol (9), having a low redox potential, as well as ascorbic acid exhibited the strongest anti lipid-peroxidation activity (IC50 = 4.2 x 10(-7) M). Structure-activity relationship studies demonstrated that the inhibitory effect of hydroquinone monoalkyl ethers on lipid peroxidation was increased by the acquisition of an optimum hydrophobicity and decreased by an insufficient or excessive hydrophobicity.
Assuntos
Hidroquinonas/síntese química , Peroxidação de Lipídeos/efeitos dos fármacos , Éteres Fenílicos/síntese química , Animais , Hidroquinonas/farmacologia , Técnicas In Vitro , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Éteres Fenílicos/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
A number of hydroxychalcones were synthesized to evaluate their protective effects against oxidative cell damage and the production of superoxide anion. The hydroxychalcones which have a 3,4-dihydroxycinnamoyl structure were potent inhibitors of lipid peroxidation in rat liver microsomes. In particular, we found that 2',4',3,4-tetrahydroxychalcone (3) exhibited a potent inhibitory effect on H2O2-induced hemolysis due to an antioxidant effect. In addition, this compound strongly inhibited CCl4-induced cytotoxicity in primary cultured hepatocytes and substantially decreased the production of superoxide anion by rat peritoneal exudate macrophages.
Assuntos
Chalcona/análogos & derivados , Chalcona/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Superóxidos/metabolismo , Animais , Tetracloreto de Carbono/toxicidade , Células Cultivadas , Chalcona/síntese química , Chalconas , Hemólise/efeitos dos fármacos , Peróxido de Hidrogênio/toxicidade , Macrófagos Peritoneais/metabolismo , Microssomos Hepáticos/metabolismo , Ratos , Ratos WistarRESUMO
A novel series of 3,4-dihydroxychalcones was synthesized to evaluate their effects against 5-lipoxygenase and cyclooxygenase. Almost all compounds exhibited potent inhibitory effects on 5-lipoxygenase with antioxidative effects, and some also inhibited cyclooxygenase. The 2',5'-disubstituted 3,4-dihydroxychalcones with hydroxy or alkoxy groups exhibited optimal inhibition of cyclooxygenase. We found that 2',5'-dimethoxy-3,4-dihydroxychalcone (37; HX-0836) inhibited cyclooxygenase to the same degree as flufenamic acid and 5-lipoxygenase, more than quercetin. Finally, these active inhibitors of 5-lipoxygenase inhibited arachidonic acid-induced mouse ear edema more than phenidone.
Assuntos
Anti-Inflamatórios/síntese química , Chalcona/análogos & derivados , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Lipoxigenase , Administração Tópica , Animais , Anti-Inflamatórios/uso terapêutico , Ácido Araquidônico , Linhagem Celular , Chalcona/síntese química , Chalcona/farmacologia , Chalcona/uso terapêutico , Chalconas , Inibidores de Ciclo-Oxigenase/farmacologia , Edema/induzido quimicamente , Edema/tratamento farmacológico , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Ovinos , Relação Estrutura-AtividadeRESUMO
Structural modification of ascorbic acid by substitution of the 3-hydroxy group with lipophilic moieties has allowed the development of agents for treating reperfusion injury. These ascorbic acid derivatives inhibited lipid peroxidation, and some of them also reduced coronary reperfusion-induced arrhythmias in anesthetized rats. We found that 3-O-[(dodecylcarbonyl)methyl]ascorbic acid (8) was protective against reperfusion injury without directly influencing hemodynamics. 2-O-Octadecylascorbic acid (19) and 5,6-O-dodecylideneascorbic acid (15) also exhibited a marked effect on reperfusion injury, but significantly reduced the arterial blood pressure and heart rate in rats.
Assuntos
Antiarrítmicos/farmacologia , Arritmias Cardíacas/prevenção & controle , Ácido Ascórbico/análogos & derivados , Sequestradores de Radicais Livres , Traumatismo por Reperfusão Miocárdica/complicações , Anestesia , Animais , Arritmias Cardíacas/etiologia , Ácido Ascórbico/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Cobaias , Átrios do Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Peroxidação de Lipídeos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Ratos Endogâmicos , Verapamil/farmacologiaRESUMO
We previously found that 3-O-dodecylcarbomethylascorbic acid (3-RASA,3,HX-0112) exhibited a potent inhibitory effect on biochemical lipid peroxidation and that 3-RASA (3) alleviated myocardial lesions induced by ischemia-reperfusion treatment in rats. In this study we examined the mode of action of 3-RASA (3) on the inhibition of lipid peroxidation. There was no reducing activity by 3-RASA (3) (i.e., no oxide was produced) against ferric ions and superoxide anion radicals. The low reducing activity of 3-RASA (3) against a radical as compared to that of alpha-tocopherol was obtained by using a stable radical. However, 3-RASA (3) had a potent inhibitory effect, almost equal to that of alpha-tocopherol, in the model of lipid peroxidation dependent on enzymatic superoxide generation. 3-RASA (3) very strongly inhibited the chain-reaction of the peroxidation induced by Fe(2+)-linoleic acid hydroxyperoxide. On the basis of these findings, it appears that the anti-lipid-peroxidative effects of 3-RASA (3) are due to the inhibition of the radical chain-reaction, as a chain-breaking antioxidant.
