ABSTRACT
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.
Subject(s)
Hydroquinones/chemical synthesis , Lipid Peroxidation/drug effects , Phenyl Ethers/chemical synthesis , Animals , Hydroquinones/pharmacology , In Vitro Techniques , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Phenyl Ethers/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Chalcone/analogs & derivatives , Chalcone/pharmacology , Lipid Peroxidation/drug effects , Macrophages, Peritoneal/drug effects , Microsomes, Liver/drug effects , Superoxides/metabolism , Animals , Carbon Tetrachloride/toxicity , Cells, Cultured , Chalcone/chemical synthesis , Chalcones , Hemolysis/drug effects , Hydrogen Peroxide/toxicity , Macrophages, Peritoneal/metabolism , Microsomes, Liver/metabolism , Rats , Rats, WistarABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Chalcone/analogs & derivatives , Cyclooxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors , Administration, Topical , Animals , Anti-Inflammatory Agents/therapeutic use , Arachidonic Acid , Cell Line , Chalcone/chemical synthesis , Chalcone/pharmacology , Chalcone/therapeutic use , Chalcones , Cyclooxygenase Inhibitors/pharmacology , Edema/chemically induced , Edema/drug therapy , Lipid Peroxidation/drug effects , Male , Mice , Mice, Inbred ICR , Molecular Structure , Sheep , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Anti-Arrhythmia Agents/pharmacology , Arrhythmias, Cardiac/prevention & control , Ascorbic Acid/analogs & derivatives , Free Radical Scavengers , Myocardial Reperfusion Injury/complications , Anesthesia , Animals , Arrhythmias, Cardiac/etiology , Ascorbic Acid/pharmacology , Blood Pressure/drug effects , Guinea Pigs , Heart Atria/drug effects , Heart Rate/drug effects , In Vitro Techniques , Lipid Peroxidation/drug effects , Microsomes, Liver/metabolism , Rats , Rats, Inbred Strains , Verapamil/pharmacologyABSTRACT
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.
