quercetin and Edema

Topics: Animals; Anti-Inflammatory Agents; Arachidonate 15-Lipoxygenase; Benzimidazoles; Carrageenan; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Drug Design; Edema; Lipoxygenase Inhibitors; Male; Molecular Structure; Rats; Structure-Activity Relationship; Thiazoles

Because atherosclerosis is an inflammatory process involving a series of pathological events such as dyslipidemia, oxidative stress, and blood clotting mechanisms, we hereby report the synthesis and evaluation of novel compounds in which antioxidant, anti-inflammatory, and squalene synthase (SQS) inhibitory/hypolipidemic activities are combined in simple molecules through design. The coupling of two different pharmacophores afforded compounds 1-12, whose biological profile was markedly improved compared to those of parent lead structures (i.e., the hypolipidemic 2-hydroxy-2-aryl-(benzo)oxa(or thia)zine and the antioxidant phenothiazine). Most derivatives strongly inhibited in vitro microsomal lipid and LDL peroxidation, exhibiting potent free-radical scavenging activity. They further significantly inhibited SQS activity and showed remarkable antidyslipidemic activity in vivo in animal models of acute and high-fat-induced hyperlipidemia. Finally, several compounds showed anti-inflammatory activity in vitro, inhibiting cycloxygenase (COX-1/2) activity. The multimodal properties of the new compounds and especially their combined antioxidant/SQS/COX inhibitory activity render them interesting lead compounds for further evaluation against atherosclerosis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Atherosclerosis; Biphenyl Compounds; Carrageenan; Cholesterol, Dietary; Cyclooxygenase Inhibitors; Diet, High-Fat; Drug Design; Edema; Enzyme Inhibitors; Farnesyl-Diphosphate Farnesyltransferase; Hypolipidemic Agents; In Vitro Techniques; Indicators and Reagents; Lipid Peroxidation; Magnetic Resonance Spectroscopy; Male; Mice; Microsomes; Phenothiazines; Picrates; Rats

We report the synthesis, theoretical calculations, the antioxidant, anti-inflammatory, and neuroprotective properties, and the ability to cross the blood-brain barrier (BBB) of (Z)-α-aryl and heteroaryl-N-alkyl nitrones as potential agents for stroke treatment. The majority of nitrones compete with DMSO for hydroxyl radicals, and most of them are potent lipoxygenase inhibitors. Cell viability-related (MTT assay) studies clearly showed that nitrones 1-3 and 10 give rise to significant neuroprotection. When compounds 1-11 were tested for necrotic cell death (LDH release test) nitrones 1-3, 6, 7, and 9 proved to be neuroprotective agents. In vitro evaluation of the BBB penetration of selected nitrones 1, 2, 10, and 11 using the PAMPA-BBB assay showed that all of them cross the BBB. Permeable quinoline nitrones 2 and 3 show potent combined antioxidant and neuroprotective properties and, therefore, can be considered as new lead compounds for further development in specific tests for potential stroke treatment.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Blood-Brain Barrier; Cell Hypoxia; Cell Survival; Cells, Cultured; Cerebral Cortex; Edema; Female; Free Radical Scavengers; Hydroxyl Radical; Lipid Peroxidation; Lipoxygenase Inhibitors; Male; Necrosis; Neurons; Neuroprotective Agents; Nitric Oxide Donors; Nitrogen Oxides; Oximes; Permeability; Quinolines; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Stereoisomerism; Stroke; Structure-Activity Relationship; Superoxides

A new anthraquinone, 1,5,15-tri-O-methylmorindol (1), and two new saccharide fatty acid esters, 2-O-(beta-D-glucopyranosyl)-1-O-hexanoyl-beta-D-gluropyranose (4) and 2-O-(beta-D-glucopyranosyl)-1-O-octanoyl-beta-D-gluropyranose (5), have been isolated from a methanol extract of the fruits of Morinda citrifolia (noni) along with 10 known compounds, namely, two anthraquinones (2, 3), six saccharide fatty acid esters (6-11), an iridoid glycoside (12), and a flavanol glycoside (13). Upon evaluation of six compounds (5-7, 9, 10, and 13) for inhibitory activity against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation (1 microg/ear) in mice, four saccharide fatty acid esters, 5-7 and 9, exhibited potent anti-inflammatory activity, with ID50 values of 0.46-0.79 mg per ear. In addition, when compounds 1-13 were evaluated against the Epstein-Barr virus early antigen (EBV-EA) activation induced by TPA, all of the compounds exhibited moderate inhibitory effects (IC50 values of 386-578 mol ratio/32 pmol TPA).

Topics: Animals; Anthraquinones; Anti-Inflammatory Agents; Anticarcinogenic Agents; Antigens, Viral; Caproates; Caprylates; Ear; Edema; Fruit; Glucosides; Japan; Mice; Molecular Structure; Morinda; Plants, Medicinal; Tetradecanoylphorbol Acetate

Three new compounds, cadalen-15-oic acid (1), 3,7-dihydroxy-3(4H)-isocadalen-4-one (2), and dicadalenol (3), were isolated from the aerial parts of Heterotheca inuloides (Mexican arnica), together with the known compounds 7-hydroxycadalene (4), 7-hydroxy-4alphaH-3,4-dihydrocadalene (5), 1alpha-hydroxy-1(4H)-isocadalen-4-one (6), 1alpha-hydroxy-4alphaH-1,2,3,4-tetrahydrocadalen-15-oic acid (7), 7-(3,3-dimethylallyloxy)coumarin, caryolan-1,9beta-diol, and quercetin. The structures of the new compounds were elucidated by spectroscopic methods. The antiinflammatory activities of the extracts and the isolated compounds were evaluated by determining the inhibition of TPA-induced mouse ear edema. The natural products 3, caryolan-1,9beta-diol, and quercetin were the most active substances tested and displayed dose-dependent activities.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Asteraceae; Disease Models, Animal; Dose-Response Relationship, Drug; Ear; Edema; Flavonoids; Gas Chromatography-Mass Spectrometry; Magnetic Resonance Spectroscopy; Mexico; Mice; Naphthalenes; Plant Leaves; Plant Stems; Plants, Medicinal; Quercetin; Tetradecanoylphorbol Acetate

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.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Arachidonic Acid; Cell Line; Chalcone; Chalcones; Cyclooxygenase Inhibitors; Edema; Lipid Peroxidation; Lipoxygenase Inhibitors; Male; Mice; Mice, Inbred ICR; Molecular Structure; Sheep; Structure-Activity Relationship

The synthesis of a series of pentadienoic and hexadienoic acid derivatives is reported. These compounds were tested as inhibitors of 5-lipoxygenase (5 LO) and cyclooxygenase (CO) in vitro and as inhibitors of arachidonic acid (AA) induced ear edema in mice in vivo. Their potency is compared with that of the standard inhibitors nafazatrom, BW 755C, NDGA, KME4, quercetine, and L 652,243. The most potent compound in vivo, diethyl 2-hydroxy-5-(ethylthio)-2(Z),4(Z)-hexadienedioate (20) inhibited AA-induced ear edema when administered topically or orally, with an ED50 value of 0.01 mg/ear and 20 mg/kg, respectively. Among the standard compounds tested, L 652,243 was the most active compound in this test with an ED50 value of 0.01 mg/ear and 1 mg/kg po, but unlike this compound, 20 is a selective inhibitor of 5-LO (IC50 = 2 microM) without any significant activity against CO (IC50 greater than 50 microM). Most of the other compounds in this series are also selective 5-LO inhibitors.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological Assay; Dose-Response Relationship, Drug; Edema; Fatty Acids, Unsaturated; Lipoxygenase Inhibitors; Mice; Sorbic Acid; Structure-Activity Relationship