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Asymmetric synthesis of novel N-(1-phenyl-2,3-dihydroxypropyl)arachidonylamides and evaluation of their anti-inflammatory activity.

ABSTRACT: To design and synthesize novel N-(1-phenyl-2,3-dihydroxypropyl)arachidonylamides and evaluate their analgesic and anti-inflammatory potential.The murine macrophage cell line RAW 264.7 has been widely used as a model for inflammatory responses in vitro. Our model consists of cultured monolayers of RAW 264.7 cells in which media concentrations of 15-deoxy-?(13,14)-PGJ2 (PGJ) are measured by ELISA following LPS (10ng/ml) stimulation and treatment with 0.1, 0.3, 1.0, 3.0 and 10?M concentrations of the compounds.Our data indicate that several of our compounds have the capacity to increase production of PGJ and may also increase the occurrence of programmed cell death (apoptosis).Thus these agents are potential candidates for the therapy of conditions characterized by ongoing (chronic) inflammation and its associated pain.

SUBMITTER: Kattamuri PV

PROVIDER: S-EPMC3516634 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Asymmetric synthesis of novel N-(1-phenyl-2,3-dihydroxypropyl)arachidonylamides and evaluation of their anti-inflammatory activity.

Kattamuri Padmanabha V PV Salmonsen Rebecca R McQuain Catherine C Burstein Sumner S Sun Hao H Li Guigen G

Life sciences 20120720 8-9

<h4>Aims</h4>To design and synthesize novel N-(1-phenyl-2,3-dihydroxypropyl)arachidonylamides and evaluate their analgesic and anti-inflammatory potential.<h4>Main methods</h4>The murine macrophage cell line RAW 264.7 has been widely used as a model for inflammatory responses in vitro. Our model consists of cultured monolayers of RAW 264.7 cells in which media concentrations of 15-deoxy-Δ(13,14)-PGJ2 (PGJ) are measured by ELISA following LPS (10ng/ml) stimulation and treatment with 0.1, 0.3, 1.0 ...[more]

PMID: 22820546

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Project description:PurposeNonsteroidal anti-inflammatory drugs cause a series of adverse reactions. Thus, the search for new cyclooxygenase-2 selective inhibitors have become the main direction of research on anti-inflammatory drugs. Gentiopicroside is a novel selective inhibitor of cyclooxygenase-2 from Chinese herbal medicine. However, it is highly hydrophilic owing to the presence of the sugar fragment in its structure that reduces its oral bioavailability and limits efficacy. This study aimed to design and synthesize novel cyclooxygenase-2 inhibitors by modifying gentiopicroside structure and reducing its polarity.Materials and methodsWe introduced hydrophobic acyl chloride into the gentiopicroside structure to reduce its hydrophilicity and obtained some new derivatives. Their in vitro anti-inflammatory activities were evaluated against NO, TNF-α, PGE2, and IL-6 production in the mouse macrophage cell line RAW264.7 stimulated by lipopolysaccharide. The in vivo inhibitory activities were further tested against xylene-induced mouse ear swelling. Molecular docking predicted that whether new compounds could effectively bind to target protein cyclooxygenase-2. The inhibitory activity of new compounds to cyclooxygenase-2 enzyme were verified by the in vitro experiment.ResultsA total of 21 novel derivatives were synthesized, and exhibit lower polarities than the gentiopicroside. Most compounds have good in vitro anti-inflammatory activity. The in vivo activity results demonstrated that 8 compounds were more active than gentiopicroside. The inhibition rate of some compounds was higher than celecoxib. Molecular docking predicted that 6 compounds could bind to cyclooxygenase-2 and had high docking scores in accordance with their potency of the anti-inflammatory activity. The confirmatory experiment proved that these 6 compounds had significant inhibitory effect against cyclooxygenase-2 enzyme. Structure-activity relationship analysis presumed that the para-substitution with the electron-withdrawing groups may benefit the anti-inflammatory activity.ConclusionThese gentiopicroside derivatives especially PL-2, PL-7 and PL-8 may represent a novel class of cyclooxygenase-2 inhibitors and could thus be developed as new anti-inflammatory agents.

Project description:ObjectivesThe aim was the synthesis of novel substituted 5-[morpholino(phenyl)methyl]-thiazolidine-2,4-diones and screening for their in vivo hypoglycemic activity and in vitro anti-inflammatory activity, as well as molecular docking studies to find out active potential lead molecules.Materials and methodsSubstituted aromatic aldehydes, thiazolidine-2,4-dione, and morpholine on Mannich reaction gave the title compounds. They were characterized by physical and spectral methods. In vivo hypoglycemic activity was examined in alloxan induced Wistar albino rats by tail tipping method. In vitro anti-inflammatory activity was tested by human red blood cell (HRBC) membrane stabilization and protein denaturation. Using AutoDock, molecular docking studies were carried out to find out the best fit ligands.ResultsSeries of substituted 5-[morpholino(phenyl)methyl]-thiazolidine-2,4-diones were synthesized and chemically they were confirmed by spectral techniques. Acute toxic studies of in vivo hypoglycemic activity results revealed that compounds 4c, 4h, and 4n exhibited good activity at 35 mg/kg body weight. Chronic toxic study results indicated that compounds 4h and 4n exhibited good activity at 70 mg/kg body weight. Anti-inflammatory activity results indicated the highest inhibition was shown by compounds 4k and 4f at 500 μg/mL in HRBC membrane stabilization. In protein denaturation, the highest inhibition was shown by compound 4k at 500 μg/mL. In molecular docking studies, compounds 4h and 4n exhibited higher binding affinity at PPARγ receptor protein and compound 4k exhibited higher binding affinity at COX-1 and COX-2 actives sites.ConclusionMicrowave irradiation produced high yield in short reaction times. The presence of electron releasing groups at the para position of the phenyl ring may give the ability to produce hypoglycemic activity and the presence of electron withdrawing groups at the para position of the phenyl ring causes anti-inflammatory activity. The results showed that some compounds exhibited good hypoglycemic and anti-inflammatory activities. Compounds 4h and 4n exhibited higher binding affinity at PPARγ receptor protein and compound 4k exhibited higher binding affinity at COX isoenzymes' active sites in molecular docking studies.

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Asymmetric synthesis of novel N-(1-phenyl-2,3-dihydroxypropyl)arachidonylamides and evaluation of their anti-inflammatory activity.

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Asymmetric synthesis of novel N-(1-phenyl-2,3-dihydroxypropyl)arachidonylamides and evaluation of their anti-inflammatory activity.

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