- Peroxisome proliferator-activated receptor-γ mediates the anti-inflammatory effect of 3-hydroxy-4-pyridinecarboxylic acid derivatives: Synthesis and biological evaluation
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Seven 3-hydroxy-4-pyridinecarboxylic acid derivatives (HPs), aza-analogues of salicylic acid and structurally close to other potent inflammatory pyridine compounds such as aminopyridinylmethanols and aminopyridinamines, were synthesized, and their anti-inflammatory activity was evaluated. The synthesis was performed by adopting a general procedure involving an intramolecular Diels-Alder cycloaddition of oxazoles with acrylic acid to form various substituted pyridinic acids. The newly synthesized HPs did not exhibit cytotoxic activity on human monocytes-derived macrophages at concentrations up to 10 2 μM. Anti-inflammatory activity of the compounds was screened in vitro by evaluating the capability to inhibit cytokines release from lipopolysaccharide (LPS) stimulated human macrophages. 3-Hydroxy-1-methyl-4- pyridinecarboxylic acid (24) was found to be the most active HP. At 10 μM concentration, HP 24 reduced LPS-induced and nuclear factor-κB activation and cyclooxygenase-2 expression, while increased intracellular reactive oxygen species generation and peroxisome proliferator-activated receptor (PPAR-γ) mRNA transcript level. Indeed, pre-treatment of LPS-exposed human macrophages with PPAR-γ specific antagonist completely prevented HP 24-induced TNF-α and IL8 down regulation, demonstrating that the PPARγ pathway is mandatory for the HP 24 anti-inflammatory effect. Finally, daily treatment with HP 24 ameliorated the outcome of DSS-induced colitis in mice, significantly reducing colonic MPO activity and IL-1β tissue levels.
- Brun, Paola,Dean, Annalisa,Di Marco, Valerio,Surajit, Pathak,Castagliuolo, Ignazio,Carta, Davide,Ferlin, Maria Grazia
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p. 486 - 497
(2013/06/04)
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- Improved procedure for N-formylation of amines to formamides using formic acid, oxalyl chloride and imidazole
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The reaction of imidazole (15) with formyl chloride (14), generated in situ by the action of oxalyl chloride (10) on formic acid (3), afforded N-formylimidazole (7), which is a convenient formylating reagent. This procedure was used to prepare N-formyl derivatives (2) of aliphatic, aromatic and heteroaromatic amines (1) under mild conditions.
- Kitagawa,Ito,Tsutsui
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p. 1931 - 1934
(2007/10/02)
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