title: Peroxisome proliferator-activated receptor-γ mediates the anti-inflammatory effect of 3-hydroxy-4-pyridinecarboxylic acid derivatives: synthesis and biological evaluation.
abstract: 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.
authors: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors: Paola
authors: P
authors: Brun
authors: Annalisa
authors: A
authors: Dean
authors: Valerio
authors: V
authors: Di Marco
authors: Pathak
authors: P
authors: Surajit
authors: Ignazio
authors: I
authors: Castagliuolo
authors: Davide
authors: D
authors: Carta
authors: Maria Grazia
authors: MG
authors: Ferlin
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007539:Isonicotinic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: C478611:3-hydroxy-4-pyridinecarboxylic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D007539:Isonicotinic Acids; D008070:Lipopolysaccharides; D047495:PPAR gamma; D012333:RNA, Messenger