Anti-inflammatory effect of covalent PPARγ ligands that have a hybrid structure of GW9662 and a food-derived cinnamic acid derivative.

ABSTRACT

Peroxisome proliferator-activated receptor γ (PPARγ) belongs to nuclear receptor superfamily and is involved in inflammatory process. Previously, we synthesized the ligands of PPARγ which possess the hybrid structure of a food-derived cinnamic acid derivative (CA) and GW9662, an irreversible PPARγ antagonist. These ligands activate the transcription of PPARγ through the covalent bond formation with the Cys285 residue of PPARγ, whereas their anti-inflammatory effect has not been examined yet. Here, we show the anti-inflammatory effect of the covalent PPARγ ligands in RAW264 cells, murine macrophage-like cells. GW9662 suppressed the production of nitric oxide (NO) stimulated by lipopolysaccharide and exerted a synergistic effect in combination with CA. The compounds bearing their hybrid structure dramatically inhibited NO production and transcription of proinflammatory cytokines. A comparison study suggested that 2-chloro-5-nitrobenzoyl group of the ligands is important for anti-inflammation. Furthermore, we synthesized an alkyne-tagged analogue which become an activity-based probe for future mechanistic study.