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.
摘要：
过氧化物酶体增殖物激活受体γ（PPARγ）属于核受体超家族，参与炎症过程。以前,我们合成了PPARγ的配体，该配体具有食物衍生的肉桂酸衍生物（CA）和不可逆的PPARγ拮抗剂GW9662的混合结构。这些配体通过与PPARγ的Cys285残基形成共价键来激活PPARγ的转录，而它们的抗炎作用尚未被检查。这里,我们显示了共价PPARγ配体在RAW264细胞中的抗炎作用，小鼠巨噬细胞样细胞。GW9662抑制了脂多糖刺激的一氧化氮（NO）的产生，并与CA结合发挥了协同作用。具有其杂合结构的化合物显着抑制了NO的产生和促炎细胞因子的转录。比较研究表明，配体的2-氯-5-硝基苯甲酰基对于抗炎很重要。此外，我们合成了一种炔烃标记的类似物，该类似物成为未来机理研究的基于活性的探针。
