To remove the toxicity of 10-Pterostilbene methylamine hydrochloride derivatives (PMDS ． HCl) and develop novel anti-inflammatory agents, twenty-five Pterostilbene-urea derivatives (PUDs, Q1-Q25) derived from PMDs were designed, synthesized, characterized by spectroscopic techniques and their anti-inflammatory activity in vitro were evaluated. Results exhibited that compounds (Q1-Q25) were low toxic or non-toxic toward RAW264.7 and L02 cell lines at 20 μM/L. Eight bioactive agents (Q4-Q10, Q20) displayed obvious inhibition ability against LPS-induced NO release, with IC50(NO) values ranged from 9.96 to 33.89 μM/L. Meanwhile, they were potential COX-2 inhibitors with IC50(COX-2) values ranging from 39.42 to 179.84 nM/L. A roughly positive correlation were observed between the inhibitory abilities on LPS-induced NO release and those on COX-2. Q7 , Q10and Q20 manifested stronger COX-2 inhibitory abilities than Celecoxib . The strongest anti-inflammatory agent, Q20 (IC50 (NO) = 9.96 μM/L, IC50(COX-2) = 39.42 nM/L) effectively inhibited the secretion of pro-inflammatory factors such as IL-1β (IC50 = 12.30 μM/L) and TNF-α (IC50 = 9.07 μM/L) in a dose-dependent manner. Western Blot analysis indicated that at low micromolar concentrations, Q20 obviously down-regulated the expression of COX-2, iNOS as well as TLR4 protein, and suppressed the activation of NLRP3 inflammasome and NF-κB signal pathway.
Keywords: Pterostilbene-urea derivatives NRLP3 inflammasome COX-2 inhibition NF-κB signal pathway Molecular docking.
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