Structurally diverse triterpenes obtained from the fruits of Ziziphus jujuba Mill. as inflammation inhibitors by NF-κB signaling pathway

Abstract

Twenty-nine triterpenes were obtained from the fruits of Ziziphus jujuba Mill. through various chromatography methods, and their stereo-structures were confirmed by spectroscopic methods. Among them, 2α,3β,20-trihydroxylupane-28-oic acid (1) was identified as a new compound, and the ¹H and ¹³C NMR data of 7, 8 and 23, as well as the ¹³C NMR data of 17 are reported here for the first time. Meanwhile, the nitric oxide (NO) inhibitory activities of all compounds were examined in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. As results, compounds 2, 7, 10–13, 15, 16, 18–21, 26–29 were found to play important roles in suppressing NO production at 5 μM. The structure–activity relationships (SARs) on NO inhibition indicated that the ursolic and oleanolic acid skeletons, p-coumaroyl group substitution, six-membered A ring, and deoxygenation (loss of CO) in the C ring showed a more positive effect on the NO inhibitory activity of triterpenes, while the reduction of the A ring CO to OH was a negative factor. Moreover, it was found that compounds 15 and 19 could suppress the phosphorylation of IκBα and NF-κB/p65 to prevent it from shifting into the nucleus and downregulate the expression of inflammatory factors, such as iNOS, IL-6 and TNF-α. Our investigations revealed that the NO inhibitory effects of the active triterpenes obtained from Z. jujuba were mediated, at least in part, through the NF-κB signaling pathway.