ANTI-INFLAMMATORY ACTIVITY OF LIMONOIDS FROM Xylocarpus spp. AND THEIR DERIVATIVES

Abstract

In a phytochemical investigation of anti-inflammatory compounds from Xylocarpus spp., seven new limonoid, xylorumphiins E−J (42-43 and 45−48) and 2-hydroxyxylorumphiin F (44), together with three known derivatives, xyloccensin X (49), xyloccensin E (50) and xyloccensin K (51) were isolated from the seeds of Xylocarpus rumphii (Kostel.) Mabb. In addition to limonoids from X. rumphii, the ones from X. granatum and X. moluccensis, totally thirty-eight compounds, were further evaluated for their in vitro anti-inflammatory activities by monitoring the inhibition of nitric oxide (NO) production in LPS and IFN-γ-induced RAW264.7 murine macrophages. Only 7-deacetylgedunin (54), a gedunin-type limonoid, exhibited the most potent activity with an IC50 value of 4.85 µM along with the suppression of mRNA gene and protein expression of inducible NO synthase (iNOS) in LPS and IFN-γ-stimulated RAW264.7 cells. Furthermore, transcriptional activity of NF-κB as well as the phosphorylations of MAPKs (p38, ERK1/2, SAPK/JNK), induced by LPS and IFN-γ, was suppressed by 54, which was associated with the protection of IκBα degradation and subsequently decreased the phosphorylation level of p65. Additionally, the structure-activity relationships of dysobinin (80) and andrographolide (81) derivatives were studied. Seven derivatives of dysobinin (139-145) and twenty five analogues of andrographolide (146-170) were thus synthesized and examined for their anti-inflammatory activities. Among dysobinin derivatives, it was found that C-6, C-7 diol 139 provided the most promising activity, while the reduction of α, ß-unsaturated ketone moiety led to the loss of activity. Thus these two functionalities play crucial role for anti-inflammatory activity of dysobinin-type compound. In the case of compounds in andrographolide series, the acetylated derivatives provided the most potent activity. It could thus be concluded that α-alkylidene-γ-butyrolactone, Δ8,17 exomethylene and Δ12,13 double bond originally in parent compound played important role for anti-inflammatory activity.