Synthesis of new ent-labdane diterpene derivatives from andrographolide and evaluation of their anti-inflammatory activities

Abstract

Two series of andrographolide derivatives with nitrogen-containing heterocycles, phenols and aromatic acids as bioisostere moiety of lactone ring were synthesized. 8 from 18 tested compounds showed stronger inhibitory effect on LPS-induced NO production in RAW264.7 macrophage than hydrocortisone. Among them, compound 8m exhibited the most potent inhibition with IC₅₀ of 3.38 ± 1.03 μM. The structure-activity relationships (SARs) suggested that the replacement of lactone ring with small-molecule phenols could improve the anti-inflammatory efficacy. Furthermore, compound 8m significantly reduced the levels of pro-inflammatory cytokine IL-1β and IL-6 with no influence on cell survival, decreased the expression of iNOS and COX-2, and down-regulated the level and phosphorylation of IκBα, as well as the expression of NF-κB. Also it blocked the nuclear translocation of NF-κB in LPS-induced macrophage. Therefore, the anti-inflammation mechanism of compound 8m was related to the inhibition of COX-2, iNOS and NF-κB signal pathway.

Keywords: Andrographolide; Anti-inflammatory effect; Bioisostere; Structure modification.