New jasmonate analogues as potential anti-inflammatory agents

In an effort to develop new anti-inflammatory agents, methyl jasmonate analogues ( 2– 20) were synthesized and evaluated for their inhibitory effects on the production of pro-inflammatory mediators (NO, IL-6, and TNF-α) in lipopolysaccharide (LPS)-activated RAW264.7 murine macrophage cells. The introduction of an enone functionality to the structure of a plant hormone ( 1) rendered the product ( 2) a significant anti-inflammatory activity. Analogues further derived from 2 ( 7, 9, 13, and 15) exhibited even more enhanced activity, and these compounds were much more potent than natural anti-inflammatory prostaglandins (PGA 1, PGA 2, and 15-deoxy-Δ 12,14-PGJ 2). Among them, compounds 9 and 15 showed the highest potency, while compounds 7 and 13 would be more desirable with respect to safety. This is the first study demonstrating the anti-inflammatory potential of jasmonate derivatives, and the present results suggest that α-haloenone jasmonates ( 7, 9, 13, and 15) may serve as potential anti-inflammatory leads.