Anti-inflammatory and pro-resolving properties of benzo-lipoxin A4 analogs

Lipoxins (LXs) are potent endogenous counter-regulatory lipid mediators that dampen acute inflammation and promote its resolution. Here, we present our investigation of a new class of thermally and metabolically stable benzo-LXA4 analogs that are potently anti-inflammatory and easier to synthesize. Replacement of the tetraene unit of native LXA4 with a benzo-fused ring system not only increases the thermal stability but also enables highly convergent and efficient syntheses of these analogs. In addition, they resist rapid catalysis and inactivation by eicosanoid oxidoreductase. Like native LXs, o-[9, 12]-benzo-ω6-epi-LXA4, o-[9, 12]-benzo-deoxy-LXA4, m-[9, 12]-benzo-ω6-epi-LXA4 and [9, 14]-benzo-ω6-(R/S)-LXA4 demonstrated potent time-dependent reduction, at nanogram dosages, of PMN infiltration and pro-inflammatory cytokine generation in vivo in murine peritonitis and were organ protective in hind limb ischemia-reperfusion injury of the lung. The o-[9, 12]-benzo-ω6-epi-LXA4 and m-[9, 12]-benzo-ω6-epi-LXA4 were most potent in nanogram doses; both decreased PMN infiltration by ∼32%, while o-[9, 12]-benzo-deoxy-LXA4 and [9, 15]-ω6-(R/S)-LXA4 were less potent. The [9,12]-benzo-ω6-epi-LXA4 also activated a lipoxin A4 GPCR and increased macrophage phagocytic activity. Taken together, these findings demonstrate a new generation of LXA4 stable analogs that are easy to synthesize and anti-inflammatory. These benzo-LXA4 analogs are promising tools for new therapeutic approaches as well as assessing endogenous mechanisms in anti-inflammation and resolution.