Julian Egger

Phospholipid oxidation generates potent anti-inflammatory lipid mediators that mimic structurally related pro-resolving eicosanoids by activating Nrf2.

Exposure of biological membranes to reactive oxygen species creates a complex mixture of distinct oxidized phospholipid (OxPL) species, which contribute to the development of chronic inflammatory diseases and metabolic disorders. While the ability of OxPL to modulate biological processes is increasingly recognized, the nature of the biologically active OxPL species and the molecular mechanisms underlying their signaling remain largely unknown. We have employed a combination of mass spectrometry, synthetic chemistry, and immunobiology approaches to characterize the OxPL generated from the abundant phospholipid 1‐palmitoyl‐2‐arachidonoyl‐sn‐glycero‐3‐phosphocholine (PAPC) and investigated their bioactivities and signaling pathways in vitro and in vivo. Our study defines epoxycyclopentenones as potent anti‐inflammatory lipid mediators that mimic the signaling of endogenous, pro‐resolving prostanoids by activating the transcription factor nuclear factor E2‐related factor 2 (Nrf2). Using a library of OxPL variants, we identified a synthetic OxPL derivative, which alleviated endotoxin‐induced lung injury and inhibited development of pro‐inflammatory T helper (Th) 1 cells. These findings provide a molecular basis for the negative regulation of inflammation by lipid peroxidation products and propose a novel class of highly bioactive compounds for the treatment of inflammatory diseases.

Synthesis of epoxyisoprostanes: effects in reducing secretion of pro-inflammatory cytokines IL-6 and IL-12.

Anti-inflammatory: The efficient and general synthetic route to the elusive epoxyisoprostanoid phospholipids PECPC and PEIPC, along with the isoprostanoids EC and EI, relies on a number of stereo- and chemoselective steps, including a C[BOND]H insertion for the rapid construction of the cyclopentanone ring. The synthesized compounds display unprecedented biological activity in reducing the secretion of pro-inflammatory cytokines.

Total Synthesis of Prostaglandin 15d-PGJ(2) and Investigation of its Effect on the Secretion of IL-6 and IL-12.

An efficient synthesis of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2, 1) is reported. The route described allows for diversification of the parent structure to prepare seven analogues of 1 in which the positioning of electrophilic sites is varied. These analogues were tested in SAR studies for their ability to reduce the secretion of proinflammatory cytokines. It was shown that the endocyclic enone is crucial for the bioactivity investigated and that the conjugated ω-side chain serves in a reinforcing manner.

Discovery of a highly potent anti-inflammatory epoxyisoprostane-derived lactone

Epoxyisoprostanes EI (1) and EC (2) are effective inhibitors of the secretion of proinflammatory cytokines IL-6 and IL-12. In detailed studies toward the investigation of the molecular mode of action of these structures, a highly potent lactone (3) derived from 1 was identified. The known isoprostanoids 1 and 2 are most likely precursors of 3, the product of facile intramolecular reaction between the epoxide with the carboxylic acid in 2.