A Stereocontrolled Total Synthesis of Lipoxin B4 and its Biological Activity as a Pro‐Resolving Lipid Mediator of Neuroinflammation

Abstract

Two stereocontrolled, efficient, and modular syntheses of eicosanoid lipoxin B4 (LXB4) are reported. One features a stereoselective reduction followed by an asymmetric epoxidation sequence to set the vicinal diol stereocentres. The dienyne was installed via a one‐pot Wittig olefination and base‐mediated epoxide ring opening cascade. The other approach installed the diol through an asymmetric dihydroxylation reaction followed by a Horner‐Wadsworth‐Emmons olefination to afford the common dienyne intermediate. Finally, a Sonogashira coupling and an alkyne hydrosilylation/proto‐desilylation protocol furnished LXB4 in 25 % overall yield in just 10 steps. For the first time, LXB4 has been fully characterized spectroscopically with its structure confirmed as previously reported. We have demonstrated that the synthesized LXB4 showed similar biological activity to commercial sources in a cellular neuroprotection model. This synthetic route can be employed to synthesize large quantities of LXB4, enable synthesis of new analogs, and chemical probes for receptor and pathway characterization.

Phytochemical Analysis, Antioxidant and Enzyme-Inhibitory Activities, and Multivariate Analysis of Insect Gall Extracts of Picea koraiensis Nakai

“…Peak 15 had a [M + Na] + ion at m/z 375.2142, and its main fragment ion was at m/z 309.0986 ([M − C 3 H 7 ] + ). These results were characteristic of lipoxin B4 [38]. Peak 16 had a [M + H] + peak at m/z 299.1283 that generated a main fragment ion at m/z 91.0419 ([C 7 H 7 ] + ) and 77.0386 ([C 6 H 5 ] + ), which was characteristic of benzyl succinate [39].…”

Promising Anti-Inflammatory Tools: Biomedical Efficacy of Lipoxins and Their Synthetic Pathways

“…A study focusing on molecular mechanisms showed that LXs analogues could enhance reprogramming and crosstalk between classical and non-classical innate immune cells, thus inducing the termination of the pro-inflammatory state and promoting the subsequent regression stage, which provided a possible treatment for inflammatory heart metabolic diseases [20]. In addition, research was performed for the asymmetric synthesis of four bicyclo-pentanes, including synthetic aromatic LXA4 mimetics, and the biological evaluation of analogues demonstrated the therapeutic potential of BCP-sLXms as a novel inflammatory regulator [63]. Moreover, it was found that the LXA4 analog BML-111 could reduce oxidative stress and glomerular podocyte injury by regulating the Nrf2 pathway [64].…”

Lipoxins A4 and B4 inhibit glial cell activation via CXCR3 signaling in acute retinal neuroinflammation

“…We recently demonstrated that LXA 4 is reduced in patient samples and attenuates T-cell activities and metabolism in a model of autoimmune uveitis [ 32 ]. Previously, we also reported on direct neuroprotective lipoxin actions using models of both retinal and cortical neurodegeneration, and demonstrated that the relevant synthetic circuit and receptor components are expressed in glial cells and neurons [ 33 , 34 ]. In particular, LXB 4 consistently exhibited more potent protective activities than LXA 4 [ 34 ].…”