Polyunsaturated methoxylated ether lipids display a range of potentially important biological properties, yet their mechanism of action remain poorly understood due to the difficulty of isolating pure material from natural sources. Herein, a novel synthetic approach to form a docosahexaenoic acid (DHA)-like methoxylated ether lipid is reported. By utilising a modular semi-synthetic approach, from natural DHA, all six methylene skipped cis-configured double bonds were incorporated into the final product, via a stereocontrolled semi-hydrogenation reaction to achieve the n-18 double bond. The synthesis was accomplished with an overall yield of 5.3% over 10 steps as the longest linear sequence, providing reliable access to this elusive polyunsaturated natural product. In addition to the synthetic efforts, the biological relevance of the methoxylated ether lipid was further validated via molecular docking and molecular dynamics simulations with soybean 15-lipoxygenase-1. The simulations predict a moderate binding affinity (Boltz-2 predicted IC50 = 4.6 μM, Glide score = -9.0 kcal mol-1, MM/GBSA ΔGbind = -60 kcal mol-1), comparable to that of arachidonic acid. Finally, a substrate assay with soybean 15-lipoxygenase-1 confirms that the DHA like methoxylated ether lipid is a substrate for the enzyme, displaying 15% relative activity compared to arachidonic acid.
Bathen et al. (2026) studied this question.