Synthesis of 13(R)-Hydroxy-7Z10Z13R14E16Z19Z Docosapentaenoic Acid(13R-HDPA) and Its Biosynthetic Conversionto the 13-Series Resolvins

摘要

Specialized pro-resolving lipid mediators are biosynthesized during the resolution phase of acute inflammation from n-3 polyunsaturated fatty acids. Recently, the isolation and identification of the four novel mediators denoted 13-series resolvins, namely, RvT1 (>1), RvT2 (>2), RvT3 (>3) and RvT4 (>4), were reported, which showed potent bioactions characteristic for specialized pro-resolving lipid mediators. Herein, based on results from LC/MS-MS metabololipidomics and the stereoselective synthesis of 13(R)-hydroxy-7Z,10Z,13R,14E,16Z,19Z docosapentaenoic acid (13R-HDPA, >5), we provide direct evidence that the four novel mediators >1–>4 are all biosynthesized from the pivotal intermediate >5. The UV and LC/MS-MS results from synthetic 13R-HDPA (>5) matched those from endogenously and biosynthetically produced material obtained from in vivo infectious exudates, endothelial cells, and human recombinant COX-2 enzyme. Stereochemically pure >5 was obtained with the use of a chiral pool starting material that installed the configuration at the C-13 atom as R. Two stereoselective Z-Wittig reactions and two Z-selective reductions of internal alkynes afforded the geometrically pure alkene moieties in >5. Incubation of >5 with isolated human neutrophils gaveall four RvTs. The results presented herein provide new knowledgeon the biosynthetic pathways and the enzymatic origin of RvTs >1–>4.