Journal
JOURNAL OF NATURAL PRODUCTS
Volume 79, Issue 10, Pages 2693-2702Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jnatprod.6b00634
Keywords
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Funding
- Norwegian Research Council
- School of Pharmacy, University of Oslo
- Norwegian Ph.D. School of Pharmacy (Nasjonal forskerskole i farmasi, NFIF)
- Sir Henry Dale Fellowship - Wellcome Trust
- Royal Society [107613/Z/15/Z]
- National Institutes of Health GM Grant [PO1GM095467]
- [FRIPRO-FRINATEK 230470]
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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. Stereo chemically 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 gave all four RvTs. The results presented herein provide new knowledge on the biosynthetic pathways and the enzymatic origin of RvTs 1-4.
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