Synthesis of 13(R)-Hydroxy-7Z,10Z,13R,14E,16Z,19Z Docosapentaenoic Acid (13R-HDPA) and Its Biosynthetic Conversion to the 13-Series Resolvins

J Nat Prod. 2016 Oct 28;79(10):2693-2702. doi: 10.1021/acs.jnatprod.6b00634. Epub 2016 Oct 5.

Abstract

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 gave all four RvTs. The results presented herein provide new knowledge on the biosynthetic pathways and the enzymatic origin of RvTs 1-4.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromatography, Liquid
  • Docosahexaenoic Acids
  • Eicosapentaenoic Acid / analogs & derivatives*
  • Eicosapentaenoic Acid / chemical synthesis
  • Eicosapentaenoic Acid / chemistry
  • Fatty Acids, Unsaturated / chemical synthesis*
  • Fatty Acids, Unsaturated / chemistry
  • Fatty Acids, Unsaturated / metabolism
  • Humans
  • Inflammation / metabolism
  • Inflammation Mediators
  • Macrophages / metabolism
  • Molecular Structure
  • Neutrophils / metabolism
  • Nuclear Magnetic Resonance, Biomolecular
  • Stereoisomerism

Substances

  • Fatty Acids, Unsaturated
  • Inflammation Mediators
  • Docosahexaenoic Acids
  • Eicosapentaenoic Acid
  • docosapentaenoic acid