Total Synthesis of the Lipid Mediator PD1n-3 DPA: Configurational Assignments and Anti-inflammatory and Pro-resolving Actions

The polyunsaturated lipid mediator PD1n-3 DPA (5) was recently isolated from self-resolving inflammatory exudates of 5 and human macrophages. Herein, the first total synthesis of PD1n-3 DPA (5) is reported in 10 steps and 9% overall yield. These efforts, together with NMR data of its methyl ester 6, confirmed the structure of 5 to be (7Z,10R,11E,13E,15Z,17S,19Z)-10,17-dihydroxydocosa-7,11,13,15,19-pentaenoic acid. The proposed biosynthetic pathway, with the involvement of an epoxide intermediate, was supported by results from trapping experiments. In addition, LC-MS/MS data of the free acid 5, obtained from hydrolysis of the synthetic methyl ester 6, matched data for the endogenously produced biological material. The natural product PD1n-3 DPA (5) demonstrated potent anti-inflammatory properties together with pro-resolving actions stimulating human macrophage phagocytosis and efferocytosis. These results contribute new knowledge on the n-3 DPA structure–function of the growing numbers of specialized pro-resolving lipid mediators and pathways.

[1]  M. Aursnes,et al.  Stereoselective synthesis of protectin D1: a potent anti-inflammatory and proresolving lipid mediator. , 2014, Organic & biomolecular chemistry.

[2]  C. Serhan,et al.  Neuroprotectin/protectin D1 protects against neuropathic pain in mice after nerve trauma , 2013, Annals of neurology.

[3]  C. Serhan,et al.  Resolution phase lipid mediators of inflammation: agonists of resolution. , 2013, Current opinion in pharmacology.

[4]  C. Serhan,et al.  Resolvin D3 and aspirin-triggered resolvin D3 are potent immunoresolvents. , 2013, Chemistry & biology.

[5]  Ira Tabas,et al.  Anti-Inflammatory Therapy in Chronic Disease: Challenges and Opportunities , 2013, Science.

[6]  A. Nagar,et al.  A quantum theory for the irreplaceable role of docosahexaenoic acid in neural cell signalling throughout evolution. , 2013, Prostaglandins, leukotrienes, and essential fatty acids.

[7]  T. Hansen,et al.  Concise syntheses of three ω-3 polyunsaturated fatty acids , 2012 .

[8]  C. Serhan,et al.  Specific lipid mediator signatures of human phagocytes: microparticles stimulate macrophage efferocytosis and pro-resolving mediators. , 2012, Blood.

[9]  C. Serhan,et al.  Resolvins and protectins in inflammation resolution. , 2011, Chemical reviews.

[10]  M. Fornage,et al.  Genetic Loci Associated with Plasma Phospholipid n-3 Fatty Acids: A Meta-Analysis of Genome-Wide Association Studies from the CHARGE Consortium , 2011, PLoS genetics.

[11]  M. Garg,et al.  Docosapentaenoic acid (22:5n-3): a review of its biological effects. , 2011, Progress in lipid research.

[12]  D. Gilroy.  ACUTE AND CHRONIC INFLAMMATION , 2010 .

[13]  K. Hamazaki,et al.  Artificial Rearing of Infant Mice Leads to n-3 Fatty Acid Deficiency in Cardiac, Neural and Peripheral Tissues , 2009, Lipids.

[14]  C. Serhan,et al.  Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions , 2009, The Journal of experimental medicine.

[15]  C. Serhan,et al.  Endogenous pro‐resolving and anti‐inflammatory lipid mediators: a new pharmacologic genus , 2008, British journal of pharmacology.

[16]  C. Serhan.  Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. , 2007, Annual review of immunology.

[17]  A. Ochoa-Terán,et al.  Model studies on the ring construction of the auriside macrolactone , 2006 .

[18]  Yan Lu,et al.  Anti-Inflammatory Actions of Neuroprotectin D1/Protectin D1 and Its Natural Stereoisomers: Assignments of Dihydroxy-Containing Docosatrienes1 , 2006, The Journal of Immunology.

[19]  C. Serhan,et al.  The Docosatriene Protectin D1 Is Produced by TH2 Skewing and Promotes Human T Cell Apoptosis via Lipid Raft Clustering* , 2005, Journal of Biological Chemistry.

[20]  John Savill,et al.  Resolution of inflammation: the beginning programs the end , 2005, Nature Immunology.

[21]  P. Mukherjee,et al.  Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[22]  C. Serhan,et al.  Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their aspirin-triggered endogenous epimers: an overview of their protective roles in catabasis. , 2004, Prostaglandins & other lipid mediators.

[23]  C. Serhan,et al.  Novel Docosatrienes and 17S-Resolvins Generated from Docosahexaenoic Acid in Murine Brain, Human Blood, and Glial Cells , 2003, The Journal of Biological Chemistry.

[24]  C. Serhan,et al.  Resolvins , 2002, The Journal of experimental medicine.

[25]  C. Clish,et al.  Novel Functional Sets of Lipid-Derived Mediators with Antiinflammatory Actions Generated from Omega-3 Fatty Acids via Cyclooxygenase 2–Nonsteroidal Antiinflammatory Drugs and Transcellular Processing , 2000, The Journal of experimental medicine.

[26]  F. Lee.  Cells Tissues and Disease , 1997 .

[27]  G. Majno,et al.  Cells, tissues, and disease : principles of general pathology , 1996 .

[28]  C. Serhan.  Lipoxin biosynthesis and its impact in inflammatory and vascular events. , 1994, Biochimica et biophysica acta.

[29]  K. Nicolaou,et al.  Stereokontrollierte Totalsynthesen der Lipoxine A5 und B5 , 1987 .

[30]  K. Nicolaou,et al.  A General Strategy for the Synthesis of Monohydroxy-eicosatetraenoic Acids: Total Synthesis of 5(S)-Hydroxy-6(E),8,11,14(Z)-eicosatetraenoic Acid (5-HETE) and 12(S)-Hydroxy-5,8,14(Z), 10(E)-eicosatetraenoic Acid (12-HETE) , 1986 .

[31]  E. Corey,et al.  A stereoselective and practical synthesis of 5,6(S,S)-epoxy-15(S)-hydroxy-7(E),9(E),11(Z),13(E)-eicosatetraenoic acid (4), possible precursor of the lipoxins , 1986 .

[32]  Y. Tohda,et al.  A convenient synthesis of acetylenes: catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines , 1975 .

[33]  E. Corey,et al.  Protection of hydroxyl groups as tert-butyldimethylsilyl derivatives , 1972 .