Total Synthesis of the Lipid Mediator PD1_n-3 DPA: Configurational Assignments and Anti-inflammatory and Pro-resolving Actions

Abstract

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.

Protectin D1 n-3 DPA and resolvin D5 n-3 DPA are effectors of intestinal protection

“…Of note, levels of these mediators were within their bioactive concentration (femtomolar to nanomolar) (13,14), a feature aligned with recent findings where SPM at bioactive concentrations were identified in human tissues including spleen, lymph nodes, plasma (25), and also milk (26). The protective role of endogenous SPM was tested using a 15-lipoxygenase inhibitor that decreased the formation of PD1 n-3 DPA and that was associated with an increase in the production of proinflammatory molecules and colon inflammation.…”

“…Production of these novel SPMs was temporally regulated in self-limited inflammatory exudates. In addition, n-3 DPA-derived 10R,17S-dihydroxydocosa-7Z,11E,13E,15Z,19Z-pentaenoic acid (PD1 n-3 DPA ) and 7R,14S-dihydroxydocosa-8E,10E,12Z,16Z,19Z-pentaenoic acid (MaR1 n-3 DPA ) exerted potent proresolving actions stimulating human macrophage phagocytosis and efferocytosis (13,14). Herein we identified the presence of n-3 DPA-derived SPM in human colon and characterized their antiinflammatory and tissue-protective actions of two DPA-derived mediators, denoted as PD1 n-3 DPA and RvD5 n-3 DPA (7S,17S-dihydroxydocosa-8E,10Z,13Z,15E,19Z-pentaenoic acid) in settings of intestinal inflammation.…”

Selective identification of specialized pro-resolving lipid mediators from their biosynthetic double di-oxygenation isomers

“…29 In Figure 3, the chromatograms of the two DHA-derived SPMs protectin D1 ( 2 ) and maresin 1 ( 3 ), together with their respective double di-oxygenation isomers 10 and 11 , are depicted. To be able to develop a protocol for the selective identification of SPMs we employed validated synthetic protectin D1 ( 2 ) 30 and its congener PD1 n-3 DPA ( 13 ) 18 that were each separately reacted with 4-phenyl-1,2,4-triazole-3,5-dione ( 14 ) and separately profiled using LC-MS/MS-based lipid mediator metabololipidomics (see Experimental section for details). 21 The results are depicted in Figure 4.…”

“…5,6 Moreover, novel n-3 docosapentaenoic acid derived SPMs have also been reported, 14 such as PD1 n-3 DPA ( 13 ) (Figure 2), which is biosynthesized, via a pathway analogous to that described above for protectin D1 ( 2 ). 18 PD1 n-3 DPA also carries potent pro-resolution and anti-inflammatory actions. 18 Hence, the isolation and structural elucidation of novel SPMs with such biologically fascinating actions is of considerable interest in the biomedical research community.…”

“…18 PD1 n-3 DPA also carries potent pro-resolution and anti-inflammatory actions. 18 Hence, the isolation and structural elucidation of novel SPMs with such biologically fascinating actions is of considerable interest in the biomedical research community. 19 Towards these ends, advances in LC-MS/MS metabololipidomics techniques have emerged.…”