RESUMO
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.
Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Ácido Eicosapentaenoico/metabolismo , Ácidos Graxos Insaturados/química , Animais , Anti-Inflamatórios/química , Cromatografia Líquida , Ácidos Docosa-Hexaenoicos/química , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/química , Ácido Eicosapentaenoico/farmacologia , Humanos , Macrófagos/metabolismo , Camundongos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Resolvins are a family of n-3 lipid mediators initially identified in resolving inflammatory exudates that temper inflammatory responses to promote catabasis. Here, temporal metabololipidomics with self-limited resolving exudates revealed that resolvin (Rv) D3 has a distinct time frame from other lipid mediators, appearing late in the resolution phase. Using synthetic materials prepared by stereocontrolled total organic synthesis and metabololipidomics, we established complete stereochemistry of RvD3 and its aspirin-triggered 17R-epimer (AT-RvD3). Both synthetic resolvins potently regulated neutrophils and mediators, reducing murine peritonitis and dermal inflammation. RvD3 and AT-RvD3 displayed leukocyte-directed actions, e.g., blocking human neutrophil transmigration and enhancing macrophage phagocytosis and efferocytosis. These results position RvD3 uniquely within the inflammation-resolution time frame to vantage and contribute to the beneficial actions of aspirin and essential n-3 fatty acids.