ABSTRACT
The resolution of inflammation is governed by the active biosynthesis of specialized pro-resolving mediators using ω-6 and ω-3 polyunsaturated fatty acids as substrates. These mediators act as resolution agonists and display several interesting bioactivities. PD2n-3 DPA is an oxygenated polyunsaturated fatty acid biosynthesized from n-3 docosapentaenoic acid belonging to the specialized pro-resolving lipid mediator family named protectins. The protectins exhibit anti-inflammatory properties and pro-resolving bioactivities. These endogenously produced compounds are of interest as leads in resolution pharmacology and drug development. Herein, together with its NMR, MS, and UV data, a stereoselective total synthesis of PD2n-3 DPA is presented.
Subject(s)
Fatty Acids, Unsaturated/chemical synthesis , Animals , Fatty Acids, Unsaturated/chemistry , Humans , Molecular Structure , Spectrum Analysis/methods , Substrate SpecificityABSTRACT
PD1n-3 DPA belongs to the protectin family of specialized pro-resolving lipid mediators. The protectins are endogenously formed mediators that display potent anti-inflammatory properties and pro-resolving bioactivities and have attracted interest in drug discovery. However, few studies have been reported of the secondary metabolism of the protectins. To investigate the metabolic formation of the putative C22 mono-hydroxylated product, coined 22-OH-PD1n-3 DPA, a stereoselective synthesis was performed. LC/MS-MS data of synthetic 22-OH-PD1n-3 DPA matched the data for the biosynthetic formed product. Cellular studies revealed that 22-OH-PD1n-3 DPA is formed from n-3 docosapentaenoic acid in human serum, and we confirmed that 22-OH-PD1n-3 DPA is a secondary metabolite produced by ω-oxidation of PD1n-3 DPA in human neutrophils and in human monocytes. The results reported are of interest for enabling future structure-activity relationship studies and provide useful molecular insight of the metabolism of the protectin class of specialized pro-resolving mediators.
Subject(s)
Docosahexaenoic Acids/chemistry , Biosynthetic Pathways , Chemistry Techniques, Synthetic , Chromatography, Liquid , Docosahexaenoic Acids/biosynthesis , Docosahexaenoic Acids/chemical synthesis , Humans , Molecular Conformation , Molecular Structure , Monocytes/immunology , Monocytes/metabolism , Neutrophils/immunology , Neutrophils/metabolism , Structure-Activity Relationship , Tandem Mass SpectrometryABSTRACT
The halolactonization reaction is a useful chemical transformation for the construction of lactones from γ- or δ-substituted alkenoic carboxylic acids or carboxylic esters. Traditionally, the stereoselectivity of these reactions has been controlled by the substrates or the reagents. The substrate-controlled method has been extensively studied and applied in the synthesis of many natural products. However, catalytic, enantioselective iodolactonizations of γ- or δ-substituted alkenoic carboxylic acids have only recently been developed. This review article highlights the advances that have emerged over the last decade.
ABSTRACT
New drugs that can resolve inflammation without immunosuppressive effects are at the medicinal chemistry frontier. Pro-resolving endogenously formed small molecules, that is, the resolvins, are excellent candidates displaying such bioactions. The first total synthesis of the specialized pro-resolving mediator RvD1n-3 DPA has been achieved using the underutilized sp3 -sp3 Negishi cross coupling reaction and an alkyne hydrosilylation-protodesilylation protocol. Biological evaluations revealed that this novel mediator displays low nanomolar pro-resolving properties and potently activates the human DRV1/GPR32 receptor. As such, this endogenous natural product is a lead compound for the development of novel immunoresolvents.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Docosahexaenoic Acids/chemistry , Fatty Acids, Unsaturated/chemistry , Animals , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Humans , Inflammation/pathology , Inflammation/prevention & control , Macrophages/cytology , Macrophages/drug effects , Macrophages/metabolism , Neutrophils/cytology , Neutrophils/drug effects , Neutrophils/metabolism , Quantum Theory , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/metabolism , StereoisomerismABSTRACT
PD1n-3 DPA is a specialized pro-resolving lipid mediator that displays potent anti-inflammatory properties and pro-resolving bioactivities. Such naturally occurring compounds are of current interest in biomolecular chemistry and drug discovery. To investigate the involvement of an epoxide intermediate in the biosynthesis of PD1n-3 DPA from n-3 docosapentaenoic acid, the epoxy acid 16(S),17(S)-epoxy-PDn-3 DPA, herein named ePDn-3 DPA, was prepared by stereoselective total synthesis. The synthetic material of ePDn-3 DPA allowed investigations of its role in the biosynthesis of PD1n-3 DPA. The obtained results establish that the biosynthesis of PD1n-3 DPA in neutrophils occurs with ePDn-3 DPA as the intermediate, and that 15-LOX produces ePDn-3 DPA from n-3 docosapentaenoic acid. Furthermore, support for the involvement of a hydrolytic enzyme in the biosynthetic conversion of ePDn-3 DPA to PD1n-3 DPA was found. In addition, ePDn-3 DPA was found to regulate the formation of the potent neutrophil chemoattractant LTB4 with equal potencies to that obtained with PD1n-3 DPA.
Subject(s)
Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/pharmacology , Epoxy Compounds/metabolism , Fatty Acids, Unsaturated/biosynthesis , Anti-Inflammatory Agents/chemistry , Arachidonate 15-Lipoxygenase/metabolism , Epoxy Compounds/chemistry , Epoxy Compounds/pharmacology , Fatty Acids, Unsaturated/chemistry , Fatty Acids, Unsaturated/pharmacology , Humans , Leukotriene B4/antagonists & inhibitors , Leukotriene B4/biosynthesis , Leukotriene B4/chemistry , Molecular Structure , Neutrophils/chemistry , Neutrophils/drug effects , Neutrophils/metabolism , StereoisomerismABSTRACT
Docosahexaenoic acid (DHA), a polyunsaturated ω-3 fatty acid enriched in oily fish, contributes to better health by affecting multiple targets. Large-conductance Ca2+- and voltage-gated Slo1 BK channels are directly activated by nanomolar levels of DHA. We investigated DHA-channel interaction by manipulating both the fatty acid structure and the channel composition through the site-directed incorporation of unnatural amino acids. Electrophysiological measurements show that the para-group of a Tyr residue near the ion conduction pathway has a critical role. To robustly activate the channel, ionization must occur readily by a fatty acid for a good efficacy, and a long nonpolar acyl tail with a Z double bond present at the halfway position for a high affinity. The results suggest that DHA and the channel form an ion-dipole bond to promote opening and demonstrate the channel druggability. DHA, a marine-derived nutraceutical, represents a promising lead compound for rational drug design and discovery.
Subject(s)
Docosahexaenoic Acids/chemistry , Fatty Acids, Omega-3/chemistry , Fatty Acids, Unsaturated/chemistry , Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/metabolism , Docosahexaenoic Acids/metabolism , Docosahexaenoic Acids/therapeutic use , Fatty Acids, Omega-3/metabolism , Fatty Acids, Unsaturated/metabolism , Fatty Acids, Unsaturated/therapeutic use , Fish Oils/chemistry , Fish Oils/metabolism , Humans , Ion Channel Gating/genetics , Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/chemistry , Large-Conductance Calcium-Activated Potassium Channels/chemistry , Large-Conductance Calcium-Activated Potassium Channels/metabolismABSTRACT
Lipid mediators have attracted great interest from scientists within the chemical, medicinal, and pharmaceutical research community. One such example is leukotriene B4 which has been the subject of many pharmacological studies. Herein, we report a convergent and stereoselective synthesis of this potent lipid mediator in 5% yield over 10 steps in the longest linear sequence from commercial starting materials. The key steps were a stereocontrolled acetate-aldol reaction with Nagao's chiral auxiliary and a Z-selective Boland reduction. All spectroscopic data were in agreement with those previously reported.
Subject(s)
Leukotriene B4/chemical synthesis , Aldehydes/chemical synthesis , Aldehydes/chemistry , Alkynes/chemical synthesis , Alkynes/chemistry , Leukotriene B4/biosynthesis , Leukotriene B4/chemistryABSTRACT
The first total synthesis of the lipid mediator MaR1n-3 DPA (5) has been achieved in 12 % overall yield over 11â steps. The stereoselective preparation of 5 was based on a Pd-catalyzed sp(3) -sp(3) Negishi cross-coupling reaction and a stereocontrolled Evans-Nagao acetate aldol reaction. LC-MS/MS results with synthetic material matched the biologically produced 5. This novel lipid mediator displayed potent pro-resolving properties stimulating macrophage efferocytosis of apoptotic neutrophils.