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Design and synthesis of novel prostaglandin E2 ethanolamide and glycerol ester probes for the putative prostamide receptor(s).

ABSTRACT: Novel prostaglandin-ethanolamide (PGE2-EA) and glycerol ester (2-PGE2-G) analogs were designed and synthesized to aid in the characterization of a putative prostamide receptor. Our design incorporates the electrophilic isothiocyanato and the photoactivatable azido groups at the terminal tail position of the prototype. Stereoselective Wittig and Horner-Wadsworth-Emmons reactions install the head and the tail moieties of the PGE2 skeleton. The synthesis is completed using Mitsunobu azidation and peptide coupling as the key steps. A chemoenzymatic synthesis for the 2-PGE2-G is described for first time.

SUBMITTER: Shelnut EL

PROVIDER: S-EPMC4422110 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Design and synthesis of novel prostaglandin E2 ethanolamide and glycerol ester probes for the putative prostamide receptor(s).

Shelnut Erin L EL Nikas Spyros P SP Finnegan David F DF Chiang Nan N Serhan Charles N CN Makriyannis Alexandros A

Tetrahedron letters 20150301 11

Novel prostaglandin-ethanolamide (PGE2-EA) and glycerol ester (2-PGE2-G) analogs were designed and synthesized to aid in the characterization of a putative prostamide receptor. Our design incorporates the electrophilic isothiocyanato and the photoactivatable azido groups at the terminal tail position of the prototype. Stereoselective Wittig and Horner-Wadsworth-Emmons reactions install the head and the tail moieties of the PGE2 skeleton. The synthesis is complete ...[more]

PMID: 25960577

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Project description:Human monocytic cells in blood have important roles in host defense and express the enzyme carboxylesterase 1 (CES1). This metabolic serine hydrolase plays a critical role in the metabolism of many molecules, including lipid mediators called prostaglandin glyceryl esters (PG-Gs), which are formed during cyclooxygenase-mediated oxygenation of the endocannabinoid 2-arachidonoylglycerol. Some PG-Gs have been shown to exhibit anti-inflammatory effects; however, they are unstable compounds, and their hydrolytic breakdown generates pro-inflammatory prostaglandins. We hypothesized that by blocking the ability of CES1 to hydrolyze PG-Gs in monocytes/macrophages, the beneficial effects of anti-inflammatory prostaglandin D2-glyceryl ester (PGD2-G) could be augmented. The goals of this study were to determine whether PGD2-G is catabolized by CES1, evaluate the degree to which this metabolism is blocked by small-molecule inhibitors, and assess the immunomodulatory effects of PGD2-G in macrophages. A human monocytic cell line (THP-1 cells) was pretreated with increasing concentrations of known small-molecule inhibitors that block CES1 activity [chlorpyrifos oxon (CPO), WWL229, or WWL113], followed by incubation with PGD2-G (10 μM). Organic solvent extracts of the treated cells were analyzed by liquid chromatography with tandem mass spectrometry to assess levels of the hydrolysis product PGD2. Further, THP-1 monocytes with normal CES1 expression (control cells) and "knocked-down" CES1 expression (CES1KD cells) were employed to confirm CES1's role in PGD2-G catabolism. We found that CES1 has a prominent role in PGD2-G hydrolysis in this cell line, accounting for about 50% of its hydrolytic metabolism, and that PGD2-G could be stabilized by the inclusion of CES1 inhibitors. The inhibitor potency followed the rank order: CPO > WWL113 > WWL229. THP-1 macrophages co-treated with WWL113 and PGD2-G prior to stimulation with lipopolysaccharide exhibited a more pronounced attenuation of pro-inflammatory cytokine levels (interleukin-6 and TNFα) than by PGD2-G treatment alone. In contrast, prostaglandin E2-glyceryl ester (PGE2-G) had opposite effects compared to those of PGD2-G, which appeared to be dependent on the hydrolysis of PGE2-G to PGE2. These results suggest that the anti-inflammatory effects induced by PGD2-G can be further augmented by inactivating CES1 activity with specific small-molecule inhibitors, while pro-inflammatory effects of PGE2-G are attenuated. Furthermore, PGD2-G (and/or its downstream metabolites) was shown to activate the lipid-sensing receptor PPARγ, resulting in altered "alternative macrophage activation" response to the Th2 cytokine interleukin-4. These findings suggest that inhibition of CES1 and other enzymes that regulate the levels of pro-resolving mediators such as PGD2-G in specific cellular niches might be a novel anti-inflammatory approach.

Dataset Information

Design and synthesis of novel prostaglandin E2 ethanolamide and glycerol ester probes for the putative prostamide receptor(s).

Publications

Design and synthesis of novel prostaglandin E<sub>2</sub> ethanolamide and glycerol ester probes for the putative prostamide receptor(s).

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