Total Synthesis and Biological Activity of the Arachidonic Acid Metabolite Hemiketal E<sub>2</sub>

Boer, Robert E.; Giménez‐Bastida, Juan Antonio; Boutaud, Olivier; Jana, Somnath; Schneider, Claus; Sulikowski, Gary A.

doi:10.1021/acs.orglett.8b01578

Cited by 14 publications

(21 citation statements)

References 26 publications

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“…New in vitro studies using a range of relevant cell lines (with different features) and correctly designed [ 52 ] will be essential to enlarge our knowledge about further mechanisms of action. Based on the reported effects of caffeic acid on the well-defined 5-lypoxygenase (5-LOX) [ 53 ] and COX-2 (see above) pathways, an interesting approach could be the study of its effects on the formation of the more recently described 5-LOX/COX-2 hemiketal (HK) eicosanoids, HKE 2 and HKD 2 [ 54 , 55 , 56 , 57 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

Caffeic Acid Modulates Processes Associated with Intestinal Inflammation

et al. 2021

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Caffeic acid is one of the most abundant hydroxycinnamic acids in fruits, vegetables, and beverages. This phenolic compound reaches relevant concentrations in the colon (up to 126 µM) where it could come into contact with the intestinal cells and exert its anti-inflammatory effects. The aim of this investigation was to study the capacity of caffeic acid, at plausible concentrations from an in vivo point of view, to modulate mechanisms related to intestinal inflammation. Consequently, we tested the effects of caffeic acid (50–10 µM) on cyclooxygenase (COX)-2 expression and prostaglandin (PG)E2, cytokines, and chemokines (IL-8, monocyte chemoattractant protein-1 -MCP-1-, and IL-6) biosynthesis in IL-1β-treated human myofibroblasts of the colon, CCD-18Co. Furthermore, the capacity of caffeic acid to inhibit the angiotensin-converting enzyme (ACE) activity, to hinder advanced glycation end product (AGE) formation, as well as its antioxidant, reducing, and chelating activity were also investigated. Our results showed that (i) caffeic acid targets COX-2 and its product PGE2 as well as the biosynthesis of IL-8 in the IL-1β-treated cells and (ii) inhibits AGE formation, which could be related to (iii) the high chelating activity exerted. Low anti-ACE, antioxidant, and reducing capacity of caffeic acid was also observed. These effects of caffeic acid expands our knowledge on anti-inflammatory mechanisms against intestinal inflammation.

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Section: Discussionmentioning

confidence: 99%

Caffeic Acid Modulates Processes Associated with Intestinal Inflammation

et al. 2021

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“…The spectroscopic data was in agreement with previously reported data. 35 R f (5% Et 2 O in hexane, visualized by UV and KMnO 4 stain) = 0.23; [α] D 20 = −25.8 ( c 1.7, CHCl 3 ) [Lit. 35 [α] D 20 = −25.8 ( c 1.7, CHCl 3 )]; 1 H NMR (400 MHz, CDCl 3 ): δ 6.50 (dd, J = 14.4, 6.0 Hz, 1H), 6.22 (dd, J = 14.4, 1.3 Hz, 1H), 4.10 (app qd, J = 5.9, 1.3 Hz, 1H), 3.67 (s, 3H), 2.31 (t, J = 7.3 Hz, 2H), 1.86–1.56 (m, 2H), 1.56–1.46 (m, 2H), 0.89 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13 C{ 1 H} NMR (101 MHz, CDCl 3 ): δ 174.0, 148.9, 76.2, 74.9, 52.2, 36.9, 34.0, 25.9 (3C), 20.4, 18.3, −4.4, −4.8; HRESIMS m / z : 421.0666 [M + Na] + (calcd for C 14 H 27 IO 3 SiNa, 421.0666).…”

Section: Methodsmentioning

confidence: 99%

Stereoselective Synthesis and Structural Confirmation of the Specialized Pro-Resolving Mediator Resolvin E4

et al. 2021

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Herein, we report the stereoselective and convergent synthesis of resolvin E4, a newly identified specialized pro-resolving mediator. This synthesis proves the absolute configuration and exact olefin geometry. Key elements of the successful strategy include a highly stereoselective MacMillan organocatalytic oxyamination, a Midland Alpine borane reduction, and the use of a 1,4-pentadiyne unit as a linchpin building block. The application of reaction telescoping in several of the synthetic transformations enabled the preparation of the resolvin E4 methyl ester in 10% yield over 10 steps (longest linear sequence). The physical property (UV–Vis and LC–MS/MS) data of synthetic resolvin E4 matched those obtained from biologically produced material.

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“…These eicosanoids promote migration and tubulogenesis of endothelial cells [ 6 ] and inhibit platelet aggregation. [ 12 ] A common anti‐inflammatory strategy involves the reduction of the biosynthesis of PGs and LTs via inhibition of the COX‐2 and 5‐LOX pathways. Aspirin is a paradigmatic inhibitor of PGs synthesis through blocking COX‐2 activity, [ 13 ] while drugs such as zileuton or montelukast target the 5‐LOX pathway.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of 5‐Lipoxygenase‐Derived Leukotrienes and Hemiketals as a Novel Anti‐Inflammatory Mechanism of Urolithins

Giménez‐Bastida

González‐Sarrías

Espı́n

et al. 2020

Molecular Nutrition Food Res

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Scope Urolithins (Uro), gut microbial metabolites derived from ellagic acid (EA), reach significant concentrations in the human colon. Uro‐A exerts anti‐inflammatory activity in animal models of inflammatory bowel diseases (IBDs). It is hypothesized that Uro can modulate the biosynthesis of leukocyte‐derived inflammatory eicosanoids from the 5‐lipoxygenase (5‐LOX), cyclooxygenase‐2 (COX‐2), and 5‐LOX/COX‐2 pathways, relevant in the onset and progression of IBDs, including 5‐hydroxyeicosatetraenoic acids (5‐HETEs), leukotriene‐B4 (LTB4), prostaglandin E2 (PGE2), and hemiketals (HKE2 and HKD2). Methods and results Leukocytes, obtained from six healthy donors, are stimulated with lipopolysaccharide and calcium ionophore A23187. Uro, at concentrations found in the human colon (1–15 µm), decrease eicosanoid biosynthesis and COX‐2 levels in the activated leukocytes. In contrast, EA and conjugated Uro (glucuronides and sulfates) are inactive. Uro‐A and isourolithin‐A reduce the formation of the 5‐LOX/COX‐2 products HKE2 and HKD2 through the COX‐2 pathway (down‐regulation of COX‐2 and PGE2), whereas Uro‐C reduces 5‐HETE and LTB4 via inhibition of 5‐LOX. Conclusions The results show that physiologically relevant colonic Uro target eicosanoid biosynthetic pathways. The effect on HKs and LTB4 formation is unprecedented and expands the knowledge on anti‐inflammatory mechanisms of Uro against IBDs.

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Total Synthesis and Biological Activity of the Arachidonic Acid Metabolite Hemiketal E₂

Cited by 14 publications

References 26 publications

Caffeic Acid Modulates Processes Associated with Intestinal Inflammation

Caffeic Acid Modulates Processes Associated with Intestinal Inflammation

Stereoselective Synthesis and Structural Confirmation of the Specialized Pro-Resolving Mediator Resolvin E4

Inhibition of 5‐Lipoxygenase‐Derived Leukotrienes and Hemiketals as a Novel Anti‐Inflammatory Mechanism of Urolithins

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Total Synthesis and Biological Activity of the Arachidonic Acid Metabolite Hemiketal E2

Cited by 14 publications

References 26 publications

Caffeic Acid Modulates Processes Associated with Intestinal Inflammation

Caffeic Acid Modulates Processes Associated with Intestinal Inflammation

Stereoselective Synthesis and Structural Confirmation of the Specialized Pro-Resolving Mediator Resolvin E4

Inhibition of 5‐Lipoxygenase‐Derived Leukotrienes and Hemiketals as a Novel Anti‐Inflammatory Mechanism of Urolithins

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Total Synthesis and Biological Activity of the Arachidonic Acid Metabolite Hemiketal E₂