Stereochemical Determination of Fistularins Isolated from the Marine Sponge Ecionemia acervus and Their Regulatory Effect on Intestinal Inflammation

Abstract

By activity-guided fractionation based on inhibition of nitric oxide (NO) and prostaglandin E2 (PGE2), six fistularin compounds (1–6) were isolated from the marine sponge Ecionemia acervus (order Astrophorida). Based on stereochemical structure determination using Mosher’s method, fistularin-3 was assigned as a new stereoisomer. On the basis of the stereochemistry of fistularin-3, the stereochemical homogeneity of all six compounds was established by comparing carbon and proton chemical shifts. For fistularin-1 (1) and -2 (2), quantum calculations were performed to confirm their stereochemistry. In a co-culture system of human epithelial Caco-2 cells and THP-1 macrophages, all six isolated compounds showed potent anti-inflammatory activities. These bioactive fistularins inhibited the production of NO, PGE2, TNF-α, IL-1β, and IL-6 induced by lipopolysaccharide and interferon gamma. Inducible NO synthase and cyclooxygenase-2 expression and MAPK phosphorylation were downregulated in response to the inhibition of NF-κB nuclear translocation. Among the compounds tested, fistularin-1 (1) and 19-deoxyfistularin-3 (4) showed the highest activity. These findings suggest the potential use of the marine sponge E. acervus and its metabolites as pharmaceuticals for the treatment of inflammation-related diseases including inflammatory bowel disease.

Development of an Inflammation-Triggered In Vitro “Leaky Gut” Model Using Caco-2/HT29-MTX-E12 Combined with Macrophage-like THP-1 Cells or Primary Human-Derived Macrophages

“…IFN-γ priming of Caco-2 cells together with the stimulation of differentiated THP-1 cells by LPS and IFN-γ, induced an inflammation-like response in their diseased intestine model, evident by intestinal barrier disruption and pro-inflammatory cytokine release. Based on this model of Kämpfer, co-culture models with differentiated Caco-2 cells and PMA-differentiated THP-1 cells in the presence of inflammatory stimulators (e.g., LPS with/without IFN-γ) have been used to evaluate the potential immunomodulatory and anti-inflammatory effects of phytochemicals [ 43 , 72 , 73 ], marine natural products [ 74 , 75 , 76 ], bacterial β-glucans [ 77 ], siRNA-based nanomedicine [ 42 ], bovine milk-derived extracellular vesicles [ 78 ], and probiotic bacteria [ 41 ].…”

Marine natural products

“…438,439 Bromotyrosine-derived alkaloids were reported from a Greek Aplysina 1025-1028, Vietnamese Ecionemia acervus 1029 and an Egyptian Pseudoceratina arabica 1030, respectively. 421,440,441 Bromotyrosines are also commonly encountered in Suberea sponges. A Solomon Islands Suberea clavata yielded eight new bromotyrosines, subereins 1-8 1032-1039 that predicated a structural revision of two known stularin alkaloids 1031 and 1040.…”

A Survey of Recently Discovered Naturally Occurring Organohalogen Compounds

“…22 Of several known fistularins isolated from Ecionemia acervus collected in Vietnam, a new stereoisomer of fistularin-3 was identified, 57. 23 The new tryptophan-derived alkaloid, thorectandrin A (58) was identified in the Southern Australian sponge Thorectandra choanoides. 24 Together with three known analogues, the new pyrrolactam stylissaol (59) is present in the Myanmar sponge Stylissa massa.…”

“…The authors depict 54 as a sulfonic acid, but it may have been isolated as a sulfonate salt . Of several known fistularins isolated from Ecionemia acervus collected in Vietnam, a new stereoisomer of fistularin-3 was identified, 57 . The new tryptophan-derived alkaloid, thorectandrin A ( 58 ) was identified in the Southern Australian sponge Thorectandra choanoides .…”