Bioorg Chem 2020 Oct 01;103:104140. doi: 10.1016/j.bioorg.2020.104140.

Stomopneulactone D from long-spined sea urchin Stomopneustes variolaris: Anti-inflammatory macrocylic lactone attenuates cyclooxygenase-2 expression in lipopolysaccharide-activated macrophages.

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Cyclooxygenase-2 is one of the prominent enzymes to cause an increased production of prostaglandins during inflammation and immune responses. Cyclooxygenase-2 expression is up-regulated in inflammatory conditions owing to the induction by different inflammatory stimuli including cytokines, and therefore, the expression studies of cyclooxygenase-2 in lipopolysaccharide-induced macrophage cells (RAW 264.7 cell line) could be used for screening of the compounds with anti-inflammatory potential. The present study evaluated the anti-inflammatory properties of four homologous stomopneulactones A-D, classified under the class of macrocyclic lactones isolated from the solvent extract of the long-spined sea urchin Stomopneustes variolaris (familyStomopneustidae) in the lipopolysaccharide-induced macrophages. The structures of these isolated compounds were assigned using detailed spectroscopic techniques. Stomopneulactone D bearing 5-butyl-4-hydroxy-12-oxo-1-oxa-5,9-cyclododecadienyl moiety exhibited relatively greater anti-inflammatory potentials against cyclooxygenase-2 (IC50 ~ 2 mM) and 5-lipoxygenase (IC50 2.6 mM) than those displayed by other macrocyclic lactones. The studied compounds displayed higher selectivity index values (anti-cyclooxygenase-1IC50/anti-cyclooxygenase-2IC50 > 1), which designated the selective anti-inflammatory potentials of the macrocyclic lactones against inducible inflammatory mediators than those exhibited by the anti-inflammatory agent ibuprofen (0.43). The in silico molecular modelling analyses of the stomopneulactones with cyclooxygenase-2/5-lipoxygenase enzymes recorded lowest binding energy (-7.71 and -9.60 kcal mol-1, respectively) and docking score (-8.82 and -11.12 kcal mol-1, respectively) for stomopneulactone D along with its higher electronic parameter (topological polar surface area of 72.83), which further confirmed its greater anti-inflammatory potential than other compounds in the series. Stomopneulactone D also inhibited the generation of inducible nitric oxide synthase, intracellular reactive oxygen species, along with 5-lipoxygenase and cyclooxygenase-2 in the lipopolysaccharide-stimulated macrophage cells. Additionally, the studied macrocyclic lactone decreased the mRNA expression of cyclooxygenase-2 in the inflammatory cells in dose-dependent manner, which demonstrated the therapeutic potential of stomopneulactone D in down-regulating the inflammatory pathogenesis.

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