Anti-Inflammatory Activity of Monosubstituted Xestoquinone Analogues from the Marine Sponge .

Chronic inflammation is recognized as a contributor to multiple chronic diseases, such as cancer, cardiovascular, and autoimmune disorders. Here, a natural products-initiated discovery of anti-inflammatory agents from marine sponges was undertaken. From the screening of 231 crude extracts, a total of 30 extracts showed anti-inflammatory activity with no direct cytotoxic effects at 50 μg/mL on RAW 264.7 (ATCCTIB-71™) murine macrophage cells stimulated with 1 μg/mL lipopolysaccharide (LPS). Bioactivity-guided purification of the anti-inflammatory extract from the sponge led to the isolation of xestoquinone (), adociaquinone B (), adociaquinone A (), 14-hydroxymethylxestoquinone (), 15-hydroxymethylxestoquinone (), and an inseparable 2:1 mixture of 14-methoxyxestoquinone and 15-methoxyxestoquinone (). Compounds - caused a concentration-dependent reduction of nitric oxide (NO) production in LPS-stimulated RAW 264.7 cells, with - having low micromolar IC and acceptable selectivity index. Gene expression analysis using qRT-PCR showed that , , and downregulated and expression by 2.1- to 14.8-fold relative to the solvent control at 10 μM. Xestoquinone () and monosubstituted analogues (-), but not the disubstituted adociaquinones ( and ), caused Nrf2 activation in a luciferase reporter MCF7 stable cells. Compounds and caused a modest increase in gene expression at 10 μM. The anti-inflammatory activity of xestoquinone () and monosubstituted analogues (-) may, in part, be mediated by Nrf2 activation, leading to attenuation of inflammatory mediators such as IL-1β and NOS2.