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

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 (ATCC ® TIB-71™) murine macrophage cells stimulated with 1 μg/mL lipopolysaccharide (LPS). Bioactivity-guided purification of the anti-inflammatory extract from the sponge Neopetrosia compacta led to the isolation of xestoquinone ( 1 ), adociaquinone B ( 2 ), adociaquinone A ( 3 ), 14-hydroxymethylxestoquinone ( 4 ), 15-hydroxymethylxestoquinone ( 5 ), and an inseparable 2:1 mixture of 14-methoxyxestoquinone and 15-methoxyxestoquinone ( 6 ). Compounds 1 - 6 caused a concentration-dependent reduction of nitric oxide (NO) production in LPS-stimulated RAW 264.7 cells, with 4 - 6 having low micromolar IC 50 and acceptable selectivity index. Gene expression analysis using qRT-PCR showed that 1 , 5 , and 6 downregulated Il1b and Nos2 expression by 2.1- to 14.8-fold relative to the solvent control at 10 μM. Xestoquinone ( 1 ) and monosubstituted analogues ( 4 - 6 ), but not the disubstituted adociaquinones ( 2 and 3 ), caused Nrf2 activation in a luciferase reporter MCF7 stable cells. Compounds 5 and 6 caused a modest increase in Nqo1 gene expression at 10 μM. The anti-inflammatory activity of xestoquinone ( 1 ) and monosubstituted analogues ( 4 - 6 ) may, in part, be mediated by Nrf2 activation, leading to attenuation of inflammatory mediators such as IL-1β and NOS2.