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


In this study, we capitalized on the chemical diversity from Philippine marine sponges to discover anti-inflammatory compounds. The anti-inflammatory activity was evaluated in LPS-stimulated murine macrophage cells and an antiproliferative activity testing was also used as a counter-screen. This allowed for selecting priority extracts that decrease NO production in RAW 264.7 cells with minimal effects on the cell viability, hence, excluding promiscuous and non-selective agents. Screening and subsequent validation of the bioactivity identified a Neopetrosia compacta sponge as bioactive and the priority for purification. Bioactivity-guided purification afforded xestoquinone (1), and five analogues, namely 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). The mechanism of anti-inflammatory activity was evaluated using various cell-based assays. Xestoquinone and analogues (1–6) attenuated the NO production in a concentration-dependent manner in LPS-stimulated RAW 264.7 murine macrophage cells. The less studied monosubstituted derivatives 4–6 offer the advantage of lower toxicity and potent anti-inflammatory activity. Minor modifications in the quinoid moiety allow for the fine-tuning of the bioactivity of the xestoquinone family of compounds.



Chronic inflammation is recognized as a contributor to multiple chronic diseases, such as cancer, cardiovascular, and autoimmune disorders. Due to the side effects and toxicities accompanied with the intake of existing anti-inflammatory drugs, the discovery of compounds with unique target and/or mechanisms of anti-inflammation and with cytoprotective properties is very crucial. In this study, a natural products-initiated discovery of anti-inflammatory agents from marine sponges was undertaken. The study aims to expand the potential of xestoquinone and monosubstituted derivatives from Neopetrosia compacta as anti-inflammatory agents and Nrf2 activators. Structure-activity relationship shows that while the anti-inflammatory activity was unaffected by structural modifications in the para-quinone moiety, the monosubstituted analogues had significantly reduced cytotoxicity. The partial functionalization of the para-quinone moiety significantly improved the selectivity of the monosubstituted analogues of xestoquinone. The anti-inflammatory activity and Nrf2 activation by xestoquinone and monosubstituted derivatives were correlated to the downregulation of the pro-inflammatory Nos2 and Il1b genes, leading to a decrease in NO production. Hence, xestoquinone and monosubstituted derivatives can be used as drug leads to develop more effective anti-inflammatory and cytoprotective drugs with reduced unwanted effects. Moreover, the compounds could be structurally modified to generate less cytotoxic compounds with increased potency and selectivity.



Shalice R. Susana (Marine Science Institute, University of the Philippines)
Lilibeth A. Salvador-Reyes (Marine Science Institute, University of the Philippines)

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