Identification of tetragocarbone C and sideroxylin as the most potent anti-inflammatory components of Syncarpia glomulifera

In contrast to ancient Western and Asian cultures, medicinal plants of the Aboriginal and Torres Strait Islanders in Australia have not been as intensively studied for their molecular composition and molecular bioactivity. Syncarpia glomulifera subsp. glomulifera is a species in the plant family Myrtaceae. The resin of the plant has been traditionally used by the D'harawal people of Western Sydney to heal inflamed sores and ulcers. Hence, the anti-inflammatory activity of its leaf extract was investigated in RAW 264.7 macrophage and N11 microglia cell lines to isolate and identify the most active compounds. One new compound, tetragocarbone C, and three known compounds, tetragocarbone B, sideroxylin, and lumaflavanone A showed potent anti-inflammatory activity by downregulating nitric oxide and TNF-alpha production in LPS and IFN-gamma stimulated cells. Except for the less potent tetragocarbone B, all compounds had an IC50 value (for nitric oxide downregulation) of <10mug/mL and moderate cytotoxicity in both cell lines. The molecular targets along pro-inflammatory signaling pathways were further investigated in RAW 264.7 cells. All four compounds suppressed phosphorylation of ERK, c-Jun, and limited the phosphorylation of STAT-1 and STAT-3 in response to LPS and IFN-gamma activation. The four compounds also suppressed NF-kappaB activation by preventing the translocation of the p65 subunit into the nucleus. Collectively, these findings suggest that the compounds isolated from Syncarpia glomulifera, especially tetragocarbone C and sideroxylin are promising anti-inflammatory agents, and could be further investigated for the treatment of diseases characterized by chronic inflammation.