Natural and\nSemisynthetic Immunomodulatory Luakuliide\nLabdane Diterpenoids

Spectroscopy-guided isolation of extracts of the Tongan\nmarine\nsponge <i>Hyattella</i> cf. <i>intestinalis</i> (Lamarck, 1814) has resulted in the reisolation of the labdane diterpenoid\nluakuliide A (<b>1</b>) and one new congener, luakulialactam\nA (<b>2</b>). In addition to establishing the absolute configuration\nof <b>1</b>, synthetic modifications to the luakuliide framework\nat key positions has created a set of six derivatives (<b>3</b>–<b>8</b>) which were used to interrogate a structure–activity\nrelationship relating to the immunomodulatory effects of luakuliide\nA. This revealed that compounds <b>4</b>, <b>5</b>, and <b>6</b>, bearing substituted furan motifs, show potent activity\nin primary macrophages by inhibiting pro-inflammatory cytokine production,\nwhile upregulating cellular metabolism and anti-inflammatory IL-10\nproduction at nanomolar concentrations. This is an activity profile\nconsistent with macrophages modulated toward an anti-inflammatory\nphenotype associated with wound-healing and resolution of inflammation.