Natural and Semisynthetic Immunomodulatory Luakuliide Labdane Diterpenoids

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