Spectroscopy-guided isolation of extracts of the Tongan marine sponge Hyattella cf. intestinalis (Lamarck, 1814) has resulted in the reisolation of the labdane diterpenoid luakuliide A (1) and one new congener, luakulialactam A (2). In addition to establishing the absolute configuration of 1, synthetic modifications to the luakuliide framework at key positions has created a set of six derivatives (3-8) which were used to interrogate a structure-activity relationship relating to the immunomodulatory effects of luakuliide A. This revealed that compounds 4, 5, and 6, 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.