Natural and Semisynthetic Immunomodulatory Luakuliide Labdane Diterpenoids

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.