Enhancing Bioactivities and Chemical Properties of A Marine Briarane-type Diterpenoid With Late-Stage Diversification

Excavatolide B (1, ExcB), a briarane-type diterpenoid isolated from Formosan gorgonian Briareum stechei, exhibits promising anti-inflammatory activity with low cytotoxicity. In this study, we report the structure-activity relationship of ExcB derivatives with late-stage modifications around the carboframe of 1. We identified a potent analog 22 with improved in vitro inhibitory activities against the inducible nitric oxide synthase gene expression, nitric oxide production, IL-6, and TNF- production in LPS-stimulated RAW264.7 macrophages. The esterification of piperidyl with proper spacer length in analog 22 also substantially increased the aqueous solubility >100-fold. More importantly, under similar dosing regimen compared to that of parent 1, 22 in its salt form showed an 80% increase in anti-inflammatory activity to alleviate carrageenan-induced paw edema in rats. Overall, these findings would greatly facilitate the further development of more potent analogs with enhanced bioactivities and improved drug-like properties of the underexplored class of briarane-type natural diterpenoids.