Brominated polyunsaturated lipids from the Chinese sponge Xestospongia testudinaria as a new class of pancreatic lipase inhibitors

• Eight new brominated polyunsaturated lipids (3–10) have been characterized.
• The reported compounds represent a new class of pancreatic lipase (PL) inhibitors.
• Compound 14 exhibited the strongest inhibitory activity against PL.
• 14 strongly suppressed serum triglyceride elevation in olive oil-loaded mice.
• No signs related death or abnormality were observed after 14 administration.

Chemical analysis of the Chinese marine sponge Xestospongia testudinaria afforded a library of brominated polyunsaturated lipids including eight new compounds, named xestonarienes A–H (3–10) and thirteen known analogues (11–23). The structures of the new compounds were elucidated by detailed spectroscopic analysis and by comparison with literature data. The isolated lipids were evaluated for their inhibitory activity against pancreatic lipase (PL), an essential enzyme for efficient fat digestion and the major metabolite, 14, exhibited a marked inhibitory activity (IC50 = 3.11 μM), similar to that of the positive control Orlistat (IC50 = 0.78 μM). The preliminary structure–activity relationships on the series of compounds clearly evidenced that a terminal (E)-enyne functionality, a diyne within the chain, and methyl ester group are all key functional groups for the activity of this class of PL inhibitors. Further biological investigation on compound 14 revealed a significant decrease in the plasma triglyceride level following an oral lipid challenge in C57BLKS/J male mice. Acute toxicology study demonstrated that compound 14 was non-toxic up to 1600 mg/kg p.o in mice. This is the first report of the PL inhibitory activity for brominated polyunsaturated lipids and the obtained results qualify compound 14 as a potent and bioavailable drug candidate for a mild and safe treatment to prevent and reduce obesity.

Methyl xestospongic ester (14) exhibited a marked inhibitory activity against pancreatic lipase, representing a new structural class of inhibitors. In the acute toxicity study, no signs related death or abnormality were observed after compound 14 administration.Figure optionsDownload as PowerPoint slide