Brasilterpenes A–E, Bergamotane Sesquiterpenoid Derivatives with Hypoglycemic Activity from the Deep Sea-Derived Fungus Paraconiothyrium brasiliense HDN15-135

Abstract

Five bergamotane sesquiterpenoid derivatives, brasilterpenes A-E (<b>1</b>-<b>5</b>), bearing an unreported spiral 6/4/5 tricyclic ring system, were isolated from the deep sea-derived ascomycete fungus <i>Paraconiothyrium brasiliense</i> HDN15-135. Their structures, including absolute configurations, were established by extensive spectroscopic methods complemented by single-crystal X-ray diffraction analyses, electronic circular dichroism (ECD), and density-functional theory (DFT) calculations of nuclear magnetic resonance (NMR) data including DP4+ analysis. The hypoglycemic activity of these compounds was assessed using a diabetic zebrafish model. Brasilterpenes A (<b>1</b>) and C (<b>3</b>) significantly reduced free blood glucose in hyperglycemic zebrafish in vivo by improving insulin sensitivity and suppressing gluconeogenesis. Moreover, the hypoglycemic activity of compound <b>3</b> was comparable to the positive control, anti-diabetes drug rosiglitazone. These results suggested brasilterpene C (<b>3</b>) had promising anti-diabetes potential.