Novel araucarene diterpenes from Agathis dammara exert hypoglycemic activity by promoting pancreatic β cells regeneration and glucose uptake

In this study, araucarene is described as a series of diterpenes characterized by a pimarene skeleton with a side chain oxidized to varying degrees at C-13. In this study, 16 araucarene diterpenoids and their derivatives were isolated from the woods of Agathis dammara. Among them, 11 new compounds, namely dammaradione (1), dammarones D−G (2, 5, 14, 15), dammaric acids B−F (8−12), and dammarol (16), were reported for the first time. The structure of the new compounds was determined using HR-ESI-MS and 1D/2D NMR spectroscopy, while their absolute configuration was established using the electronic circular dichroism (ECD) exciton chirality method and Snatzke’s method. The hypoglycemic effects of all compounds were evaluated using a transgenic zebrafish model, and the structure-activity relationship was analyzed. Araucarone (3) and dammaric acid C (9), as representative compounds, exhibit significant hypoglycemic effects on zebrafish. The mechanism primarily involves promoting pancreatic β cell regeneration and glucose uptake. Specifically, these drugs promote the differentiation of pancreatic endocrine precursor cells into β cells in zebrafish.