Skeleton Rearranged and Oxygenated ent-Rosane Diterpenoids with Antiadipogenic Activity from Euphorbia milii

Five unreported and oxygenated ent-rosane diterpenoids (ent-RDs), Euphomillanols A-E (1-5), were isolated from Euphorbia milii. Among them, compounds 1 and 2 are unprecedented 7/7/6-fused tricyclic 5,10-seco-ent-RDs and possess a unique 11-oxabicyclo[4.4.1]undeca-1(10),5-diene moiety, while 3 is characterized by a 1-methyl-6-oxabicyclo[3.2.1]oct-2-ene motif of ring A. Their structures with absolute configurations were unambiguously determined by the extensive spectroscopic methods, X-ray crystallography, and ECD calculation. Putative biosynthetic pathways for compounds 1-3 are proposed. All compounds exhibited antiadipogenic effects in 3T3-L1 adipocytes, and the most potent compound 4 showed an EC50 value of 3.92 mu mol/L with low cytotoxicity (IC50 > 89.54 mu mol/L).