Structurally diverse diterpenoids from Euphorbia milii: Discovery and RORγt-binding evaluation.

Ten previously undescribed diterpenoids (1-10), representing four diverse architectural types, along with eight known analogs (11-18), were isolated from Euphorbia milii. Compounds 1-3 were characterized as ent-atisane diterpenoids, with 1 and 2 featuring a C-19-nor- and a 3,4-seco-19-nor-ent-atisane framework, respectively, and their plausible biosynthetic pathways were proposed. The remaining new isolates were established to be ent-pimarane (4-7), ent-abietane (8 and 9), and ent-verticillane (10) diterpenoids. Binding affinity assays revealed that compounds 6, 7, and 14 bound directly to retinoic acid-related orphan receptor γt (RORγt), of which 14 demonstrated the highest affinity (Kd = 4.2 × 10-5 M) and significantly suppressed Th17 cell differentiation.