Structurally diverse diterpenoids with eight carbon skeletons from Rhododendron micranthum and their antinociceptive effects

Abstract Seventeen diterpenoids (1–17), classified into eight diverse carbon skeleton types, grayanane (1, 2, and 12), micranthane (3, 4, and 13), mollane (5–7 and 14), 1,5-seco-grayanane (8), kalmane (9–11), 1,5-seco-kalmane (15), A-homo-B-nor-ent-kaurane (16), and leucothane (17), respectively, were isolated from the leaves extract of Rhododendron micranthum. Among them, diterpenoids 1–9 are new compounds and their structures were elucidated via extensive spectroscopic methods, quantum chemical calculations including the 13C NMR-DP4+ analysis and electronic circular dichroism (ECD) calculations, and the single-crystal X-ray diffraction analysis. Micranthanol A (1) represents the first example of a 5αH,9αH-grayanane diterpenoid and a 6-hydroxy-6,10-epoxygrayanane diterpenoid, and micranthanone B (3) is the first 6,10-epoxymicranthane and the 5α-hydroxy-micranthane diterpenoids. 14-epi-Mollanol A (5) and mollanol B (6) represent the first examples of 14β-hydroxymollane diterpenoids. It is the first time to report mollane, 1,5-seco-kalmane, and A-homo-B-nor-ent-kaurane type diterpenoids from Rhododendron micranthum. All the seventeen diterpenoids showed significant antinociceptive activities at a dose of 5.0 mg/kg, and it is the first time to evaluate the antinociceptive activity of 1,5-seco-kalmane diterpenoid. Among them, compounds 3, 11, 14, and 15 exhibited significant antinociceptive activities even at a lower dose of 1.0 mg/kg. A preliminary structure–activity relationship for the antinociceptive effects of diterpenoids 1–17 is discussed, which provided a new basis to develop novel potent analgesics.