Discovery of Kalmane Diterpenoids as Potent Analgesics from the Flowers of Rhododendron dauricum

Kalmane diterpenoids,featuring a 5/8/5/5 tetracyclic carbon skeleton,are very rare in nature.The flowers of Rhododendron dauricum L.(Ericaceae)were phytochemically investigated for the first time,leading to the isolation of eight kalmane diterpenoids(1-8)including four new ones,named rhodokalmanols A-D(1-4).The structures of 1-8 were elucidated by comprehensive spectroscopic methods and ic NMR-DP4+analysis,and the absolute configurations of 1,2,4,and 5 were defined by single-crystal X-ray diffraction analysis with Cu Kαradiation.Rhodokalmanol A(1)represents the first 5,8-epoxykalmane diterpenoid and also the first kalm-15(16)-ene diterpenoid.Rhodokalmanols BD(2-4)are the first examples of kalm-7(8)-ene,kalm-16(17)-ene,and 8α-methoxykalmane diterpenoids,respectively.All the isolated kalmane diterpenoids 1-8 exhibited significant analgesic effects,and rhodokalmanol C(3)and kalmanoi(8)expressed more potent analgesic activity than morphine at doses of 0.2 and 0.04 mg/kg.The preliminary structure-activity relationships of kalmane diterpenoids as potent analgesics are discussed.