Epoxymicranthols A-N, 5,9-Epoxygrayanane Diterpenoids as Potent Analgesics from Rhododendron micranthum

Main observation and conclusion Fifteen 5,9-epoxygrayanane diterpenoids (1-15) including fourteen new ones, epoxymicranthols A-N (1-14), were isolated from the leaves extract of Rhododendron micranthum. Their structures were elucidated via extensive spectroscopic methods and C-13 NMR-DP4+ analysis, and the absolute configurations of 1, 3-10, 14, and 15 were confirmed by single-crystal X-ray diffraction analysis. Epoxymicranthols A-C (1-3) represent the first examples of 14 alpha-hydroxygrayanane diterpenoids, and epoxymicranthols C-F (3-6) are the first examples of 10 beta-hydroxy-5,9-epoxygrayanane diterpenoids. Meanwhile, epoxymicranthols K (11) and N (14) represent the first examples of 13-hydroxy-5,9-epoxygrayanane and 5,9-epoxygrayan-3-one diterpenoids, respectively. All the diterpenoids (1-15) were assayed for their analgesic activities, and all of them exhibited significant analgesic activities at a dose of 5.0 mg/kg. Among them, compounds 2, 7, 8, and 10 also exhibited significant analgesic activities even at lower doses of 1.0 and 0.2 mg/kg. More importantly, epoxymicranthol G (7) still expressed potent analgesic activity at a lower dose of 0.04 mg/kg. A preliminary structure-activity relationship for the analgesic effects of 5,9-epoxygrayanane diterpenoids 1-15 is discussed. These results not only enlarged the structural diversity of 5,9-epoxygrayanane diterpenoids, but also provided a basis to develop novel potent analgesics.