Structurally diverse analgesic diterpenoids from the flowers of Rhododendron molle.

Thirteen diterpenoids (1-13), classified into four structurally diverse carbon skeletons, including 1,5-seco-kalmane (1 and 6), grayanane (2-11), kalmane (12), and rhodomollane (13), were isolated from the flowers extract of Rhododendron molle. Among them, rhodomollinols A - E (1-5) were five new diterpenoids and their structures were elucidated by extensive spectroscopic methods including HRESIMS, UV, IR, 1D and 2D NMR, as well as quantum ECD calculations. Rhodomollinol A (1) is the first representative of a 6-deoxy-1,5-seco-kalmane diterpenoid. The abnormal NMR phenomenon of the presence of only 9 carbon resonances instead of 20 carbons in the 13C NMR spectrum of 1 was observed and elucidated by the quantum NMR calculations. All diterpenoids 1-13 showed significant analgesic activities in an acetic acid-induced writhing model. It's the first time to report the analgesic activity of a rhodomollane-type diterpenoid. At a dose of 1.0 mg/kg, diterpenoids 1-3, 6, 8, 9, and 12 reduced the writhe numbers with inhibition rates over 50%, and 9 exhibited stronger analgesic activity with a writhe inhibition rate of 89.7% than that of the positive control morphine. Importantly, even at the lowest dose of 0.04 mg/kg, rhodomollinols A (1) and B (2), rhodomollein X (7), and 2-O-methylrhodojaponin VI (9) still showed more potent analgesic effects than morphine with the writhe inhibition rates of 51.8%, 48.0%, 61.7%, and 60.0%, respectively. A preliminary structure-activity relationship might provide some clues to design potential analgesics on the basis of structurally diverse Ericaceae diterpenoids.

Discovery of highly functionalized grayanane diterpenoids from the flowers of Rhododendron molle as potent analgesics.

A systematical investigation on the chemical constituents of the flowers of Rhododendron molle (Ericaceae) led to the isolation and characterization of thirty-eight highly functionalized grayanane diterpenoids (1-38), including twelve novel analogues molleblossomins A-L (1-12). Their structures were elucidated by comprehensive methods, including 1D and 2D NMR analysis, calculated ECD, 13C NMR calculations with DP4+ probability analysis, and single crystal X-ray diffraction. Molleblossomins A (1), B (2), and E (5) are the first representatives of 2ß,3ß:9ß,10ß-diepoxygrayanane, 2,3-epoxygrayan-9(11)-ene, and 5,9-epoxygrayan-1(10),2(3)-diene diterpenoids, respectively. Molleblossomins G (7) and H (8) represent the first examples of 1,3-dioxolane-grayanane conjugates furnished with the acetaldehyde and 4-hydroxylbenzylidene acetal moieties, respectively. All grayanane diterpenoids 1-38 were screened for their analgesic activities in the acetic acid-induced writhing model, and all of them exhibited significant analgesic activities. Diterpenoids 6, 13, 14, 17, 20, and 25 showed more potent analgesic effects than morphine at a lower dose of 0.2 mg/kg, with the inhibition rates of 51.4%, 68.2%, 94.1%, 66.9%, 97.7%, and 60.0%, respectively. More importantly, even at the lowest dose of 0.04 mg/kg, rhodomollein X (14), rhodojaponin VI (20), and rhodojaponin VII (22) still significantly reduced the number of writhes in the acetic acid-induced pain model with the percentages of 61.7%, 85.8%, and 64.6%, respectively. The structure-activity relationship was summarized and might provide some hints to design novel analgesics based on the functionalized grayanane diterpenoids.