Ryanodane Diterpenoids from Cinnamon and Their Analgesic and Hepatoprotective Effects

Cinnaditerpenoid A (1), a novel ring C-seco ryanodane diterpenoid, was isolated from a popular spice and widespread traditional medicine known as cinnamon (Cinnamomum cassia Presl's bark), together with two new (2 and 3) and seven known analogues (4-10). Their structures were elucidated through a spectroscopic technique, an X-ray crystallography method, and quantum chemical calculations. Ryanodane diterpenoids, characterized by complex 6/5/5/6/6 fused ring skeletons, are a limited number of pentacyclic natural products. Notably, compound 1 represents the first instance of a ryanodane diterpenoid characterized by a new 5/6/6/7 tetracyclic skeleton. Illuminated by the traditional medicinal uses of cinnamon, the analgesic capacities of ryanodane diterpenoids were assessed. In a CH₃COOH-stimulated zebrafish pain model, compounds 7 and 10 displayed significant analgesic effects. Moreover, in a formalin-stimulated mouse paw licking test, the representative ryanodane diterpenoid 10 exhibited a dose-dependent analgesic response, with potency exceeding that of the positive drug diclofenac sodium. Evaluation of the hepatoprotective activity of ryanodane diterpenoids also revealed that all tested isolates possessed significant activity, and most compounds were more potent than the positive control drug silymarin. Collectively, these discoveries establish ryanodane diterpenoids as promising lead compounds for treating pain and liver diseases.