Picrotoxane-type sesquiterpenoids from Dendrobium improve insulin resistance and increase glucose-stimulated insulin secretion

Twelve picrotoxane-type sesquiterpenoids were isolated from Dendrobium wardianum, of which dendrowardins K-N (1-4) are new compounds and dendrowardins O and P (9, 10) are new natural products. Notably, the structure of dendrowardin K contains the rarely observed 10,11-γ-lactone ring. The structural configurations of these compounds were determined through comprehensive 1D and 2D nuclear magnetic resonance (NMR), single-crystal X-ray diffraction, and other spectroscopic analyses. Additionally, the hypoglycaemic activities of the picrotoxane-type sesquiterpenes and their analogues were systematically evaluated by determining the antidiabetic activities of these compounds and six others (13-18) obtained from genus Dendrobium. Twelve compounds (1, 2, 4-6, 8, 12, 13 - 15, 17, and 18) significantly improved insulin resistance. Further experiments revealed that compound 6 improved insulin resistance by increasing GLUT-4 expression. The possible mechanism is related to AKT-related pathways, and the effects of treatment with 50 μM compound 6 were comparable to those of the positive control drug metformin. Compounds 4-6 and 13-15, 17 displayed great increases in the secretion of insulin from β-TC-6 cells. On the basis of these findings, the structure-activity relationships (SARs) of picrotoxane-type sesquiterpenoids were discussed for the first time.