Synthesis of Rottlerone Analogues and Evaluation of Their alpha-Glucosidase and DPP-4 Dual Inhibitory and Glucose Consumption-Promoting Activity

Our previous study found that desmethylxanthohumol (1) inhibited alpha-glucosidase in vitro. Recently, further investigations revealed that dehydrocyclodesmethylxanthohumol (2) and its dimer analogue rottlerone (3) exhibited more potent alpha-glucosidase inhibitory activity than 1. The aim of this study was to synthesize a series of rottlerone analogues and evaluate their alpha-glucosidase and DPP-4 dual inhibitory activity. The results showed that compounds 4d and 5d irreversibly and potently inhibited alpha-glucosidase (IC50 = 0.22 and 0.12 mu M) and moderately inhibited DPP-4 (IC50 = 23.59 and 26.19 mu M), respectively. In addition, compounds 4d and 5d significantly promoted glucose consumption, with the activity of 5d at 0.2 mu M being comparable to that of metformin at a concentration of 1 mM.