Nineteen New Flavanol-Fatty Alcohol Hybrids with α-Glucosidase and PTP1B Dual Inhibition: One Unusual Type of Antidiabetic Constituent from Amomum tsao-ko

The dried fruits of Amomum tsao-ko were first revealed to have hypoglycemic effects on db/db mice at a concentration of 200 mg/kg. In order to clarify the antidiabetic constituents, 19 new flavanol-fatty alcohol hybrids, tsaokoflavanols A-S (1-19), were isolated and determined by extensive spectroscopic data and ECD calculations. Most of the compounds showed alpha-glucosidase and PTP1B dual inhibition, among which 1, 2, 6, 11, and 18 exhibited obvious activity against alpha-glucosidase with IC50 values of 5.2-9.0 mu M, 20-35 times stronger than that of acarbose (IC50, 180.0 mu M); meanwhile, 6, 10-12, and 19 were PTP1B/TCPTP-selective inhibitors with IC50 values of 56.4-80.4 mu M, 2-4 times stronger than that of suramin sodium (IC50, 200.5 mu M). Enzyme kinetics study indicated that compounds 1, 2, 6, and 11 were alpha-glucosidase and PTP1B mixed-type inhibitors with K-i values of 13.0, 11.7, 2.9, and 5.3 mu M and 142.3, 88.9, 39.2, and 40.8 mu M, respectively. Docking simulations proved the importance of hemiacetal hydroxy, the orientation of 3,4-dihydroxyphenyl, and the length of alkyl in binding with a-glucosidase and PTP1B.