Nineteen New Flavanol-Fatty Alcohol Hybrids with α-Glucosidase and PTP1B Dual Inhibition: One Unusual Type of Antidiabetic Constituent from Amomum tsao-ko
Nineteen New Flavanol-Fatty Alcohol Hybrids with α-Glucosidase and PTP1B Dual Inhibition: One Unusual Type of Antidiabetic Constituent from Amomum tsao-ko
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DOI：
10.1021/acs.jafc.0c04615
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发表时间：
2020-10-14
影响因子：
6.1
通讯作者：
Geng, Chang-An
中科院分区：
文献类型：
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作者：
He, Xiao-Feng;Chen, Ji-Jun;Geng, Chang-An
首次发现草果干果在200 mg/kg浓度下对db/db小鼠有降血糖作用。为了进一步阐明其抗糖尿病活性成分，从草果中分离得到19个新的黄烷醇-脂肪醇杂合物，即草果黄烷醇A-S（1-19）。大多数化合物对α-葡萄糖苷酶和PTP 1B有双重抑制作用，其中化合物1、2、6、11和18对α-葡萄糖苷酶有明显的抑制作用，IC 50值为5.2-9.0 μ M，比阿卡波糖强20-35倍6、10-12和19是PTP 1B/TCPTP选择性抑制剂，IC 50值为56.4-80.4 μ M，比苏拉明钠（IC 50，200.5 μ M）强2-4倍。酶动力学研究表明，化合物1、2、6和11是α-葡萄糖苷酶和PTP 1B混合型抑制剂，Ki值分别为13.0、11.7、2.9和5.3 μ M和142.3、88.9、39.2和40.8 μ M。对接模拟证明了半缩醛羟基、3，4-二羟基苯基的取向以及烷基的长度在与α-葡萄糖苷酶和PTP 1B结合中的重要性。
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.