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

• Published in: Journal of agricultural and food chemistry Vol. 68; no. 41; pp. 11434 - 11448
• Main Authors: He, Xiao-Feng, Chen, Ji-Jun, Li, Tian-Ze, Zhang, Xu-Ke, Guo, Yuan-Qiang, Zhang, Xue-Mei, Hu, Jing, Geng, Chang-An
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.10.2020; Amer Chemical Soc
• Subjects: Agriculture; Agriculture, Multidisciplinary; alpha-Glucosidases - chemistry; Amomum - chemistry; Bioactive Constituents, Metabolites, and Functions; Chemistry; Chemistry, Applied; Fatty Alcohols - chemistry; Fatty Alcohols - isolation & purification; Flavanones - chemistry; Flavanones - isolation & purification; Food Science & Technology; Fruit - chemistry; Glycoside Hydrolase Inhibitors - chemistry; Glycoside Hydrolase Inhibitors - isolation & purification; Humans; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - isolation & purification; Life Sciences & Biomedicine; Physical Sciences; Plant Extracts - chemistry; Plant Extracts - isolation & purification; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - chemistry; Science & Technology; tsaokoflavanols A−S; α-glucosidase inhibitors; Amomum tsao-ko; PTP1B/TCPTP selective inhibitors; antidiabetic effects; alpha-glucosidase inhibitors; tsaokoflavanols A-S
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/acs.jafc.0c04615

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 α-glucosidase and PTP1B dual inhibition, among which 1, 2, 6, 11, and 18 exhibited obvious activity against α-glucosidase with IC50 values of 5.2–9.0 μM, 20–35 times stronger than that of acarbose (IC50, 180.0 μM); meanwhile, 6, 10–12, and 19 were PTP1B/TCPTP-selective inhibitors with IC50 values of 56.4–80.4 μM, 2–4 times stronger than that of suramin sodium (IC50, 200.5 μM). Enzyme kinetics study indicated that compounds 1, 2, 6, and 11 were α-glucosidase and PTP1B mixed-type inhibitors with K i values of 13.0, 11.7, 2.9, and 5.3 μM and 142.3, 88.9, 39.2, and 40.8 μM, respectively. Docking simulations proved the importance of hemiacetal hydroxy, the orientation of 3,4-dihydroxyphenyl, and the length of alkyl in binding with α-glucosidase and PTP1B.