Protein tyrosine phosphatase 1B inhibitory activity of lavandulyl flavonoids from roots of Sophora flavescens.
Protein tyrosine phosphatase 1B is a non-transmembrane protein tyrosine phosphatase and major negative regulator in insulin signaling cascades, and much attention has been paid to protein tyrosine phosphatase 1B inhibitors as potential therapies for diabetes. The screening of a natural compound library led to the discovery of five lavandulyl flavonoids, which were isolated from the roots of Sophora flavescens, as novel PTP1B inhibitors: kuraridin (1), norkurarinone (2), kurarinone (3), 2'-methoxykurarinone (4), and kushenol T (5). The three most potent compounds, 1, 2, and 4 (IC50 < 30 µM), were demonstrated to be noncompetitive inhibitors of protein tyrosine phosphatase 1B based on a kinetic analysis, and they exhibited different inhibitory selectivities against four homologous protein tyrosine phosphatases (T cell protein tyrosine phosphatase, vaccinia H1-related phosphatase, and Src homology domain 2-containing protein tyrosine phosphatases 1 and 2). Compounds 1, 2, and 4 also exhibited cellular activity in the insulin signaling pathway by increasing the insulin-stimulated Akt phosphorylation level in human hepatocellular liver carcinoma HepG2 cells, suggesting their potential for new anti-insulin-resistant drug developments.
Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Japan.
Tatsunori
T
Sasaki
Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Japan.
Wei
W
Li
Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Japan.
Koji
K
Higai
College of Pharmacy, Chungnam National University, Daejeon, Korea.
Tran Hong
TH
Quang
College of Pharmacy, Chungnam National University, Daejeon, Korea.
Young Ho
YH
Kim
Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Japan.
Kazuo
K
Koike
D047188:Chalcones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007328:Insulin / Q000378:metabolism; D007700:Kinetics; D039821:Monoterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D018517:Plant Roots / Q000737:chemistry; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries; D029909:Sophora / Q000737:chemistry*
C411318:2'-methoxykurarinone; D047188:Chalcones; D005419:Flavonoids; D007328:Insulin; D039821:Monoterpenes; D010936:Plant Extracts; D054852:Small Molecule Libraries; C554822:kuraridin; C411319:kurarinone; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases