Planta Med 2014; 80(07): 557-560
DOI: 10.1055/s-0034-1368400
Biological and Pharmacological Activity
Letters
Georg Thieme Verlag KG Stuttgart · New York

Protein Tyrosine Phosphatase 1B Inhibitory Activity of Lavandulyl Flavonoids from Roots of Sophora flavescens

Tatsunori Sasaki
1   Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Japan
,
Wei Li
1   Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Japan
,
Koji Higai
1   Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Japan
,
Tran Hong Quang
2   College of Pharmacy, Chungnam National University, Daejeon, Korea
,
Young Ho Kim
2   College of Pharmacy, Chungnam National University, Daejeon, Korea
,
Kazuo Koike
1   Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Japan
› Author Affiliations
Further Information

Publication History

received 18 January 2014
revised 13 March 2014

accepted 18 March 2014

Publication Date:
29 April 2014 (online)

Abstract

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.

 
  • References

  • 1 Byon CHJ, Kusari BA, Kusari J. Protein-tyrosine phosphatase-1B acts as a negative regulator of insulin signal transduction. Mol Cell Biochem 1998; 182: 101-108
  • 2 Kennedy BP. Role of protein tyrosine phosphatase-1B in diabetes and obesity. Biomed Pharmacother 1999; 53: 466-470
  • 3 Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy AL, Normandin D, Cheng A, Himms-Hagen J, Chan CC, Ramachandran C, Gresser MJ, Tremblay ML, Kennedy BP. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 1999; 283: 1544-1548
  • 4 Zhang S, Zhang ZY. PTP1B as a drug target: recent developments in PTP1B inhibitor discovery. Drug Discov Today 2007; 12: 373-381
  • 5 Yip SC, Saha S, Chernoff J. PTP1B: A double agent in metabolism and oncogenesis. Trends Biochem Sci 2010; 35: 442-449
  • 6 Jiang C, Liang L, Guo Y. Natural products possessing protein tyrosine phosphatase 1B (PTP1B) inhibitory activity found in the last decades. Acta Pharmacol Sin 2012; 33: 1217-1245
  • 7 Li S, Li W, Wang Y, Asada Y, Koike K. Prenylflavonoids from Glycyrrhiza uralensis and their protein tyrosine phosphatase-1B inhibitory activities. Bioorg Med Chem Lett 2010; 20: 5398-5401
  • 8 Li W, Li S, Higai K, Sasaki T, Asada Y, Ohshima S, Koike K. Evaluation of licorice flavonoids as protein tyrosine phosphatase 1B inhibitors. Bioorg Med Chem Lett 2013; 23: 5836-5839
  • 9 Quang TH, Ngan NTT, Minh CV, Kiem PV, Tai BH, Thao NP, Kwon S, Lee Y, Kang H, Kim YH. α-Glucosidase inhibitors from the roots of Sophora flavescens . Bull Korean Chem Soc 2012; 33: 1791-1793
  • 10 Tabernero L, Aricescu AR, Jones EY, Szedlacsek SE. Protein tyrosine phosphatases: structure-function relationships. FEBS J 2008; 275: 867-882
  • 11 Tiganis T. PTP1B and TCPTP – nonredundant phosphatases in insulin signaling and glucose homeostasis. FEBS J 2013; 280: 445-458
  • 12 Bousquet C, Delesque N, Lopez F, Saint-Laurent N, Estève JP, Bedecs K, Buscail L, Vaysse N, Susini C. Sst2 somatostatin receptor mediates negative regulation of insulin receptor signaling through the tyrosine phosphatase SHP-1. J Biol Chem 1998; 273: 7099-7106
  • 13 Yazaki K, Sasaki K, Tsurumaru Y. Prenylation of aromatic compounds, a key diversification of plant secondary metabolites. Phytochemistry 2009; 70: 1739-1745
  • 14 Jung HA, Jin SE, Park JS, Choi JS. Antidiabetic complications and anti-Alzheimer activities of sophoflavescenol, a prenylated flavonol from Sophora flavescens, and its structure-activity relationship. Phytother Res 2011; 25: 709-715