High-Resolution Inhibition Profiling Combined with HPLC-HRMS-SPE-NMR for Identification of PTP1B Inhibitors from Vietnamese Plants

Protein tyrosine phosphatase 1B (PTP1B) plays a key role as a negative regulator in insulin signal transduction by deactivating the insulin receptor. Thus, PTP1B inhibition has emerged as a potential therapeutic strategy for curing insulin resistance. In this study, 40 extracts from 18 different plant species were investigated for PTP1B inhibitory activity in vitro. The most promising one, the EtOAc extract of Ficus racemosa, was investigated by high-resolution PTP1B inhibition profiling combined with HPLC-HRMS-SPE-NMR analysis. This led to the identification of isoderrone (1), derrone (2), alpinumisoflavone (3) and mucusisoflavone B (4) as PTP1B inhibitors. IC50 of these compounds were 22.7 ± 1.7, 12.6 ± 1.6, 21.2 ± 3.8 and 2.5 ± 0.2 µM, respectively. Kinetics analysis revealed that these compounds inhibited PTP1B non-competitively with Ki values of 21.3 ± 2.8, 7.9 ± 1.9, 14.3 ± 2.0, and 3.0 ± 0.5 µM, respectively. These findings support the important role of F. racemosa as a novel source of new drugs and/or as a herbal remedy for treatment of type 2 diabetes.

[1]  Zhon-Yin Zhang,et al.  PTP1B inhibitors as potential therapeutics in the treatment of Type 2 diabetes and obesity , 2003, Expert opinion on investigational drugs.

[2]  B. Hamberger,et al.  Identification of PTP1B and α-Glucosidase Inhibitory Serrulatanes from Eremophila spp. by Combined use of Dual High-Resolution PTP1B and α-Glucosidase Inhibition Profiling and HPLC-HRMS-SPE-NMR. , 2016, Journal of natural products.

[3]  Sheng Zhang,et al.  PTP1B as a drug target: recent developments in PTP1B inhibitor discovery. , 2007, Drug discovery today.

[4]  A. Lourenço,et al.  A pterocarpan from Ulex parviflorus , 1998 .

[5]  S. Prigge,et al.  Isoflavone dimers and other bioactive constituents from the figs of Ficus mucuso. , 2011, Journal of natural products.

[6]  K. Bae,et al.  Screening of protein tyrosine phosphatase 1B inhibitory activity from some Vietnamese medicinal plants. , 2010 .

[7]  Dan Staerk,et al.  Dual high-resolution α-glucosidase and radical scavenging profiling combined with HPLC-HRMS-SPE-NMR for identification of minor and major constituents directly from the crude extract of Pueraria lobata. , 2015, Journal of natural products.

[8]  Paul Zimmet,et al.  Type 2 diabetes in the young: the evolving epidemic: the international diabetes federation consensus workshop. , 2004, Diabetes care.

[9]  Demin Zhou,et al.  Bioactive Constituents of Glycyrrhiza uralensis (Licorice): Discovery of the Effective Components of a Traditional Herbal Medicine. , 2016, Journal of natural products.

[10]  N. Seeram,et al.  Phloroglucinol Derivatives with Protein Tyrosine Phosphatase 1B Inhibitory Activities from Eugenia jambolana Seeds. , 2017, Journal of natural products.

[11]  M. Fowler.  Microvascular and Macrovascular Complications of Diabetes , 2008, Clinical Diabetes.

[12]  D. Staerk,et al.  High-resolution screening combined with HPLC-HRMS-SPE-NMR for identification of fungal plasma membrane H(+)-ATPase inhibitors from plants. , 2014, Journal of agricultural and food chemistry.

[13]  Z. Bloomgarden,et al.  Type 2 diabetes in the young: the evolving epidemic. , 2004, Diabetes care.

[14]  M. Marcovecchio,et al.  Role of chronic and acute hyperglycemia in the development of diabetes complications. , 2011, Diabetes technology & therapeutics.

[15]  A. Rai,et al.  PTP1B inhibitors for type 2 diabetes treatment: a patent review (2011 – 2014) , 2014, Expert opinion on therapeutic patents.

[16]  Y. Shirataki,et al.  Isoflavonoids from Sophora secundiflora, S. arizonica and S. gypsophila , 1998 .

[17]  Cheng-Shi Jiang,et al.  Natural products possessing protein tyrosine phosphatase 1B (PTP1B) inhibitory activity found in the last decades , 2012, Acta Pharmacologica Sinica.

[18]  J. Ahn,et al.  Genistein-derivatives from Tetracera scandens stimulate glucose-uptake in L6 myotubes. , 2009, Biological & pharmaceutical bulletin.

[19]  B. Kennedy,et al.  Therapeutic strategies for targeting PTP1B in diabetes , 2005 .

[20]  D. Staerk,et al.  Combined use of high-resolution α-glucosidase inhibition profiling and high-performance liquid chromatography-high-resolution mass spectrometry-solid-phase extraction-nuclear magnetic resonance spectroscopy for investigation of antidiabetic principles in crude plant extracts. , 2015, Journal of agricultural and food chemistry.

[21]  D. Staerk,et al.  Edible seaweed as future functional food: Identification of α-glucosidase inhibitors by combined use of high-resolution α-glucosidase inhibition profiling and HPLC-HRMS-SPE-NMR. , 2016, Food chemistry.

[22]  P. O S I T I O N S T A T E M E N T,et al.  Diagnosis and Classification of Diabetes Mellitus , 2011, Diabetes Care.

[23]  K. Srinivasan,et al.  Antidiabetic effect of Ficus racemosa Linn. stem bark in high-fat diet and low-dose streptozotocin-induced type 2 diabetic rats: a mechanistic study. , 2012, Food chemistry.

[24]  D. Staerk,et al.  High-resolution bioactivity profiling combined with HPLC-HRMS-SPE-NMR: α-Glucosidase inhibitors and acetylated ellagic acid rhamnosides from Myrcia palustris DC. (Myrtaceae). , 2015, Phytochemistry.

[25]  V. Singh,et al.  Aldose reductase and protein tyrosine phosphatase 1B inhibitory active compounds from Syzygium cumini seeds , 2015, Pharmaceutical biology.

[26]  Birger Lindberg Møller,et al.  High-resolution PTP1B inhibition profiling combined with high-performance liquid chromatography-high-resolution mass spectrometry-solid-phase extraction-nuclear magnetic resonance spectroscopy: Proof-of-concept and antidiabetic constituents in crude extract of Eremophila lucida. , 2016, Fitoterapia.

[27]  A. E. Nkengfack,et al.  Urease inhibitory isoflavonoids from different parts of Calopogonium mucunoides (Fabaceae) , 2013, Journal of Enzyme Inhibition and Medicinal Chemistry.