Protein tyrosine phosphatase 1B (PTP1B) inhibitors from Morinda citrifolia (Noni) and their insulin mimetic activity.

As part of our ongoing search for new antidiabetic agents from medicinal plants, we found that a methanol extract of Morinda citrifolia showed potential stimulatory effects on glucose uptake in 3T3-L1 adipocyte cells. Bioassay-guided fractionation of this active extract yielded two new lignans (1 and 2) and three new neolignans (9, 10, and 14), as well as 10 known compounds (3-8, 11-13, and 15). The absolute configurations of compounds 9, 10, and 14 were determined by ECD spectra analysis. Compounds 3, 6, 7, and 15 showed inhibitory effects on PTP1B enzyme with IC50 values of 21.86 ± 0.48, 15.01 ± 0.20, 16.82 ± 0.42, and 4.12 ± 0.09 μM, respectively. Furthermore, compounds 3, 6, 7, and 15 showed strong stimulatory effects on 2-NBDG uptake in 3T3-L1 adipocyte cells. This study indicated the potential of compounds 3, 6, 7, and 15 as lead molecules for antidiabetic agents.

[1]  A. Kinghorn,et al.  Anthraquinones with quinone reductase-inducing activity and benzophenones from Morinda citrifolia (noni) roots. , 2007, Journal of natural products.

[2]  E. Reinhard,et al.  Major cardenolide glycosides in embryogenic suspension cultures of Digitalis lanata. , 1987, Planta medica.

[3]  L. Merlini,et al.  Asymmetric synthesis of 3-methyl-2-phenyl-1,4-benzodioxanes. Absolute configuration of the neolignans eusiderin and eusiderin C and D , 1985 .

[4]  D. Kingston,et al.  Bioactive iridoids and a new lignan from Allamanda cathartica and Himatanthus fallax from the Suriname rainforest. , 1997, Journal of natural products.

[5]  Darren R. Williams,et al.  Development of a highly visual, simple, and rapid test for the discovery of novel insulin mimetics in living vertebrates. , 2013, ACS chemical biology.

[6]  J. Marx.  Unraveling the Causes of Diabetes , 2002, Science.

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

[8]  B. Kennedy,et al.  Protein tyrosine phosphatase 1B: a novel target for type 2 diabetes and obesity. , 2003, Current topics in medicinal chemistry.

[9]  J. Shaw,et al.  Global and societal implications of the diabetes epidemic , 2001, Nature.

[10]  W. Lee,et al.  Stereochemistry of Phellinsin A: A Concise Synthesis of α‐Arylidene‐γ‐Lactones , 2005 .

[11]  A. Kinghorn,et al.  An anthraquinone with potent quinone reductase-inducing activity and other constituents of the fruits of Morinda citrifolia (noni). , 2005, Journal of natural products.

[12]  S. Michel,et al.  Alcaloïdes Des Écorces De Tiges De Strychnos dinklagei , 1982 .

[13]  Kazumi Matsumoto,et al.  Anti-inflammatory and potential cancer chemopreventive constituents of the fruits of Morinda citrifolia (Noni). , 2007, Journal of natural products.

[14]  Jun-Li Yang,et al.  Cycloartane-type triterpenoids and sesquiterpenoids from the resinous exudates of Commiphora opobalsamum. , 2012, Phytochemistry.

[15]  L. Kong,et al.  Biotransformation of caffeic acid by Momordica charantia peroxidase , 2008 .

[16]  O. Hensens,et al.  Lignans with platelet activating factor antagonist activity from Magnolia biondii , 1987 .

[17]  Jinho Lee,et al.  Visualizing Sweetness: Increasingly Diverse Applications for Fluorescent-Tagged Glucose Bioprobes and Their Recent Structural Modifications , 2012, Sensors.

[18]  Z. Shen,et al.  2-NBDG as a fluorescent indicator for direct glucose uptake measurement. , 2005, Journal of biochemical and biophysical methods.

[19]  A. Kinghorn,et al.  Chemical constituents of the fruits of Morinda citrifolia (Noni) and their antioxidant activity. , 2005, Journal of natural products.

[20]  D. Jeong,et al.  Protein tyrosine phosphatase 1B inhibitors from Morus root bark. , 2006, Bioorganic & medicinal chemistry letters.

[21]  Yoshimasa Nakamura,et al.  Antioxidative catechol lignans converted from sesamin and sesaminol triglucoside by culturing with Aspergillus. , 2005, Journal of agricultural and food chemistry.

[22]  Hyeongjin Cho,et al.  PTP1B inhibitor Ertiprotafib is also a potent inhibitor of IκB kinase β (IKK-β) , 2007 .

[23]  B. Kennedy,et al.  Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. , 1999, Science.

[24]  T. Tiganis,et al.  PTP1B and TCPTP – nonredundant phosphatases in insulin signaling and glucose homeostasis , 2013, The FEBS journal.

[25]  F. Ye,et al.  Chemical constituents from the aerial parts of Artemisia minor. , 2009, Journal of natural products.

[26]  F. Haj,et al.  Protein Tyrosine Phosphatase 1B Deficiency Potentiates PERK/eIF2α Signaling in Brown Adipocytes , 2012, PloS one.

[27]  A. Barnett.  Insulin Glargine in the Treatment of Type 1 and Type 2 Diabetes , 2006, Vascular health and risk management.

[28]  P. Zhou,et al.  A protein tyrosine phosphatase 1B activity inhibitor from the fruiting bodies of Ganoderma lucidum (Fr.) Karst and its hypoglycemic potency on streptozotocin-induced type 2 diabetic mice. , 2011, Journal of agricultural and food chemistry.

[29]  Artur M. S. Silva,et al.  A new 4′,7-epoxy-8,3′-oxyneolignan from the acetone extract of Juniperus brevifolia leaves , 2010 .

[30]  B. West,et al.  Lipoxygenase inhibitory constituents of the fruits of noni (Morinda citrifolia) collected in Tahiti. , 2007, Journal of natural products.

[31]  B. Kwon,et al.  Phellinsin A, a novel chitin synthases inhibitor produced by Phellinus sp. PL3. , 2000, The Journal of antibiotics.

[32]  W. Washburn.  Development of the renal glucose reabsorption inhibitors: a new mechanism for the pharmacotherapy of diabetes mellitus type 2. , 2009, Journal of medicinal chemistry.

[33]  Yohei Tanaka,et al.  Chemical constituents of Morinda citrifolia fruits inhibit copper-induced low-density lipoprotein oxidation. , 2004, Journal of agricultural and food chemistry.

[34]  K. Lee,et al.  The Cytotoxic Principles of Prunella vulgaris, Psychotria serpens, and Hyptis capitata: Ursolic Acid and Related Derivatives1 , 1988, Planta medica.

[35]  Timothy J. Muldoon,et al.  Molecular imaging of glucose uptake in oral neoplasia following topical application of fluorescently labeled deoxy‐glucose , 2009, International Journal of Cancer.

[36]  Young-Bum Kim,et al.  PTP1B regulates leptin signal transduction in vivo. , 2002, Developmental cell.

[37]  Julie H. Ostrander,et al.  Uptake of 2-NBDG as a method to monitor therapy response in breast cancer cell lines , 2011, Breast Cancer Research and Treatment.

[38]  Da-Woon Jung,et al.  Novel use of fluorescent glucose analogues to identify a new class of triazine-based insulin mimetics possessing useful secondary effects. , 2011, Molecular bioSystems.

[39]  T. Hofmann,et al.  Identification of novel orosensory active molecules in cured vanilla Beans (Vanilla planifolia). , 2009, Journal of agricultural and food chemistry.