Protein Tyrosine Phosphatase 1B Inhibitors Research Articles

The Protective Effect of Vanadium on Cognitive Impairment and the Neuropathology of Alzheimer's Disease in APPSwe/PS1dE9 Mice.

Alzheimer’s disease (AD) is a widely distributed neurodegenerative disease characterized clinically by cognitive deficits and pathologically by formation of amyloid-β (Aβ) plaque and neurofibrillary tangles (NFTs) in the brain. Vanadium is a biological trace element that has a function to mimic insulin for diabetes. Bis(ethylmaltolato) oxidovanadium (IV) (BEOV) has been reported to have a hypoglycemic property, but its effect on AD remains unclear. In this study, BEOV was supplemented at doses of 0.2 and 1.0 mmol/L to the AD model mice APPSwe/PS1dE9 for 3 months. The results showed that BEOV substantially ameliorated glucose metabolic disorder as well as synaptic and behavioral deficits of the AD mice. Further investigation revealed that BEOV significantly reduced Aβ generation by increasing the expression of peroxisome proliferator-activated receptor gamma and insulin-degrading enzyme and by decreasing β-secretase 1 in the hippocampus and cortex of AD mice. BEOV also reduced tau hyperphosphorylation by inhibiting protein tyrosine phosphatase-1B and regulating the pathway of insulin receptor/insulin receptor substrate-1/protein kinase B/glycogen synthase kinase 3 beta. Furthermore, BEOV could enhance autophagolysosomal fusion and restore autophagic flux to increase the clearance of Aβ deposits and phosphorylated tau in the brains of AD mice. Collectively, the present study provides solid data for revealing the function and mechanism of BEOV on AD pathology.

Identification of natural products as selective PTP1B inhibitors via virtual screening.

Protein tyrosine phosphatase 1B (PTP1B) is emerging as a promising yet challenging target for drug discovery. To identify natural products as new prototypes for PTP1B inhibitors, we employed a hierarchical protocol combining ligand-based and structure-based approaches for virtual screening against natural product libraries. Twenty-six compounds were prioritized for enzymatic evaluation against PTP1B, and ten of them were recognized as potent PTP1B inhibitors with IC50 values at the micromolar level. Notably, nine compounds demonstrated evident selectivity to PTP1B over four other PTPs, including the most homologous T-cell protein tyrosine phosphatase (TCPTP). The results implicated that the structural uniqueness of the natural products might be a potential solution to the selectivity issue associated with the target PTP1B.

Phytopharmacological Strategies in the Management of Type 2 Diabetes Mellitus.

Type 2 Diabetes Mellitus (T2DM) is a chronic disease which corresponds to 90% of the worldwide cases of diabetes, mainly due to epigenetic factors such as unhealthy lifestyles. First line therapeutic approaches are based on lifestyle changes, most of the time complemented with medication mostly associated with several side effects and high costs. As a result, the scientific community is constantly working for the discovery and development of natural therapeutic strategies that provide lower financial impact and minimize side effects. This review focus on these nature-based therapeutic strategies for prevention and control of T2DM, with a special emphasis on natural compounds that present pharmacological activity as dipeptidyl peptidase-4 (DPP4), alpha-amylase, alpha-glucosidase, lipase, and protein tyrosine phosphatase 1B (PTP1B) inhibitors.

Protein Tyrosine Phosphatase-1B Inhibition Disrupts IL13Rα2-Promoted Invasion and Metastasis in Cancer Cells.

Background: Interleukin 13 receptor alpha 2 subunit (IL13Rα2) is overexpressed in glioblastoma (GBM), metastatic colorectal cancer (CRC) and ovarian cancer (OC). Here, we investigated the IL13Rα2 interactome searching for novel targets in cancer invasion and metastasis. Methods: The interactome of IL13Rα2 was determined in GBM by using a proteomic analysis and then validated in CRC and OC. Cell signaling was investigated using siRNA interference, protein tyrosine phosphatase-1B (PTP1B) inhibitors and Western blot analysis. Animal models of GBM and metastatic CRC were used for testing PTP1B inhibitors. Results: PTP1B was identified and validated as a mediator of IL13Rα2 signaling. An in silico analysis revealed that PTP1B overexpression is associated with lower overall survival of patients in the three types of cancer. PTP1B silencing or treatment with Claramine, a PTP1B inhibitor, caused a significant decrease in IL-13-mediated adhesion, migration and invasion of IL13Rα2-expressing cancer cells by inhibiting the dephosphorylation of Src Tyr530 and consequently, the phosphorylation of Src Tyr419, AKT and ERK1/2. In addition, Claramine inhibited EGF-mediated activation of EGFR Tyr1068. In vivo treatment with Claramine caused a total inhibition of liver metastasis in mice inoculated with CRC cells and a significant increase in the survival of mice bearing intracranial GBM patient-derived xenografts. Conclusions: We have uncovered that IL13 signaling through IL13Rα2 requires PTP1B activity and therefore, PTP1B inhibition represents a promising therapeutic strategy in multiple types of cancer, including glioblastoma.

Impact of global PTP1B deficiency on the gut barrier permeability during NASH in mice

ObjectiveNon-alcoholic steatohepatitis (NASH) is characterized by a robust pro-inflammatory component at both hepatic and systemic levels together with a disease-specific gut microbiome signature. Protein tyrosine phosphatase 1 B (PTP1B) plays distinct roles in non-immune and immune cells, in the latter inhibiting pro-inflammatory signaling cascades. In this study, we have explored the role of PTP1B in the composition of gut microbiota and gut barrier dynamics in methionine and choline-deficient (MCD) diet-induced NASH in mice. MethodsGut features and barrier permeability were characterized in wild-type (PTP1B WT) and PTP1B-deficient knockout (PTP1B KO) mice fed a chow or methionine/choline-deficient (MCD) diet for 4 weeks. The impact of inflammation was studied in intestinal epithelial and enteroendocrine cells. The secretion of GLP-1 was evaluated in primary colonic cultures and plasma of mice. ResultsWe found that a shift in the gut microbiota shape, disruption of gut barrier function, higher levels of serum bile acids, and decreased circulating glucagon-like peptide (GLP)-1 are features during NASH. Surprisingly, despite the pro-inflammatory phenotype of global PTP1B-deficient mice, they were partly protected against the alterations in gut microbiota composition during NASH and presented better gut barrier integrity and less permeability under this pathological condition. These effects concurred with higher colonic mucosal inflammation, decreased serum bile acids, and protection against the decrease in circulating GLP-1 levels during NASH compared with their WT counterparts together with increased expression of GLP-2-sensitive genes in the gut. At the molecular level, stimulation of enteroendocrine STC-1 cells with a pro-inflammatory conditioned medium (CM) from lipopolysaccharide (LPS)-stimulated macrophages triggered pro-inflammatory signaling cascades that were further exacerbated by a PTP1B inhibitor. Likewise, the pro-inflammatory CM induced GLP-1 secretion in primary colonic cultures, an effect augmented by PTP1B inhibition. ConclusionAltogether our results have unraveled a potential role of PTP1B in the gut–liver axis during NASH, likely mediated by increased sensitivity to GLPs, with potential therapeutic value.

Protein tyrosine phosphatase 1B (PTP1B) inhibitorsfrom the deep-sea fungus Penicillium chrysogenum SCSIO 07007.

Three new compounds, including two new 3,4,6-trisubstituted α-pyrone derivatives, chrysopyrones A and B (1 and 2), and one new indolyl diketopiperazine derivative, penilline C (3), along with twelve known compounds (4-15), were isolated and identified from the fungus Penicillium chrysogenum SCSIO 07007, separated from deep-sea hydrothermal vent environment sample collected from the Western Atlantic. Their structures and absolute configurations were determined by extensive spectroscopic analysis and electronic circular dichroism (ECD) calculations. All of the isolated compounds (1-15) were evaluated for their cytotoxic, antibacterial activities and enzyme inhibitory activities against acetylcholinesterase (AChE), α-glycosidase, and protein tyrosine phosphatase 1B (PTP1B). Among them, new compounds chrysopyrones A and B (1 and 2) displayed obvious inhibitory activities against PTP1B with IC50 values of 9.32 and 27.8μg/mL, respectively. Furthermore, molecular docking was performed to investigate the inside perspective of the action in PTP1B enzyme.

Docking-based virtual screening in search for natural PTP1B inhibitors in treating type-2 diabetes mellitus and obesity

Introduction: Growing incidence of type-2 diabetes mellitus (T2DM), together with obesity, shows the complexity and progressive nature of these metabolic disorders and alarms the necessity to explore new and alternative therapeutic pathways and drugs. Diabetes has also been proven to be a key cause of premature aging through different mechanisms. Understanding these mechanisms could lead us to manage diabetes more efficiently, thus curtailing its age-related complications. Insulin and leptin resistance are the most common pathophysiological link between T2DM and obesity. Protein tyrosine phosphatase 1B (PTP1B) is thought to interfere with glucose homeostasis and satiety through down-regulation of insulin and leptin signaling pathways. Thus, drugs that are potent to impede this enzyme should be effective in treating T2DM and obesity.
 Method: In line with that, our current study involved screening of potent PTP1B inhibitors from the Natural Product Discovery System (NADI) database using in silico virtual screening and in vitro PTP1B inhibition study. The compounds that showed promising interaction with PTP1B catalytic site were traced down to their plant of origin. Further, the extracts of the plants were tested in vitro for PTP1B inhibition activity.
 Results: Our results showed promising PTP1B inhibition activity of Pandanus amaryllifolius, Vitex negundo and Piper nigrum with 94.38%, 89.03% and 81.39% inhibition, respectively.
 Conclusion: Therefore, the compounds of these plants might be an attractive option to develop drugs for T2DM and obesity.

Anti‐obesity effect of plant diterpenes and their derivatives: A review

Obesity is a medical condition in which excess body fat is accumulated by a combination of excessive food intake, lack of physical activity, and genetic susceptibility. Obesity increases the risk of various diseases and conditions, including cardiovascular diseases, diabetes, cancer, and depression. This review focuses on most recent reports pertaining to the antiobesity activity of plant-derived diterpenes in different databases. For this, a search (until August 2019) was conducted in the PubMed and Science Direct databases with the following keywords: "plant diterpenes" or "plant diterpenoids" paired with "obesity" or "antiobesity effects." Overall, 729 references that used the aforementioned keywords were selected, among which 34 articles have been included in this review. Results from this search suggest that a number of diterpenes and their derivatives have been found to exert antiobesity effects through various mechanisms, such as overweight reduction or modification of body mass index, protein-tyrosine phosphatase 1B inhibition, lipase activity inhibition, antiadipogenesis effect, among others. Carnosic acid, carnosol and the derivatives of abietic acid, steviol, and andrographolide are examples of important antiobesity diterpenes and their derivatives. Of note, plant-derived diterpenes may be potential candidates for managing obesity and obesity-related diseases and disorders in human and other animals.

Stilbenes with Potent Protein Tyrosine Phosphatase-1B Inhibitory Activity from the Roots of Polygonum multiflorum

Seven new stilbene glycosides including three dimers (1-3) and four monomers (4-7) were isolated from the roots of Polygonum multiflorum along with nine previously identified stilbenes (8-16). In addition, two deglucosylated stilbenes, 2a and 3a, were also obtained as new dimeric stilbenes. The structures of the purified phytochemicals were elucidated by interpreting their spectroscopic data (NMR, HRMS, and ECD). To the best of our knowledge, this represents the first isolation of a phenylpropanoid (C6-C3) substituted with a stilbene unit (7) from the Polygonaceae family. In an in vitro enzyme assay with human recombinant protein tyrosine phosphatase-1B (PTP1B), compounds 2-5 showed weak PTP1B inhibition with an IC50 value range of 27.4-37.6 μM, while three deglucosylated stilbenes 2a, 3a, and 8a exhibited IC50 values of 2.1, 1.9, and 12.1 μM, respectively. The inhibition modes and binding mechanism of selected inhibitors (2a and 3a) were investigated using kinetic methods and molecular docking simulations.

Neuronal Protein Tyrosine Phosphatase 1B Hastens Amyloid β-Associated Alzheimer's Disease in Mice.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, resulting in the progressive decline of cognitive function in patients. Familial forms of AD are tied to mutations in the amyloid precursor protein, but the cellular mechanisms that cause AD remain unclear. Inflammation and amyloidosis from amyloid β (Aβ) aggregates are implicated in neuron loss and cognitive decline. Inflammation activates the protein-tyrosine phosphatase 1B (PTP1B), and this could suppress many signaling pathways that activate glycogen synthase kinase 3β (GSK3β) implicated in neurodegeneration. However, the significance of PTP1B in AD pathology remains unclear. Here, we show that pharmacological inhibition of PTP1B with trodusquemine or selective ablation of PTP1B in neurons prevents hippocampal neuron loss and spatial memory deficits in a transgenic AD mouse model with Aβ pathology (hAPP-J20 mice of both sexes). Intriguingly, while systemic inhibition of PTP1B reduced inflammation in the hippocampus, neuronal PTP1B ablation did not. These results dissociate inflammation from neuronal loss and cognitive decline and demonstrate that neuronal PTP1B hastens neurodegeneration and cognitive decline in this model of AD. The protective effect of PTP1B inhibition or ablation coincides with the restoration of GSK3β inhibition. Neuronal ablation of PTP1B did not affect cerebral amyloid levels or plaque numbers, but reduced Aβ plaque size in the hippocampus. In summary, our preclinical study suggests that targeting PTP1B may be a new strategy to intervene in the progression of AD.SIGNIFICANCE STATEMENT Familial forms of Alzheimer's disease (AD) are tied to mutations in the amyloid precursor protein, but the cellular mechanisms that cause AD remain unclear. Here, we used a mouse model expressing human amyloid precursor protein bearing two familial mutations and asked whether activation of a phosphatase PTP1B participates in the disease process. Systemic inhibition of this phosphatase using a selective inhibitor prevented cognitive decline, neuron loss in the hippocampus, and attenuated inflammation. Importantly, neuron-targeted ablation of PTP1B also prevented cognitive decline and neuron loss but did not reduce inflammation. Therefore, neuronal loss rather than inflammation was critical for AD progression in this mouse model, and that disease progression could be ameliorated by inhibition of PTP1B.

α-Glucosidase and Protein Tyrosine Phosphatase 1B Inhibitors from Malbranchea circinata.

During a search for new α-glucosidase and protein tyrosine phosphatase 1B inhibitors from fungal sources, eight new secondary metabolites, including two anthranilic acid-derived peptides (1 and 2), four glycosylated anthraquinones (3-6), 4-isoprenylravenelin (7), and a dimer of 5,8-dihydroxy-4-methoxy-α-tetralone (8), along with four known compounds (9-12), were isolated from solid rice-based cultures of Malbranchea circinata. The structural elucidation of these metabolites was performed using 1D and 2D NMR techniques and DFT-calculated chemical shifts. Compounds 1-3, 9, and 10 showed inhibitory activity to yeast α-glucosidase (αGHY), with IC50 values ranging from 57.4 to 261.3 μM (IC50 acarbose = 585.8 μM). The effect of 10 (10.0 mg/kg) was corroborated in vivo using a sucrose tolerance test in normoglucemic mice. The most active compounds against PTP-1B were 8-10, with IC50 values from 10.9 to 15.3 μM (IC50 ursolic acid = 27.8 μM). Docking analysis of the active compounds into the crystal structures of αGHY and PTP-1B predicted that all compounds bind to the catalytic domains of the enzymes. Together, these results showed that M. circinata is a potential source of antidiabetic drug leads.

Modified diterpenoids from the tuber of Icacina oliviformis as protein tyrosine phosphatase 1B inhibitors

Two modified diterpenoids featuring a novel 4,12-dioxatetracyclo[8.6.0.02,7.010,14]hexadecane core, together with a 3,4-seco-pimarane, a 3,4-seco-cleistanthane, and eight pimarane derivatives were isolated from the tuber of Icacina oliviformis.

Ficus deltoidea extract down-regulates protein tyrosine phosphatase 1B expression in a rat model of type 2 diabetes mellitus: a new insight into its antidiabetic mechanism.

Ficus deltoidea var. deltoidea Jack (FD) is a well-known plant used in Malay folklore medicine to lower blood glucose in diabetic patients. For further research of the antihyperglycemic mechanisms, the protein tyrosine phosphatase 1B (PTP1B)-inhibitory effect of FD was analysed both in vitro and in vivo. To optimise a method for FD extraction, water, 50, 70, 80, 90 and 95% ethanol extracts were prepared and determined for their total phenolic and triterpene contents, and PTP1B-inhibition capacity. Among the tested extracts, 70% ethanol FD extract showed a significant PTP1B inhibition (92·0% inhibition at 200 µg/ml) and high phenolic and triterpene contents. A bioassay-guided fractionation of the 70% ethanol extract led to the isolation of a new triterpene (3β,11β-dihydroxyolean-12-en-23-oic acid; F3) along with six known compounds. In vivo, 4 weeks' administration of 70% ethanol FD extract (125, 250 and 500 mg/kg/d) to streptozotocin-nicotinamide-induced type 2 diabetic rats reversed the abnormal changes of blood glucose, insulin, total Hb, GLUT2, lipid profile, and oxidative stress in liver and pancreas. Moreover, FD reduced the mRNA expression of the key gluconeogenic enzymes (phosphoenolpyruvate carboxykinase and glucose 6-phosphatase) and restored insulin receptor and GLUT2 encoding gene (Slc2a2) expression. In addition, FD significantly down-regulated the hepatic PTP1B gene expression. These results revealed that FD could potentially improve insulin sensitivity, suppress hepatic glucose output and enhance glucose uptake in type 2 diabetes mellitus through down-regulation of PTP1B. Together, our findings give scientific evidence for the traditional use of FD as an antidiabetic agent.

PTP1B Inhibitory Flavonoids From Orthosiphon stamineus Benth. and Their Growth Inhibition on Human Breast Cancer Cells

In our preliminary screening study on the protein tyrosine phosphatase 1B (PTP1B) inhibitory and cytotoxic activities, an ethyl acetate soluble fraction of the aerial part of Orthosiphon stamineus Benth. was found to inhibit PTP1B activity. Thus, based on assay-guided isolation of this active fraction, ten compounds (1-10) were purified and evaluated for their inhibitory effects on PTP1B and their growth inhibition on MCF7, tamoxifen-resistant MCF7 (MCF7/TAMR), and MDA-MB-231 human breast cancer cell lines. Among the isolates, compounds 5, 6, 9, and 10 showed potencies against PTP1B with IC50 values of 9.76, 10.12, 6.88, and 8.92 μM, respectively, followed by compounds 1 and 4 with IC50 values of 16.92 and 22.25 μM. Kinetic study showed that the active compounds (1, 5, 9, and 10) possessed mixed-competitive inhibition, which was similar to the positive control (ursolic acid, IC50 value of 3.42 μM, mixed-competitive). The others showed noncompetitive inhibition (4 and 6). In addition, all these active compounds (1, 4-6, and 9-10) displayed growth inhibition on three cancer cell lines, especially the most PTP1B inhibitory flavanones (9 and 10) exhibited comparable inhibitory effects on MCF7, MCF7/TAMR, and MDA-MB-231 cancer cells (IC50 values of 11.5 and 15.4, 8.9 and 10.5, and 17.6 and 21.3 μM, respectively) with tamoxifen, the positive control used in this assay (IC50 values of 11.9, 12.1, and 12.7 μM, respectively). The results suggest that these active constituents from O. stamineus might be considered as new natural compounds for the development of anticancer agents via PTP1B inhibition.

Potent and selective PTP1B inhibition by a platinum(ii) complex: possible implications for a new antitumor strategy.

Showing anti-proliferation activity against MCF7 cells better than cisplatin, a platinum(ii) complex, [PtL(DMSO)Cl], was found to potently and selectively inhibit protein tyrosine phosphatase 1B (PTP1B), a putative target for anticancer agents, suggesting a new possible anticancer strategy based on platinum drugs.

Identification of Cyanidin-3-arabinoside Extracted from Blueberry as a Selective Protein Tyrosine Phosphatase 1B Inhibitor.

Protein tyrosine phosphatase 1B (PTP1B) is an important target for type 2 diabetes. PTP1B inhibitors can reduce blood glucose levels by increasing insulin sensitivity. Anthocyanins often play a hypoglycemic effect, but the research about them have mainly focused on glucosidase. At present, the research about protein tyrosine phosphatase 1B (PTP1B) target is less, and the corresponding molecular mechanism is still unclear. Therefore, in this present study, anthocyanins isolated from blueberry were used to study the inhibitory activity on PTP1B. The isolated cyanidin-3-arabinoside (Cya-3-Ara) exhibited a better inhibitory activity with IC50 = 8.91 ± 0.63 μM, which was higher than the positive control (oleanolic acid, IC50 = 13.9 ± 1.01 μM), and the mechanism of PTP1B inhibition was reversible mixed pattern. The structure-activity relationship (SAR) between anthocyanins and PTP1B inhibition was investigated. The enzyme activity inhibition and molecular docking showed that anthocyanins had high selectivity for PTP1B inhibition. Further study showed that Cya-3-Ara could promote glycogen synthesis through ameliorating PTP1B-involved IRS-1/PI3K/Akt/GSK3β pathways. Cya-3-Ara could also be regarded as a synergistic inhibitor (CI ≤ 0.54) of oleanolic acid to obtain a better inhibitory effect on PTP1B. Taken together, our study clearly illustrates the SAR between anthocyanins and PTP1B inhibition and the mechanism of Cya-3-Ara in the insulin signaling pathway.

Design and synthesis of tricyclic terpenoid derivatives as novel PTP1B inhibitors with improved pharmacological property and in vivo antihyperglycaemic efficacy

Overexpression of protein tyrosine phosphatase 1B (PTP1B) induces insulin resistance in various basic and clinical research. In our previous work, a synthetic oleanolic acid (OA) derivative C10a with PTP1B inhibitory activity has been reported. However, C10a has some pharmacological defects and cytotoxicity. Herein, a structure-based drug design approach was used based on the structure of C10a to elaborate the smaller tricyclic core. A series of tricyclic derivatives were synthesised and the compounds 15, 28 and 34 exhibited the most PTP1B enzymatic inhibitory potency. In the insulin-resistant human hepatoma HepG2 cells, compound 25 with the moderate PTP1B inhibition and preferable pharmaceutical properties can significantly increase insulin-stimulated glucose uptake and showed the insulin resistance ameliorating effect. Moreover, 25 showed the improved in vivo antihyperglycaemic potential in the nicotinamide–streptozotocin-induced T2D. Our study demonstrated that these tricyclic derivatives with improved molecular architectures and antihyperglycaemic activity could be developed in the treatment of T2D.

Inhibition of PTP1B blocks pancreatic cancer progression by targeting the PKM2/AMPK/mTOC1 pathway

Pancreatic cancer is a highly malignant cancer and lacks effective therapeutic targets. Protein-tyrosine phosphatase 1B (PTP1B), a validated therapeutic target for diabetes and obesity, also plays a critical positive or negative role in tumorigenesis. However, the role of PTP1B in pancreatic cancer remains elusive. Here, we initially demonstrated that PTP1B was highly expressed in pancreatic tumors, and was positively correlated with distant metastasis and tumor staging, and indicated poor survival. Then, inhibition of PTP1B either by shRNA or by a specific small-molecule inhibitor significantly suppressed pancreatic cancer cell growth, migration and colony formation with cell cycle arrest in vitro and inhibited pancreatic cancer progression in vivo. Mechanism studies revealed that PTP1B targeted the PKM2/AMPK/mTOC1 signaling pathway to regulate cell growth. PTP1B inhibition directly increased PKM2 Tyr-105 phosphorylation to further result in significant activation of AMPK, which decreased mTOC1 activity and led to inhibition of p70S6K. Meanwhile, the decreased phosphorylation of PRAS40 caused by decreased PKM2 activity also helped to inhibit mTOC1. Collectively, these findings support the notion of PTP1B as an oncogene and a promising therapeutic target for PDAC.

Phytochemical identification of Lithocarpus polystachyus extracts by ultra-high-performance liquid chromatography-quadrupole time-of-flight-MS and their protein tyrosine phosphatase 1B and α-glucosidase activities.

Lithocarpus polystachyus leaves exhibit antidiabetic activity and is consumed as a herbal tea in China. In this study, phytochemical profiles of L. polystachyus leaves were identified and characterized by ultra-high-performance liquid chromatography-quadrupole time-of-flight-MS in both positive and negative ion modes. A total of 17 compounds were tentatively characterized and identified by accurate mass and characteristic fragment ions. The total phenolic contents in the leaf extracts ranged from 9.0 to 13.4 g gallic acid equivalents/100 g of dry weight (DW). In addition, the effect of these extracts on inhibiting the activities of α-glucosidase and protein tyrosine phosphatase 1B (PTP1B) were evaluated. L. polystachyus extracts demonstrated significant inhibition of α-glucosidase (more than 88.1% at a concentration of 1.25 mg/mL) and acarbose (93.6% at a concentration of 5 mg/mL) while the PTP1B inhibition rate was over 84.3%. The antioxidant capacities of the leaf extracts were determined using 2,2-diphenyl-1-picrylhydrazyl, ABTS, and ferric reducing ability of plasma methods and ranged from 50.5 to 72.5 g trolox, from 43.2 to 77.7 g trolox, and from 5.0 to 10.6 g butylated hydroxytoluene (BHT; equaling trolox or BHT per 100 g of DW), respectively. Based on these results, L. polystachyus can be considered as a functional food owing to its antidiabetic and antioxidative activities, which are attributed to its rich phenolic and dihydrochalcone contents.

(S)-1,2,3,4-Tetrahydroisoquinoline Derivatives Substituted with an Acidic Group at the 6-Position as a Selective Peroxisome Proliferator-Activated Receptor γ Partial Agonist.

A novel series of 2,6,7-substituted 3-unsubstituted 1,2,3,4-tetrahydroisoquinoline derivatives were synthesized to find a peroxisome proliferator-activated receptor γ (PPARγ) partial agonist. Among the derivatives, (E)-7-[2-(cyclopent-3-eny)-5-methyloxazol-4-ylmethoxy]-2-[3-(2-furyl)acryloyl]-6-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydroisoquinoline (20g) exhibited potent partial agonist activity (EC50 = 13 nM, maximal response 30%) and very weak protein tyrosine phosphatase 1B (PTP1B) inhibition (IC50 = 1100 nM), indicating a selective PPARγ partial agonist. A computational docking calculation revealed that 20g bound to PPARγ in a similar manner to that of known partial agonists. In male and female KK-Ay mice with insulin resistance and hyperglycemia, 20g at 30 mg/kg for 7 d significantly reduced plasma glucose levels, but not triglyceride levels. The effects of 20g were similar to those of pioglitazone at 10 mg/kg. In conclusion, the 2,6,7-substituted 1,2,3,4-tetrahydroisoquinoline with an acidic group at the 6-position provides a novel scaffold for selective PPARγ partial agonists and 20g exerted anti-diabetic effects via the partial activation of PPARγ.