Ursolic acid and its derivative inhibit protein tyrosine phosphatase 1B, enhancing insulin receptor phosphorylation and stimulating glucose uptake

Zhang, Wei; Hong, Deshun; Zhou, Yuwei; Zhang, Yinan; Shen, Qiang; Li, Jingya; Hu, Lihong; Li, Jia

doi:10.1016/j.bbagen.2006.05.009

Cited by 245 publications

(177 citation statements)

References 41 publications

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“…The activity of this standard positive control recorded in the present study (Table 1) was in good agreement with those reported for the compound previously 17,23 . Betulinic acid is another pentacyclic triterpene in which hydroxyl and carboxyl groups located at similar positions but differ from ursolic acid in one of the ring system (5-membered ring in betulinic acid, Figure 1).…”

Section: Resultssupporting

confidence: 81%

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Protein tyrosine phosphatase 1B inhibitors isolated from Artemisia roxburghiana

Shah

Ishtiaq

Hizbullah

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Artemisia roxburghiana is used in traditional medicine for treating various diseases including diabetes. The present study was designed to evaluate the antidiabetic potential of active constituents by using protein tyrosine phosphatase 1B (PTP1B) as a validated target for management of diabetes. Various compounds were isolated as active principles from the crude methanolic extract of aerial parts of A. roxburghiana. All compounds were screened for PTP1B inhibitory activity. Molecular docking simulations were performed to investigate the mechanism behind PTP1B inhibition of the isolated compound and positive control, ursolic acid. Betulinic acid, betulin and taraxeryl acetate were the active PTP1B principles with IC 50 values 3.49 ± 0.02, 4.17 ± 0.03 and 87.52 ± 0.03 mM, respectively. Molecular docking studies showed significant molecular interactions of the triterpene inhibitors with Gly220, Cys215, Gly218 and Asp48 inside the active site of PTP1B. The antidiabetic activity of A. roxburghiana could be attributed due to PTP1B inhibition by its triterpene constituents, betulin, betulinic acid and taraxeryl acetate. Computational insights of this study revealed that the C-3 and C-17 positions of the compounds needs extensive optimization for the development of new lead compounds.

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Section: Resultssupporting

confidence: 81%

“…Ursolic acid and its derivatives are reported with significant PTP1B inhibitory activities. Through this mechanism, they are known to enhance insulin receptor phosphorylation and stimulate glucose uptake 23 . Mechanism and molecular modeling studies of ursolic acid against PTP1B enzyme has been reported 29 .…”

Section: Resultsmentioning

confidence: 99%

Protein tyrosine phosphatase 1B inhibitors isolated from Artemisia roxburghiana

Shah

Ishtiaq

Hizbullah

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…The assay was conducted as described by Zhang et al [27]. Briefly, the tested compounds were solubilized in DMSO and serially diluted into concentrations for the inhibitory test.…”

Section: Biological Activity Against Ptp1b and Tcptpmentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of Stilbene Derivatives as Novel Inhibitors of Protein Tyrosine Phosphatase 1B

Dai

et al. 2016

Molecules

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Abstract:By imitating the scaffold of lithocholic acid (LCA), a natural steroidal compound displaying Protein Tyrosine Phosphatase 1B (PTP1B) inhibitory activity, a series of stilbene derivatives containing phenyl-substituted isoxazoles were designed and synthesized. The structures of the title compounds were confirmed by 1 H-NMR, 13 C-NMR and HRMS. Activities of the title compounds were evaluated on PTP1B and the homologous enzyme TCPTP by using a colorimetric assay. Most of the target compounds had good activities against PTP1B. Among them, compound 29 (IC 50 = 0.91 ± 0.33 µM), characterized by a 5-(2,3-dichlorophenyl) isoxazole moiety, exhibited an activity about 14-fold higher than the lead compound LCA and a 4.2-fold selectivity over TCPTP. Compound 29 was identified as a competitive inhibitor of PTP1B with a K i value of 0.78 µM in enzyme kinetic studies.

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“…A known phosphatase inhibitor, ursolic acid (IC 50 ¼3.1 mM), was used as a positive control in the assay. 11 Although the magnitude of inhibitory activity of these compounds against PTP1B was modest, a structure-activity relationship was conferred upon examination of the structures and their corresponding activities. First, the length of the acyl chain appears to be important, because botcinin A (1) is less active than boticin B (2), whose acyl chain is longer than that of 1.…”

mentioning

confidence: 99%

Two new botcinin derivatives encountered in the studies of secondary metabolites from the marine-derived fungus Botryotinia sp. SF-5275

et al. 2012

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Keywords: bioactive secondary metabolites; botcinins; botryotinia sp.; marine-derived fungus Marine microorganisms are recognized as an important source of structurally diverse bioactive secondary metabolites. 1,2 Studies of marine fungi as potential sources of new bioactive compounds have been relatively limited to date, but such studies have led to the discovery of new natural products, including many with novel carbon skeletons, providing compelling evidence that marine-derived fungi have the potential to be a rich source of pharmaceutical leads. 3,4 The insulin-antagonizing activity of protein tyrosine phosphatase 1B (PTP1B) is a factor in the negative regulation of the insulin pathway and a promising target for treatment of diabetes and obesity. Anchored to the endoplasmic reticulum, PTP1B is involved in the insulin receptor dephosphorylation process, negatively regulating insulin pathway signaling. 5,6 Several studies indicate that PTP1B is also implicated in the inhibition of leptin signaling, which inhibits food intake and promote energy expenditure. 7 As a part of our ongoing studies on PTP1B inhibitory secondary metabolites from marine microorganisms from Korea, we have investigated the chemical constituents of an extract obtained from cultures of the marine-derived fungus Botryotinia sp. SF-5275, of which the organic extract displayed PTP1B inhibitory effect (60% inhibition at the 30 mg ml À1 level). This paper describes the isolation, structure elucidation and biological activity of the metabolites encountered in this investigation.Botryotinia sp. SF-5275 (deposited at the College of Medical and Life Sciences fungal strain repository, Silla University) was isolated from an unidentified marine algae sample collected from Seongsan Port area at Cheju, Korea in February, 2009. The sample was diluted 10-fold using sterile seawater. One milliliter of the diluted sample was processed utilizing the spread plate method using a medium consisting of 24 g of potato dextrose broth (Difco, Sparks, MD, USA) and 20 g of agar (Bio Basics, Inc., Ontario, Canada) in 1 l of 75% filtered natural seawater. The plate was incubated at 25 1C for 14 days. The fungal culture SF-5275 was identified based on analysis of the ribosomal RNA (rRNA) sequences. A GenBank search with the 28S rRNA gene of SF-5275 (Genbank accession number HQ602686) indicated Botryotinia fuckeliana (AY544651) as the closest match showing sequence identity of 99%. Therefore, the marine-derived fungal strain SF-5275 was characterized as Botryotinia sp.The fungal strain was cultured on 27 petri plates (90 mm), each containing 20 ml of potato dextrose agar medium (2.4% (w/v) potato dextrose broth, 2.0% (w/v) agar) prepared with 75% seawater. Plate cultures were incubated at 25 1C for 14 days. Extraction of the agar media with MEK (1 l) provided an organic phase, which was then concentrated in vacuo to yield 633 mg of an extract. This MEK extract was subjected to C 18 flash column chromatography (5Â40 cm, YMC ODS-A, S-75 mm, YMC Co., Ltd., Kyoto, Japan),...

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Ursolic acid and its derivative inhibit protein tyrosine phosphatase 1B, enhancing insulin receptor phosphorylation and stimulating glucose uptake

Cited by 245 publications

References 41 publications

Protein tyrosine phosphatase 1B inhibitors isolated from Artemisia roxburghiana

Protein tyrosine phosphatase 1B inhibitors isolated from Artemisia roxburghiana

Design, Synthesis and Biological Evaluation of Stilbene Derivatives as Novel Inhibitors of Protein Tyrosine Phosphatase 1B

Two new botcinin derivatives encountered in the studies of secondary metabolites from the marine-derived fungus Botryotinia sp. SF-5275

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