Tyrosine Phosphatase 1B Inhibitory Activity Research Articles

Four new neolignans isolated from Eleutherococcus senticosus and their protein tyrosine phosphatase 1B inhibitory activity (PTP1B)

Four new compounds, erythro-7′E-4-hydroxy-3,3′-dimethoxy-8,5′-oxyneoligna-7′-ene-7,9-diol-9′-al (1), (7S,8S)-4-hydroxy-3,1′,3′-trimethoxy-4′,7-epoxy-8,5′-neolign-9-ol (5), (7S,8S,7′E)-5-hydroxy-3,3′-dimethoxy-4′,7-epoxy-8,5′-neolign-7′-ene-9,9′-diol (6) and (7S,8S,7′E)-5-hydroxy-3,3′,9′-trimethoxy-4′-7-epoxy-8,5′-neolign-7′-ene-9-ol (7). Along with four known compounds (2–4, 8) were isolated from the EtOAc-soluble extract of Eleutherococcus senticosus. Their structures were elucidated on the basis of spectroscopic and physicochemical analyses. All the compounds were evaluated for in vitro inhibitory activity against PTP1B, VHR and PP1. Among them, compounds 1–4 and 6–8 were found to exhibit selective inhibitory activity on PTP1B with IC50 values ranging from 17.2±1.6 to 32.7±1.2μM.

A 2,4'-linked tetrahydroxanthone dimer with protein tyrosine phosphatase 1B inhibitory activity from the Okinawan freshwater Aspergillus sp.

A 2,4′-linked tetrahydroxanthone dimer with protein tyrosine phosphatase 1B inhibitory activity from the Okinawan freshwater Aspergillus sp.

Anti-diabetic functional food with wasted litchi seed and standard of quality control

The prevalence of diabetes has become a huge health burden in parts of quality of life and economic cost for overcoming this chronic disease. We followed a bioactivity-guided isolation using α-glucosidase inhibitory assay, four major compounds were isolated, and their structures were elucidated using nuclear magnetic resonance, mass spectrometry, and ultra-performance liquid chromatography quadrupole time of flight mass spectrometry in litchi seed. As a result, the IC50 of α-glucosidase inhibitory assay of the crude extract, sugar-removed layer, pavetannin B2, procyanidin A2, and acarbose was 0.691 μg/mL, 3.686 μg/mL, 0.04 μM, 0.08 μM, and 55.845 μg/mL, respectively. With those compounds, we examined the protein tyrosine phosphatase 1B inhibitory activity. And the IC50 of pavetannin B2, procyanidin A2, and ursolic acid was 450.295, 338.257, and 19.686 μM, respectively. Contents analysis method for bioactive compounds, which can be used in manufacturing for extract preparations, was established. The findings of this study, litchi seed can be a cost-effective medicinal food in terms of recyclable resources in the litchi food industry and as a natural alternative medicine against type-2 diabetes.

N-alkylated thiazolidine-2,4-dione analogs as PTP1B inhibitors: synthesis, biological activity, and docking studies

Protein tyrosine phosphatase 1B enzyme has been found to be a negative regulator of insulin and leptin signaling pathway. It has gained considerable attention to medicinal chemists as a new therapeutic target for intervention in the treatment of type2 diabetes. A series of N-substituted-5-(thiophen-2-ylmethylene)thiazolidine-2,4-dione derivatives were synthesized and screened in vitro for protein tyrosine phosphatase 1B inhibitory activity and in vivo for anti-hyperglycaemic activity. The introduction of alkyl/halo alkyl moiety onto the amidic nitrogen of thiazolidine-2,4-dione ring was intended to enhance the inhibitor-enzyme affinity and hence, good protein tyrosine phosphatase 1B inhibition. The nature of interactions which governs the binding mode of ligands inside the active site of protein tyrosine phosphatase 1B was further studied by molecular docking simulation. Compound 7 was found to be a potent protein tyrosine phosphatase 1B inhibitor with IC50 9.96 µM. The synthesized compounds have also shown significant lowering of blood glucose level.

Phloroglucinol Derivatives with Protein Tyrosine Phosphatase 1B Inhibitory Activities from Eugenia jambolana Seeds.

Fifteen new phloroglucinol derivatives, jamunones A-O (1-8 and 10-16, respectively), along with one known analogue spiralisone C (9), were isolated from Eugenia jambolana seeds. Their structures were elucidated by detailed nuclear magnetic resonance and mass spectrometry spectroscopic data interpretation. Compounds 1-9, 11, 12, and 14-16 inhibited protein tyrosine phosphatase 1B activity with IC50 values ranging from 0.42 to 3.2 μM.

Biphenyl ether derivatives with protein tyrosine phosphatase 1B inhibitory activity from the freshwater fungus Phoma sp.

Biphenyl ether derivatives with protein tyrosine phosphatase 1B inhibitory activity from the freshwater fungus Phoma sp.

Pyrrolo-isoquinoline and glycosylated pyrrolidine alkaloids from Nigella glandulifera and their anti-PTP1B activity

Two new alkaloids, nigellisoquinomine (1) with a novel pyrrolo-isoquinoline skeleton, and nigellapyrrolidine (2) possessing a rare glycosylated pyrrolidine moiety, together with two known alkaloids, agrocybenine (3) and 4,6,6-trimethyl-3,4-epoxypiperidin-2-one (4), were isolated from the seeds of Nigella glandulifera Freyn. Their structures were identified by extensive NMR and HR-ESIMS analysis. Compound 1 exhibited potent protein tyrosine phosphatase 1B (PTP1B) inhibitory activity with an IC50 value of 3.65±0.08μM.

Synthesis and Cell Division Cycle 25B Phosphatase and Protein Ty-rosine Phosphatase 1B Inhibitory Activity Evaluation of Novel 3,6-Disubstituted Triazolothiadiazole Derivatives

Synthesis and Cell Division Cycle 25B Phosphatase and Protein Ty-rosine Phosphatase 1B Inhibitory Activity Evaluation of Novel 3,6-Disubstituted Triazolothiadiazole Derivatives

A tetramic acid derivative with protein tyrosine phosphatase 1B inhibitory activity and a new nortriterpene glycoside from the Indonesian marine sponge Petrosia sp.

During the search for protein tyrosine phosphatase 1B (PTP1B) inhibitors from marine organisms, the known tetramic acid derivative, melophlin C (1), was isolated as an active component together with the new nortriterpenoid saponin, sarasinoside S (2), and three homologues: sarasinosides A1 (3), I1 (4), and J (5), from the Indonesian marine sponge Petrosia sp. The structure of 2 was elucidated on the basis of its spectroscopic data. Compound 1 inhibited PTP1B activity with an IC50 value of 14.6μM, while compounds 2–5 were not active at 15.2–16.0μM. This is the first study to report the inhibitory effects of a tetramic acid derivative on PTP1B activity.

Anti-diabetic effect of three new norditerpenoid alkaloids in vitro and potential mechanism via PI3K/Akt signaling pathway.

Diabetes is a metabolic disease with the characteristic of high blood glucose (hyperglycemia). In our previous study, we found that nigelladines A-C (compounds A-C), three norditerpenoid alkaloids from the seeds of Nigella glandulifera Freyn (Ranunculaceae) exhibited protein of tyrosine phosphatase 1B (PTP1B) inhibitory activity in vitro. In the present study, we further investigated their anti-diabetes activities in L6 moytubes and illuminated the mechanisms of action of compounds A-C. Several parameters of glucose metabolism such as glucose consumption, glycogen content and hexokinase activity were increased by compounds A-C. The results suggested that compounds A-C improved glucose metabolism through promoting synthesis of glycogen. Expression of PTP1B protein was inhibited by compounds A-C in L6 moytubes. PI3K-dependent Akt phosphorylation was found to be activated by compounds A-C and completely blocked by wortmannin (a PI3K inhibitor). Moreover, the insulin-mediated induction of insulin receptor substrate-1 (IRS-1) and glycogen synthase kinase-3β (GSK-3β) were also suppressed by wortmannin. Western blot results indicated that compounds A-C-induced IRS-1/Akt activation was likely a consequence of PTP1B inhibition. Compounds A-C promoted glycogen synthesis through Akt-mediated GSK3 phosphorylation. Therefore, activation of PI3K/Akt insulin signaling pathway and suppression of PTP1B is the molecular mechanism that contributes to the anti-diabetic effect of compounds A-C in cellular models. The three alkaloids potentially serve as lead compounds for the development of antidiabetic drugs.

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

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 1H-NMR, 13C-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 (IC50 = 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 Ki value of 0.78 μM in enzyme kinetic studies.

Bioassay-guided isolation of an active compound with protein tyrosine phosphatase 1B inhibitory activity from Sargassum fusiforme by high-speed counter-current chromatography.

A rapid and efficient method using high-speed counter-current chromatography was established for the bioassay-guided separation of an active compound with protein tyrosine phosphatase 1B inhibitory activity from Sargassum fusiforme. Under the bioassay guidance, the ethyl acetate extract with the best IC50 value of 0.37 ± 0.07 μg/mL exhibited a potential protein tyrosine phosphatase 1B inhibitory activity, which was further separated by high-speed counter-current chromatography. The separation was performed with a two-phase solvent system composed of n-hexane/methanol/water (5:4:1, v/v). As a result, dibutyl phthalate (19.7 mg) with the purity of 95.3% was obtained from 200 mg of the ethyl acetate extract. Its IC50 was 14.05 ± 0.06 μM, which was further explained by molecular docking. The result of molecular docking showed that dibutyl phthalate enfolded in the catalytic site of protein tyrosine phosphatase 1B. The main force between dibutyl phthalate and protein tyrosine phosphatase 1B was the hydrogen bond interaction with Gln266. In addition, hydrogen bond, van der Waals force and hydrophobic interaction with the amino acids (Ala217, Ile219, and Gly220) were also responsible for the stable protein-ligand complex.

Protein tyrosine phosphatase 1B and α-glucosidase inhibitory activities of Pueraria lobata root and its constituents

Ethnopharmacological relevancePueraria lobata root was used to treat wasting-thirst regarded as diabetes mellitus and was included in the composition of Okcheonsan, which is prescribed for thirst-waste in traditional Chinese medicine. Aim of the studyThe objective of this study was to evaluate the anti-diabetic potential of the root of Pueraria lobata and its constituents via protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase inhibitory activities. Materials and methodsIn this study, anti-diabetic activities of the 70% ethanolic (EtOH) extract from P. lobata roots and its solvent soluble fractions with the isolated compounds were investigated by evaluating in vitro PTP1B and α-glucosidase inhibitory activities. We also examined the potentials of active compounds as PTP1B and α-glucosidase inhibitors via enzyme kinetics and in silico molecular docking simulation between the enzymes and active compounds. ResultsTriterpenoids lupeol and lupenone were potent PTP1B inhibitors with IC50 values of 38.89±0.17 and 15.11±1.23μM. Kinetic study using the Lineweaver-Burk and Dixon plots demonstrated that these compounds showed a noncompetitive-type inhibition against PTP1B with respective Ki values of 13.88μM and 21.24μM. In addition, molecular docking simulation showed lupeol and lupenone has negative binding energy values of −8.03 and −8.56kcal/mol. Considering the α-glucosidase inhibitory potential, daidzein, genistein, and calycosin exhibited the most potent α-glucosidase inhibition with IC50 values of 8.58±0.94, 2.37±0.52 and 6.84±1.58μM, respectively. Kinetic study demonstrated that these 3 compounds showed a noncompetitive-type inhibition against α-glucosidase with respective Ki values of 17.64μM, 5.03μM and 13.83μM. Moreover, molecular docking simulation showed daidzein, genistein and calycosin has more lower binding energy (−7.16kcal/mol, −7.42kcal/mol and −7.31kcal/mol) with higher binding affinity and tight binding capacity in the molecular docking studies than standard ligand α-D-glucose (−6.74kcal/mol). ConclusionOur results of the present study clearly demonstrate the potential of P. lobata extract and its constituents to inhibit PTP1B and α-glucosidase, contributing to the development of therapeutic or preventive agents that can be used in the treatment of diabetes.

Sesquiterpene Hydroquinones with Protein Tyrosine Phosphatase 1B Inhibitory Activities from a Dysidea sp. Marine Sponge Collected in Okinawa.

Three new sesquiterpene hydroquinones, avapyran (1), 17-O-acetylavarol (2), and 17-O-acetylneoavarol (3), were isolated from a Dysidea sp. marine sponge collected in Okinawa together with five known congeners: avarol (4), neoavarol (5), 20-O-acetylavarol (6), 20-O-acetylneoavarol (7), and 3'-aminoavarone (8). The structures of 1-3 were assigned on the basis of their spectroscopic data. Compounds 1-3 inhibited the activity of protein tyrosine phosphatase 1B with IC50 values of 11, 9.5, and 6.5 μM, respectively, while known compounds 4-8 gave IC50 values of 12, >32, 10, 8.6, and 18 μM, respectively. In a preliminary investigation on structure-activity relationships, six ester and methoxy derivatives (9-14) were prepared from 4 and 5.

ChemInform Abstract: Asperdichrome, an Unusual Dimer of Tetrahydroxanthone Through an Ether Bond, with Protein Tyrosine Phosphatase 1B Inhibitory Activity, from the Okinawan Freshwater Aspergillus sp. TPU1343.

Abstract A new unusual bis-tetrahydroxanthone connected through an ether bond, named asperdichrome ( 1 ), was isolated from a culture broth of Aspergillus sp. TPU1343 together with two known dimeric polyketides, secalonic acids D ( 2 ) and F ( 3 ). The fungus was isolated from a freshwater sample in Okinawa, Japan. The structure of 1 was elucidated on the basis of its spectroscopic data and comparisons were made with related compounds. Compounds 1 and 3 (heterodimers) inhibited the activity of protein tyrosine phosphatase 1B (PTP1B) with IC 50 values of 6.0 and 9.6 μM, respectively. Compound 2 (homodimer) showed reduced activity against PTP1B (40% inhibition at 15.7 μM). This is the first study on the inhibitory activities of tetrahydroxanthones against PTP1B.

Asperdichrome, an unusual dimer of tetrahydroxanthone through an ether bond, with protein tyrosine phosphatase 1B inhibitory activity, from the Okinawan freshwater Aspergillus sp. TPU1343

A new unusual bis-tetrahydroxanthone connected through an ether bond, named asperdichrome (1), was isolated from a culture broth of Aspergillus sp. TPU1343 together with two known dimeric polyketides, secalonic acids D (2) and F (3). The fungus was isolated from a freshwater sample in Okinawa, Japan. The structure of 1 was elucidated on the basis of its spectroscopic data and comparisons were made with related compounds. Compounds 1 and 3 (heterodimers) inhibited the activity of protein tyrosine phosphatase 1B (PTP1B) with IC50 values of 6.0 and 9.6μM, respectively. Compound 2 (homodimer) showed reduced activity against PTP1B (40% inhibition at 15.7μM). This is the first study on the inhibitory activities of tetrahydroxanthones against PTP1B.

New neo-lignan from Acanthopanax senticosus with protein tyrosine phosphatase 1B inhibitory activity

New neo-lignan, (7S, 8R)-3-hydroxyl-4-methoxyl-balanophonin (1), together with seven known compounds (2-8) were isolated from the EtOAc-soluble extract of Acanthopanax senticosus. The structure of the new neo-lignan was elucidated with spectroscopic and physico-chemical analyses. All the isolates were evaluated for in vitro inhibitory activity against PTP1B, VHR and PP1. Among them, the new compound (1) was found to exhibit selective inhibitory activity on PTP1B with IC50 value 15.2±1.4µM.

Antihyperglycemic and antioxidant activities of twig extract from Cinnamomum osmophloeum

This is the first report concerning the α-glucosidase, α-amylase and protein tyrosine phosphatase 1B (PTP1B) inhibitory activities of cinnamon twig extracts. Comparing the antihyperglycemic activity of renewable plant parts, indigenous cinnamon (Cinnamomum osmophloeum; 土肉桂 tǔ ròu guì) twig extracts (CoTE) showed better α-glucosidase and α-amylase activities than leaf, 2-cm branch and 5-cm branch extracts. Chemotype of C. osmophloeum has no influence on the antihyperglycemic activities and proanthocyanidin contents of CoTE. Among four soluble fractions obtained from CoTE by following bioactivity-guided fractionation procedure, the n-butanol soluble fraction (BSF) with abundant proanthocyanidins and condensed tannins, exhibited the best antihyperglycemic and PTP1B inhibitory activities. In addition, the BSF displayed the excellent DPPH free-radical scavenging and ferrous ion-chelating activities. The antihyperglycemic and antioxidant activities of all four soluble fractions from CoTE showed high correlation coefficient with their proanthocyanidin and condensed tannin contents. Furthermore, CoTE had no toxicity on 3T3-L1 preadiocytes. Results obtained demonstrated that CoTE has excellent antihyperglycemic, antioxidant and PTP1B inhibitory activities, and thus has great potential as a source for natural health products.

Six selaginellin derivatives with protein tyrosine phosphatase 1B inhibitory activity from Selaginella tamariscina

As part of an ongoing search for new PTP1B inhibitors from medicinal plants, the methanol extract of the aerial parts of Selaginella tamariscina was found to inhibit 70% PTP1B enzyme activity at a concentration of 30 µg/mL. Thus, bioassay-guided isolation of this active extract yielded six selaginellin derivatives (1-6), comprising four new compounds (selariscinas A˜D; 2˜6). These compounds were found to possess inhibitory effect on PTP1B enzyme activity with IC50 values ranging from 5.5 ± 0.1 to 21.6 ± 1.5µM. Furthermore, compound 2 which served as mixed-competitive inhibitor showed the greatest potency, with IC50 value of 5.5 ± 0.1µM, when compared with the positive control (ursolic acid, IC50= 3.4 ± 0.1). This result indicated the potential of these selaginellin derivatives as lead molecules for the development of antidiabetic agents and the beneficial use of S. tamariscina against hyperglycemia.

Protein tyrosine phosphatase 1B (PTP1B) inhibitory activity and glucosidase inhibitory activity of compounds isolated from Agrimonia pilosa

Context: Despite phytochemical studies of Agrimonia pilosa Ledeb. (Rosaceae), the antidiabetic effects of this plant are unknown.Objective: This study characterizes the isolated compounds from the aerial parts of A. pilosa and evaluates their PTP1B and α-glucosidase inhibitory properties.Materials and methods: Ethanol extract of A. pilosa was found to inhibit 64% PTP1B activity at 30 μg/mL. The ethanol extract was partitioned with methylene chloride, ethyl acetate, n-butanol, and water fractions. Among these, the ethyl acetate fraction displayed the most potent PTP1B activity. The ethyl acetate extract was separated by chromatographic methods to obtain flavonoids and triterpenoids (1–11); which were evaluated for their inhibitory effects on PTP1B activity with p-nitrophenyl phosphate (p-NPP) as a substrate, and also α-glucosidase enzyme.Results: Compounds 1–11 were identified as apigenin-7-O-β-d-glucuronide-6″-methyl ester, triliroside, quercetin-7-O-β-d-glycoside, quercetin-3-O-β-d-glycoside, kaempferol, kaempferol-3-O-α-l-rhamnoside, β-sitosterol, ursolic acid, tormentic acid, methyl 2-hydroxyl tricosanoate, and palmitic acid. Compounds 8, 9, and 11 displayed inhibitory effects on PTP1B activity with IC50 values of 3.47 ± 0.02, 0.50 ± 0.06, and 0.10 ± 0.03 μM, respectively. Compounds 3, 4, 6, and 9 exhibited inhibition of the α-glucosidase activity with IC50 values of 11.2 ± 0.2, 29.6 ± 0.9, 28.5 ± 0.1, and 23.8 ± 0.4 μM, respectively.Discussion and conclusion: As major ingredients of A. pilosa, compounds 1, 6, 8, and 9 showed the greatest inhibitory potency on PTP1B activity. Compounds 3, 6, 8, and 9 also showed potent inhibitory effects on α-glucosidase enzyme. This result suggested the potential of these compounds for developing antidiabetic agents.