PTP1B inhibitory effects of tridepside and related metabolites isolated from the Antarctic lichen Umbilicaria antarctica

The selective inhibition of PTP1B has been widely recognized as a potential drug target for the treatment of type 2 diabetes and obesity. In the course of screening for PTP1B inhibitory natural products, the MeOH extract of the dried sample of the Antarctic lichen Umbilicaria antarctica was found to exhibit significant inhibitory effect, and the bioassay-guided fractionation and purification afforded three related lichen metabolites 1-3. Compounds 1-3 were identified as gyrophoric acid (1), lecanoric acid (2), and methyl orsellinate (3) mainly by analysis of NMR and MS data. These compounds inhibited PTP1B activity with 50% inhibitory concentration values of 3.6 ± 0.04 μM, 31 ± 2.7 μM, and 277 ± 8.6 μM, respectively. Furthermore, the kinetic analysis of PTP1B inhibition by compound 1 suggested that the compound inhibited PTP1B activity in a non-competitive manner.     

PTP1B inhibitory activity of kaurane diterpenes isolated from Siegesbeckia glabrescens

Protein tyrosine phosphatase 1B (PTP1B) is considered as a therapeutic target for the treatment of diabetes and obesity. In our preliminary screening study, a MeOH extract of the aerial part of Siegesbeckia glabrescens was found to inhibit PTP1B activity at 30 μg/mL. Bioassay‐guided fractionation led to the isolation of two active diterpenes, ent-16βH,17-isobutyryloxy-kauran-19-oic acid (1) and ent-16βH,17-acetoxy-18-isobutyryloxy-kauran-19-oic acid (2), along with ent-16βH,17-hydroxy-kauran-19-oic acid (3). Compounds 1 and 2 inhibited the PTP1B activity with IC₅₀ values of 8.7 ± 0.9 and 30.6 ± 2.1 μM, respectively. Kinetic studies suggest that both 1 and 2 are non-competitive inhibitors of PTP1B. However, compound 3 substituted with a hydroxyl group at C-17 in kaurane-type showed no inhibitory effects towards PTP1B.     

Synthesis and characterization of 5,7-dihydroxyflavanone derivatives as novel protein tyrosine phosphatase 1B inhibitors

A series of 5,7-dihydroxyflavanone derivatives were synthesized and identified as reversible and competitive protein tyrosine phosphatase (PTP) 1B inhibitors with IC₅₀ values in the micromolar range. Compound 4k had the most potent in vitro inhibition activity against PTP1B (IC₅₀ = 2.37?±?0.37 μM) and the greatest selectivity (3.7-fold) for PTP1B relative to T-cell protein tyrosine phosphatase. Cell-based studies revealed that 4k was membrane-permeable and enhanced insulin receptor tyrosine phosphorylation in CHO/hIR cells.     

Inhibition of protein tyrosine phosphatase (PTP1B) and α-glucosidase by geranylated flavonoids from Paulownia tomentosa

Protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase are important targets to treat obesity and diabetes, due to their deep correlation with insulin and leptin signalling, and glucose regulation. The methanol extract of Paulownia tomentosa fruits showed potent inhibition against both enzymes. Purification of this extract led to eight geranylated flavonoids (1–8) displaying dual inhibition of PTP1B and α-glucosidase. The isolated compounds were identified as flavanones (1–5) and dihydroflavonols (6–8). Inhibitory potencies of these compounds varied accordingly, but most of the compounds were highly effective against PTP1B (IC₅₀?=?1.9–8.2?μM) than α-glucosidase (IC₅₀?=?2.2–78.9?μM). Mimulone (1) was the most effective against PTP1B with IC₅₀?=?1.9?μM, whereas 6-geranyl-3,3′,5,5′,7-pentahydroxy-4′-methoxyflavane (8) displayed potent inhibition against α-glucosidase (IC₅₀?=?2.2?μM). All inhibitors showed mixed type Ι inhibition toward PTP1B, and were noncompetitive inhibitors of α-glucosidase. This mixed type behavior against PTP1B was fully demonstrated by showing a decrease in V_max, an increase of K_m, and K_ik/K_iv ratio ranging between 2.66 and 3.69.     

Protein tyrosine phosphatase 1B inhibitors isolated from Artemisia roxburghiana

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 IC₅₀ values 3.49?±?0.02, 4.17?±?0.03 and 87.52?±?0.03?µM, 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.     

Identification of flavonolignans from Silybum marianum seeds as allosteric protein tyrosine phosphatase 1B inhibitors

Protein tyrosine phosphatase 1B (PTP1B) is an attractive molecular target for anti-diabetes, anti-obesity, and anti-cancer drug development. From the seeds of Silybum marianum, nine flavonolignans, namely, silybins A, B (1, 2), isosilybins A, B (3, 4), silychristins A, B (5, 6), isosilychristin A (7), dehydrosilychristin A (8), and silydianin (11) were identified as a novel class of natural PTP1B inhibitors (IC₅₀ 1.3 7–23.87?µM). Analysis of structure–activity relationship suggested that the absolute configurations at C-7" and C-8" greatly affected the PTP1B inhibitory activity. Compounds 1–5 were demonstrated to be non-competitive inhibitors of PTP1B based on kinetic analyses. Molecular docking simulations resulted that 1–5 docked into the allosteric site, including α3, α6, and α7 helix of PTP1B. At a concentration inhibiting PTP1B completely, compounds 1–5 moderately inhibited VHR and SHP-2, and weakly inhibited TCPTP and SHP-1. These results suggested the potentiality of these PTP1B inhibitors as lead compounds for further drug developments.     

Synthesis,carbonic anhydrase I and II inhibition studies of the 1,3,5-trisubstituted-pyrazolines

4-(3-(4-Substituted-phenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) benzenesulfonamides (9–16) were successfully synthesized and their chemical structures were confirmed by ¹H NMR, ¹³C NMR, and HRMS spectra. Carbonic anhydrase I and II inhibitory effects of the compounds were investigated. K_i values of the compounds were in the range of 316.7?±?9.6–533.1?±?187.8?nM towards hCA I and 412.5?±?115.4–624.6?±?168.2?nM towards hCA II isoenzymes. While K_i values of the reference compound Acetazolamide were 278.8?±?44.3?nM and 293.4?±?46.4?nM towards hCA I and hCA II izoenzymes, respectively. Compound 14 with bromine and compound 13 with fluorine substituents can be considered as the leader compounds of the series because of the lowest K_i values in series to make further detailed carbonic anhydrase inhibiton studies.     

LC-ESI-MS/MS Chemical Characterization,Antioxidant and Antidiabetic Properties of Propolis Extracted with Organic Solvents from Eastern Anatolia Region

Geographic conditions (altitude, climate, and local flora) lead to significant differences in the chemical composition of propolis. Therefore, more research is needed for propolis in different geographical regions. So, the aim of this study was to evaluate the phenolic profile, total phenolic content, antioxidant, and antidiabetic properties of Pülümür propolis from Turkey. Methanol (MeOH), chloroform (CHCl₃), and hexane extracts of propolis were analyzed. LC-ESI-MS/MS analysis of the extracts showed that the most abundant phenolic compound is caffeic acid in the MeOH extract (2943.12±11.12 μg phenolics/g extract), while on the other hand, CHCl₃ extract had the highest total phenolic content (125.75±1.02 mg GAE/g extract). Antioxidant activity was measured using ABTS and DPPH assays, whereas CHCl₃ extract (IC₅₀=6.35±0.11 and 28.84±0.10 μg/mL, respectively) and MeOH extracts (IC₅₀=5.04±0.07 and 28.80±0.09 μg/mL, respectively) showed relatively high antioxidant activity. The MeOH extract showed better antidiabetic activity than the standard compound, acarbose (IC₅₀=0.544 and 0.805 mg/mL, respectively).     

THE BIOLOGICAL ACT'IVITIES OF YELLOW AZALEA,RHODODENDRON MOLLE G. DON AGAINST THE VEGETABLE LEAFMINER,LIRIOMYZA SATIVAE (DIPTERA: AGROMYZIDAE) *

Abstract The results of laboratory and greenhouse bioassays indicated that Rhodojaponin‐ III (Abbr. R‐ 1) and extracts of flowers from Rhododendron molle G. Don possessed signficant feeding inhibition and insectcidal properties against the larvae and adults of Liromyzia sativae. Treated with 500 mg/L R‐ III 1 000 mg/L molosul‐tap, and 10 000 mg/L methanol(MeOH) ethyl acetate (EtOAc), CH₂Cl₂, methanol‐water (MeOH‐H₂O) extracts the rates of feeding inhibition were 77. 34 % 74.30 % 82.15 % 77.50 % 67. 33 % 62.85 % against the 2nd instar larvae, and were 67.66% 55.21 % 49.72% 54.26% 46.81 % 38.53% against the 3rd instar larvae, respectively;LC₅₀ values against the 2nd instar larvae were 208.65, 166.05, 2.74 ± 10³,766.72, 5.95 ± 10³, 1.85 ± 10³mg/L, and against 3rd larvae were 300.62, 256.00, 4.33 ±10³, 1.03 ± 10³,9.79 ± 10³, and 2.62± 10³mg/L, respectively. Against the adults, LC₅₀ values of R‐III EtOAc extract and molosultap were 159.07.723.87 and 134.55mgL respectively after treatment for 24 h.     

Discovery of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups as potential PTP1B inhibitors

Two series of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups were identified as competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors. Among the compounds studied, IIIv was found to have the best in vitro inhibition activity against PTP1B (IC₅₀?=?0.67?±?0.09?µM) and the best selectivity (9-fold) between PTP1B and T-cell protein tyrosine phosphatase (TCPTP). Molecular docking studies demonstrated that compounds IIIm, IIIv and IVg could occupy simultaneously at both the catalytic site and the adjacent pTyr binding site. These results provide novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs.     

Synthesis and antitumor activity of novel 2, 3-didithiocarbamate substituted naphthoquinones as inhibitors of pyruvate kinase M2 isoform

The M2 isoform of pyruvate kinase (PKM2) is a potential antitumor therapeutic target. In this study, we designed and synthesised a series of 2, 3-didithiocarbamate substituted naphthoquinones as PKM2 inhibitors based on the lead compound 3k that we previously reported. Among them, compound 3f (IC₅₀?=?1.05?±?0.17 µM) and 3h (IC₅₀?=?0.96?±?0.18 µM) exhibited potent inhibition of PKM2, and their inhibitory activities are superior to compound 3k (IC₅₀?=?2.95?±?0.53 µM) and the known PKM2 inhibitor shikonin (IC₅₀?=?8.82?±?2.62 µM). In addition, we evaluated in vitro antiproliferative effects of target compounds using MTS assay. Most target compounds exhibited dose-dependent cytotoxicity with IC₅₀ values in nanomolar concentrations against HCT116, MCF7, Hela, H1299 and B16 cells. These small molecule PKM2 inhibitors not only provide candidate compounds for cancer therapy, but also offer a tool to probe the biological effects of PKM2 inhibition on cancer cells.     

PTP1B inhibitors from the seeds of Iris sanguinea and their insulin mimetic activities via AMPK and ACC phosphorylation

To find PTP1B inhibitors from natural products, two new compounds (1 and 2), along with nine known compounds (3–11), were isolated from a methanol-soluble extract of Iris sanguinea seeds. The structures of compounds 1 and 2 were determined based on extensive spectroscopic data analysis including UV, IR, NMR, and MS. The IC₅₀ value of compound 5 on protein tyrosine phosphatase 1B (PTP1B) inhibitory activity is 7.30 ± 0.88 µM with a little activity compared to the IC₅₀ values of the tested positive compound. Compound 5 significantly enhanced glucose uptake and activation of pACC, pAMPK and partially Erk1/2 signaling. These results suggest that compound 5 from Iris sanguinea seeds are utilized as both PTP1B inhibitors and regulators of glucose uptake. These beneficial effects could be applied to treat metabolic diseases such as diabetes and obesity.     

New prenylated isoflavonoids as protein tyrosine phosphatase 1B (PTP1B) inhibitors from Erythrina addisoniae

Bioassay-guided fractionation of the EtOAc extract of the root of Erythrina addisoniae (Leguminosae) resulted in the isolation of four new (1–4), along with 2 known prenylated isoflavonoids (5–6). The structures of the isolates were assigned on the basis of spectroscopic data analysis, focusing on interpretation of 1D and 2D NMR, and MS data. All the isolates were evaluated for their inhibitory effects on protein tyrosine phosphatase 1B (PTP1B), as well as their growth inhibition on MCF7, adriamycin-resistant MCF7 (MCF7/ADR), and MDA-MB-231 breast cancer cell lines. Compounds which exhibited PTP1B inhibitory activity (IC₅₀ values ranging from 4.6 ± 0.3 to 24.2 ± 2.1 μM) showed potential cytotoxic activity (IC₅₀ values ranging from 3.97 ± 0.17 to 11.4 ± 1.9 μM). Taken together, our data suggest that prenylated isoflavonoids, especially the isoflavone-type skeleton could be considered as new lead compounds against breast cancer via PTP1B inhibition.     

Monoamine oxidase inhibition by monoterpene indole alkaloids and fractions obtained from Psychotria suterella and Psychotria laciniata

Alkaloid fractions of Psychotria suterella (SAE) and Psychotria laciniata (LAE) as well as two monoterpene indole alkaloids (MIAs) isolated from these fractions were evaluated against monoamine oxidases (MAO-A and -B) obtained from rat brain mitochondria. SAE and LAE were analysed by HPLC-PDA and UHPLC/HR-TOF-MS leading to the identification of the compounds 1, 2, 3 and 4, whose identity was confirmed by NMR analyses. Furthermore, SAE and LAE were submitted to the enzymatic assays, showing a strong activity against MAO-A, characterized by IC₅₀ values of 1.37?±?1.05 and 2.02?±?1.08 μg/mL, respectively. Both extracts were also able to inhibit MAO-B, but in higher concentrations. In a next step, SAE and LAE were fractionated by RP-MPLC affording three and four major fractions, respectively. The RP-MPLC fractions were subsequently tested against MAO-A and -B. The RP-MPLC fractions SAE-F3 and LAE-F4 displayed a strong inhibition against MAO-A with IC₅₀ values of 0.57?±?1.12 and 1.05?±?1.15 μg/mL, respectively. The MIAs 1 and 2 also inhibited MAO-A (IC₅₀ of 50.04?±?1.09 and 132.5?±?1.33 μg/mL, respectively) and -B (IC50 of 306.6?±?1.40 and 162.8?±?1.26 μg/mL, respectively), but in higher concentrations when compared with the fractions. This is the first work describing the effects of MIAs found in neotropical species of Psychotria on MAO activity. The results suggest that species belonging to this genus could consist of an interesting source in the search for new MAO inhibitors.     

Triterpenoids from <i>Uncaria rhynchophylla</i> and Their PTP1B Inhibitory Activity

Uncaria rhynchophylla (Gouteng) is a famous traditional Chinese medicine used for psychiatric and hypotensive purposes in China. In this study, the ethyl acetate (EtOAc) part of U. rhynchophylla was revealed with protein tyrosine phosphatase 1B (PTP1B) inhibitory activity. Subsequent investigation on the EtOAc part yielded one new triterpenoid, 3β-formyloxy-6β,19α-dihydroxyurs-12-en-28-oic acid (1) and four known ones, 3β,6β,19α-trihydroxyurs-12-en-28-oic acid (2), 2-oxopomolic acid (3), 3β,19α-dihydroxy-6-oxo-olean-12-en-28-oic acid (4) and sumaresinolic acid (5). The structure of compound 1 was determined by extensive HRESIMS, IR, 1D and 2D NMR spectroscopic analyses. Two ursane-type triterpenoids (2 and 3) showed selective inhibition on PTP1B with IC₅₀ values of 48.2 and 178.7 μM. The enzyme kinetic study suggested that compounds 2 and 3 were mix-type inhibitors on PTP1B with K_i values of 15.6 and 132.5 μM. This investigation manifests the antidiabetic potency of U. rhynchophylla with triterpenoids as the active constituents.     

Antioxidative iridoid glycosides from the sky flower (Duranta repens Linn)

Phytochemical investigations were performed on the EtOAc-soluble fraction of the whole plant of the sky flower (Duranta repens) which led to the isolation of the iridoid glycosides 1–6. Their structures were elucidated by both 1D and 2D NMR spectroscopic analysis. All the compounds showed potent antioxidative scavenging activity in four different tests, with half maximal inhibitory concentration (IC₅₀) values in the range 0.481–0.719?mM against DPPH radicals, 4.07–17.21 µM for the hydroxyl radical (^?OH) inhibitory activity test, 43.3–97.37 µM in the total reactive oxygen species (ROS) inhibitory activity test, and 3.39–18.94 µM in the peroxynitrite (ONOO^?) scavenging activity test. Duranterectoside A (1) displayed the strongest scavenging potential with IC₅₀ values of (0.481?±?0.06?mM, 4.07?±?0.03, 43.30?±?0.05, 3.39?±?0.02?µM) for the DPPH radicals, ^?OH inhibitory activity test, total ROS inhibitory activity test and the ONOO^? scavenging activity test, respectively.     

New diterpene furanoids from the Antarctic lichen Huea sp

In the course of ongoing research on protein tyrosine phosphatase 1B (PTP1B) inhibitory compounds from Antarctic lichens, four new diterpene furanoids, hueafuranoids A–D (1–4) have been isolated from the MeOH extract of Antarctic lichen Huea sp. by various chromatographic methods. The structures of these compounds were elucidated by analysis of NMR and MS data, and comparing their spectral data with those in the literature. Compound 1 showed inhibitory activity against therapeutically targeted protein, PTP1B with an IC₅₀ value of 13.9 μM. The kinetic analysis of PTP1B inhibition by hueafuranoid A (1) suggested that the diterpene furanoids encountered in this study inhibited PTP1B activity in a non-competitive manner.     

Antioxidant phenylpropanoid glycosides from Buddleja davidii

Phytochemical investigations on the n-BuOH-soluble fraction of the whole plant of Buddleja davidii led to the isolation of the phenylpropanoid glycosides 1-10. Their structures were determined by 1D and 2D NMR spectroscopic techniques. All the compounds showed potent antioxidative activity in three different tests, with IC₅₀ values in the range 4.15-9.47 μM in the hydroxyl radical (˙OH) inhibitory activity test, 40.32-81.15 μM in the total ROS (reactive oxygen species) inhibitory activity test, and 2.26-7.79 μM in the peroxynitrite (ONOO^?) scavenging activity test. Calceolarioside A (1) displayed the strongest scavenging potential with IC₅₀ values of (4.15?±?0.07, 40.32?± 0.09, 2.26?±?0.03μM) for ˙OH, total ROS and scavenging of ONOO^?, respectively.     

Constituents with tyrosinase inhibitory activities from branches of Ficus erecta var. sieboldii King

Phytochemical investigation of the branches of Ficus erecta var. sieboldii King resulted in the isolation of eight constituents: p-hydroxybenzoic acid (1), methyl p-hydroxybenzoate (2), vanillic acid (3), methyl vanillate (4), syringic acid (5), β-sitosterol (6), α-amyrin acetate (7), and ethyl linoleate (8). Their chemical structures were identified via spectroscopic means as well as by comparing their data with literature values. Studies on tyrosinase inhibition activities were conducted for the isolated compounds. Among them, p-hydroxybenzoic acid (1) and methyl p-hydroxybenzoate (2) were identified as active tyrosinase inhibitors with IC₅₀ values of 0.98?±?0.042 and 0.66?±?0.025?mM, respectively, showing comparable activities to that of arbutin (IC₅₀?=?0.32?±?0.015?mM), a standard control. Inhibition kinetics, as analyzed by Lineweaver-Burk plots, indicated that compounds 1 and 2 were competitive inhibitors of diphenolase of mushroom tyrosinase. Notably, isolated compounds 1–8 were reported for the first time as constituents of F. erecta.     

Urease inhibitors from Hypericum oblongifolium WALL.

The bioassay-guided fractionation of H. oblongifolium has led to the isolation of potent urease inhibitors 1–3. The structures were elucidated by NMR and mass spectroscopic techniques. Compound 2 showed a potent enzyme inhibition activity (IC₅₀ 20.96?±?0.93), which is comparatively higher than that for the standard thiourea (IC₅₀ 21.01?±?0.51 μM). Compounds 1 and 3 also showed a significant activity, with IC₅₀ 37.95?±?1.93 and 138.43?±?1.23 μM, respectively. The sub crude fractions (F1, F2, F3, and F4) were tested in vitro for their urease inhibition activity. Fractions F2 and F4 showed significant activity with IC₅₀ 140.37?±?1.93 and 167.43?±?3.03 μM, respectively.