OBJECTIVETo synthesize (2'-bromo-4',5'-dimethoxy-phenyl)-( 2,3- dibromo-4,5-dimethoxy-phenyl)-methane (6) as protein tyrosine phosphatase 1B (PTP1B) inhibitor.

METHODCompound 6 was synthesized by Friedel-Crafts reaction, bromination and decarbonylation and screened inhibitory activity against PTP1B by the colorimetric assay. The structure of synthetic intermediates and target product were identified on the basis of spectral analysis.

RESULTCompound 6 was synthesized successfully in four steps and evaluated for its PTP1B inhibitory activity, the screening result shown that compound 6 displayed good inhibitory activity against PTP1B.

CONCLUSIONThe target compound 6 was synthesized with the overall yield of 20%, which was a new compound and shown good inhibitory activity against PTP1B (inhibition 40.16% at 5 mg x L(-1)).

Enzyme Inhibitors ; chemical synthesis ; chemistry ; Kinetics ; Protein Tyrosine Phosphatase, Non-Receptor Type 1 ; antagonists & inhibitors

Protein tyrosine phosphatase (PTP) 1B is a potential target for the treatment of diabetes and obesity. We have previously identified the benzoyl sulfathiazole derivative II as a non-competitive PTP1B inhibitor with in vivo insulin sensitizing effects. Preliminary SAR study on this compound series has been carried out herein, and thirteen new compounds have been designed and synthesized. Among them, compound 10 exhibited potent inhibition against human recombinant PTP1B with the IC50 value of 3.97 micromol x L(-1), and is comparable to that of compound II.
Humans ; Protein Tyrosine Phosphatase, Non-Receptor Type 1 ; antagonists & inhibitors ; Structure-Activity Relationship ; Sulfathiazoles ; chemistry ; pharmacology

Reversible protein phosphorylation regulates multiple biochemical events. Mycobacterium tuberculosis phosphatases play important roles in regulating the pathogen physiology and interference of host signaling. They are also involved in the evasion of host immune response and blockage of the phagosome-lysosome fusion. Selective inhibition of phosphatase represents an ideal new avenue of anti-tuberculosis drug design. In this paper, we update the progresses about the regulation network of Mycobacterium tuberculosis phosphatases including MptpA, MptpB, MstP, SapM and their inhibitors. These serve as the basis for further antituberculosis drug target.
Acid Phosphatase ; antagonists & inhibitors ; metabolism ; Animals ; Antitubercular Agents ; pharmacology ; Bacterial Proteins ; antagonists & inhibitors ; metabolism ; Humans ; Mycobacterium tuberculosis ; drug effects ; enzymology ; Protein Tyrosine Phosphatases ; antagonists & inhibitors ; metabolism

OBJECTIVETo study the protein tyrosine phosphatase-1B (PTP1B) inhibitory activity of natural products from algae aiming at searching for new way for the treatment of type 2 diabetes mellitus (T2DM) and obesity.

METHODBromophenols derivatives from algae were screened against the PTP1B by the colorimetric assay with GST/PTP1B fusion protein. The Me2SO was distributed as the full enzyme activity, and Na3VO4 (IC50 2 micromol L(-1)) was distributed as the positive control. Inhibition rate was assayed and IC50 were calculated by LOGIT method.

RESULTThree bromophenols from Rhodomela confervoides and Leathesia nana, 3, 4-dibromo-5-(methoxymethyl)-1, 2-benzenediol (1), 2-methyl-3-(2, 3-dibromo4, 5-dihydroxy)-propylaldehyde (2) and 3-(2, 3-dibromo-4, 5-dihydroxy-phenyl)-4-bromo-5, 6-dihydroxy-1, 3-dihydroiso-benzofuran (3) showed significant inhibitory activity against PTP1B. IC50 values were 3.4 +/- micromol L(-1), 4.5 micromol L(-1) and 2.8 micromol L(-1), respectively.

CONCLUSIONThe results prove that three bromophenol derivatives from algae with significant inhibitory activity against PTP1B were potential and effective therapeutic agents for treatment of T2DM and obesity.

Diabetes Mellitus, Type 2 ; drug therapy ; metabolism ; Eukaryota ; chemistry ; Phaeophyta ; chemistry ; Phenols ; chemistry ; therapeutic use ; Protein Tyrosine Phosphatase, Non-Receptor Type 1 ; antagonists & inhibitors ; Rhodophyta ; chemistry

Two new 2-carboxymethyl-3-hexyl-maleic anhydride derivatives, arthrianhydride A (1) and B (2), along with three known compounds 3-5, were isolated from the fermentation broth of a grasshopper-associated fungus Arthrinium sp. NF2410. The structures of new compounds 1 and 2 were determined based on the analysis of the HR-ESI-MS and NMR spectroscopic data. Furthermore, compounds 1 and 2 were evaluated on inhibitory activity against the enzyme SHP2 and both of them showed moderate inhibitory activity against SHP2.
Anhydrides/pharmacology* ; Animals ; Biological Products/pharmacology* ; Enzyme Inhibitors/pharmacology* ; Fungi/chemistry* ; Grasshoppers/microbiology* ; Molecular Structure ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/antagonists & inhibitors* ; Secondary Metabolism

Eleven flavonoids were isolated from the twigs of Broussonetia papyrifera by column chromatography over silica gel,ODS,MCI gel,and Sephadex LH-20,as well as RP-HPLC.Their structures were identified by spectroscopic methods including NMR,MS,UV,and IR as broupapyrin A(1),5,7,3',4'-tetrahydroxy-3-methoxy-8-geranylflavone(2),8-prenylquercetin-3-methyl ether(3),broussonol D(4),broussoflavonol B(5),uralenol(6),broussonol E(7),8-(1,1-dimethylallyl)-5'-(3-methylbut-2-enyl)-3',4',5,7-tetrahydroxyflanvonol(8),broussoflavonol E(9),4,2',4'-trihydroxychalcone(10),and butein(11).Compound 1 is a new isoprenylated flavonol.Compounds 3,6,10,and 11 were obtained from the genus Broussonetia for the first time,and 4 and 7 were firstly discovered in B.papyrifera.Compounds 1-5 and 7-9 showed significant inhibitory effects on PTP1 B with IC50 values ranging from(0.83±0.30) to(4.66±0.83) μmol·L-1.
Broussonetia ; chemistry ; Chromatography, High Pressure Liquid ; Flavonoids ; isolation & purification ; pharmacology ; Magnetic Resonance Spectroscopy ; Phytochemicals ; isolation & purification ; pharmacology ; Protein Tyrosine Phosphatase, Non-Receptor Type 1 ; antagonists & inhibitors

Protein tyrosine phosphatase 1B (PTP1B) has led to an intense interest in developing its inhibitors as anti-diabetes, anti-obesity and anti-cancer agents. The fruits of Rubus chingii (Chinese raspberry) were used as a kind of dietary traditional Chinese medicine. The methanolic extract of R. chingii fruits exhibited significant PTP1B inhibitory activity. Further bioactivity-guided fractionation resulted in the isolation of three PTP1B inhibitory ursane-type triterpenes: ursolic acid (1), 2-oxopomolic acid (2), and 2α, 19α-dihydroxy-3-oxo-urs-12-en-28-oic acid (3). Kinetics analyses revealed that 1 was a non-competitive PTP1B inhibitor, and 2 and 3 were mixed type PTP1B inhibitors. Compounds 1-3 and structurally related triterpenes (4-8) were further analyzed the structure-activity relationship, and were evaluated the inhibitory selectivity against four homologous protein tyrosine phosphatases (TCPTP, VHR, SHP-1 and SHP-2). Molecular docking simulations were also carried out, and the result indicated that 1, 3-acetoxy-urs-12-ene-28-oic acid (5), and pomolic acid-3β-acetate (6) bound at the allosteric site including α3, α6, and α7 helix of PTP1B.
Enzyme Inhibitors ; chemistry ; metabolism ; Fruit ; chemistry ; Humans ; Kinetics ; Methanol ; chemistry ; Molecular Docking Simulation ; Molecular Structure ; Plant Extracts ; chemistry ; Protein Binding ; Protein Tyrosine Phosphatase, Non-Receptor Type 1 ; antagonists & inhibitors ; metabolism ; Protein Tyrosine Phosphatases ; antagonists & inhibitors ; Rubus ; chemistry ; Structure-Activity Relationship ; Triterpenes ; chemistry ; metabolism

Diabetes mellitus is a common metabolic disease with a high and growing prevalence affecting 4% of the population worldwide, the development of safe and effective therapeutic drug is the major thrust for chemists and pharmacists. To search for active antidiabetic lead compound, we designed and synthesized some novel beta-amino ketone derivatives containing sulfamethoxazole moiety directly through Mannich reaction of sulfamethoxazole, 4-bromoacetophenone and some aromatic aldehydes catalyzed by concentrated hydogen chloride or iodine in the solution of ethanol at 24-40 degrees C with convenient operation, mild reaction condition and satisfactory yield (32%-90%). Their chemical structures were characterized by 1H NMR, 13C NMR, MS and HR-MS. Biological activity tests showed that, in the range of low concentration (5-10 microg x mL(-1)), these title compounds to a certain degree possess protein tyrosine phosphatase 1B (PTP1B) inhibitory activity and a-glucosidase inhibitory activity, moreover, some could activate peroxisome proliferator-activated receptor response element (PPRE) moderately. The PPRE agonist activities of seven compounds are almost 40% of that of Pioglitazone (the positive control), compound 12 shows the strongest activity (66.35%) among them. Thus, it was found that some of 4-(3-(4-bromophenyl)-3-oxo-1-arylpropylamino)-N-(5-methyl-isoxazol-3-yl) benzenesulfonamide containing sulfamethoxazole moiety exhibited antidiabetic activity for the first time.
Glycoside Hydrolase Inhibitors ; Humans ; Hypoglycemic Agents ; chemical synthesis ; chemistry ; pharmacology ; Molecular Structure ; Oxazoles ; chemistry ; Peroxisome Proliferator-Activated Receptors ; agonists ; Protein Tyrosine Phosphatase, Non-Receptor Type 1 ; antagonists & inhibitors ; Response Elements ; Structure-Activity Relationship ; Sulfonamides ; chemistry ; Thiazolidinediones ; pharmacology

To screen potential human soluble protein tyrosine phosphatase 1B (PTP1B) inhibitors, a high-throughput screening (HTS) model in 384-well microplate with total volume of 50 microL was established. Recombinant PTP1B was cloned and expressed in E. coli. with its specific substrate 4-nitrophenyl phosphate disodium salt hexahydrate (PNPP). The HTS model was based on enzyme reaction rate with enhanced sensitivity and specificity (Z' = 0.78). A total of 24,240 samples were screened, among them 80 samples with inhibition greater than 70% were selected for further rescreening. Finally, six compounds with high inhibitory activity were identified, whose IC50 values were 21.58, 18.39, 15.37, 11.92, 37.27, and 36.61 microg x mL(-1), separately. The results indicated that the method was stable, sensitive, reproducible and also suitable for high-throughput screening.
Drug Evaluation, Preclinical ; methods ; Enzyme Inhibitors ; analysis ; pharmacology ; Escherichia coli ; metabolism ; High-Throughput Screening Assays ; methods ; Humans ; Inhibitory Concentration 50 ; Protein Tyrosine Phosphatase, Non-Receptor Type 1 ; antagonists & inhibitors ; metabolism ; Sensitivity and Specificity ; Vanadates ; pharmacology

An in vitro screening model was applied to test the inhibitory activities of 17 Salvia species on protein tyrosine phosphatase 1B (PTP1B). Root methanol extracts from wild-collected Salvia species were analyzed using this model. Most of the samples tested showed positive activities on human PTP1B. The inhibition rates of Salvia crude extracts varied from 9.76% to 100% at 30 microg x mL(-1), with the most convincing effects coming from Salvia evansiana and Salvia castanea. HPLC analysis revealed seven components shared by Salvia samples could be related to the inhibitory activities.
Chromatography, High Pressure Liquid ; Drugs, Chinese Herbal ; isolation & purification ; pharmacology ; Enzyme Inhibitors ; isolation & purification ; pharmacology ; Humans ; Plant Roots ; chemistry ; Plants, Medicinal ; chemistry ; Protein Tyrosine Phosphatase, Non-Receptor Type 1 ; antagonists & inhibitors ; Salvia ; chemistry ; classification