Design and synthesis of paracaseolide A analogues as selective protein tyrosine phosphatase 1B inhibitors.

A series of structurally related analogues of the natural product paracaseolide A were synthesized and identified as potent PTP1B inhibitors. Among these analogues, compound 10 in particular showed improved PTP1B enzyme inhibitory activity, high selectivity for PTP1B over TC-PTP, and improved cellular effects.

Discovery, synthesis, and structure-activity relationships of 20(S)-protopanaxadiol (PPD) derivatives as a novel class of AMPKα2β1γ1 activators.

Adenosine 5'-monophosphate-activated protein kinase (AMPK) has been demonstrated as a promising drug target due to its regulatory function in glucose and lipid metabolism. 20(S)-protopanoxadiol (PPD) was firstly identified from high throughput screening as a small molecule activator of AMPK subtype α2β1γ1. In order to enhance its potency on AMPK, a series of PPD derivatives were synthesized and evaluated.

Azoxystrobin, a mitochondrial complex III Qo site inhibitor, exerts beneficial metabolic effects in vivo and in vitro.

Background: Several anti-diabetes drugs exert beneficial effects against metabolic syndrome by inhibiting mitochondrial function. Although much progress has been made toward understanding the role of mitochondrial function inhibitors in treating metabolic diseases, the potential effects of these inhibitors on mitochondrial respiratory chain complex III remain unclear.

Methods: We investigated the metabolic effects of azoxystrobin (AZOX), a Qo inhibitor of complex III, in a high-fat diet-fed mouse model with insulin resistance in order to elucidate the mechanism by which AZOX improves glucose and lipid metabolism at the metabolic cellular level.

Matrine reduces proliferation of human lung cancer cells by inducing apoptosis and changing miRNA expression profiles.

Matrine, a main active component extracted from dry roots of Sophora flavecens , has been reported to exert antitumor effects on A549 human non-small lung cancer cells, but its mechanisms of action remain unclear. To determine effects of matrine on proliferation of A549 cells and assess possible mechanisms, MTT assays were employed to detect cytotoxicity, along with o flow cytometric analysis of DNA content of nuclei of cells following staining with propidium iodide to analyze cell cycle distribution. Western blotting was performed to determined expression levels of Bax, Bcl-2, VEGF and HDAC1, while a microarray was used to assessed changes of miRNA profiles.

Synthesis and biological evaluation of novel bis-aromatic amides as novel PTP1B inhibitors.

A series of bis-aromatic amides was designed, synthesized, and evaluated as a new class of inhibitors with IC50 values in the micromolar range against protein tyrosine phosphatase 1B (PTP1B). Among them, compound 15 displayed an IC50 value of 2.34±0.

Discovery of a novel inhibitor of NAD(P)(+)-dependent malic enzyme (ME2) by high-throughput screening.

Aim: Malic enzymes are oxidative decarboxylases with NAD(+) or NAD(P)(+) as cofactor that catalyze the conversion of L-malate to pyruvate and CO2. The aim of this study was to discover and characterize a potent inhibitor of human NAD(P)(+)-dependent malic enzyme 2 (ME2).

Methods: Recombinant human ME2-His-Tag fusion protein was overexpressed in E coli and purified with Ni-NTA resin.

Hepatic IRE1α regulates fasting-induced metabolic adaptive programs through the XBP1s-PPARα axis signalling.

Although the mammalian IRE1α-XBP1 branch of the cellular unfolded protein response has been implicated in glucose and lipid metabolism, the exact metabolic role of IRE1α signalling in vivo remains poorly understood. Here we show that hepatic IRE1α functions as a nutrient sensor that regulates the metabolic adaptation to fasting. We find that prolonged deprivation of food or consumption of a ketogenic diet activates the IRE1α-XBP1 pathway in mouse livers.

Preparation of tert-butyl esters via Pd-catalyzed tert-butoxycarbonylation of (hetero)aryl boronic acid derivatives.

A novel protocol to synthesize tert-butyl esters from boronic acids or boronic acid pinacol esters and di-t-butyl dicarbonate has been successfully achieved. The cross-coupling reactions can produce up to 94% yields by using palladium acetate and triphenylphosphine as catalyst system, dioxane as a solvent. Moreover, a wide range of substrates including benzenes, pyridines, and quinolines boronic acids or boronic acid pinacol esters can fit with this system as well.

Design, synthesis and biological evaluation of hetero-aromatic moieties substituted pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors.

A series of novel hetero-aromatic moieties substituted α-amino pyrrole-2-carbonitrile derivatives was designed and synthesized based on structure-activity relationships (SARs) of pyrrole-2-carbonitrile inhibitors. All compounds demonstrated good dipeptidyl peptidase IV (DPP4) inhibitory activities (IC50 = 0.004-113.

1H-2,3-dihydroperimidine derivatives: a new class of potent protein tyrosine phosphatase 1B inhibitors.

A series of 1H-2,3-dihydroperimidine derivatives was designed, synthesized, and evaluated as a new class of inhibitors of protein tyrosine phosphatase 1B (PTP1B) with IC50 values in the micromolar range. Compounds 46 and 49 showed submicromolar inhibitory activity against PTP1B, and good selectivity (3.48-fold and 2.

[Lung ultrasound for diagnosis of neonatal atelectasis].

Objective: The diagnosis of neonatal atelectasis (NA) is usually based on clinical manifestations and chest X-rays, lung ultrasounds are not included in the diagnostic work-up of NA.Recently, ultrasounds have been used extensively and successfully in the diagnosis of many kinds of lung diseases, but few studies have addressed NA. The aim of this study was to evaluate the ultrasound imaging features of NA-and to evaluate the value of lung ultrasound in diagnosing NA.

Identification of wood between Phoebe zhennan and Machilus pingii using the gas chromatography-mass spectrometry direct injection technique.

In this paper, the technique of direct injection gas chromatography-mass spectrometer (GC-MS) was employed to discriminate between two batches of wood (Phoebe zhennan and Machilus pingii) with characteristic smells. Based on the GC-MS fingerprints obtained, similarities between samples were evaluated via correlation coefficient, hierarchical clustering and characteristic constituents analysis. The results showed that distinct differences in total ion chromatograms existed between the two species of wood and their correlation coefficients were low; however, the relationship between the same species of different batches showed the opposite; meanwhile, the analysis of hierarchical clustering and characteristic constituents also demonstrated an interrelationship.

Facile synthesis of trifluoroethyl compounds by the Suzuki cross-coupling reactions of CF3CH2OTs with arylboronic acids.

This research provides a novel approach for introducing a CF3CH2 group onto aromatic rings using Pd(OAc)2/palladacycle as a catalyst for the Suzuki cross-coupling reaction of CF3CH2OTs (OTs = 4-methylbenzene sulfonate) with arylboronic acids.

Design, synthesis, and biological evaluation of novel 2-ethyl-5-phenylthiazole-4-carboxamide derivatives as protein tyrosine phosphatase 1B inhibitors with improved cellular efficacy.

Protein tyrosine phosphatase 1B (PTP1B) is implicated as a key negative regulator of the insulin and leptin signal-transduction pathways. PTP1B inhibitors have emerged as attractive and potent pharmaceutical agents for the treatment of type 2 diabetes and obesity. We identified a series of 2-ethyl-5-phenylthiazole-4-carboxamide (PTA) derivatives, inspired from the ACT scaffold of Scleritodermin A, as a novel class of PTP1B inhibitors.

Novel small-molecule AMPK activator orally exerts beneficial effects on diabetic db/db mice.

AMP-activated protein kinase (AMPK), which is a pivotal guardian of whole-body energy metabolism, has become an attractive therapeutic target for metabolic syndrome. Previously, using a homogeneous scintillation proximity assay, we identified the small-molecule AMPK activator C24 from an optimization based on the original allosteric activator PT1. In this paper, the AMPK activation mechanism of C24 and its potential beneficial effects on glucose and lipid metabolism on db/db mice were investigated.

Novel small-molecule AMP-activated protein kinase allosteric activator with beneficial effects in db/db mice.

AMP-activated protein kinase (AMPK) is an energy sensor of metabolism that is an attractive therapeutic target for type 2 diabetes mellitus and metabolic syndrome. Using a homogeneous scintillation proximity assay (SPA), we identified a new small-molecule AMPK activator, ZLN024, which allosterically stimulated active AMPK heterotrimers and the inactive α1 subunit truncations α1 (1-394) and α1 (1-335) but not α1 (1-312). AMPK activation by ZLN024 requires the pre-phosphorylation of Thr-172 by at least one upstream kinase and protects AMPK Thr-172 against dephosphorylation by PP2Cα.

The first synthesis of natural disulfide bruguiesulfurol and biological evaluation of its derivatives as a novel scaffold for PTP1B inhibitors.

Bruguiesulfurol (1), a cyclic 4-hydroxy-dithiosulfonate isolated from mangrove plant Bruguiera gymnorrhiza, was concisely synthesized for the first time in four steps, and a series of its synthetic derivatives were evaluated for in vitro inhibitory effects on PTP1B and related PTPs. Some derivatives were found to have improved pharmacological profile compared with hit 1. Among them, 5a showed the potent selectivity towards PTP1B over other PTPs, including TCPTP, and 7j exhibited the strongest PTP1B inhibitory activity with an IC50 value of 4.

Design and synthesis of 4-(2,4,5-trifluorophenyl)butane-1,3-diamines as dipeptidyl peptidase IV inhibitors.

The worldwide prevalence of diabetes has spurred numerous studies on the development of new antidiabetic medicines. As a result, dipeptidyl peptidase IV (DPP4) has been recognized as a validated target. In our efforts to discover new DPP4 inhibitors, we analyzed the complexed structures of DPP4 available in Protein Data Bank and designed a series of triazole compounds.

The derivation of a chiral substituent code for secondary alcohols and its application to the prediction of enantioselectivity.

A chiral substituent code was proposed based on the features of secondary alcohols, in which a chiral center is attached to two substituents in addition to OH and H substituents. The new chirality code, which was generated by predefining positional information of four substituents attached to stereocenter, was applied to two datasets composed of secondary alcohols as the enantioselective products of asymmetric reactions. In the first dataset, the chemical reaction was catalyzed by a biocatalyst, lipase from Candida rugosa.

HPN, a synthetic analogue of bromophenol from red alga Rhodomela confervoides: synthesis and anti-diabetic effects in C57BL/KsJ-db/db mice.

3,4-Dibromo-5-(2-bromo-3,4-dihydroxy-6-(isopropoxymethyl)benzyl)benzene-1,2-diol (HPN) is a synthetic analogue of 3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(ethoxymethyl)benzyl)benzene-1,2-diol (BPN), which is isolated from marine red alga Rhodomela confervoides with potent protein tyrosine phosphatase 1B (PTP1B) inhibition (IC(50) = 0.84 μmol/L). The in vitro assay showed that HPN exhibited enhanced inhibitory activity against PTP1B with IC(50) 0.

Novel small-molecule PGC-1α transcriptional regulator with beneficial effects on diabetic db/db mice.

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) has been shown to influence energy metabolism. Hence, we explored a strategy to target PGC-1α expression to treat metabolic syndromes. We developed a high-throughput screening assay that uses the human PGC-1α promoter to drive expression of luciferase.

Synthesis and antiviral activity of conformational analogues of leucamide A.

In order to study the effect of heterocyclic core conformational state of leucamide A on its anti-influenza virus A activity, five conformational analogues were prepared by replacing the Pro-Leu dipeptide in the molecule with various amino acids. The amino acids used were of 2 to 6 carbons. The results showed that these replacements not only changed the conformational relationship between the 4,2-bisheterocycle tandem pair and the third heterocycle, but also had dramatic effect on its activity against influenza virus A.

Arylation of 2-substituted pyridines via Pd-catalyzed decarboxylative cross-coupling reactions of 2-picolinic acid.

The novel palladium-catalyzed decarboxylative cross-coupling reactions of 2-picolinic acid with aryl and heteroaryl bromides including benzenes, naphthalenes, pyridines and quinolines for C-C bond formation have been successfully achieved.

Discovery of di-indolinone as a novel scaffold for protein tyrosine phosphatase 1B inhibitors.

A series of di-indolinone derivatives was designed and synthesized to optimize our lead compounds basing on molecular docking study as PTP1B inhibitors. Successive enzymatic assay identified the synthetic di-indolinone as novel PTP1B inhibitors with low micromole-ranged inhibitory activity and at least several-fold selectivity over other tested homologous PTPs.

Synthesis and biological evaluation of 4,4-dimethyl lithocholic acid derivatives as novel inhibitors of protein tyrosine phosphatase 1B.

Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of both insulin and leptin signals. For years, inhibiting of PTP1B has been considered to be a potential therapeutics for treating Type 2 diabetes and obesity. Recently, we recognized lithocholic acid (LCA) as a natural inhibitor against PTP1B (IC(50)=12.