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With the aim of developing small molecular non-peptide β-secretase (BACE) inhibitors, Leu∗Ala hydroxyethylene (HE) was investigated as a scaffold to design and synthesize a series of compounds. Taking advantage of efficient combinatorial synthesis approaches and molecular modeling, extensive structure–activity relationship (SAR) studies were carried out on the N- and C-terminal residues of the Leu∗Ala HE scaffold. Isobutyl amine was found to be an optimal C-cap, and suitable hydroxylalkylamines at the 3-position and nitro or methyl(methylsulfonyl)amine at the 5-position of isophthalamide as the N-terminus could form additional hydrogen bonds with BACE active sites and help improve potency. Many new potent non-peptide BACE inhibitors were identified in this study. Among them, compounds 37 and 44 exhibited excellent enzyme-inhibiting potency, comparable to that of OM99-2, and obvious inhibitory effects in cell-based assay with low molecular weights (

A new sesquiterpenoid, O-methyl nakafuran-8 lactone (1) has been isolated from a Hainan sponge Dysidea sp. and the structure of the new compound proposed by spectral data, was confirmed by X-ray diffraction analysis. The complete 1H- and 13C-NMR assignments were made on the basis of detailed 2D NMR spectral analysis. Compound 1 showed strong inhibitory bioactivity against PTP1B with IC50 value of 1.58 microM.

Three new chalcones, xanthoangelols K-M (1-3), together with 19 known compounds were isolated from the stems of Angelica keiskei Koidzumi, a well-known rejuvenated and anti-diabetic plant originated from Japan. The structures of compounds 1-3 were elucidated on the basis of spectroscopic data and Mosher's method. All compounds were evaluated for their inhibitory activity against protein tyrosine phosphatase 1B (PTP1B). Among them, six chalcones, xanthoangelol K (1), xanthoangelol (4), xanthoangelol F (5), 4-hydroxyderricin (6), xanthoangelol D (7), xanthoangelol E (8), and a coumarin, methoxsalen (17), showed strong PTP1B inhibitory effect with IC50 values of 0.82, 1.97, 1.67, 2.47, 3.97, 1.43, and 2.53μg/mL, respectively. A kinetic study revealed that compound 1 inhibited PTP1B with characteristics typical of a competitive inhibitor. Molecular docking simulations elucidated that ring B of 1 may anchor in a pocket of PTP1B and the molecule is stabilized by hydrogen bonds with Arg47, Asp48, and π-π interaction with Phe182 of PTP1B.

A series of novel 4,2-bisheterocycle tandem derivatives consisting of a methyloxazole and thiazole subunit were synthesized. Many compounds were found to inhibit human influenza A virus. Several analogues exhibited moderate biological activity and could serve as leads for further optimizations for antivirus research.

(±)-Cryptotanshinone and its simplified analogues were synthesized via SmI2 promoted radical cyclization to construct the furan ring. Analogues 18 and 26 were identified as effective inhibitors of dual specificity protein phosphatase CDC25B which is a key enzyme for cell cycle progression, and they also inhibited growth in A-549 human lung cancer cell line.

Twenty one chromogenic thiopeptolide substrates were designed and synthesized as the active site probes and analyzed with each S1 site of mutant residues and enzymes of wild-type MetAP1s. The preliminary enzymatic experiments indicate that cysteine 70 or 202, at either Escherichia coli or human MetAP1, played a crucial role in the methionine hydrolysis.

Methionine aminopeptidase (MetAP) catalyzes the removal of methionine from newly synthesized polypeptides. MetAP carries out this cleavage with high precision, and Met is the only natural amino acid residue at the N terminus that is accepted, although type I and type II MetAPs use two different sets of residues to form the hydrophobic S1 site. Characteristics of the S1 binding pocket in type I MetAP were investigated by systematic mutation of each of the seven S1 residues in Escherichia coli MetAP type I (EcMetAP1) and human MetAP type I (HsMetAP1). We found that Tyr-65 and Trp-221 in EcMetAP1, as well as the corresponding residues Phe-197 and Trp-352 in HsMetAP1, were essential for the hydrolysis of a thiopeptolide substrate, Met-S-Gly-Phe. Mutation of Phe-191 to Ala in HsMetAP1 caused inactivity in contrast to the full activity of EcMetAP1(Y62A), which may suggest a subtle difference between the two type I enzymes. The more striking finding is that mutation of Cys-70 in EcMetAP1 or Cys-202 in HsMetAP1 opens up the S1 pocket. The thiopeptolides Leu-S-Gly-Phe and Phe-S-Gly-Phe, with previously unacceptable Leu or Phe as the N-terminal residue, became efficient substrates of EcMetAP1(C70A) and HsMetAP1(C202A). The relaxed specificity shown in these S1 site mutants for the N-terminal residues was confirmed by hydrolysis of peptide substrates and inhibition by reaction products. The structural features at the enzyme active site will be useful information for designing specific MetAP inhibitors for therapeutic applications.

The synthesis and MMP inhibitory activity of a series of tetrahydroisoquinoline based sulfonamide hydroxamates are described. In nine MMPs tested, most of the compounds display potent inhibition activity except for MMP-7. Some subtle isozyme selectivity is observed by varying the substituents at the 6- and 7-positions and aromatic ring of arylsulfonyl groups.

A series of pyridine-2-carboxylic acid derivatives were synthesized according to the leads from the screening, and potent inhibitors have been obtained by structural modification. They have shown submicromolar inhibition of the enzymes (for example, for 9n, IC(50) = 130 nM for EcMetAP1 and IC(50) = 380 nM for ScMetAP1). They represent small-molecule MetAP inhibitors with novel structures different from alkylating fumagillin derivatives and peptidic bestatin-based MetAP inhibitor.

PET fiber was preprocessed by means of microwave radiation. Different reaction parameters such as the time, the power and the Ph value of solution were optioned to study the degree of the fiber hydrolysis. The changes of mechanical performance and hygroscopicity of the fiber were analyzed, which showed that the best power of microwave radiation was the 250W, the best reaction time was 5 min, and the Ph value of solution was 9. Compared with the untreated fiber, the fracture strength of treated fiber is 1.686cN/dtex and the moisture regain is 0.58%. The morphology structure were characterized by SEM and the fracture strength were tested by filament electronic strength tester. The results showed that the surface of PET fibers became rough and the quantities of the -OH and -COOH functional groups on the surface increased after etching. Meanwhile the hygroscopicity of the treated fibers had been enhanced obviously and the fiber strength had been reduced.

Six new grayanane diterpenoids, principinols A–F (1–6), were isolated from Rhododendron principis. Compounds 1 and 2 possess unprecedented 6,10-epoxy and 5α-OH moieties, and 1 and 3 are the first two examples of 9α-H in grayanoids. Their structures were determined by extensive spectroscopic analysis, and the absolute configurations of 1–4 were assigned by single-crystal X-ray crystallography. Compounds 4 and 5 inhibit PTP1B phosphatase activity in vitro. A preliminary structure–activity relationship discussion is presented.

Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2–10 fold selectivity over a panel of PTP’s. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies.

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.

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. In the MTT assay, matrine suppressed growth of human lung cancer cell A549 in a dose- and time- dependent manner at doses of 0.25-2.5 mg/ml for 24h, 48h or 72h. Matrine induced cell cycle arrest in G0/G1 phase and decreased the G2/M phase, while down-regulating the expression of Bcl2 protein, leading to a reduction in the Bcl-2/Bax ratio. In addition, matrine down regulated the expression level of VEGF and HDAC1 of A549 cells. Microarray analysis demonstrated that matrine altered the expression level of miRNAs compared with untreated control A549 cells. In conclusion, matrine could inhibit proliferation of A549 cells, providing useful information for understanding anticancer mechanisms.

With the aim of discovering a novel class of non-phosphorus-based fructose-1,6-bisphosphatase (FBPase) inhibitors, a series of 2,5-diphenyl-1,3,4-oxadiazoles were synthesized based on the hit compound (1) resulting from a high-throughput screening (HTS). Structure-activity relationship (SAR) studies led to the identification of several compounds with comparable inhibitory activities to AMP, the natural allosteric inhibitor of FBPase. Notably, compound 22 and 27b, bearing a terminal carboxyl or 1H-tetrazole, demonstrated remarkable inhibition to gluconeogenesis (GNG). In addition, both inhibition and binding mode to the enzyme were investigated by enzymatic kinetics and in silico experiments for representative compounds 16 and 22.

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. Structure–activity relationship study showed that the amine derivatives at the 24-position (groups I–VI) can improve the potency (EC50: 0.7–2.3 μM) and efficacy (fold: 2.5–3.8). Among them, compounds 12 and 13 exhibited the best potency (EC50: 1.2 and 0.7 μM) and efficacy (fold: 3.7 and 3.8). Further study suggested the mechanism of AMPK activation may functioned at the allosteric position, resulting the inhibition of the lipid synthesis in HepG2 cell model.

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.From May, 2012 to June, 2013, 40 newborn infants with NA and another 40 neonates without lung disease were enrolled into this study.Lung ultrasound was performed at the bedside by a single expert physician.In a quiet state, the infants were positioned in supine, side or prone postures. The lung field was divided into three areas by the anterior auxilary and posterior auxilary line. The regions of the bilateral lungs were scanned by the probe which was vertical or parallel with the ribs, then compared the results with conventional chest X-ray findings.(1) The main ultrasound imaging features of neonatal NA include lung consolidation with air bronchograms, pleural line abnormalities and A-line disappearance. Besides, lung pulse and lung sliding disappearance could be seen by real-time ultrasound. (2) The sensitivity of lung ultrasound for diagnosis of NA was 100%, while it was only 70% for conventional chest X-rays.Use of ultrasound to diagnose NA is accurate and reliable, the sensitivity was superior to that of conventional chest X-ray examination, which also has many other advantages including easy-operating, non-ionizing, can be performed at the bedside, therefore, ultrasonic can provide important value for clinicians.

The synthesis and magnetic properties of have been investigated. The formation of is found to depend strongly on annealing temperature. Pure single-phase compound can be synthesized at ambient pressure when . The main phase of the Laves structure can still be observed up to x = 0.8. The study of crystalline parameters, magnetic moments and Mossbauer spectra for single-phase is performed. Curie temperature and local Fe magnetic moment increase with the increasing Pr concentration. Extrapolating the trends the spontaneous magnetization and anisotropy constant of are 4.98 and at 1.5 K, respectively. Magnetostriction increases with increasing x and the largest saturation magnetostriction, 200 ppm, is observed for x = 0.5. With the increase of Pr concentration, lattice parameter and spontaneous magnetization anomalies exist in a specific range 0.2 < x < 0.5 that can be attributed to the change of Ce ion valence toward tetravalent.

The synthesis and matrix metalloproteinase (MMP) inhibitory activity of a series of gamma-keto carboxylic acids are described. Among nine MMP isozymes tested, compound 1j displays selective inhibition of MMP-2, -9, and -12 with IC(50) values between 0.20 and 1.51 microuM, and in male golden Syrian hamsters, it shows protection against PPE-induced emphysema.

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 Q o 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. Results Acute administration of AZOX in mice increased the respiratory exchange ratio. Chronic treatment with AZOX reduced body weight and significantly improved glucose tolerance and insulin sensitivity in high-fat diet-fed mice. AZOX treatment resulted in decreased triacylglycerol accumulation and down-regulated the expression of genes involved in liver lipogenesis. AZOX increased glucose uptake in L6 myotubes and 3T3-L1 adipocytes and inhibited de novo lipogenesis in HepG2 cells. The findings indicate that AZOX-mediated alterations to lipid and glucose metabolism may depend on AMP-activated protein kinase (AMPK) signaling. Conclusions AZOX, a Q o inhibitor of mitochondrial respiratory complex III, exerts whole-body beneficial effects on the regulation of glucose and lipid homeostasis in high-fat diet-fed mice. General significance These findings provide evidence that a Q o inhibitor of mitochondrial respiratory complex III could represent a novel approach for the treatment of obesity.

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 = 0.004-113.6 μM). Moreover, compounds 6h (IC50 = 0.004 μM) and 6n (IC50 = 0.01 μM) showed excellent inhibitory activities against DPP4, good selectivity (compound 6h, selective ratio: DPP8/DPP4 = 450.0; DPP9/DPP4 = 375.0; compound 6n, selective ratio: DPP8/DPP4 = 470.0; DPP9/DPP4 = 750.0) and good efficacy in an oral glucose tolerance test in ICR mice. Furthermore, compounds 6h and 6n demonstrated moderate PK properties (compound 6h, F% = 37.8%, t1/2 = 1.45 h; compound 6n, F% = 16.8%, t1/2 = 3.64 h).

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. Hepatocyte-specific abrogation of Ire1α results in impairment of fatty acid β-oxidation and ketogenesis in the liver under chronic fasting or ketogenic conditions, leading to hepatosteatosis; liver-specific restoration of XBP1s reverses the defects in IRE1α null mice. XBP1s directly binds to and activates the promoter of PPARα, the master regulator of starvation responses. Hence, our results demonstrate that hepatic IRE1α promotes the adaptive shift of fuel utilization during starvation by stimulating mitochondrial β-oxidation and ketogenesis through the XBP1s-PPARα axis.

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 4.54 μM.

To date, epidemiological studies have assessed the association between Toll-like receptor 2 (TLR2) gene polymorphisms and cancer risk. However, the results of these studies remain controversial. We aimed to examine the associations between three SNPs (Delta22, rs3804099 and rs3804100) of TLR2 gene and cancer risk by conducting a meta-analysis of case-control studies. A total of eight studies eligible for TLR2 Delta22 polymorphism (2,061 cancer cases and 3,490 controls), six studies for rs3804099 polymorphism (1,681 cases and 1,996 controls), and five studies for rs3804100 polymorphism (3,131 cases and 2,969 controls) were included in this meta-analysis. Our results suggested that Delta22 represented a risk factor on cancers (del-allele versus ins-allele, OR=1.35, 95% CI: 1.05-1.72; del/del versus ins/ins, OR=1.91, 95% CI: 1.03-3.56; del/del + del/ins versus ins/ins, OR=1.33, 95% CI: 1.02-1.73; del/del versus del/ins + ins/ins, OR=1.79, 95% CI: 1.02-3.13), especially in Caucasian population and among population-based studies. For TLR2 rs3804099 polymorphism, we found a decreased cancer risk associated with CC/CT genotype only in Asians compared with TT genotype. TLR2 rs3804100 polymorphism was significantly associated with an elevated cancer risk in overall analysis (CC versus CT, OR=1.70, 95% CI: 1.20-2.42; CC versus CT/TT, OR=1.61, 95% CI: 1.15-2.25). In a stratified analysis, a statistically significant correlation was also observed in non-Caucasian population and population-based studies. In conclusion, the Delta22 and rs3804100 polymorphisms in TLR2 are risk factors for cancer susceptibility while the TLR2 rs3804099 dominant genotype is a protective factor, especially in Asians. Further large and well-designed studies are needed to confirm these conclusions.

Decreasing mitochondrial coupling efficiency has been shown to be an effective therapy for obesity and related metabolic symptoms. Here we identified a novel mitochondrial uncoupler that promoted uncoupled respiration in a cell type-specific manner and investigated its effects on modulation of energy metabolism in vivo and in vitro.We screened a collection of mitochondrial membrane potential depolarising compounds for a novel chemical uncoupler on isolated skeletal muscle mitochondria using a channel oxygen system. The effect on respiration of metabolic cells (L6 myotubes, 3T3-L1 adipocytes and rat primary hepatocytes) was examined and metabolic pathways sensitive to cellular ATP content were also evaluated. The chronic metabolic effects were investigated in high-fat diet-induced obese mice and standard diet-fed (SD) lean mice.The novel uncoupler, CZ5, promoted uncoupled respiration in a cell type-specific manner. It stimulated fuel oxidation in L6 myotubes and reduced lipid accumulation in 3T3-L1 adipocytes but did not affect gluconeogenesis or the triacylglycerol content in hepatocytes. The administration of CZ5 to SD mice increased energy expenditure (EE) but did not affect body weight or adiposity. Chronic studies in mice on high-fat diet showed that CZ5 reduced body weight and improved glucose and lipid metabolism via both increased EE and suppressed energy intake. The reduced adiposity was associated with the restoration of expression of key metabolic genes in visceral adipose tissue.This work demonstrates that a cell type-specific mitochondrial chemical uncoupler may have therapeutic potential for treating high-fat diet-induced metabolic diseases.

Compound (Ia) is discovered as a potential FBPase inhibitor by high-throughput screening of a library of 56,000 lead-like compounds.

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. ZLN024 activated AMPK in L6 myotubes and stimulated glucose uptake and fatty acid oxidation without increasing the ADP/ATP ratio. ZLN024 also activated AMPK in primary hepatocytes, decreased fatty acid synthesis and glucose output. Treatment of db/db mice with 15 mg/kg/day ZLN024 improved glucose tolerance; liver tissue weight, triacylglycerol and the total cholesterol content were decreased. The hepatic transcriptional level of G6Pase, FAS and mtGPAT were reduced. The transcription of genes involved in fatty acid oxidation and the mitochondrial biogenesis of muscle tissue were elevated. The ACC phosphorylation was increased in muscle and liver. This study provides a novel allosteric AMPK activator for functional study in vitro and in vivo and demonstrates that AMPK allosteric activators could be a promising therapeutic approach for type 2 diabetes mellitus and metabolic syndrome.

Diacylglycerol acyltransferase (DGAT), the only limited enzyme in the synthesis of triacylglyc- erol (TAG), is regarded as an important therapeutic target for human obesity and other metabolic syndromes. Compounds 5-8 were designed and synthesized, which the lactone group of aphadilactone C was introduced into the PF-04620110 and AZD-7687, which have entered into the clinical research, and to verify whether the lactone in aphadilactone C played the same role as carboxylic group in PF-04620110 and AZD-7687. The final vitro assay showed that compounds 5-8 no longer have the inhibition activity to DGAT1. This might suggest that inhibition mechanism of aphadilactone C was not the same as PF-04620110 and AZD-7687 and need further study. Keywords aphadilactone C,DGAT1,selective inhibitor,PF-04620110,AZD-7687

The title derivatives are obtained by reaction of aminobenzoic acid with formamide/isothiocyanate or by reaction of 4-substituted aminobenzoic acid derivatives (I) with phenyl isothiocyanate (II), followed by further derivatization.

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. The catalyst for the second dataset was (-)-diisopinocampheylchloroborane. The structure-enantioselectivity relationship models were constructed using random forests with the chiral substituent code as the input. The resulting models were assessed both in terms of single enantiomers and pairs of enantiomers. Satisfactory results were obtained for both datasets. Although the chiral substituent code was specifically developed for secondary alcohols, it can easily be extended to represent chiral compounds possessing a specific chiral center bonded to two variable substituents. (c) 2013 Elsevier Inc. All rights reserved.

A series of novel oleanolic acid derivatives with five-membered heterocyclic rings, fused at the C-2, C-3 positions, e.g. (II) and (V), as well some C-ring modified derivatives, e.g. (I), (III) and (IV), is synthesized.

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.

The introduction of the multi-objective optimization has dramatically changed the virtual combinatorial library design, which can consider many objectives simultaneously, such as synthesis cost and drug-likeness, thus may increase positive rates of biological active compounds. Here we described a software called CCLab (Combinatorial Chemistry Laboratory) for combinatorial library design based on the multi-objective genetic algorithm. Tests of the convergence ability and the ratio to re-take the building blocks in the reference library were conducted to assess the software in silico, and then it was applied to a real case of designing a 5 × 6 HDAC inhibitor library. Sixteen compounds in the resulted library were synthesized, and the histone deactetylase (HDAC) enzymatic assays proved that 14 compounds showed inhibitory ratios more than 50% against tested 3 HDAC enzymes at concentration of 20 μg/mL, with IC50 values of 3 compounds comparable to SAHA. These results demonstrated that the CCLab software could enhance the hit rates of the designed library and would be beneficial for medicinal chemists to design focused library in drug development (the software can be downloaded at: http://202.127.30.184:8080/drugdesign.html ).

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is the major clinical impediment to chemotherapy of breast cancers. Down-regulation of PI3K/Akt pathway has been described as related to reversal of MDR in cancer cells. Here, we investigated the reversal effect on MDR phenotype of perifosine, a new Akt inhibitor, in breast cancer cell lines. In this study, MCF-7/ADM cells and MCF-7 cells were treated with different concentrations of perifosine. Our results suggested that perifosine reversed MDR partially by downregulation of P-gp expression and inhibition of PI3K/Akt/NF-κB pathway in the MCF-7/ADM cell line. The novel Akt inhibitor perifosine may be a promising new drug due to its ability to reverse MDR in human breast cancer cells.

Secreted Frizzled-related protein 1 (sFRP1), as one of most important Wnt antagonists, is frequently silenced by promoter hypermethylation in many types of tumor, including hepatocellular carcinoma (HCC). In this study, we aimed to investigate whether restoration of sFRP1 affected HCC metastatic behavior. sFRP1 mRNA expression and promoter methylation in HCC tissues and cell lines were examined using RT-PCR and methylation-specific PCR (MS-PCR), respectively. sFRP1 protein expression was assessed by Western Blot. We generated stable HCC cell line restoration of sFRP1 in HepG2 cells, which naturally do not express detectable sFRP1 mRNA. The effects of exogenous sFRP1 on HepG2 cell invasion were investigated using trans-well assay. Also the effects of sFRP1 re-expression on the β-catenin/T-cell factor-dependent transcription activity was measured by luciferase assay.sFRP1 promoter methylation was frequently observed in HCC tissues (60%) and cell lines (75%). All samples with sFRP1 methylation showed down-regulation of sFRP1 expression in HCC cell lines. Demethylation treatment with 5-aza-20-deoxycytidine in HCC cells restored sFRP1 expression. Restoration of sFRP1 substantially impaired the invasive potentials of HepG2 cells. Moreover, exogenous sFRP1 caused significant decrease of β-catenin/T-cell factor-dependent transcription activity.These findings demonstrate that sFRP1 silencing due to promoter hypermethylation is a major event during tumorigenesis. sFRP1 is also a negative modulator of canonical Wnt signaling, which could contribute to metastasis in HCC progression, thus providing a possible therapeutic strategy against HCC.

Two new isoprenylated flavanones, ficustikousins A and B (1 and 2), together with seven known compounds (3–9) were isolated from the whole plant of Ficus tikoua (Moraceae). The structures of the new compounds were elucidated on the basis of spectroscopic methods. Compounds 1–7 exhibited moderate inhibitory activities against PTP1B in vitro.

Protein tyrosine phosphatases PTP-sigma (PTPσ) plays an important role in the development of the nervous system and nerve regeneration. Although cumulative studies about the function of PTPσ have been reported, yet limited data have been reported about the crystal structure and in vitro activity of mouse PTPσ. Here we report the crystal structure of mouse PTPσ tandem phosphatase domains at 2.4 A resolution. Then we compared the crystal structure of mouse PTPσ with human PTPσ and found that they are very similar, superimposing with a root mean square deviation of 0.45 A for 517 equivalent Cα atoms. But some residues in mouse PTPσ form loops while corresponding residues in human PTPσ form β-sheets or α-helices. Furthermore, we also compared in vitro activities of mouse PTPσ with human PTPσ and found that mouse PTPσ has 25-fold higher specific activity than human PTPσ does toward O-methyl fluorescein phosphate (OMFP) as the substrate. However, there is no significant activity difference between the mouse and the human enzyme detected with p-nitrophenylphosphate (pNPP) as the substrate. Mouse PTPσ and human PTPσ have different substrate specificities toward OMFP and pNPP as substrates. This work gives clues for further study of PTPσ.

Respiratory distress syndrome (RDS) is one of the most common causes of neonatal respiratory failure and neonatal death, however, its clinical characteristics are very different from premature RDS, and these characteristics have not been well documented as yet. This study was to investigate the pathogenesis, clinical characteristics and management strategies of RDS in full-term neonates, with the aim of developing a working protocol for improving the outcome in full-term neonates with RDS.A total of 125 full-term infants with RDS were enrolled in this study. Their clinical and laboratory data were collected for analyzing the characteristics of full-term neonatal RDS.(1) The 125 cases included 94 male and 31 female infants, vaginal delivery occurred in 80 cases and cesarean section in 45 cases. (2) The onset time of RDS was (3.11 ± 3.59) hours after birth. (3) The possible reasons included severe perinatal infections in 63 patients, elective cesarean section in 34 cases, severe birth asphyxia in 12 patients, meconium aspiration syndrome in 9 patients, pulmonary hemorrhage in 4 patients and maternal diabetes in 3 patients. (4) Complications included multiple organ system failure (MOSF) in 49 patients, persistent pulmonary hypertension of newborn (PPHN) in 25 patients, acute renal failure in 18 patients, severe hyperkalemia in 25 patients, severe metabolic acidosis in 6 cases, severe myocardial injury in 9 cases, pulmonary hemorrhage in 3 cases, disseminated intravascular coagulation in 14 patients and shock in 12 patients. (5) Four patients died, the mortality was therefore 3.2% with the main cause of septicemia complicating of MOSF, but their prognosis was improved while comprehensive treatment measures including early mechanical ventilation and broad spectrum antibiotics were taken into account.RDS is not an uncommon disease in full-term infants and is associated with a higher mortality, its clinical characteristics are very different from premature RDS, and its onset is earlier and is more likely to develop into PPHN and/or MOSF. The main cause of death is severe infection complicating of MOSF and most patients require prolonged mechanical ventilation. Comprehensive management strategies will help to improve patient's prognosis.

To discover and optimize a series of novel PTP1B inhibitors containing a thiazolidinone-substituted biphenyl scaffold and to further evaluate the inhibitory effects of these compounds in vitro and in vivo.A total of 36 thiazolidinone substituted biphenyl scaffold derivatives were prepared. An in vitro biological evaluation was done by Enzyme-based assay. The in vivo efficacy of 7Fb as an antihyperglycemic agent was evaluated in a BKS db/db diabetic mouse model with a dose of 50 mg.kg(-1).d(-1) for 4 weeks.The in vitro biological evaluation showed that compounds 7Fb and 7Fc could increase the insulin-induced tyrosine phosphorylation of IRbeta in CHO/hIR cells. In in vivo experiments, compound 7Fb significantly lowered the postprandial blood glucose, from 29.4+/-1.2 mmol/L with the vehicle to 24.7+/-0.6 mmol/L (P0.01), and the fasting blood glucose from 27.3+/-1.5 mmol/L with the vehicle to 23.6+/-1.2 mmol/L (P0.05).A novel series of compounds were discovered to be PTP1B inhibitors. Among them, compound 7Fb significantly lowered the postprandial and fasting glucose levels, and the blood glucose level declined more rapidly than in metformin-treated mice. Thus, 7Fb may be a potential lead compound for developing new agents for the treatment of type II diabetes.

In the title mononuclear salen-type complex, [Eu(NO(3))(3)(C(22)H(26)N(2)O(4))]·CH(3)OH, the Eu(III) ion is ten-coordinated by three bidentate nitrate counter-ions and one organic salen-type ligand, which acts in a bis-bidentate chelating mode through its phenolate and meth-oxy O atoms. The protonated imine groups are involved in intra-molecular N-H⋯O hydrogen bonds to the phenolate O atomss, emphasizing the zwitterionic nature of the ligand. An O-H⋯O hydrogen bond links the complex and solvent mol-ecules.

Coordinated multi-point (CoMP) joint transmission is considered in the 3rd generation partnership project (3GPP) long term evolution (LTE)-advanced as a key technique to mitigate inter-cell interference and improve the cell-edge performance. To effectively apply CoMP joint transmission, efficient frequency reuse schemes need to be designed to support resource management cooperation among coordinated cells. However, most of the existing frequency reuse schemes are not suitable for CoMP systems due to not considering multi-point joint transmission scenarios in their frequency reuse rules. In addition, the restrictions of frequency resources in those schemes result in a high blocking probability. To solve the above two problems, a multi-beam cooperative frequency reuse (MBCFR) scheme is proposed in this paper, which reuses all the available frequency resources in each sector and supports multi-beam joint transmission for cell-edge users. Besides, the blocking probability is proved to be efficiently reduced. Moreover, a frequency-segment-sequence based MBCFR scheme is introduced to further reduce the inter-cell interference. System level simulations demonstrate that the proposed scheme results in higher cell-edge average throughput and cell-average throughput with lower blocking probability.

To explore the molecular mechanism of the matrix metalloproteinases (MMPs) in tumor processes, two photoaffinity trimodular probes were designed and synthesized based on the structure activity relationship and the following photoaffinity labelling experiments afforded positive results.

To discover novel cell division cycle 25 (CDC25) B inhibitors and elucidate the mechanisms of inhibition in cancer cells.Cell growth inhibition was detected by MTT assay, the cell cycle was analyzed by flow cytometry, and protein expression and phosphorylation was examined by Western blot analysis.LGH00031 inhibited CDC25B irreversibly in vitro in a dose-dependent manner, and impaired the proliferation of tumor cell lines. In synchronized HeLa cells, LGH00031 delayed the cell cycle progression at the G(2)/M phase. LGH00031 increased cyclin-dependent kinase 1 (CDK1) tyrosine 15 phosphorylation and cyclin B1 protein level. The activity of LGH00031 against CDC25B in vitro relied on the existence of 1,4-dithiothreitol (DTT) or dihydrolipoic acid and oxygen. The oxygen free radical scavenger catalase and superoxide dismutase reduced the inactivation of CDC25 by LGH00031, confirming that reactive oxygen species (ROS) mediate the inactivation process in vitro. LGH00031 accelerated cellular ROS production in a dose-dependent manner, and N-acetyl cysteine (NAC) markedly decreased the ROS production induced by LGH00031. Correspondingly, the LGH00031-induced decrease in cell viability and cell cycle arrest, cyclin B1 protein level, and phosphorylation of CDK1 tyrosine 15 were also rescued by NAC that decreased ROS production.The activity of LGH00031 at the molecular and cellular level is mediated by ROS.

Protein tyrosine phosphatase 1B (PTP1B) is a key factor in negative regulation of the insulin pathway, and is a promising target for the treatment of type-II diabetes, obesity and cancer. Herein, compound (4) was first observed to have moderate inhibitory activity against PTP1B with an IC50 value of 13.72 ± 1.53 µM. To obtain more potent PTP1B inhibitors, we synthesized a series of chalcone derivatives using compound (4) as the lead compound. Compound 4l (IC50 = 3.12 ± 0.18 µM) was 4.4-fold more potent than the lead compound 4 (IC50 = 13.72 ± 1.53 µM), and more potent than the positive control, ursolic acid (IC50 = 3.40 ± 0.21 µM). These results may help to provide suitable drug-like lead compounds for the design of inhibitors of PTP1B as well as other PTPs.

To explore novel effective drugs for the treatment of Alzheimer’s disease (AD), a series of dual inhibitors of acetylcholineterase (AChE) and β-secretase (BACE-1) were designed based on the multi-target-directed ligands strategy. Among them, inhibitor 28 exhibited good dual potency in enzyme inhibitory potency assay (BACE-1: IC 50 = 0.567 μM; AChE: IC 50 = 1.83 μM), and also showed excellent inhibitory effects on Aβ production of APP transfected HEK293 cells (IC 50 = 98.7 nM) and mild protective effect against hydrogen peroxide (H 2 O 2 )-induced PC12 cell injury. Encouragingly, intracerebroventricular injection of 28 into amyloid precursor protein (APP) transgenic mice caused a 29% reduction of Aβ 1–40 production. Therefore, 28 was demonstrated as a good lead compound for the further study and more importantly, the strategy of AChE and BACE-1 dual inhibitors might be a promising direction for developing novel drugs for AD patients.