Calix[4]arene Bridge Mononitration with tert-Butyl Nitrite: Synthesis of Bridging Chiral p-tert-Butylcalix[4]arene with a Mononitro Bridge Substituent.

To explore the reaction universality of bridge nitration, the mononitration of different p-tert-butylcalix[4]arene derivatives was executed with tert-butyl nitrite as a nitration reagent. The effects of calix[4]arene conformations, substituents on the lower rim, and reaction conditions on bridge mononitration are systematically studied. The bridge nitration of p-tert-butylcalix[4]arene derivatives in 1,3-alternate, 1,2-alternate, and partial cone conformations can be smoothly executed while that of p-tert-butylcalix[4]arene derivatives strictly regulated in a cone conformation cannot. The nitration product complexity shows a positive correlation with the bridge-hydrogen types, and the optimal bridge-mononitrated substrate is calix[4]arene with only one bridge-hydrogen type. The electron-withdrawing substituent on the lower rim is apparently beneficial for the bridge mononitration. As a result, a variety of bridging chiral p-tert-butylcalix[4]arenes with a mononitro bridge substituent have been successfully synthesized. The highest bridge-mononitrated yield can reach 27% from 1,3-alternate p-tert-butylcalix[4]arene biscrown-5 under optimal reaction conditions.

Characterization of the complete mitochondrial genome of Marshallagia marshalli and phylogenetic implications for the superfamily Trichostrongyloidea.

Marshallagia marshalli (Nematoda: Trichostrongylidae) infection can lead to serious parasitic gastroenteritis in sheep, goat, and wild ruminant, causing significant socioeconomic losses worldwide. Up to now, the study concerning the molecular biology of M. marshalli is limited. Herein, we sequenced the complete mitochondrial (mt) genome of M. marshalli and examined its phylogenetic relationship with selected members of the superfamily Trichostrongyloidea using Bayesian inference (BI) based on concatenated mt amino acid sequence datasets. The complete mt genome sequence of M. marshalli is 13,891 bp, including 12 protein-coding genes, 22 transfer RNA genes, and 2 ribosomal RNA genes. All protein-coding genes are transcribed in the same direction. Phylogenetic analyses based on concatenated amino acid sequences of the 12 protein-coding genes supported the monophylies of the families Haemonchidae, Molineidae, and Dictyocaulidae with strong statistical support, but rejected the monophyly of the family Trichostrongylidae. The determination of the complete mt genome sequence of M. marshalli provides novel genetic markers for studying the systematics, population genetics, and molecular epidemiology of M. marshalli and its congeners.

WITHDRAWN: WSTF Phosphorylation Specifically Links H3K9ac with H4K16ac through PCAF/WSTF/MOF Complex.

This article has been withdrawn by the authors.

Asymmetric Michael Addition Induced by (R)-tert-Butanesulfinamide and Syntheses of Chiral Pyrazolidinone Derivatives.

A highly diastereoselective Michael addition of (R)-N-tert-butanesulfinyl imidates 8 to α,ß-unsaturated pyrazolidinone 3a has been developed to afford pyrazolidinones 10 possessing three contiguous stereocenters with good to excellent yield and excellent diastereoselectivity. A two-step conversion of reduction and cyclization provides the bicyclic pyrazolopiperidine 12 in a good yield. A series of pyrazolopiperidine derivatives 18 with a quaternary carbon center at C-3a are stereoselectively synthesized via alkylation or Michael addition.

[Correction of Fiber Throughput Variation Due to the Focal Ratio Degradation].

The focal ratio degradation (FRD) of optical fiber is one of major sources causing light loss in multi-fiber astronomical instruments. Meanwhile, the sky subtraction is crucial to multi-fiber spectra reduction, especially for the objects which are as faint as the sky background, not to mention for those even fainter ones. To improve the accuracy of sky subtraction, it is necessary to normalize the throughput among object fibers and sky sampling fibers. The rotation and twist during mounting and rotating could change the FRD of individual fibers, which means the variation of the transmission throughput among fibers. We investigate such throughput variation among LAMOST fibers and its correlation with the intensity of sky emission lines on all wavelength coverage in this paper. On the basis of this work, we present an approach to correcting the varied fiber throughput by measuring the intensity of the sky emission lines as the secondary throughput correction. This approach has been applied to LAMOST 2D Pipeline.

Effects of Smilaxchinoside A and Smilaxchinoside C, two steroidal glycosides from Smilax riparia, on hyperuricemia in a mouse model.

The roots and rhizomes of Smilax riparia, called 'Niu-Wei-Cai' in traditional Chinese medicine, are believed to be effective in treating the symptoms of gout. However, the active constituents and their uricosuric mechanisms are unknown. In this study, we isolated two steroidal glycosides, named smilaxchinoside A and smilaxchinoside C, from the total saponins obtained from the ethanol extract of the roots of S. riparia. We then examined if these two compounds were effective in reducing serum uric acid levels in a hyperuricemic mouse model induced by potassium oxonate. We observed that these two steroidal glycosides possess potent uricosuric activities, and the observed effects accompanied the reduction of renal mURAT1 and the inhibition of xanthine oxidase, which contribute to the enhancement of uric acid excretion and the reduction of hyperuricemia-induced renal dysfunction. Smilaxchinoside A and smilaxchinoside C may have a clinical utility in treating gout and other medical conditions caused by hyperuricemia.

Design, synthesis, biological activity and molecular dynamics studies of specific protein tyrosine phosphatase 1B inhibitors over SHP-2.

Over expressing in PTPN1 (encoding Protein tyrosine phosphatase 1B, PTP1B), a protein tyrosine phosphatase (PTP) that plays an overall positive role in insulin signaling, is linked to the pathogenesis of diabetes and obesity. The relationship between PTP1B and human diseases exhibits PTP1B as the target to treat these diseases. In this article, small weight molecules of the imidazolidine series were screened from databases and optimized on silicon as the inhibitors of PTP1B based on the steric conformation and electronic configuration of thiazolidinedione (TZD) compounds. The top three candidates were tested using an in vitro biological assay after synthesis. Finally, we report a novel inhibitor, Compound 13, that specifically inhibits PTP1B over the closely related phosphatase Src homology 2 (SH2) domain-containing phosphatase 2 (SHP-2) at 80 µΜ. Its IC50 values are reported in this paper as well. This compound was further verified by computer analysis for its ability to combine the catalytic domains of PTP1B and SHP-2 by molecular dynamics (MD) simulations.

[Serum level of intercellular adhesion molecule-1 in patients with clonorchiasis and its impact on liver function].

OBJECTIVE: To investigate the serum level of intercellular adhesion molecule-1 (ICAM-1) in patients with clonorchiasis, and the relationship between ICAM-1 and liver function. METHODS: Fifty untreated clonorchiasis patients and 20 normal controls were subjected in the present study. Plasma levels of total bilirubin (TBIL), albumin (ALB) and alanine aminotransferase (ALT) were determined by automatic biochemical analyzer. The patients were divided into three experiment groups (I, II, and III) by Child-Pugh classification. Serum level of sICAM-1 was determined by double-antibody sandwich ELISA. Radioimmunoassay was used to detect the content of interleukin-4(IL-4), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in serum. LAL tripeptide substrate staining quantitative method was used to detect the level of bacterial lipopolysaccharide (LPS) in plasma. RESULTS: The level of sICAM-1, LPS, IL-4, IL-6, TNF-alpha, TBIL, and ALT [(729.34 +/- 75.67) microg/ml, (0.18 +/- 0.08) Eu/ml, (3.46 +/- 0.38) ng/ml, (223.48 +/- 46.90) pg/ml, (1.39 +/- 0.62) ng/ml, (15.45 +/- 10.81) micromol/L, and (39.25 +/- 8.82)IU/L, respectively] in serum or plasma of clonorchiasis patients were significantly higher than that of the control group [(269.15 +/- 38.21) microg/ml, (0.07 +/- 0.03) Eu/ml, (0.74 +/- 0.22) ng/ml, (106.06 +/- 32.96) pg/ml, (0.56 +/- 0.14) ng/ml, (6.31 +/- 4.70) micromol/L, (18.43 +/- 9.81) IU/L](P < 0.05 or P < 0.01). Plasma level of ALB [(28.35 +/- 5.38) g/L] was significantly lower than that of the control [(39.43 +/- 7.91) g/L] (P < 0.05). Correlation test showed that the sICAM-1 level in patients' sera was positively correlated with TBIL, ALT, and LPS (r = 0.662, 0.514, 0.499, P < 0.01), while negatively correlated with ALB (r = -0.423, P < 0.01). IL-4 level did not correlate with liver function parameters (P > 0.05). According to the Child-Pugh classification, the more serious the liver function damaged, the higher level of sICAM-1, LPS, IL-6 and TNF-alpha in the experiment groups. Significant differences were found between groups III and I (P < 0.01). CONCLUSION: Higher serum levels of sICAM-1, LPS, IL-6, and TNF-alpha in patients with clonorchiasis take part in the process of liver injury induced by Clonorchis sinensis.

Structure-based and multiple potential three-dimensional quantitative structure-activity relationship (SB-MP-3D-QSAR) for inhibitor design.

The inhibitions of enzymes (proteins) are determined by the binding interactions between ligands and targeting proteins. However, traditional QSAR (quantitative structure-activity relationship) is a one-side technique, only considering the structures and physicochemical properties of inhibitors. In this study, the structure-based and multiple potential three-dimensional quantitative structure-activity relationship (SB-MP-3D-QSAR) is presented, in which the structural information of host protein is involved in the QSAR calculations. The SB-MP-3D-QSAR actually is a combinational method of docking approach and QSAR technique. Multiple docking calculations are performed first between the host protein and ligand molecules in a training set. In the targeting protein, the functional residues are selected, which make the major contribution to the binding free energy. The binding free energy between ligand and targeting protein is the summation of multiple potential energies, including van der Waals energy, electrostatic energy, hydrophobic energy, and hydrogen-bond energy, and may include nonthermodynamic factors. In the foundational QSAR equation, two sets of weighting coefficients {aj} and {bp} are assigned to the potential energy terms and to the functional residues, respectively. The two coefficient sets are solved by using iterative double least-squares (IDLS) technique in the training set. Then, the two sets of weighting coefficients are used to predict the bioactivities of inquired ligands. In an application example, the new developed method obtained much better results than that of docking calculations.

Optimal soil Eh, pH for simultaneous decrease of bioavailable Cd, As in co-contaminated paddy soil under water management strategies.

The co-contamination with cadmium (Cd) and arsenic (As) in the paddy soil is the most seriously combined pollution of toxic elements in China, and it is rather difficult to decrease bioavailable Cd and As levels in soil because of the opposite ionic forms of bioavailable Cd (cation) and As (anion). This study explored the optimal conditions of Eh and pH in different soils for simultaneous decrease of Cd and As bioavailabilities in the soil-rice system through soil culture and rice pot experiments under water management strategies. The results showed that near neutral soil pH (7.0) were eventually observed under long-term flooding conditions. Under unflooded conditions, soil pH is the dominant factor influencing bioavailabilities of Cd and As, while under flooded conditions, Eh becomes the most important factor. Pot experiments showed that flooding significantly reduced the Cd concentration in rice grains from 54.5% to 95.5%, but concomitantly increased rice As concentration substantially (214%-302%). By evaluating the trade-off value between the bioavailabilities of Cd and As in the soil, the minimal trade-off value was obtained when the soil Eh was -130 mV and the pH was 6.8.

Ethyl 4-[(4-chloro-phen-oxy)meth-yl]-2-(4-nitro-phen-yl)-1,3-thia-zole-5-carboxyl-ate.

The title compound, C(19)H(15)ClN(2)O(5)S, contains two mol-ecules (A and B) in the asymmetric unit. In mol-ecule A, the dihedral angles between the thia-zole ring and the pendant chloro-benzene and nitro-benzene rings are 72.14 (15) and 3.03 (15)°, respectively. The corresponding angles for mol-ecule B are 45.56 (16) and 1.51 (14)°, respectively. In the crystal, both mol-ecules form inversion dimers linked by pairs of weak C-H⋯O inter-actions.

[Correlation of CT presentation with histo-differentiation and p53 and Ki67 expressions in gastric cancer].

OBJECTIVE: To study the relationship between spiral CT findings and histological differentiation and expressions of p53 and Ki67 in gastric carcinoma. METHODS: Triphasic spiral CT was performed in 158 patients. CT findings included maximal diameter and thickness of tumor in three dimensional CT images, degree of enhancement, mucous situation, lymph nodes, and visceral metastasis were recorded. The expressions of p53 and Ki67 were detected with immunohistochemistry and reverse transcription polymerase chain reaction. RESULTS: The thickness of tumor (chi2 = 5.554, P = 0.018), degree of enhancement (chi2 = 4.978, P = 0.026), and lymph nodes metastasis (chi2 = 6.061, P = 0.014) in the three dimensional CT images were significantly correlated with tumor histological differentiation. Lymph nodes metastasis was significantly correlated with the expression of p53 (chi2 = 5.028, P = 0.025). The expression of Ki67 was significantly correlated with the thickness of tumor (chi2 = 5.674, P = 0.017) and lymph nodes metastasis (chi2 = 5.028, P = 0.025). CONCLUSION: Multi-slice CT is a simple and noninvasive technique, and can be used for assessing the histological differentiation of gastric cancer as well as the expressions of p53 and Ki67 before the operation.

Three new powerful oseltamivir derivatives for inhibiting the neuraminidase of influenza virus.

Owing to its unique function in assisting the release of newly formed virus particles from the surface of an infected cell, neuraminidase, an antigenic glycoprotein enzyme, is a main target for drug design against influenza viruses. The group-1 neuraminidase of influenza virus possesses a 150-cavity, which is adjacent to the active pocket, and which renders conformational change from the 'open' form to the 'closed' form when the enzyme is binding with a ligand. Using AutoGrow evolutionary algorithm, one very unique fragment is screened out from the fragment databases by exploiting additional interactions with the 150-cavity. Subsequently, three derivatives were constructed by linking the unique fragment to oseltamivir at its three different sites. The three derivatives thus formed show much stronger inhibition power than oseltamivir, and hence may become excellent candidates for developing new and more powerful drugs for treating influenza. Or at the very least, the findings may stimulate new strategy or provide useful insights for working on the target vitally important to the health of human beings.

Methyl 4-(cyclopropylmethoxy)-3-hydroxybenzoate [corrected].

In the title compound, C(12)H(14)O(4), the dihedral angle between the benzene ring and the cyclo-propyl ring is 60.3 (4)°. In the crystal structure, mol-ecules are linked by inter-molecular O-H⋯O hydrogen bonds into chains running parallel to [101].

[Value of multi slice spiral computed tomography in diagnosing lymph node metastasis of gastric cancer].

OBJECTIVE: To study the value of multi-slice spiral computed tomography (CT) in the preoperative evaluation of lymph node metastasis. METHODS: Totally 45 patients with gastric cancer detected by 64-slice spiral CT were enrolled in this study. The potential lymph node metastasis was evaluated by measuring or calculating the long diameter, extent of enhancement, and short-to-long diameter ratio of the lymph nodes. The results were compared with postoperative pathological findings. RESULT: A long diameter ≥ 8mm,enhanced density ≥ 80Hu, and short-to-long diameter ratio ≥ 0.7 had the best consistency with postoperative pathological findings. CONCLUSION: As a simple and noninvasive technique, multi-slice spiral CT is helpful to identify potential lymph node metastasis of gastric cancer based on long diameter, extent of enhancement, and short-to-long diameter ratio of the lymph nodes, and thus provide important information for surgery selection, prognosis, and development of new procedures.

Design, synthesis, biological evaluation and molecular dynamics studies of 4-thiazolinone derivatives as protein tyrosine phosphatase 1B (PTP1B) inhibitors.

Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signaling pathway, and more and more studies have shown that it is a potential target for the treatment of type 2 diabetes mellitus (T2DM). In this study, 17 new 4-thiazolinone derivatives were designed and synthesized as novel PTP1B inhibitors, and ADMET prediction confirmed that these compounds were to be drug-like. In vitro enzyme activity experiments were performed on these compounds, and it was found that a plurality of compounds had good inhibitory activity and high selectivity against PTP1B protein. Among them, compound 7p exhibited the best inhibitory activity with an IC50 of 0.92 µM. The binding mode of compound 7p and PTP1B protein was explored, revealing the reason for its high efficiency. In addition, molecular dynamics simulations for the PTP1BWT and PTP1Bcomp#7p systems revealed the effects of compound 7p on PTP1B protein at the molecular level. In summary, the study reported for the first time that 4-thiazolinone derivatives as a novel PTP1B inhibitor had good inhibitory activity and selectivity for the treatment of T2DM, providing more options for the development of PTP1B inhibitors. AbbreviationsBBBblood-brain barrierCDC25Bcell division cycle 25 homolog BCYP2D6Cytochrome P450 2D6 bindingDCCMdynamic cross-correlation mapDSDiscovery StudioH bondhydrogen bondHIAhuman intestinal absorptionLARleukocyte antigen-related phosphataseMDmolecular dynamicsMEG-2maternal-effect germ-cell defective 2MM-PBSAmolecular mechanics Poisson Boltzmann surface area)PCAprincipal component analysisPDBProtein Data BankpNPPp-nitrophenyl phosphatePPBplasma protein bindingPTP1Bprotein tyrosine phosphotase 1BRMSDroot mean square deviationRMSFroot mean square fluctuationSHP-1src homologous phosphatase-1SHP-2src homologous phosphatase-2SPCsingle-point chargeTCPTPT cell protein tyrosine phosphataseT2DMType 2 diabetes mellitusVDWvan der WaalsCommunicated by Ramaswamy H. Sarma.

Anticancer Melatplatin Prodrugs: High Effect and Low Toxicity, MT1-ER-Target and Immune Response In Vivo.

Multitargeted therapy could rectify various oncogenic pathways to block tumorigenesis and progression. The combination of endocrine-, immune-, and chemotherapy might exert a highly synergistic effect against certain tumors. Herein, a series of smart Pt(IV) prodrugs 3-6, named Melatplatin, were rationally designed not only to multitarget DNA, MT1, and estrogen receptor (ER) but also to activate immune response. Melatplatin, conjugating first-line chemotherapeutic Pt drugs with human endogenous melatonin (MT), significantly enhanced drug efficacy especially in ER high-expression (ER+) cells, among which 3 presented the most potent cytotoxicity toward ER+ MCF-7 with nanomolar IC50 values 100-fold lower than cisplatin. Melatplatin could bind well to melatonin receptor (MT1) according to molecular docking. Besides, 3 evidently increased intracellular accumulation and DNA damage, upregulated γH2AX and P53, and silenced NF-κB to induce massive apoptosis. Most strikingly, 3 effectively inhibited tumor growth and attenuated systemic toxicity compared to cisplatin in vivo, promoting lymphocyte proliferation in spleen to achieve immune modulation.

WSTF acetylation by MOF promotes WSTF activities and oncogenic functions.

Williams syndrome transcription factor (WSTF) is a transcription factor and tyrosine kinase. WSTF overexpression promotes migration and proliferation of various cancers, and Ser158 (WSTFS158) phosphorylation plays an important role in this process. However, the role of the other posttranslational modifications of WSTF is unknown. Here, we report that lysine (K) 426 on WSTF is acetylated by MOF and deacetylated by SIRT1. Mechanistically, male-specific lethal (MSL) 1v1 interaction with WSTF facilitates its interaction with MOF for WSTF acetylation, which in turn promotes WSTFS158 phosphorylation. The kinase and transcriptional regulatory activity of WSTF were enhanced by acetylation. WSTFK426ac levels positively and significantly correlated with tumor size, histological grade, and age. Moreover, we demonstrated that acetylated WSTF promotes cancer cell proliferation, migration, invasion, and tumor formation. In conclusion, we identified the enzymes regulating WSTF K426 acetylation, and demonstrated an acetylation-dependent mechanism that modulates the activities of WSTF and contributes to tumorigenesis. Our findings provide new clues to study WSTF-mediated normal development and disease.

Insights from investigating the interaction of oseltamivir (Tamiflu) with neuraminidase of the 2009 H1N1 swine flu virus.

The neuraminidase (NA) of influenza virus is the target of anti-flu drugs oseltamivir and zanamivir. Clinical practices showed that oseltamivir was effective to treat the 2009-H1N1 influenza but failed to the 2006-H5N1 avian influenza. To perform an in-depth analysis on such a drug-resistance problem, the 2009-H1N1-NA structure was developed. To compare it with the crystal 2006-H5N1-NA structure as well as the 1918 influenza virus H1N1-NA structure, the multiple sequential and structural alignments were performed. It has been revealed that the hydrophobic residue Try347 in H5N1-NA does not match with the hydrophilic carboxyl group of oseltamivir as in the case of H1N1-NA. This may be the reason why H5N1 avian influenza virus is drug-resistant to oseltamivir. The finding provides useful insights for how to modify the existing drugs, such as oseltamivir and zanamivir, making them not only become more effective against H1N1 virus but also effective against H5N1 virus.

Metformin inhibited colitis and colitis-associated cancer (CAC) through protecting mitochondrial structures of colorectal epithelial cells in mice.

Although a mountain of papers have showed that metformin plays a role in inhibiting cancers, but the mechanism underpinning this has not yet fully elucidated. Herein, we used AOM/DSS model, the clinicopathological features are similar to those found in humans, to investigate the effects of metformin as well as combination with 5-FU in the prevention of colitis and colitis associated cancer (CAC). Oral metformin significantly inhibited DSS-induced ulcerative colitis and AOM/DSS-induced CAC. Metformin also ameliorated 5-FU-induced colorectal gastrointestinal symptoms in mice. Metformin combination with 5-FU strongly inhibited colorectal cancer. Metformin reduced levels of the NFκB signaling components p-IKKα/ß, p-NFκB, p-IκBα in colorectal mucosal cells. Transmission electron microscopy analysis suggested that the inhibition of metformin on colitis and CAC might associate with its biological activity of protecting mitochondrial structures of colorectal epithelial cells. Further analysis by Mito Tracker Red staining assay indicated that metformin prevented H2O2-induced mitochondrial fission correlated with a decrease of mitochondrial perimeter. In addition, metformin increased the level of NDUFA9, a Q-module subunit required for complex I assembly, in colorectal epithelial cells. These observations of metformin in the inhibition of colitis and CAC might associate with its activity of activating the LKB1/AMPK pathway in colorectal epithelial cells. In conclusion, metformin inhibited colitis and CAC through protecting the mitochondrial structures of colorectal epithelial cells.