Reactive blends derived from modified soybean oil and silicone

Reactive blends prepared from methoxysilane terminated silicone polymers and silylated soybean oil are described and characterized. Although simple mixing of soy and silicones results in gross phase separation, homogeneous polymeric products are obtained by introducing reactive sites. These products can be used as protective coatings, additives to adhesives and new sealants. Exposure of the mixtures to moisture leads to hydrolysis of the methoxysilanes and subsequent condensation of the resulting silanols that yields stable siloxane linkages between the two immiscible phases. FTIR, TGA, and swell‐gel analyses indicate effective formation of these siloxane crosslinks. Reactive blends containing less than 20% silylated oil appeared completely transparent but increasing the soy content decreased the optical transparency. SEM micrographs reveal the silicone polymer as the continuous phase with individual spherical silylated soy oil particles distributed in it. The properties of these reactive blends vary from high elongation elastomers to high modulus resins depending on the composition. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3086–3093     

Ferrocene derivatives supported on poly(N-vinylpyrrolidin-2-one) (PVP): Synthesis of new water-soluble electrochemically active probes for biomolecules

Carboxy-terminated polyvinylpyrrolidin-2-one (PVP) has been used as a new water-soluble and biocompatible polymeric support for a series of ferrocene labeled amino acid and peptide nucleic acid (PNA) monomer derivatives 4-7. The organometallic polymer-conjugates thus obtained are new and potentially useful as water-soluble electrochemically active probes for biomolecules. In view of such application, their electrochemical activity has been evaluated and has proved very high notwithstanding the complexity and bulkiness of the molecule, affording detection limits down to 10⁻⁸ M in the aqueous medium.     

Discovery of novel inhibitors for <Emphasis Type="Italic">Leishmania</Emphasis> nucleoside diphosphatase kinase (NDK) based on its structural and functional characterization

Nucleoside diphosphate kinases (NDKs) are ubiquitous enzymes that catalyze the transfer of the γ-phosphate moiety from an NTP donor to an NDP acceptor, crucial for maintaining the cellular level of nucleoside triphosphates (NTPs). The inability of trypanosomatids to synthesize purines de novo and their dependence on the salvage pathway makes NDK an attractive target to develop drugs for the diseases they cause. Here we report the discovery of novel inhibitors for Leishmania NDK based on the structural and functional characterization of purified recombinant NDK from Leishmania amazonensis. Recombinant LaNDK possesses auto-phosphorylation, phosphotransferase and kinase activities with Histidine 117 playing an essential role. LaNDK crystals were grown by hanging drop vapour diffusion method in a solution containing 18% PEG-MME 500, 100 mM Bis-Tris propane pH 6.0 and 50 mM MgCl₂. It belongs to the hexagonal space group P6₃22 with unit cell parameters a?=?b?=?115.18, c?=?62.18 Å and α?=?β?=?90°, γ?=?120°. The structure solved by molecular replacement methods was refined to crystallographic R-factor and R_free values of 22.54 and 26.52%, respectively. Molecular docking and dynamics simulation-based virtual screening identified putative binding compounds. Protein inhibition studies of selected hits identified five inhibitors effective at micromolar concentrations. One of the compounds showed ~45% inhibition of Leishmania promastigotes proliferation. Analysis of inhibitor-NDK complexes reveals the mode of their binding, facilitating design of new compounds for optimization of activities as drugs against leishmaniasis.     

Serendipitous discovery of light-induced (<Emphasis Type="Italic">In Situ</Emphasis>) formation of an Azo-bridged dimeric sulfonated naphthol as a potent PTP1B inhibitor

Background

Protein tyrosine phosphatases (PTPs) like dual specificity phosphatase 5 (DUSP5) and protein tyrosine phosphatase 1B (PTP1B) are drug targets for diseases that include cancer, diabetes, and vascular disorders such as hemangiomas. The PTPs are also known to be notoriously difficult targets for designing inihibitors that become viable drug leads. Therefore, the pipeline for approved drugs in this class is minimal. Furthermore, drug screening for targets like PTPs often produce false positive and false negative results.

Results

Studies presented herein provide important insights into: (a) how to detect such artifacts, (b) the importance of compound re-synthesis and verification, and (c) how in situ chemical reactivity of compounds, when diagnosed and characterized, can actually lead to serendipitous discovery of valuable new lead molecules. Initial docking of compounds from the National Cancer Institute (NCI), followed by experimental testing in enzyme inhibition assays, identified an inhibitor of DUSP5. Subsequent control experiments revealed that this compound demonstrated time-dependent inhibition, and also a time-dependent change in color of the inhibitor that correlated with potency of inhibition. In addition, the compound activity varied depending on vendor source. We hypothesized, and then confirmed by synthesis of the compound, that the actual inhibitor of DUSP5 was a dimeric form of the original inhibitor compound, formed upon exposure to light and oxygen. This compound has an IC₅₀ of 36 μM for DUSP5, and is a competitive inhibitor. Testing against PTP1B, for selectivity, demonstrated the dimeric compound was actually a more potent inhibitor of PTP1B, with an IC₅₀ of 2.1 μM. The compound, an azo-bridged dimer of sulfonated naphthol rings, resembles previously reported PTP inhibitors, but with 18-fold selectivity for PTP1B versus DUSP5.

Conclusion

We report the identification of a potent PTP1B inhibitor that was initially identified in a screen for DUSP5, implying common mechanism of inhibitory action for these scaffolds.

     

Ultrasensitive small molecule fluorogenic probe for human heparanase

Heparanase (HPA) is a critical enzyme involved in the remodeling of the extracellular matrix (ECM), and its elevated expression has been linked with diseases such as various types of cancer and inflammation. The detection of heparanase enzymatic activity holds tremendous value in the study of the cellular microenvironment, and search of molecular therapeutics targeting heparanase, however, no structurally defined probes are available for the detection of heparanase activity. Here we present the development of the first ultrasensitive fluorogenic small-molecule probe for heparanase enzymatic activity via tuning the electronic effect of the substrate. The probe exhibits a 756-fold fluorescence turn-on response in the presence of human heparanase, allowing one-step detection of heparanase activity in real-time with a picomolar detection limit. The high sensitivity and robustness of the probe are exemplified in a high-throughput screening assay for heparanase inhibitors.

Heparanase, a critical enzyme involved in the remodeling of the extracellular matrix, activates a disaccharide probe HADP to give a strong fluorescence signal.     

DISTRIBUTION OF VOTAW'S λ_1(vc) CRITERION FOR TESTING COMPOUND SYMMETRY OF A COVARIANCE MATRIX

1IntroductionLetnbeanormalt--variatepopulationandXj,j=1,'',t(t23)bethej--thvariateinn.Letthesetofvariatesxl,''txtbepartitionedintoqmutuanyexclusivesubsetsofwhich.say,esubsetscontainexactlyonevariateandthereasoningk=q--esubsets(k21)containti,''ttkvariatesrespectively,wheref.22(y=1,''tk;e Z:=,t.=f).Nogeneralityislostinassumingthatthetvariatesareorderedsothatthefirst,belongtothe,subsetscontainingoneyaxiateeach,andnexttivariatesbelongto(I 1)--fhsubset,'',thelasttivariatestotheq--thsubset,whe…     

Estimation and inference for dependence in multivariate data

In this paper, a new measure of dependence is proposed. Our approach is based on transforming univariate data to the space where the marginal distributions are normally distributed and then, using the inverse transformation to obtain the distribution function in the original space. The pseudo-maximum likelihood method and the two-stage maximum likelihood approach are used to estimate the unknown parameters. It is shown that the estimated parameters are asymptotical normally distributed in both cases. Inference procedures for testing the independence are also studied.     

The Finite Element Method on the Sierpinski Gasket

For certain classes of fractal differential equations on the Sierpinski gasket, built using the Kigami Laplacian, we describe how to approximate solutions using the finite element method based on piecewise harmonic or piecewise biharmonic splines. We give theoretical error estimates, and compare these with experimental data obtained using a computer implementation of the method (available at the web site http://mathlab.cit.cornell.edu/\sim gibbons). We also explain some interesting structure concerning the spectrum of the Laplacian that became apparent from the experimental data. March 29, 2000. Date revised: March 6, 2001. Date accepted: March 21, 2001.     

A class of multivariate skew-normal models

The existing model for multivariate skew normal data does not cohere with the joint distribution of a random sample from a univariate skew normal distribution. This incoherence causes awkward interpretation for data analysis in practice, especially in the development of the sampling distribution theory. In this paper, we propose a refined model that is coherent with the joint distribution of the univariate skew normal random sample, for multivariate skew normal data. The proposed model extends and strengthens the multivariate skew model described in Azzalini (1985,Scandinavian Journal of Statistics,12, 171–178). We present a stochastic representation for the newly proposed model, and discuss a bivariate setting, which confirms that the newly proposed model is more plausible than the one given by Azzalini and Dalla Valle (1996,Biometrika,83, 715–726).