Design,Synthesis, and Anticancer Screening for Repurposed Pyrazolo[3,4-d]pyrimidine Derivatives on Four Mammalian Cancer Cell Lines

The present study reports the synthesis of new purine bioisosteres comprising a pyrazolo[3,4-d]pyrimidine scaffold linked to mono-, di-, and trimethoxy benzylidene moieties through hydrazine linkages. First, in silico docking experiments of the synthesized compounds against Bax, Bcl-2, Caspase-3, Ki67, p21, and p53 were performed in a trial to rationalize the observed cytotoxic activity for the tested compounds. The anticancer activity of these compounds was evaluated in vitro against Caco-2, A549, HT1080, and Hela cell lines. Results revealed that two (5 and 7) of the three synthesized compounds (5, 6, and 7) showed high cytotoxic activity against all tested cell lines with IC₅₀ values in the micro molar concentration. Our in vitro results show that there is no significant apoptotic effect for the treatment with the experimental compounds on the viability of cells against A549 cells. Ki67 expression was found to decrease significantly following the treatment of cells with the most promising candidate: drug 7. The overall results indicate that these pyrazolopyrimidine derivatives possess anticancer activity at varying doses. The suggested mechanism of action involves the inhibition of the proliferation of cancer cells.     

An open source protein gel documentation system for proteome analyses

Data organization and data mining represents one of the main challenges for modern high throughput technologies in pharmaceutical chemistry and medical chemistry. The presented open source documentation and analysis system provides an integrated solution (tutorial, setup protocol, sources, executables) aimed at substituting the traditionally used lab-book. The data management solution provided incorporates detailed information about the processing of the gels and the experimental conditions used and includes basic data analysis facilities which can be easily extended. The sample database and User-Interface are available free of charge under the GNU license from http://webber.physik.uni-freiburg.de/~fallerd/tutorial.htm.     

Development and Validation of a Stability-Indicating LC Method for Curcumin

A simple, isocratic, stability-indicating liquid chromatographic method for quantitative determination of curcumin was successfully developed. The chromatographic separations were achieved using a Hi-Q-Sil C18; 4.6 mm × 250 mm and 10 μm particle size column employing acetonitrile and acetate buffer (pH 3.0; 60: 40, v/v) as the mobile phase. The analyte was subjected to acidic, basic, oxidative, thermal and photo degradation. The method was validated with respect to linearity, precision, accuracy, limit of detection and limit of quantification. Curcumin was detected by UV-Vis detector at 425 nm whereas the degradation products were detected at 280 nm. The method was linear over the concentration range of 1–10 μg mL^?1. The limit of detection was found to be 0.06 μg mL^?1 and the quantification limit was 0.21 μg mL^?1. Considerable degradation of the analyte was observed when it was subjected to alkaline conditions. Accuracy, evaluated as recovery, was in the range of 97–103%. Intra-day precision and intermediate precision showed relative standard deviations <1% and <2% respectively.     

Shock response of a heavy tungsten alloy

This article describes the results of shock wave experiments performed on a heavy tungsten alloy containing W, Ni, and Fe in the ratio of 92.85:4.9:2.25 by weight. These experiments provide information about the shear strength under compression and tensile strength, as measured by the spall threshold, of this alloy to 24 GPa. The results of these experiments show that: (i) the magnitude of its Hugoniot elastic limit (HEL) is 2.76±0.26 GPa; (ii) this alloy deforms plastically above its HEL and thus retains its shear strength to 24 GPa; (iii) the spall strength of the alloy is found to be 1.9±0.4 GPa and is independent of the impact stress and duration of the shock compression pulse; and (iv) the tensile impedance of the alloy, determined from a new experiment designed to measure this impedance, is 68±10 Gg/m² s.     

One-Pot Multicomponent Synthesis,Molecular Docking,and In Vitro Antibacterial Activities of 1-{(Aryl)[(5-methyl-1,3-thiazol-2-yl)amino]methyl}naphthalen-2-ol

Russian Journal of Organic Chemistry - A series of new Betti bases, 1-{(aryl)[(5-methyl-1,3-thiazol-2-yl)amino]methyl}naphthalen-2-ols, have been synthesized via one-pot three-component reaction of...     

A miniature cytometry platform for capture and characterization of T-lymphocytes from human blood

Given the clinical and diagnostic importance of blood analysis, there is considerable interest in developing novel miniature devices for rapid characterization of blood constituents. The present paper describes development of a miniature cytometry platform aimed at analysis of T-lymphocytes from peripheral human blood. Microarrays of T-cell-specific antibodies (Abs), including anti-CD3, -CD4, -CD8 and mouse IgG (negative control) were robotically printed onto glass slides coated with a non-fouling poly(ethylene glycol) (PEG) hydrogel. The glass substrates containing Ab arrays were incubated with 100 μL of red blood cell (RBC)-depleted whole human blood for 15 min and then exposed to a controlled shear of ∼2 dyn cm⁻² for additional 10 min. This process led to the removal of non-specific leukocytes and “development” of patterns of T-cells captured on the Ab spots. The immunofluorescent staining of the surface-bound cells revealed the presence of purified CD4⁺ and CD8⁺ T-cells (purity >94%) on their respective Ab spots. Importantly, the proportions of CD4⁺ and CD8⁺ T-cells captured on the Ab spots correlated closely (R² − 0.9) with flow cytometry analysis of T-cell subsets in blood. Overall, this cytometry platform allowed to rapidly (under 30 min) capture pure T-cell subsets from minimally processed human blood. Significantly, our device provided quantitative information about subset abundance solely based on the location of cells within the microarray. This cytometry platform is envisioned as a miniature immunology tool for determination of T-cell phenotype and will have immediate applications in HIV diagnostics and research.     

Design,Synthesis and Evaluation of Substituted N-(3-Arylpropyl)-9,10-dihydro-9-oxoacridine-4-carboxamides as Potent MDR Reversal Agents in Cancer

A novel class of molecules with structure N‐(3‐arylpropyl)‐9,10‐dihydro‐9‐oxoacridine‐4‐carboxamides ( 20 – 29 ) were designed by generating a pharmacophore for potent MDR reversal activity using phase drug design software. The designed molecules were synthesized by a novel synthesis route and evaluated for their inhibitory effects on the transport activity of P‐glycoprotein (P‐gp) by standard Hoechst 33342 assay method. Based on the pIC₅₀ values of ten title compounds screened, three compounds exhibited better activity as compared to Verapamil used as standard.     

A hydrophobic starch polymer for nanoparticle-mediated delivery of docetaxel

A hydrophobic starch derivative is used for safe and enhanced delivery of anticancer agents. The synthesis and characterization of propyl starch with a controlled degree of substitution to modulate the release of the encapsulated hydrophobic drug is reported. The application of this polymer for formulating nanoparticles of docetaxel, an anti-cancer agent effective against numerous types of cancers but possessing intrinsic formulation difficulties is described. The solvent emulsification/diffusion technique is used and the synthesis is optimized with respect to several formulation parameters. Uptake studies with these nanoparticles indicate their enhanced internalization by the cancerous cells and their peri-nuclear localization.     

Mass spectrometry-based glycoprofiling of biopharmaceuticals by using an automated data processing tool: SimGlycan®

The therapeutic and immunological properties of biopharmaceuticals are governed by the glycoforms contained in them. Thus, bioinformatics tools capable of performing comprehensive characterization of glycans are significantly important to the biopharma industry. The primary structural elucidation of glycans using mass spectrometry is tricky and tedious in terms of spectral interpretation. In this study, the biosimilars of a therapeutic monoclonal antibody and an Fc-fusion protein with moderate and heavy glycosylation, respectively, were employed as representative biopharmaceuticals for released glycan analysis using liquid chromatography–tandem mass spectrometry instead of conventional mass spectrometry-based analysis. SimGlycan® is a software with proven ability to process tandem MS data for released glycans could identify eight additional glycoforms in Fc-fusion protein biosimilar, which were not detected during mass spectrometry analysis of released glycans or glyco-peptide mapping of the same molecule. Thus, liquid chromatography–tandem mass spectrometry analysis of released glycans not only complements conventional liquid chromatography–mass spectrometry-based glycan profiling but can also identify additional glycan structures that may otherwise be omitted during conventional liquid chromatography–tandem mass spectrometry based analysis of mAbs. The mass spectrometry data processing tools, such as PMI Byos™, SimGlycan^®, etc., can display pivotal analytical capabilities in automated liquid chromatography–mass spectrometry and liquid chromatography–tandem mass spectrometry-based glycan analysis workflows, especially for high-throughput structural characterization of glycoforms in biopharmaceuticals.     

A versatile structural domain analysis server using profile weight matrices

The WEB tool "AnDom" assigns to a given protein sequence all experimentally determined structural domains contained within it, including multidomain and large proteins. The server uses profile specific matrices from custom generated multiple sequence alignments of all known SCOP domains (SCOP version 1.50). Prediction time is short allowing numerous applications for structural genomics including investigation of complex eucaryotic protein families. The WWW server is at http://www.bork.embl-heidelberg.de/AnDom, and profiles can be downloaded at ftp.bork.embl-heidelberg.de/pub/users/ schmidt/AnDom.