Ionic liquid catalyzed synthesis of 7-phenyl-1,4,6,7-tetrahydro-thiazolo[5,4-d]pyrimidine-2,5-diones

A simple, green and catalyst free one pot synthesis of 7-phenyl-1,4,6,7-tetrahydro-thiazolo[5,4-d]pyrimidine-2,5-diones via a multicomponent reaction between thiazolidine-2, 4-dione (TZD), aromatic aldehyde and urea analogues is described. The ionic liquid has been used as a solvent as well as catalyst for this reaction. This reaction proceeded smoothly in good to excellent yields and offered several other advantages including short reaction time, simple experimental workup procedure and no by-products.     

Microfluidically-unified cell culture, sample preparation, imaging and flow cytometry for measurement of cell signaling pathways with single cell resolution

We have developed a microfluidic platform that enables, in one experiment, monitoring of signaling events spanning multiple time-scales and cellular locations through seamless integration of cell culture, stimulation and preparation with downstream analysis. A combination of two single-cell resolution techniques-on-chip multi-color flow cytometry and fluorescence imaging provides multiplexed and orthogonal data on cellular events. Automated, microfluidic operation allows quantitatively- and temporally-precise dosing leading to fine time-resolution and improved reproducibility of measurements. The platform was used to profile the toll-like receptor (TLR4) pathway in macrophages challenged with lipopolysaccharide (LPS)-beginning with TLR4 receptor activation by LPS, through intracellular MAPK signaling, RelA/p65 translocation in real time, to TNF-α cytokine production, all in one small macrophage population (< 5000 cells) while using minute reagent volume (540 nL/condition). The platform is easily adaptable to many cell types including primary cells and provides a generic platform for profiling signaling pathways.     

Interplay between charge and antiferromagnetic ordering in Bi0.6−xPrxCa0.4MnO3 (0≤x≤0.6) perovskite manganite

Structure, magnetic and transport properties of polycrystalline Bi_0.6−xPr_xCa_0.4MnO₃ (x=0.0, 0.1, 0.2, 0.3, 0.4, 0.5 and 0.6) have been studied. Systematic substitution of Pr at Bi site induces an interesting interplay between the charge ordering and antiferromagnetism. The charge ordering temperature (T_CO) decreases with increasing x. The antiferromagnetic (AFM) ordering temperature (T_N) increases sharply at both the extremes but remains nearly constant from x=0.2 to 0.4. At temperatures lower than T_N a transition to the glassy state is observed. The nature of this glass like state appears to be controlled by the Pr content, and at lower values of x this is akin to a spin glass, while at higher x it has a characteristic of cluster glass. The Pr doping also leads to enhancement in the magnetic moment. In the present work it has been proposed that the local lattice distortion induced due to size mismatch between the A-site cations and 6s² character of Bi³⁺ lone pair electron is responsible for the observed magnetic and electrical properties.     

Enhanced integrin mediated signaling and cell cycle progression on fibronectin mimetic peptide amphiphile monolayers

In recent years, a variety of biomimetic constructs have emerged which mimic the bioactive sequences found in the natural extracellular matrix (ECM) proteins such as fibronectin (FN) that promote cell adhesion as well as proliferation on artificially functionalized interfaces. Much interest lies in investigating the ability of the ECM mimetic materials in regulating a number of vital cell functions including differentiation, gene expression, migration, and proliferation. A peptide amphiphile PR_b containing both the cell adhesive GRGDSP and synergistic PHSRN peptide sequences was developed in our group that was shown to support enhanced cell proliferation and ECM FN secretion as compared to GRGDSP and FN functionalized interfaces. In this study, we have investigated the binding affinity of the PR_b peptide ligand with the FN cell surface receptor, the α(5)β(1) integrin. We compared PR_b functionalized surfaces with FN and BSA coated surfaces and GRGDSP functionalized surfaces in terms of promoting intracellular signaling cascades that are essential for enhanced cellular activity. Specifically, we studied the phosphorylation of focal adhesion kinase (FAK) at tyrosine residues Y397 and Y576 and the formation of cyclin D1, both of which are intracellular markers of integrin mediated attachment of cells, signaling pathways, and progression of cell cycle. FAK and cyclin D1 encourage enhanced cell proliferation, differentiation, and gene expression. Our results show that the PR_b peptide ligand has a specific and strong binding affinity for the α(5)β(1) integrin with a dissociation constant of 76.3 ± 6.3 nM. The PR_b peptide ligands supported enhanced FAK phosphorylation activity and increased cyclin D1 formation as compared to the widely used GRGDSP ligand, the native protein FN (positive control), and BSA nonadhesive surfaces (negative control). These results encourage the use of the FN mimetic PR_b peptide in functionalizing biomaterials for potential tissue engineering and therapeutic applications.     

PEGylated liposomal doxorubicin targeted to α5β1-expressing MDA-MB-231 breast cancer cells

Targeting drugs selectively to cancer cells can potentially benefit cancer patients by avoiding side effects generally associated with several cancer therapies. One of the attractive approaches to direct the drug cargo to specific sites is to incorporate ligands at the surface of the delivery systems. Integrin α(5)β(1) is overexpressed in tumor vasculature and cancer cells, thus making it an attractive target for use in drug delivery. Our group has developed a fibronectin-mimetic peptide, PR_b, which has been shown to bind specifically to integrin α(5)β(1), thereby providing a tool to target α(5)β(1)-expressing cancer cells in vitro as well as in vivo. Our current work focuses on designing modified stealth liposomes (liposomes functionalized with polyethylene glycol, PEG) for combining the benefits associated with PEGylation, as well as imparting specific targeting properties to the liposomes. We have designed PEGylated liposomes that incorporate in their bilayer the fibronectin-mimetic peptide-amphiphile PR_b that can target several cancer cells that overexpress α(5)β(1), including the MDA-MB-231 breast cancer cells used in this study. We have encapsulated doxorubicin inside the liposomes to enhance its therapeutic potential via PEGylation as well as active targeting to the cancer cells. Our results show that PR_b-functionalized stealth liposomes were able to specifically bind to MDA-MB-231 cells, and the binding could be controlled by varying the peptide concentration. The intracellular trafficking of the doxorubicin liposomes was examined, and within minutes after delivery the majority of them were found to be in the early endosomes, whereas after a longer period of time they had accumulated in the late endosomes and lysosomes. The functionalized liposomes were found to be equally cytotoxic as the free doxorubicin, especially at higher doxorubicin concentrations, and provided higher cytotoxicity than the nontargeted and GRGDSP-functionalized stealth liposomes. Thus, the PR_b-functionalized PEGylated nanoparticles examined in this study offer a promising strategy to deliver their therapeutic payload directly to the breast cancer cells, in an efficient and specific manner.     

The role of hydrogen bonding in pseudo-macrocyclic ring formation in 2,6-dimethyl-1,3,5,7-cyclooctatetraene 1,3,5,7-tetracarboxylic acid monohydrate

2,6-Dimethyl-1,3,5,7-cyclooctatetraene-1,3,5,7-tetracarboxylic acid 3, C₁₄H₁₄O₉, was prepared by thermolysis of the corresponding semibullvalene and characterized by spectroscopic and single-crystal X-ray diffraction studies. The monohydrate of 3 crystallizes in the tetrahedral space group P-4n2, a = 11.0924(3) Å, c = 12.6799(5) Å, V = 1560.15(9) ų, Z = 4. The cyclooctatetraene ring adopts a tub-shaped conformation with a crystallograpically imposed twofold rotational symmetry, and is composed of localized C=C double bonds in the 1,3,5, and 7 positions with an average interatomic distance of 1.327 (5) Å and C–C single bonds with an average interatomic distance of 1.489(5) Å. The average C=C–C angle in the ring is 122.6(3)°. Each symmetry generated eight-membered ring contains four carboxyl groups, two of which are coplanar with the methyl groups across the C=C ring atoms. However, across the C–C bonds the carboxyl groups and the methyl groups show a torsion angle of 64.3(4)°. The presence of a water molecule in the crystal lattice generates a three-dimensional network of close hydrogen bondings between water and the carboxyl groups of multiple rings. This creates a network of orthogonal 10-membered rings between the 8-membered rings. Two given cyclooctatetraene rings are intermolecularly hydrogen bonded not only directly through their carboxyl groups but also via a bridging water molecule. This effect is rare in polycarboxylic acids and their monohydrates which bond only with water or among themselves.     

Transition metal free one pot synthesis of aryl carboxylic acids via dehomologative oxidation of styrenes

Iodine/NaOH-catalyzed one-pot dehomologative oxidation of styrenes to aryl carboxylic acids has been reported. A wide range of carboxylic acids are obtained using iodine (I₂) as a catalyst, tert-butyl hydroperoxide (TBHP) as an oxidant and sodium hydroxide (NaOH) as a base. This reliable conversion involves dehomologation of styrene to aromatic aldehyde which on subsequent oxidation affords aryl carboxylic acid. This protocol was used for gram-scale synthesis as it is free from chromatographic purification. This is the first report for the oxidative transformation of styrenes into aryl carboxylic acids under transition metal-free conditions.     

Chemistry of the phenylglyoxal-p-diethylaminoanil and/or thiourea substituted ammine complexes

Summary Mixed ligand complexes of chromium(III), cobalt(II), cobalt(III), copper(II) and zinc(II) involving either the phenylglyoxal-p-diethylaminoanil and/or thiourea, and ammonia have been obtained by the partial or complete replacement of the strongly coordinated ammonia of ammine complexes. All the products were characterized by elemental analysis, molar conductance, magnetic susceptibility and i.r. and electronic spectral measurements for their bonding and structures.     

Transition metal-catalyzed CH functionalization of arylacetic acids for the synthesis of benzothiadiazine 1,1-dioxides

Copper-catalyzed practical route for the synthesis of benzothiadiazine 1,1-dioxides has been developed. The method involves CH functionalization of arylacetic acids to form aromatic aldehydes and their subsequent condensation with 2-aminobenzenesulfonamide. This functional group tolerant approach furnished benzothiadiazine 1,1-dioxide derivatives in good to excellent yields. Broad substrate scope, inexpensive catalyst and high product yields are notable features of this protocol.     

Drug Release From Emulsions Stabilized by Colloidal Macrocrystalline Cellulose

Drug release from water-in oil-in water (w/o/w)multiple emulsions stabilized with colloidal microcrystal-line cellulose and various surface-active agents has been studied in vitro. Lidocaine hydrochloride and lidocaine base were used as model drugs for these studies. Drug concentrations were measured by HPLC, and effective diffusion coefficients were determined.