4-dimethylamino Phenyl Research Articles

Theoretical investigation on vibrational spectroscopic and nonlinear optical activity of 1-(4-chloro phenyl)-3-(4-dimethylamino phenyl) prop-2-en-1-one

The density functional theory method was used to calculate the vibrational spectrum, geometrical structure of 1-(4-chloro phenyl)-3-(4-dimethylamino phenyl) prop-2-en-1-one in the ground state. The analysis of natural bond orbital (NBO) was also performed. The infrared spectrum was obtained and interpreted by means of potential energies distributions. NBO analysis shows that electron donation from LP(1)N atom to the anti-bonding acceptor σ*(C6–C12) of the phenyl ring results in the stabilization of 43.9 kJ/mol. The predicted NLO properties show that the βtot of the title compound is larger than that of urea and is a good candidate as a nonlinear optical material. In addition, the frontier molecular orbital is also investigated. The high βtot value and the low HOMO–LUMO energy gap assert the suitability of the grown crystal for NLO applications.

Computational modelling of panchromatic porphyrins with strong NIR absorptions for solar energy capture

Five potential push-pull porphyrin dyes (PR1-PR5) substituted with extended rylene anhydride units (n=1–5) as electron acceptors and (4-dimethylamino) phenyl ethynylene as an electron donor have been investigated computationally using density functional theory and time dependent-density functional theory. Their molecular orbital energies are reported together with their singlet and triplet electronic transition energies, oscillator strengths and charge transfer characteristics. These sensitizers are panchromatic, their fully-allowed charge transfer transitions extend well into the near infrared and their HOMO and LUMO energies appear well-matched to the band gap and electrochemical potential requirements of dye-sensitized solar cells (DSSCs).

Study of Non Linear Optical Properties of a Chalcone Doped PVA Composite Material

A chalcone, 1-phenyl-3-(4-dimethylamino phenyl) prop-2-en-1-one (PDAC) was synthesized and the structure was confirmed by FT-IR and single crystal XRD techniques. This chalcone was doped to Poly (Vinyl Alcohol) and films were prepared by solution casting method. The optical studies on pure PDAC and films were carried out with UV-Visible, Z-scan and DFWM techniques. The nonlinear parameters of the samples were obtained by z-scan. An enhancement in NLO response was observed in films. The results were compared with nonlinear parameters obtained with pico second DFWM experiment. The composite is thermally stable up to 298 0C.

Docking Studies and Synthesis of Novel Flavones Screened for Biological Activities like Anticancer and Antioxidant Activity

Flavones are the derivatives of flavonoids, possessing the wider range of biological actions. A novel series of flavonoid Derivatives with the help of substituted benzaldehyde were synthesized and screened for biological activities like anticancer and antioxidant activity. All synthesized derivatives were screened for in-vitro cytotoxicity by Brine shrimp lethality assay in which 1-(2, 4-dihydroxyphenyl)-3-(4-(dimethyl amino) phenyl) prop-2ene-1one. (MCR-001) and 2-(4-(Di-methylamino) phenyl)-7-hydroxy-4-H-chromen-4-one. (MCR-002), 2-hydroxy-2-(4-(methyl (4-nitrostyryl) amino) phenyl)-4-oxochroman-7-yl benzoate. (MCR-004) and 2-(4dimethyl amino) phenyl)-4-oxo-4H-chromen-7-yl benzoate. (MCR-005) showed highest anticancer activity as compared to 5-fluorouracil due to presence of hydroxy group. Among synthesized compounds, 4-nitro flavonoids compound derivatives were screened for antioxidant activity by using DPPH Scavenging Method. 2(4-dimethyl amino) phenyl)-2-hydroxy 4-oxochroman-6-yl benzoate (MCR-005) showed highest antioxidant activity as compared to ascorbic acid. This work has revealed the scope and potential of flavonoids for future exploration to synthesize substituted flavonoids and chalcone derivatives by the use of different substituted benzaldehyde.

α‐Bis and α,ω‐tetrakis(4‐dimethylaminophenyl) functionalized polymers by atom transfer radical polymerization using 1,1‐bis[(4‐dimethylamino)phenyl]ethylene as tertiary diamine initiator precursor and functionalizing agent

The quantitative syntheses of α-bis and α,ω-tetrakis tertiary diamine functionalized polymers by atom transfer radical polymerization (ATRP) methods are described. A tertiary diamine functionalized 1,1-diphenylethylene derivative, 1,1-bis[(4-dimethylamino)phenyl]ethylene (1), was evaluated as a unimolecular tertiary diamine functionalized initiator precursor as well as a functionalizing agent in ATRP reactions. The ATRP of styrene, initiated by a new tertiary diamine functionalized initiator adduct (2), affords the corresponding α-bis(4-dimethylaminophenyl) functionalized polystyrene (3). The tertiary diamine functionalized initiator adduct (2) was prepared in situ by the reaction of (1-bromoethyl)benzene with 1,1-bis[(4-dimethylamino)phenyl]ethylene (1) in the presence of a copper (I) bromide/2,2′-bipyridyl catalyst system. The ATRP of styrene proceeded via a controlled free radical polymerization process to afford quantitative yields of the corresponding α-bis(4-dimethylaminophenyl) functionalized polystyrene derivative (3) with predictable number-average molecular weight (Mn) and narrow molecular weight distribution (Mw/Mn) in a high initiator efficiency reaction. The polymerization process was monitored by gas chromatography analysis. Quantitative yields of α,ω-tetrakis(4-dimethylaminophenyl) functionalized polystyrene (4) were obtained by a new post ATRP chain end modification reaction of α-bis(4-dimethylaminophenyl) functionalized polystyrene (3) with excess 1,1-bis[(4-dimethylamino)phenyl]ethylene (1). The tertiary diamine functionalized initiator precursor 1,1-bis[(4-dimethylamino)phenyl]ethylene (1) and the different tertiary amine functionalized polymers were characterized by chromatography, spectroscopy and non-aqueous titration measurements. Copyright © 2012 Society of Chemical Industry

Pyridinones Are Not Antioxidants As Shown by Kinetics of Free Radical Autoxidation, but They Prevent Radical Oxidations Catalyzed by Toxic Heavy Metals

Three 2-methyl-3-hydroxypyridinones, 1-methyl-, 1; 1-(4-methoxy)phenyl-, 2; and 1-(4-dimethylamino)phenyl-, 3, were discovered not to possess strong antioxidant properties contrary to literature reports. These pyridinones were not active chain-breaking antioxidants toward peroxyl radicals generated from styrene or methyl oleate initiated by azobis-2-methylpropylnitrile (AIBN) in solution compared to known phenolic antioxidants, 2,2,5,7,8-pentamethyl-6-hydroxychroman (PMHC) or 2,6-di-tert-butyl-4-methoxyphenyl (DBHA). Pyridinone 2 exhibited weak antioxidant activity in cumene, kinh = 1.3 × 10(3) M(-1) s(-1), compared to 2,6-di-tert-butyl-4-methylphenol (BHT), kinh = 4.3 × 10(3) M(-1) s(-1). The pyridinones were not active antioxidants during lipid peroxidation initiated by azobis-2-amidinopropane·2HCl (ABAP) in aqueous-lipid dispersions of 0.50 M sodium dodecyl sulfate (SDS) micelles where 2 did not inhibit peroxidation of methyl oleate at pH 7.0 or 4.0, while BHT exhibited effective suppression of oxygen uptake. In addition, 2 did not exhibit any cooperative antioxidant effect in combination with Trolox during inhibited peroxidation of linoleic acid in micelles. Pyridinones were effective preventative antioxidants in aqueous-lipid dispersions against reactions initiated by heavy metal ions, notably copper; for example, 2 blocked peroxidation of linoleic acid initiated by Cu ions in SDS micelles. In particular, both 2 and 3 were active in preventing the rapid pro-oxidation effects, "spikes", of very rapid oxygen uptake when phenolic antioxidants PMHC or Trolox were added to peroxidations initiated by Cu(2+). A proposal is given to account for such pro-oxidant effects.

Third order nonlinear optical studies of 1-(4-chloro phenyl)-3-(4-dimethylamino phenyl) prop-2-en-1-one

A chalcone, 1-(4-chloro phenyl)-3-(4-dimethylamino phenyl) prop-2-en-1-one, abbreviated as CDAC was synthesized by the Claisen–Schmidt condensation method and single crystals were grown by the slow evaporation technique at ambient temperature. The structural confirmation was done using 1H-NMR, FT-IR, powder XRD and single crystal XRD studies. The crystal crystallizes in the monoclinic space group P21/c with a=33.082(3)Å, b=14.4722(13)Å, c=6.0799(5)Å, α=90°, β=92.030(4)°, γ=90° and Z=8. The high temperature DSC shows a phase transition at temperature 141.53°C that corresponds to the melting point of the crystal. This is confirmed in DTA study which shows an endothermic dip corresponding to this melting point. The optical studies were made with UV–visible and Z-scan techniques. The nonlinear absorption and nonlinear refraction coefficients of the sample were obtained by performing the Z-scan experimental measurements. The real and imaginary parts of third-order bulk susceptibility χ(3) were evaluated. The coefficient of nonlinear refraction (γ) of the compound is found to be negative as revealed by the signature of closed aperture data.

Δ-9,11 Modification of Glucocorticoids Dissociates Nuclear Factor-κB Inhibitory Efficacy from Glucocorticoid Response Element-Associated Side Effects

Glucocorticoids are standard of care for many inflammatory conditions, but chronic use is associated with a broad array of side effects. This has led to a search for dissociative glucocorticoids--drugs able to retain or improve efficacy associated with transrepression [nuclear factor-κB (NF-κB) inhibition] but with the loss of side effects associated with transactivation (receptor-mediated transcriptional activation through glucocorticoid response element gene promoter elements). We investigated a glucocorticoid derivative with a Δ-9,11 modification as a dissociative steroid. The Δ-9,11 analog showed potent inhibition of tumor necrosis factor-α-induced NF-κB signaling in cell reporter assays, and this transrepression activity was blocked by 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one (RU-486), showing the requirement for the glucocorticoid receptor (GR). The Δ-9,11 analog induced the nuclear translocation of GR but showed the loss of transactivation as assayed by GR-luciferase constructs as well as mRNA profiles of treated cells. The Δ-9,11 analog was tested for efficacy and side effects in two mouse models of muscular dystrophy: mdx (dystrophin deficiency), and SJL (dysferlin deficiency). Daily oral delivery of the Δ-9,11 analog showed a reduction of muscle inflammation and improvements in multiple muscle function assays yet no reductions in body weight or spleen size, suggesting the loss of key side effects. Our data demonstrate that a Δ-9,11 analog dissociates the GR-mediated transcriptional activities from anti-inflammatory activities. Accordingly, Δ-9,11 analogs may hold promise as a source of safer therapeutic agents for chronic inflammatory disorders.

Anti-Cancer Effect of IN-2001 in MDA-MB-231 Human Breast Cancer

In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anticancer activities in preclinical studies. But their precise mechanism of action has not been elucidated. In this study, a novel synthetic inhibitor of HDAC, 3-(4-dimethylamino phenyl)-N-hydroxy-2-propenamide [IN-2001] was examined for its antitumor activity and the underlying molecular mechanisms of any such activity on human breast cancer cell lines. IN-2001 effectively inhibited cellular HDAC activity (IC50 = 0.585 nM) in MDA-MB-231 human breast cancer cells. IN-2001 caused a significant dose-dependent inhibition of cell proliferation in estrogen receptor (ER) negative MDA-MB-231 human breast cancer cells. Cell cycle analysis revealed that the gowth inhibitory effects of IN-2001 might be attributed to cell cycle arrest at G0/G1 and/or G2/Mphase and subsequent apoptosis in human breast cancer cells. These events are accompanied by modulating several cell cycle and apoptosis regulatory genes such as CDK inhibitors p21WAF1 and p27KIP1 cyclin D1, and other tumor suppressor genes such as cyclin D2. Collectively, IN-2001 inhibited cell proliferation and induced apoptosis in human breast cancer cells and these findings may provide new therapeutic approaches, combination of antiestrogen together with a HDAC inhibitor, in the hormonal therapy-resistant ER-negative breast cancers. In summary, our data suggest that this histone deacetylase inhibitor, IN-2001, is a novel promising therapeutic agent with potent antitumor effects against human breast cancers.

Glucocorticoids Improve Renal Responsiveness to Atrial Natriuretic Peptide by Up-Regulating Natriuretic Peptide Receptor-A Expression in the Renal Inner Medullary Collecting Duct in Decompensated Heart Failure

In heart failure, the renal responsiveness to exogenous and endogenous atrial natriuretic peptide (ANP) is blunted. The mechanisms of renal hyporesponsiveness to ANP are complex, but one potential mechanism is decreased expression of natriuretic peptide receptor-A (NPR-A) in inner medullary collecting duct (IMCD) cells. Newly emerging evidence shows that glucocorticoids could produce potent diuresis and natriuresis in patients with heart failure, but the precise mechanism is unclear. In the present study, we found dexamethasone (Dex) dramatically increased the expression of NPR-A in IMCD cells in vitro. The NPR-A overexpression induced by Dex presented in a time- and dose-dependent manner, which emerged after 12 h and peaked after 48 h. The cultured IMCD cells were then stimulated with exogenous rat ANP. Consistent with the findings with NPR-A expression, Dex greatly increased cGMP (the second messenger for the ANP) generation in IMCD cells, which presented in a time- and dose-dependent manner as well. In rats with decompensated heart failure, Dex dramatically increased NPR-A expression in inner renal medulla, which was accompanied by a remarkable increase in renal cGMP generation, urine flow rate, and renal sodium excretion. It is noteworthy that Dex dramatically lowered plasma ANP, cGMP levels, and left ventricular end diastolic pressure. These favorable effects induced by Dex were glucocorticoid receptor (GR)-mediated and abolished by the GR antagonist 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one (RU486). Collectively, glucocorticoids could improve renal responsiveness to ANP by up-regulating NPR-A expression in the IMCD and induce a potent diuretic action in rats with decompensated heart failure.

Synthesis, Antimicrobial and Antitubercular Activities of Some Novel Trihydroxy Benzamido Azetidin-2-one Derivatives

Purpose: To synthesize and characterize novel trihydroxy benzamido azetidin-2-one derivatives and screen them for antimicrobial and antitubercular activities.Methods: A series of novel 4-aryl-3-chloro-N-(3,4,5-trihydroxy benzamido)-2-azetidinones, 3a-o, were synthesized by reacting various Schiff bases of galloyl hydrazide, 2a-o, with chloroacetyl chloride in thepresence of dioxan and triethylamine. Schiff bases of galloyl hydrazide, 2a-o, were synthesized from galloyl hydrazide. The newly synthesized compounds were characterized by infrared spectroscopy (IR),mass spectroscopy (MS) and proton nuclear magnetic spectroscopy (1H NMR) and elemental analysis; they were also screened for in vitro antibacterial, antifungal and antitubercular activities. Ciprofloxacinand ketoconazole were used as reference standards for antibacterial and antifungal activities, respectively, while isoniazid was used as reference standard for antitubercular activity.Results: Compounds 3f, 3g and 3o with chlorophenyl group and compound 3k with 4-dimethyl amino phenyl group exhibited good antimicrobial activity. Also, compounds 3f, 3g, 3k and 3o showed antitubercular activity with minimum inhibitory concentration (MIC) values equivalent to the standard drug (isoniazid). MIC values of 3f, 3g, 3k and 3o were 0.76, 0.57.0.62 and 0.83 ìg/ml, respectively, while the MIC of isoniazid was 0.56.Conclusion: We report the successful synthesis, spectral characterization, as well as in vitro antimicrobial and antitubercular evaluation of a series of novel trihydroxy benzamido azetidin-2-one derivatives. The work shows the emergence of new antimicrobial and antitubercular compounds.

Rapid, Nongenomic Stimulation of Multidrug Resistance Protein 2 (Mrp2) Activity by Glucocorticoids in Renal Proximal Tubule

In renal proximal tubule, multidrug resistance protein 2 (Mrp2) actively transports many organic anions into urine, including drugs and metabolic wastes. Upon exposure to nephrotoxicants or during endotoxemia, both Mrp2 activity and expression are up-regulated. This may result from induced de novo synthesis of Mrp2 or post-transcriptional events involving specific signaling pathways. Here, we investigated glucocorticoid signaling to Mrp2 in killifish renal proximal tubules, a model system in which transport activity can be measured using a fluorescent substrate and confocal imaging. Exposure of tubules to dexamethasone rapidly increased Mrp2-mediated fluorescein methotrexate transport. Other glucocorticoid receptor (GR) ligands, cortisol and triamcinolone acetonide, also stimulated Mrp2-mediated transport. The GR antagonist, mifepristone 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one (RU486), abolished stimulation by all three ligands, whereas the mineralocorticoid receptor antagonist, spironolactone, was ineffective. Consistent with action through a nongenomic mechanism, dexamethasone stimulation of Mrp2-mediated transport was insensitive to cycloheximide and actinomycin D, and immunohistochemistry revealed no alterations in Mrp2 expression at the luminal membrane. (9S-(9α,10β,12α))-2,3,9,10,11,12-hexahydro-10-hydroxy-10-(methoxycarbonyl)-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one (K252a), an inhibitor of the tyrosine receptor kinase subfamily, reduced the dexamethasone effect, as did the specific hepatocyte growth factor receptor (c-Met) tyrosine kinase inhibitor, (2R)-1-[[5-[(Z)-[5-[[(2,6-dichlorophenyl)methyl]sulfonyl]-1,2-dihydro-2-oxo-3H-indol-3-ylidene]methyl]-2,4-dimethyl-1H-pyrrol-3-yl]carbonyl]-2-(1-pyrrolidinylmethyl)pyrrolidine (PHA-665752). Hepatocyte growth factor (HGF), an endogenous ligand for c-Met, stimulated Mrp2-mediated transport. This effect was reversed by PHA-665752 but not by RU486. Inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK 1/2) also abolished the effects of dexamethasone and HGF. Our results disclose a novel mechanism by which glucocorticoids acting through GR, c-Met, and MEK1/2 cause rapid, nongenomic stimulation of Mrp2-mediated transport in renal proximal tubules. This up-regulation may be nephroprotective, enhancing efflux of metabolic wastes and toxicants during cell and tissue stress.

Photochemical behavior in azobenzene having acidic groups. Preparation of magnetic photoresponsive gels

The photochemistry of three azobenzenes representing contrasting photochemical behaviors is described in the present work. Thus, Methyl Orange (MO, 4-[[(4-dimethylamino)phenyl]-azo]benzenesulfonic acid sodium salt, hereinafter ( 1) and 4-hydroxyazobenzene-4′-sulfonic acid ( 2) undergo in water fast photochemical proton shift, with decays in the microsecond timescale. In contrast to the previous cases, azobenzene-4,4′-dicarboxylic acid ( 3) undergoes photoisomerization in water. This photochemical behavior allows the preparation of aqueous gels with Aerosil as gelating agent (5% weight) exhibiting high cyclability and photoreversible isomerization of the trans to cis (300 nm irradiation) and cis to trans (visible white light irradiation). Gels containing azobenzene 3 as photoresponsive molecule and well-dispersed magnetite (Fe 3O 4) nanoparticles exhibit simultaneously high photoresponse and magnetic properties. Photoisomerization of compound 3 in these gels leads to small but reliable changes (25 G coercive field) in the magnetic hysteresis loop of magnetite nanoparticles. This novel concept of optical modulation of magnetism in iron oxide nanoparticles paves the way for the study of new systems, with a stronger coupling between trans– cis photoisomerization and magnetic properties.

Microwave assisted synthesis and biological activity of novel coumarinyltriazolothiadiazoles.

A series of new 3-(4-methylcoumarinyl-7-oxymethyl)-6-substitutedphenyl-5,6-dihydro-s-triazolo (3,4-b)(1,3,4)-thiadiazoles 2(a-j) have been synthesized by reacting 5-(4-methyl coumarinyl-7-oxymethyl)-4-amino-3-mercapto(4H)-1,2,4-triazole with various aromatic aldehydes by microwave assisted organic synthesis. The structure of the compounds 2 (a-j) has been confirmed by IR, 1H NMR and mass spectral data. All the compounds were screened for antimicrobial and antioxidant activity. Among the compounds tested, compounds 2d (4-dimethyl amino phenyl derivative) and 2h (3,4-dimethoxy phenyl derivative) showed better antimicrobial and antioxidant activity than rest of the compounds in the series.

Synthesis and evaluation of antiinflammatory activity of substituted chalcone derivatives

In an effort to develop potent antiinflammatory agents, a series of substituted chalcone derivatives was synthesized and evaluated for antiinflammatory activity through monitoring of their ability to inhibit xylene-induced ear edema in mice. Some of the tested compounds exhibited significant activity, and compounds 3f [(E)-1-(2,4-dihydroxyphenyl)-3-(4-dimethylamino)phenyl)prop-2-en-1-one] and 3h [(E)-3-(4-chlorophenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one] showed the highest antiinflammatory activity (62 and 68% inhibition, respectively, 2 h before administration), comparable with or even slightly more potent than the reference drug ibuprofen (53%). Furthermore, the structure–activity relationship of these substituted chalcone derivatives was demonstrated.

6-Ketomethyl Phenanthridine as a New Carrier in the Construction of a Highly Selective Fe(III) Ion-Selective Membrane Electrode

A new Fe^{3+} ion-selective membrane electrode based on 6-ketomethyl phenanthridine (6-KMPT) and 1-(4-dimethyl aminophenyl)-2-(5H-phenanthridine-6-ylidene)-ethanone, which were incorporated in a plasticized polyvinyl chloride (PVC) membrane, is described. The optimized membrane demonstrated a linear dynamic range of 5.2 \times 10^{-6}-1.0 \times 10^{-2} M, with a near Nernstian slope of 19.5 \pm 1.5 mV per decade and a detection limit of 1.2 \times 10^{-6} M. The electrode showed high selectivity for Fe^{3+} ions in comparison to other metal ions. The effect of membrane composition on the potential response of the electrode was studied. The best performance was observed for the membrane comprised of electroactive material (6-KMPT), dioctyl phthalate (DOP) as plasticizer, and PVC in the optimum ratio of 5:67:28% w/w. The pH working range of the sensor was 1.2-3.0. The proposed Fe^{3+} sensor was successfully used for determining the presence of iron in pharmaceuticals and the results were in good agreement with the value obtained using the atomic absorption spectroscopic method.

Regulation of Aryl Hydrocarbon Receptor Expression and Function by Glucocorticoids in Mouse Hepatoma Cells

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates most biological responses to 2,3, 7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related aromatic hydrocarbons. Although the role of the AHR in control of drug metabolism and endocrine disruption is partly understood, we know little about the regulation of the AHR itself by endocrine factors. Our work with hypophysectomized rats suggested that hepatic AHR protein level is positively regulated by pituitary-dependent factors. A current hypothesis is that adrenal glucocorticoids elevate AHR expression and enhance responsiveness to AHR agonists. Dexamethasone (DEX) at concentrations that activate the glucocorticoid receptor (GR) increased AHR mRNA, protein, and TCDD-binding by approximately 50% in Hepa-1 mouse hepatoma cells. This response was blocked by the GR antagonist 17beta-hydroxy-11beta-[4-dimethylamino phenyl]-17alpha-[1-propynyl]estra-4,9-dien-3-one (RU486), suggesting GR involvement. This small magnitude increase in AHR levels was functionally significant; pretreatment of Hepa-1 cells with DEX caused a 75% increase in the maximum induction of an AHR-activated luciferase reporter plasmid by TCDD. A luciferase reporter under control of the proximal 2.5 kilobases of the mouse Ahr 5'-flanking region and promoter was induced approximately 2.5-fold by DEX when cotransfected with a mouse GR expression plasmid. This is the first demonstration that glucocorticoids increase AHR levels in hepatoma cells via a GR-dependent transcriptional mechanism, suggesting a novel aspect of cross-talk between the AHR and the GR.

PVC‐Based on Thiopyrilium Derivatives Membrane Electrodes for Determination of Histamine

AbstractThis study describes novel histamine‐selective electrodes, having their basis on thiopyrilium (TP) derivatives as suitable ionophores. The electrodes were prepared by incorporating the TP derivatives into plasticized poly(vinyl chloride) (PVC) membranes. These electrodes demonstrate high selectivity as far as the histamine response is considered, as compared with many common inorganic anions and other kinds of amino acids. The influence of membrane composition, pH and the effect of lipophilic cationic and anionic additives on the response characteristics of the electrode were investigated. The resulting sensor based on 2,6‐bis(4‐dimethyl amino phenyl)‐4‐phenyl thiopyrilium perchlorate (TP4) responds to histamine in a wide concentration range from 5.0 × 10−6 to 1.0 × 10−1 M with a slope of 54.8 ± 0.6 mV decade−1 and detection limit of 3.0 μ mol L−1 (∼0.3 ppm). The electrode illustrates fast response time and good long‐term stability (more than 2 months). The ability to design histamine‐selective electrodes based on new thiopyrilium derivatives and both to alter selectivity and improve the response characteristics through structural changes to the charged ionophore, has been investigated. The prepared electrode was used for the determination of histamine in a synthetic human serum sample. Consequently, satisfactory recovery results were obtained over a wide concentration range of histamine.

Dexamethasone-Mediated Up-Regulation of HumanCYP2A6Involves the Glucocorticoid Receptor and Increased Binding of Hepatic Nuclear Factor 4α to the Proximal Promoter

Human cytochrome P450 2A6 (CYP2A6) metabolizes various clinically relevant compounds, including nicotine- and tobacco-specific procarcinogens; however, transcriptional regulation of this gene is poorly understood. We investigated the role of the glucocorticoid receptor (GR) in transcriptional regulation of CYP2A6. Dexamethasone (DEX) increased CYP2A6 mRNA and protein levels in human hepatocytes in primary culture. This effect was attenuated by the GR receptor antagonist mifepristone (RU486; 17beta-hydroxy-11beta-[4-dimethylamino phenyl]-17alpha-[1-propynyl]estra-4,9-dien-3-one), suggesting that induction of CYP2A6 by DEX was mediated by the GR. In gene reporter assays, DEX caused dose-dependent increases in luciferase activity that was also prevented by RU486 and progressive truncations of the CYP2A6 promoter delineated DEX-responsiveness to a -95 to +12 region containing an hepatic nuclear factor 4 (HNF4) alpha response element (HNF4-RE). Mutation of the HNF4-RE abrogated HNF4alpha- and DEX-mediated transactivation of CYP2A6. In addition, overexpression of HNF4alpha increased CYP2A6 transcriptional activity by 3-fold. DEX increased HNF4alpha mRNA levels by 4-fold; however, the amount of HNF4alpha nuclear protein was unaltered. Electrophoretic mobility shift, chromatin immunoprecipitation (ChIP), and streptavidin DNA binding assays revealed that DEX increased binding of HNF4alpha to the HNF4-RE and that an interaction of GR and HNF4alpha occurred at this site. Moreover, ChIP assays indicated that histone H4 acetylation of the CYP2A6 proximal promoter chromatin was increased by DEX that may allow for increased binding of HNF4alpha to the HNF4-RE in human hepatocytes. These findings indicate that increased expression of CYP2A6 by DEX is mediated by the GR via a nonconventional transcriptional mechanism involving interaction of HNF4alpha with an HNF4-RE rather than a glucocorticoid response element.

Lithiated Thiaacetals as Initiators for Living Anionic Polymerization of Diene Elastomers: Polymerization and Compounding

Abstract Polybutadiene and poly(butadiene-co-styrene) elastomers were prepared in high conversions using 2-lithio-2- methyl-1,3-dithiane as the initiator. Polymers were readily prepared with a polydispersity index (PDI) of 1.05 to 1.26 and a Mn of up to 208 kg/mol. The replacement of the 2-methyl substituent with phenyl, trimethylsilyl or 4-dimethylamino phenyl also gave active initiators that incorporated at the head of the chain. However, initiation rates appeared to vary somewhat with the structure of the initiators. The polymerizations obtained are in all cases controlled and apparently living with the live chain ends capable of further reactions. The initiators could be generated prior to addition to the polymerization mixture or by an in-situ procedure. Model studies gave evidence that the dithiane chain end can be opened under cure conditions and react with unsaturation present in the polymer chain. Several of the product polymers were found to impart improved hysteresis to carbon and silica-filled rubbery vulcanizates possibly through an endlinking mechanism.