Synthesis and characterization of a new conducting polymer based on 4‐(2,5‐di‐2‐thiophen‐2‐yl‐pyrrol‐1‐yl)‐phthalonitrile

A new conducting polymer was synthesized by electrochemical polymerization of 4‐(2,5‐di‐2‐thiophen‐2‐yl‐pyrrol‐1‐yl)‐phthalonitrile (SNS‐PN). Electrochemical polymerization of SNS‐PN was performed in acetonitrile/0.2M LiClO₄ solvent/electrolyte couple. Characterizations of the resulting polymer P(SNS‐PN) were carried out by cyclic voltammetry, UV–vis, and Fourier transform infrared (FTIR) spectroscopic techniques. Spectroelectrochemical studies revealed that P(SNS‐PN) has an electronic band gap of 2.45 eV and exhibits electrochromic behavior. The switching ability of polymer was also monitored and the percentage transmittance change (ΔT%) was found as 24%. It is also found that P(SNS‐PN) is fluorescent and its fluorescence intensity enhances in the presence of cations. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

A Fluorescent RNA Forced‐Intercalation Probe as a Pan‐Selective Marker for Influenza A Virus Infection

The influenza A virus (IAV) genome is segmented into eight viral ribonucleoproteins, each expressing a negatively oriented viral RNA (vRNA). Along the infection cycle, highly abundant single‐stranded small viral RNAs (svRNA) are transcribed in a segment‐specific manner. The sequences of svRNAs and of the vRNA 5′‐ends are identical and highly conserved among all IAV strains. Here, we demonstrate that these sequences can be used as a target for a pan‐selective sensor of IAV infection. To this end, we used a complementary fluorescent forced‐intercalation RNA (IAV QB‐FIT) probe with a single locked nucleic acid substitution to increase brightness. We demonstrated by fluorescence in situ hybridization (FISH) that this probe is suitable and easy to use to detect infection of different cell types by a broad variety of avian, porcine, and human IAV strains, but not by other influenza virus types. IAV QB‐FIT also provides a useful tool to characterize different infection states of the host cell.     

DNA Primer Extension with Cyclopropenylated 7‐Deaza‐2′‐deoxyadenosine and Efficient Bioorthogonal Labeling in Vitro and in Living Cells

A deoxyadenosine triphosphate (dATP) analogue for DNA labeling was synthesized with the 1‐methylcyclopropene (1MCP) group at the 7‐position of 7‐deaza‐2′‐deoxyadenosine and applied for primer extension experiments. The real‐time kinetic data reveals that this 1MCP‐modified dATP analogue is incorporated into DNA much faster than that of the similarly 1MCP‐modified deoxyuridine triphosphate (dUTP) analogue. The postsynthetic fluorescent labeling of these oligonucleotides works efficiently according to PAGE analysis, and can be applied for immobilization of a functional antibody on a surface. Site‐specific labeling at two different positions in DNA was achieved and the bioorthogonality of the postsynthetic fluorescent labeling was demonstrated in living HeLa cells.     

Highly Efficient Fluorescent Interstrand Photo‐crosslinking of DNA Duplexes Labeled with 5‐Fluoro‐4‐thio‐2′‐O‐methyluridine

The formation of a fluorescent photoadduct between 5‐fluoro‐4‐thiouridine ( ^FS U ), in the sequence context 5′‐A ^FS U A‐3′ and incorporated into a synthetic oligonucleotide either at its 3′‐ or 5′‐end, and one of the thymines of the TAT motif in a complementary target DNA strand led to photo‐crosslinking of the two strands for several oligonucleotide constructs. Enzymatic digestion, MS, UV, and fluorescence spectral analyses of the interstrand crosslinked oligonucleotides revealed the identity of the thymidine that participates in the photo‐crosslinking reaction as well as the diastereomeric structures of the crosslinks. The proposed pathways of interstrand photo‐crosslinking are supported by experiments with isotopically labeled oligonucleotide constructs and visualized by means of molecular dynamics simulations.     

Potent,Metabolically Stable 2‐Alkyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐adenines as Adenosine A2A Receptor Ligands

Inhibition of adenosine A_2A receptors has been shown to elicit a therapeutic response in preclinical animal models of Parkinson’s disease (PD). We previously identified the triazolo‐9H‐purine, ST1535, as a potent A_2AR antagonist. Studies revealed that ST1535 is extensively hydroxylated at the ω‐1 position of the butyl side chain. Here, we describe the synthesis and evaluation of derivatives in which the ω‐1 position has been substituted (F, Me, OH) in order to block metabolism. The stability of the compounds was evaluated in human liver microsomes (HLM), and the affinity for A_2AR was determined. Two compounds, (2‐(3,3‐dimethylbutyl)‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐6‐amine ( 3 b ) and 4‐(6‐amino‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐2‐yl)‐2‐methylbutan‐2‐ol ( 3 c ), exhibited good affinity against A_2AR (K_i=0.4 nM and 2 nM , respectively) and high in vitro metabolic stability (89.5 % and 95.3 % recovery, respectively, after incubation with HLM for two hours).     

Preparation and characterization of poly(D,L‐lactic‐co‐glycolic acid) nanoparticles containing 3‐(benzoxazol‐2‐yl)‐7‐(N,N‐diethyl amino)chromen‐2‐one

Nanoparticles (NPs) of poly(D,L ‐lactic‐co‐glycolic acid) containing the compound 3‐(benzoxazol‐2‐yl)‐7‐(N,N‐diethyl amino)chromen‐2‐one (C2) were prepared by the solvent‐evaporation technique with a mean loading efficiency of 74.0 ± 3.0%. Size distribution studies, done with dynamic light scattering and scanning electron microscopy, revealed that these particles were spherical in shape, with a mean diameter of 253 nm, a low polydispersity, and a tendency toward aggregation; the last was confirmed by the low ζ potential. A low release profile was observed for C2 when the NPs were dispersed in Hank's buffer (pH = 7.4); this was related to the low porosity of the NPs and the extremely low diffusivity of C2 in water. Differential scanning calorimetry data presented a glass‐transition temperature depression caused by an increase in the NP molecular mobility after the incorporation of C2. Spectroscopic and photophysical data exploring the capabilities of C2 as a fluorescent probe suggested a high microviscosity for the environment in which the probe was allocated, which was most likely due to strong polar interactions involving ester groups from the polymer and the diethylamino moiety from C2. The cellular toxicity and uptake of C2 and NP–C2 systems were evaluated with B16‐F10 murine cells, which showed that C2 (in solution or encapsulated) was nontoxic and able to be located inside the neoplasic cells. Besides, the encapsulation method was capable of maintaining the drug's properties and improved the drug delivery to the target cell. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2007     

Darstellung und Atropisomerie von 1‐(2‐Aryl)‐piperidin‐2‐onen

Preparation and Atropisomerism of 1‐(2‐Aryl)‐piperidin‐2‐ones Course and rate of the dehydrogenation of N‐tertiary piperidines dependent on their substitution in 4‐position and on the hydroxy bearing neighbor group were examined, using mercury(II)‐EDTA and the model amino alcohols 1a 1e, 3a 3f, 8a 8f and 10a 10f . The results showed that increasing size of 4‐substituents and neighbor groups too decreased the rate of reaction. The products from the 2‐substituted benzylic alcohols, the 2‐piperidones 7a 7g, 9a 9g and 11a 11g demonstrated atropisomerism. In the case of chiral neighbor groups diastereomeric mixtures were formed.     

Synthesis and photopolymerization of 2‐(acryloyloxy)ethyl piperidine‐1‐carboxylate and 2‐(acryloyloxy)ethyl morpholone‐4‐carboxylate

Two low‐viscosity monomers, 2‐(acryloyloxy)ethyl piperidine‐1‐carboxylate (AEPC II) and 2‐(acryloyloxy)ethyl morpholone‐4‐carboxylate (AEMC), were synthesized with a non‐isocyanate route. The photopolymerization kinetics was monitored by real‐time infrared spectroscopy with a horizontal sample holder. The results indicated that AEPC II and AEMC had high ultraviolet curing rates and final double‐bond conversions, which could reach 90 and 95%, respectively. The glass‐transition temperatures of AEPC II/urethane acrylate resin (1/4 w/w), AEMC/urethane acrylate resin (1/4 w/w), and isobornyl acrylate/urethane acrylate resin (1/4 w/w) mixtures were 37.5, 45.6, and 57°C, respectively. The crosslink density of the AEMC/urethane acrylate resin (1/4 w/w) mixture was lower than that of the isobornyl acrylate/urethane acrylate resin (1/4 w/w) mixture. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Synthesis and Evaluation of 1‐(1‐(Benzo[b]thiophen‐2‐yl)cyclohexyl)piperidine (BTCP) Analogues as Inhibitors of Trypanothione Reductase

Thirty two analogues of phencyclidine were synthesised and tested as inhibitors of trypanothione reductase (TryR), a potential drug target in trypanosome and leishmania parasites. The lead compound BTCP ( 1 , 1‐(1‐benzo[b]thiophen‐2‐yl‐cyclohexyl) piperidine) was found to be a competitive inhibitor of the enzyme (K_i=1 μM ) and biologically active against bloodstream T. brucei (EC₅₀=10 μM ), but with poor selectivity against mammalian MRC5 cells (EC₅₀=29 μM ). Analogues with improved enzymatic and biological activity were obtained. The structure–activity relationships of this novel series are discussed.     

High cis‐1,4 polyisoprene or cis‐1,4/3,4 binary polyisoprene synthesized using 2‐(benzimidazolyl)‐6‐(1‐(arylimino)ethyl)pyridine cobalt(II) dichlorides

Polyisoprene (PI) with a high content of cis‐1,4 (up to 95%) or cis‐1,4/3,4 binary structures was synthesized using a cobalt system in toluene. The cobalt system, which exhibited high activities (up to 3.50 × 10⁶ g PI (mol Co)^?1 h^?1), contained a series of 2‐(benzimidazolyl)‐6‐(1‐(arylimino)ethyl)pyridine cobalt(II) dichlorides activated with ethylaluminium sesquichloride. The nature of the ligands and the reaction conditions significantly affected both the catalytic performance of the cobalt complexes as well as the structures of the resultant PI. The stereospecific polymerization of isoprene could be tuned via changing either the co‐catalyst or solvent: for example, increased content of 3,4 PI (up to 36.6%) was achievable in heptane in the presence of diethylaluminium chloride. Sequence distribution analysis by ¹³C NMR spectroscopy indicated that most 3,4 units occurred randomly in the PI chains. © 2013 Society of Chemical Industry     

Atom transfer radical polymerization of styrene with 2‐(1‐bromoethyl)‐anthraquinone as an initiator

2‐(1‐Bromoethyl)‐anthraquinone (BEAQ) was successfully used as an initiator in the atom transfer radical polymerization of styrene with CuBr/N,N,N′,N′,N″‐pentamethyldiethylenetriamine as the catalyst at 110°C. The polymerizations were well controlled with a linear increase in the molecular weights (M_n's) of the polymers with monomer conversion and relatively low polydispersities (1.1 < weight‐average molecular weight (M_w)/M_n < 1.5) throughout the poly merizations. The resultant polystyrene thus possessed one chromophore moiety (2‐ethyl‐anthraquinone) at the α end and one bromine atom at the ω end, both from the initiator BEAQ. The intensity of UV absorptions of the resultant polymers decreased with increasing molecular weights of the polymers. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 102: 2081–2085, 2006     

Development of 3‐Phenyl‐N‐(2‐(3‐phenylureido)ethyl)‐thiophene‐2‐sulfonamide Compounds as Inhibitors of Antiapoptotic Bcl‐2 Family Proteins

Antiapoptotic Bcl‐2 family proteins, such as Bcl‐x_L, Bcl‐2, and Mcl‐1, are often overexpressed in tumor cells, which contributes to tumor cell resistance to chemotherapies and radiotherapies. Inhibitors of these proteins thus have potential applications in cancer treatment. We discovered, through structure‐based virtual screening, a lead compound with micromolar binding affinity to Mcl‐1 (inhibition constant (K_i)=3 μM ). It contains a phenyltetrazole and a hydrazinecarbothioamide moiety, and it represents a structural scaffold not observed among known Bcl‐2 inhibitors. This work presents the structural optimization of this lead compound. By following the scaffold‐hopping strategy, we have designed and synthesized a total of 82 compounds in three sets. All of the compounds were evaluated in a fluorescence‐polarization binding assay to measure their binding affinities to Bcl‐x_L, Bcl‐2, and Mcl‐1. Some of the compounds with a 3‐phenylthiophene‐2‐sulfonamide core moiety showed sub‐micromolar binding affinities to Mcl‐1 (K_i=0.3–0.4 μM ) or Bcl‐2 (K_i≈1 μM ). They also showed obvious cytotoxicity on tumor cells (IC₅₀<10 μM ). Two‐dimensional heteronuclear single quantum coherence NMR spectra of three selected compounds, that is, YCW‐E5, YCW‐E10, and YCW‐E11, indicated that they bind to the BH3‐binding groove on Bcl‐x_L in a similar mode to ABT‐737. Several apoptotic assays conducted on HL‐60 cells demonstrated that these compounds are able to induce cell apoptosis through the mitochondrial pathway. We propose that the compounds with the 3‐phenylthiophene‐2‐sulfonamide core moiety are worth further optimization as effective apoptosis inducers with an interesting selectivity towards Mcl‐1 and Bcl‐2.     

The reactions of 2‐(4‐morpholinothio)‐ and 2‐(4‐morpholinodithio) benzothiazole in the absence of polyisoprene

2‐(4‐morpholinothio)benzothiazole (MOR) and 2‐(4‐morpholinodithio)benzothiazole (MDB) were heated with sulfur and ZnO in a DSC. The products formed at various temperatures were identified and analyzed by HPLC. At temperatures below 200°C, decomposition of the accelerator in the absence of other curatives was slow, degradation products being mainly 2‐bisbenzothiazole‐2,2′‐disulfide (MBTS) and 2‐mercaptobenzothiazole (MBT). A rapid exothermic decomposition above 200°C resulted in the formation of MBT (or its amine salt) and 2‐(4‐morpholino)benzothiazole (MB). MOR and MDB reacted with sulfur to form higher polysulfides. MDB was shown to react more readily with sulfur than MOR and the delayed action of MOR in rubber can therefore not be ascribed to a stable polysulfide as suggested by other authors. Neither MOR nor MDB was found to react with ZnO. A limited reaction between MBT and ZnO was observed. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 72: 1235–1240, 1999     

Synthesis and Biological Characterization of (3R,4R)‐4‐(2‐(Benzhydryloxy)ethyl)‐1‐((R)‐2‐hydroxy‐2‐phenylethyl)‐piperidin‐3‐ol and Its Stereoisomers for Activity toward Monoamine Transporters

A novel series of optically active molecules based on a 4‐(2‐(benzhydryloxy)ethyl)‐1‐((R)‐2‐hydroxy‐2‐phenylethyl)‐piperidin‐3‐ol template were developed. Depending on stereochemistry, the compounds exhibit various degrees of affinity for three dopamine, serotonin, and norepinephrine transporters. These molecules have the potential for treating several neurological disorders such as drug abuse, depression, and attention deficit hyperactivity disorder.

     

5′‐(E)‐Vinylphosphonate: A Stable Phosphate Mimic Can Improve the RNAi Activity of siRNA–GalNAc Conjugates

Small interfering RNA (siRNA)‐mediated silencing requires siRNA loading into the RNA‐induced silencing complex (RISC). Presence of 5′‐phosphate (5′‐P) is reported to be critical for efficient RISC loading of the antisense strand (AS) by anchoring it to the mid‐domain of the Argonaute2 (Ago2) protein. Phosphorylation of exogenous duplex siRNAs is thought to be accomplished by cytosolic Clp1 kinase. However, although extensive chemical modifications are essential for siRNA–GalNAc conjugate activity, they can significantly impair Clp1 kinase activity. Here, we further elucidated the effect of 5′‐P on the activity of siRNA–GalNAc conjugates. Our results demonstrate that a subset of sequences benefit from the presence of exogenous 5′‐P. For those that do, incorporation of 5′‐(E)‐vinylphosphonate (5′‐VP), a metabolically stable phosphate mimic, results in up to 20‐fold improved in vitro potency and up to a threefold benefit in in vivo activity by promoting Ago2 loading and enhancing metabolic stability.     

Synthesis of fluorescent methoxy poly(ethylene glycol)‐b‐Poly(ethyl cyanoacrylate)–2‐(N‐carbazolyl) ethyl methacrylate copolymer via living oxyanion‐initiated polymerization

The fluorescent amphiphilic block copolymer methoxy poly(ethylene glycol) (mPEG)‐b‐poly(ethyl cyanoacrylate) (PECA)–2‐(N‐carbazolyl) ethyl methacrylate (CzEMA) was synthesized via living oxyanion‐initiated polymerization. mPEG‐b‐PECA–CzEMA was characterized by gel permeation chromatography, ¹H‐NMR, and Fourier transform infrared spectroscopy. The results indicate that the polymerization was well controlled with a narrow molecular weight distribution. The mPEG‐b‐PECA–CzEMA nanoparticles prepared by nanoprecipitation techniques showed a narrow size distribution with an average diameter of less than 100 nm. The mPEG‐b‐PECA–CzEMA exhibited a strong carbazole fluorescence. Furthermore, it was found that the fluorescence intensity of mPEG‐b‐PECA–CzEMA was sensitive to a change in solvent. The results indicate that a subtle change in the state of the polymer micellar association may have altered the state of carbazole groups, which was responsible for the fluorescence emission. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Palladium‐nanoparticle intercalated vermiculite for selective hydrogenation of α,β‐unsaturated aldehydes

Palladium nanoparticles were generated in the interlamellar region of swelling 2:1 type vermiculite clay using an adsorption excess isotherm. An adsorption excess isotherm was constructed for vermiculite after exchanging the exchangeable Na⁺ ions in the interlamellar region using a binary liquid mixture (ethanol:toluene). Based on adsorption excess isotherm, 1% w/w palladium was intercalated into the interlamellar space of vermiculite. The Pd‐intercalated vermiculite was characterized by X‐ray diffraction, transmission electron microscopy and atomic absorption spectroscopy. The 1% w/w Pd‐intercalated vermiculite was tested for its catalytic activity towards selective hydrogenation reactions involving some α,β‐unsaturated carbonyl compounds using a pulse reactor and its catalytic activity was compared with commercial 1% Pd/C. The intercalated catalyst was found to be very selective towards the desired product of unsaturated alcohols. Copyright © 2007 Society of Chemical Industry     

Regioselective Addition of Organometallic Reagents to 2‐(1‐Alkynyl)‐2‐alken‐1‐ones for an Efficient Synthesis of Substituted 1,2‐Allenyl Ketones

Highly substituted 1,2‐allenyl ketones can be easily and efficiently prepared from organometallic reagents and readily available 2‐(1‐alkynyl)‐2‐alken‐1‐ones. The synthetic application of 1,2‐allenyl ketone products was also showcased by palladium‐catalyzed further transformation.