Structure‐Guided Discovery of Antitubercular Agents That Target the Gyrase ATPase Domain

In this study we explored the pharmaceutically underexploited ATPase domain of DNA gyrase (GyrB) as a potential platform for developing novel agents that target Mycobacterium tuberculosis. In this effort a combination of ligand‐ and structure‐based pharmacophore modeling was used to identify structurally diverse small‐molecule inhibitors of the mycobacterial GyrB domain based on the crystal structure of the enzyme with a pyrrolamide inhibitor (PDB ID: 4BAE ). Pharmacophore modeling and subsequent in vitro screening resulted in an initial hit compound 5 [(E)‐5‐(5‐(2‐(1H‐benzo[d]imidazol‐2‐yl)‐2‐cyanovinyl)furan‐2‐yl)isophthalic acid; IC₅₀=4.6±0.1 μm ], which was subsequently tailored through a combination of molecular modeling and synthetic chemistry to yield the optimized lead compound 24 [(E)‐3‐(5‐(2‐cyano‐2‐(5‐methyl‐1H‐benzo[d]imidazol‐2‐yl)vinyl)thiophen‐2‐yl)benzoic acid; IC₅₀=0.3±0.2 μm ], which was found to display considerable in vitro efficacy against the purified GyrB enzyme and potency against the H₃₇Rv strain of M. tuberculosis. Structural handles were also identified that will provide a suitable foundation for further optimization of these potent analogues.     

The Discovery of Phenylbenzamide Derivatives as Grb7‐Based Antitumor Agents

Grb7 is a non‐catalytic protein, the overexpression of which has been associated with the proliferative and migratory potentials of cancer cells. Virtual screening strategies involving a shape‐based similarity search, molecular docking, and 2D‐similarity searches complemented by experimental binding studies (Thermofluor and isothermal titration calorimetry) resulted in the identification of nine novel phenylbenzamide‐based antagonists of the Grb7 SH2 domain. Moderate binding affinities were observed, ranging from K_d=32.3 μM for lead phenylbenzamide NSC 104999 ( 1 ) to K_d=1.1 μM for a structurally related compound, NSC 57148 ( 2 ). Deconvolution of the affinity data into its components revealed differences in lead binding, from being entropy based (lead 1 ) to enthalpically driven (NSC 100874 ( 3 ), NSC 55158 ( 4 ), and compound 2 ). Finally, the lead compound 1 was found to decrease the growth of MDA‐MB‐468 breast cancer cells, with an IC₅₀ value of 39.9 μM . It is expected that these structures will serve as novel leads in the development of Grb7‐based anticancer therapeutics.     

Inversion domain network stabilization and spinel phase suppression in ZnO

The development of inversion domain networks consisting of basal‐plane and pyramidal‐plane inversion domain boundary (b‐IDB and p‐IDB) interfaces within grains in Sn‐Al dual‐doped ZnO (Zn_0.98Sn_0.01Al_0.01O) polycrystalline ceramics has been confirmed using transmission electron microscopy. The atomic structure of the b‐IDB and p‐IDB interfaces has been analyzed using atomic‐resolution scanning transmission electron microscopy. The localization of Sn and Al at the respective sites of the b‐IDBs and p‐IDBs was confirmed by energy‐dispersive X‐ray spectroscopy. In contrast to Sn or Al single‐dopant addition to ZnO, which results in the formation of spinel phase precipitates without the development of inversion domain networks, Sn‐Al dual‐doping caused the suppression of spinel phase formation and the formation of monophasic inversion domain networks composed of RMO₃(ZnO)_n homologous phase compound members, where R and M represent dopants substituting at the b‐IDB and p‐IDB sites, with a general formula of SnAlO₃(ZnO)_n. The results of this study demonstrate that the formation of inversion domain networks in ZnO‐based ceramics can be stabilized via multiple‐dopant addition. This finding has potential implications for the modification of the bulk or nanoscale properties based on the choice of the specific dopants, R and M, the control of the ratio R:M and the value of n in the RMO₃(ZnO)_n homologous phase compound members constituting the inversion domain networks.     

Inversion domain boundaries in Mn and Al dual‐doped ZnO: Atomic structure and electronic properties

The atomic and electronic structures of inversion domain boundaries in Mn‐Al dual‐doped ZnO (Zn_0.89Mn_0.1Al_0.01O) have been investigated. Using atomic‐resolution scanning transmission electron microscopy, a head‐to‐head c‐axis configuration and cation stacking sequence of αβαβ|γ|αβαβ along the c‐axis were observed at the basal‐plane inversion domain boundary. Energy‐dispersive X‐ray spectroscopy and electron energy‐loss spectroscopy revealed significant localization of Mn and minor localization of Al at the basal‐plane inversion domain boundary. Based on experimental findings, a Mn‐doped basal‐plane inversion domain boundary slab model was constructed and refined by first principles calculations. The model is in agreement with atomic‐resolution images. The local electronic density of states of the slab model basal‐plane inversion domain boundary shows a hybridization of the Mn d and O p states within the valence band and localized Mn d states in the conduction band. The thermoelectric properties of Zn_0.99?xMn_xAl_0.01O ceramics have been reported in a previous work. In this work, the effects of inversion domain boundaries on the thermoelectric properties are discussed. In comparison to Zn_0.99?xMn_xAl_0.01O ceramics with x≤0.05, inversion domain boundaries in Zn_0.89Mn_0.1Al_0.01O caused thermal and electrical conductivity reduction due to interface scattering of phonons and electrons. The Seebeck coefficient increased, suggesting electron filtering at inversion domain boundaries.     

E‐64c‐Hydrazide: A Lead Structure for the Development of Irreversible Cathepsin C Inhibitors

Cathepsin C is a papain‐like cysteine protease with dipeptidyl aminopeptidase activity that is thought to activate various granule‐associated serine proteases. Its exopeptidase activity is structurally explained by the so‐called exclusion domain, which blocks the active‐site cleft beyond the S2 site and, with its Asp 1 residue, provides an anchoring point for the N terminus of peptide and protein substrates. Here, the hydrazide of (2S,3S)‐trans‐epoxysuccinyl‐L ‐leucylamido‐3‐methylbutane (E‐64c) (k₂/K_i=140±5 M ^?1 s^?1) is demonstrated to be a lead structure for the development of irreversible cathepsin C inhibitors. The distal amino group of the hydrazide moiety addresses the acidic Asp 1 residue at the entrance of the S2 pocket by hydrogen bonding while also occupying the flat hydrophobic S1′–S2′ area with its leucine‐isoamylamide moiety. Furthermore, structure–activity relationship studies revealed that functionalization of this distal amino group with alkyl residues can be used to occupy the conserved hydrophobic S2 pocket. In particular, the n‐butyl derivative was identified as the most potent inhibitor of the series (k₂/K_i=56 000±1700 M ^?1 s^?1).     

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.     

Discovery, synthesis, and in vitro evaluation of West Nile virus protease inhibitors based on the 9,10-dihydro-3H,4aH-1,3,9,10a-tetraazaphenanthren-4-one scaffold

West Nile virus (WNV), a member of the Flaviviridae family, is a mosquito‐borne pathogen that causes a great number of human infections each year. Neither vaccines nor antiviral therapies are currently available for human use. In this study, a WNV NS2B–NS3 protease inhibitor with a 9,10‐dihydro‐3H,4aH‐1,3,9,10a‐tetraazaphenanthren‐4‐one scaffold was identified by screening a small library of non‐peptidic compounds. This initial hit was optimized by solution‐phase synthesis and screening of a focused library of compounds bearing this scaffold. This led to the identification of a novel, uncompetitive inhibitor ( 1a40 , IC₅₀=5.41±0.45 μM ) of WNV NS2B–NS3 protease. Molecular docking of this chiral compound onto the WNV protease indicates that the S enantiomer of 1a40 appears to interfere with the productive interactions between the NS2B cofactor and the NS3 protease domain; (S)‐ 1a40 is a preferred isomer for inhibition of WNV NS3 protease.     

Semirational Protein Engineering of CYP153AM.aq.‐CPRBM3 for Efficient Terminal Hydroxylation of Short‐ to Long‐Chain Fatty Acids

The regioselective terminal hydroxylation of alkanes and fatty acids is of great interest in a variety of industrial applications, such as in cosmetics, in fine chemicals, and in the fragrance industry. The chemically challenging activation and oxidation of non‐activated C?H bonds can be achieved with cytochrome P450 enzymes. CYP153A_M.aq.‐CPR_BM3 is an artificial fusion construct consisting of the heme domain from Marinobacter aquaeolei and the reductase domain of CYP102A1 from Bacillus megaterium. It has the ability to hydroxylate medium‐ and long‐chain fatty acids selectively at their terminal positions. However, the activity of this interesting P450 construct needs to be improved for applications in industrial processes. For this purpose, the design of mutant libraries including two consecutive steps of mutagenesis is demonstrated. Targeted positions and residues chosen for substitution were based on semi‐rational protein design after creation of a homology model of the heme domain of CYP153A_M.aq., sequence alignments, and docking studies. Site‐directed mutagenesis was the preferred method employed to address positions within the binding pocket, whereas diversity was created with the aid of a degenerate codon for amino acids located at the substrate entrance channel. Combining the successful variants led to the identification of a double variant—G307A/S233G—that showed alterations of one position within the binding pocket and one position located in the substrate access channel. This double variant showed twofold increased activity relative to the wild type for the terminal hydroxylation of medium‐chain‐length fatty acids. This variant furthermore showed improved activity towards short‐ and long‐chain fatty acids and enhanced stability in the presence of higher concentrations of fatty acids.     

Molecular Recognition of Two 2,4‐syn‐Functionalized (S)‐Glutamate Analogues by the Kainate Receptor GluK3 Ligand Binding Domain

The kainate receptors are the least studied subfamily of ionotropic glutamate receptors. These receptors are thought to have a neuromodulatory role and have been associated with a variety of disorders in the central nervous system. This makes kainate receptors interesting potential drug targets. Today, structures of the ligand binding domain (LBD) of the kainate receptor GluK3 are only known in complex with the endogenous agonist glutamate, the natural product kainate, and two synthetic agonists. Herein we report structures of GluK3 LBD in complex with two 2,4‐syn‐functionalized (S)‐glutamate analogues to investigate their structural potential as chemical scaffolds. Similar binding affinities at GluK3 were determined for the 2‐(methylcarbamoyl)ethyl analogue (K_i=4.0 μM ) and the 2‐(methoxycarbonyl)ethyl analogue (K_i=1.7 μM ), in agreement with the similar positioning of the compounds within the binding pocket. As the binding affinity is similar to that of glutamate, this type of Cγ substituent could be used as a scaffold for introduction of even larger substituents reaching into unexplored binding site regions to achieve subtype selectivity.     

Preparation and characterization of polystyrene/titanium dioxide composite particles containing organic ultraviolet‐stabilizer groups

Polystyrene/titanium dioxide (TiO₂) composite particles containing organic ultraviolet (UV)‐stabilizer groups were prepared by the emulsion copolymerization of styrene and 2‐hydroxy‐4‐(3‐methacryloxy‐2‐hydroxylpropoxy)benzophenone with sodium sulfopropyl lauryl maleate as a surfactant in the presence of rutile TiO₂ modified with 3‐(trimethoxysilyl) propyl methacrylate, and the product was poly[styrene‐co‐sodium sulfopropyl lauryl maleate‐co‐2‐hydroxy‐4‐(3‐methacryloxy‐2‐hydroxylpropoxy) benzophenone] [poly(St‐co‐M12‐co‐BPMA)]/TiO₂ composite particles. The structures of the composite particles were characterized with Fourier transform infrared spectroscopy, ultraviolet–visible (UV–vis) absorption spectroscopy, thermogravimetric analysis, and differential scanning calorimetry. The Fourier transform infrared and UV–vis measurements showed that poly(St‐co‐M12‐co‐BPMA) was grafted from the surface of TiO₂, and this copolymer possessed a high absorbance capacity for UV light, which is very important for improving the UV resistance of polystyrene. The thermogravimetric analysis measurements indicated that the percentage of grafting and the grafting efficiency could reach 513.9 and 59.9%, respectively. The differential scanning calorimetry measurement indicated that the glass‐transition temperature of the poly(St‐co‐M12‐co‐BPMA)/TiO₂ composite particles was higher than that of poly (St‐co‐M12‐co‐BPMA).These research results are very important for preparing polystyrene with high UV resistance. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007     

Research on the preparation and antibacterial properties of 2‐N‐thiosemicarbazide‐6‐O‐hydroxypropyl chitosan membranes with iodine

The 2‐N‐thiosemicarbazide‐6‐O‐hydroxypropyl chitosan (ATU‐HPCS) was prepared by chitosan grafted hydroxypropyl and thiosemicarbazide through the method of “amino protection‐graft‐deprotection,” while the ATU‐HPCS gel membranes were obtained from gelatin and polyvinyl pyrrolidone as additives, and the ATU‐HPCS membranes with iodine (ATU‐HPCS‐I₂‐M) were prepared by adding the ethanol solution of iodine in the ATU‐HPCS gel membranes. The ATU‐HPCS‐I₂‐M were characterized to evaluate their potential applications as antibacterial materials. The iodine releasing rule of ATU‐HPCS‐I₂‐M showed a sustained‐release effect of iodine, the maximum emission was approximately 0.80%. The inhibition zone diameters of ATU‐HPCS‐I₂‐M against Staphylococcus aureus (as Gram‐positive bacteria) and Escherichia coli (as Gram‐negative bacteria) were both greater than 15 mm, it demonstrated significant antibacterial activity compared with the ATU‐HPCS gel membranes. The double effects of the biocompatibility of chitosan and the sustained‐release of iodine provided an ideal healing environment for wound surface. These properties have made ATU‐HPCS‐I₂‐M highly potential as a novel natural macromolecule antimicrobial material preventing the bacteria from burns, surgery wounds, etc. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40535.     

Synthesis and Evaluation of Novel Acyclic Nucleoside Phosphonates as Inhibitors of Plasmodium falciparum and Human 6‐Oxopurine Phosphoribosyltransferases

Acyclic nucleoside phosphonates (ANPs) are a promising class of antimalarial therapeutic drug leads that exhibit a wide variety of K_i values for Plasmodium falciparum (Pf) and human hypoxanthine‐guanine‐(xanthine) phosphoribosyltransferases [HG(X)PRTs]. A novel series of ANPs, analogues of previously reported 2‐(phosphonoethoxy)ethyl (PEE) and (R,S)‐3‐hydroxy‐2‐(phosphonomethoxy)propyl (HPMP) derivatives, were designed and synthesized to evaluate their ability to act as inhibitors of these enzymes and to extend our ongoing antimalarial structure–activity relationship studies. In this series, (S)‐3‐hydroxy‐2‐(phosphonoethoxy)propyl (HPEP), (S)‐2‐(phosphonomethoxy)propanoic acid (CPME), or (S)‐2‐(phosphonoethoxy)propanoic acid (CPEE) are the acyclic moieties. Of this group, (S)‐3‐hydroxy‐2‐(phosphonoethoxy)propylguanine (HPEPG) exhibits the highest potency for PfHGXPRT, with a K_i value of 0.1 μM and a K_i value for human HGPRT of 0.6 μM . The crystal structures of HPEPG and HPEPHx (where Hx=hypoxanthine) in complex with human HGPRT were obtained, showing specific interactions with active site residues. Prodrugs for the HPEP and CPEE analogues were synthesized and tested for in vitro antimalarial activity. The lowest IC₅₀ value (22 μM ) in a chloroquine‐resistant strain was observed for the bis‐amidate prodrug of HPEPG.     

Structure and Binding of Peptide‐Dendrimer Ligands to Vitamin B12

The third‐generation peptide‐dendrimer B1 (AcES)₈(BEA)₄(K‐Amb‐Y)₂BCD‐NH₂ (B=branching (S)‐2,3‐diaminopropanoic acid, K=branching lysine, Amb=4‐aminomethyl‐benzoic acid) is the first synthetic model for cobalamin‐binding proteins and binds cobalamin strongly (K_a=5.0×10⁶ M ^?1) and rapidly (k₂=346 M ^?1 s^?1) by coordination of cobalt to the cysteine residue at the dendrimer core. A structure–activity relationship study is reported concerning the role of negative charges in binding. Substituting glutamates (E) for glutamines (Q) in the outer branches of B1 to form N3 (AcQS)₈(BQA)₄(B‐Amb‐Y)₂BCD‐NH₂ leads to stronger (K_a=12.0×10⁶ M ^?1) but slower (k₂=67 M ^?1 s^?1) cobalamin binding. CD and FTIR spectra show that the dendrimers and their cobalamin complexes exist as random‐coil structures without aggregation in solution. The hydrodynamic radii of the dendrimers determined by diffusion NMR either remains constant or slightly decreases upon binding to cobalamin; this indicates the formation of compact, presumably hydrophobically collapsed complexes.     

Promising Antifungal and Antibacterial Agents Based on 5-Aryl-2,2′-bipyridines and Their Heteroligand Salicylate Metal Complexes: Synthesis,Bioevaluation, Molecular Docking

A series of new 5-aryl-2,2′-bipyridines and their (polyfluoro)salicylate complexes of Cu(II), Co(II) and Mn(II) were synthesized. Their antimicrobial activity was evaluated in vitro against six strains of Trichophytons, E. floccosum, M. canis, C. ablicans and Gram-negative bacteria N. gonorrhoeae. Among azo-ligands, Ph-bipy and Tol-bipy showed promising antifungal activity (minimum inhibitory concentration (MIC)<0.8–27 μM). Their antifungal action was found can be realized via binding Fe(III) ions. Tol-bipy suppressed growth of Gram-positive bacteria S. aureus, S. aureus MRSA and their monospecies biofilms (MIC 6–16 μM). Using molecular docking, the anti-staphylococcal action mechanism based on the inhibition of S. aureus DNA gyrase GyrB was proposed for the lead compounds. Among metal complexes, Cu(II) and Mn(II) complexes based on tetrafluorosalicylic acid and Tol-bipy or Ph-bipy had the high antifungal activity (MIC<0.24–32 μM). Mn(SalF₄−2H)₂(Tol-bipy)₂] suppressed the growth of seven Candida strains at MIC 12–24 μM. [Cu(Sal−2H)(Ph-bipy)] and [Cu(SalF₃−2H)(Ph-bipy)₂] showed the promising anti-gonorrhoeae activity (MIC 4.2–5.2 μM). (Cu(SalF_n−2H)(Tol-bipy)₂], [Cu(SalF₄−2H)(Ph-bipy)₂] and [Cu(SalF₃−2H)(Ph-bipy)₂]) were found active against the bacteria of S. aureus, S. aureus MRSA and their biofilms (MIC 2.4–41.4 μM). The most active compounds were tested for toxicity in vitro against human embryonic kidney (HEK-293) cells and in vivo experiments with CD-1 mice.     

Tungsten and Molybdenum 2,4,6‐Trimethylbenzylidyne Complexes as Robust Pre‐Catalysts for Alkyne Metathesis

A series of 2,4,6‐trimethylbenzylidyne tungsten and molybdenum complexes was prepared from the tribromides mer‐[MesCMBr₃(dme)] ( 9a , M=W; 9b , M=Mo, dme=1,2‐dimethoxyethane). Successive reaction of complexes 9 with lithium or potassium hexafluoro‐tert‐butoxide and lithium 1,3‐di‐tert‐butylimidazolin‐2‐imide, (Im^t‐BuN)Li, afforded the imidazolin‐2‐iminato complexes [MesCM{OC(CF₃)₂Me}₂(Im^t‐BuN)] ( 10a , M=W; 10b , M=Mo), whereas the reactions of 9 with three equivalents of LiOSi(O‐t‐Bu)₃ or KOC(CF₃)₃ gave [MesCM{OSi(O‐t‐Bu)₃}₃] ( 11a , M=W; 11b , M=Mo) and [MesCM{OC(CF₃)₃}₃] ( 12a , M=W; 12b , M=Mo), respectively. For comparison, the benzylidyne complex [PhCMo{OSi(O‐t‐Bu)₃}₃] ( 7b ) was also prepared, and its molecular structure together with those of 10a , 10b , 11b , 12a and 12b were established by X‐ray diffraction analysis. Complexes 10 and 11 were employed as pre‐catalysts for the alkyne metathesis of the test substrate 3‐pentynyl benzyl ether ( 13 ) at low catalyst loadings (1 mol%) in the presence of molecular sieve (5 Å). Comparative studies of these 2,4,6‐trimethylbenzylidyne species (MesCM) with their benzylidyne analogues (PhCM) revealed that the increased steric bulk renders the former more stable and manageable in air in solid form for shorter periods of time, but at the expense of a slower initiation, which requires higher temperatures or longer reaction times.

     

Thermal and mechanical properties of plasticized poly(L‐lactide) nanocomposites with organo‐modified montmorillonites

Nanocomposites of poly(lactide) (PLA) and the PLA plasticized with diglycerine tetraacetate (PL‐710) and ethylene glycol oligomer containing organo‐modified montmorillonites (ODA‐M and PGS‐M) by the protonated ammonium cations of octadecylamine and poly(ethylene glycol) stearylamine were prepared by melt intercalation method. In the X‐ray diffraction analysis, the PLA/ODA‐M and plasticized PLA/ODA‐M composites showed a clear enlargement of the difference of interlayer spacing between the composite and clay itself, indicating the formation of intercalated nanocomposite. However, a little enlargement of the interlayer spacing was observed for the PLA/PGS‐M and plasticized PLA/PGS‐M composites. From morphological studies using transmission electron microscopy, a finer dispersion of clay was observed for PLA/ODA‐M composite than PLA/PGS‐M composite and all the composites using the plasticized PLA. The PLA and PLA/PL‐710 composites containing ODA‐M showed a higher tensile strength and modulus than the corresponding composites with PGS‐M. The PLA/PL‐710 (10 wt %) composite containing ODA‐M showed considerably higher elongation at break than the pristine plasticized PLA, and had a comparable tensile modulus to pure PLA. The glass transition temperature (T_g) of the composites decreased with increasing plasticizer. The addition of the clays did not cause a significant increase of T_g. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci, 2006     

Research on the preparation and characterization of chitosan grafted polyvinylpyrrolidone gel membrane with iodine

The chitosan grafted polyvinylpyrrolidone gel membrane with iodine (CS‐PVP‐I₂‐G‐M) was prepared by chitosan–polyvinylpyrrolidone–iodine complex liquid (CS‐PVP‐I₂‐L) mixed with gelatin. The intermediate product CS‐PVP‐I₂‐L was prepared by CS grafted PVP in the protection of N₂ with dimethyl 2,2′‐azobis (2‐methylpropionate) (AIBME) as initiator, then a certain amounts of iodine in ethanol solution was added. The properties of CS‐PVP‐I₂‐G‐M were characterized by IR, UV–Vis, SEM, XRD, DSC, and so forth. The iodine release results coherent with the release kinetic model—Fick diffusion laws, has a burst effect first, and then spread, and the emission of iodine was maintained within a certain range and kept at a stable level permanently, showed a sustained‐release effect of iodine. The inhibition zone diameters of CS‐PVP‐I₂‐G‐M against Staphylococcus aureus and Escherichia coli were both greater than 16 mm, it demonstrated significant antibacterial activity. Double effects sustained‐release effect of iodine and the significant antibacterial activity made CS‐PVP‐I₂‐G‐M highly potential for applications as a novel natural biomedical sterilization materials. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41797.     

Effect of acrylic acid neutralization on ‘livingness’ of poly[styrene‐ran‐(acrylic acid)] macro‐initiators for nitroxide‐mediated polymerization of styrene

BACKGROUND: The effect of acrylic acid neutralization on the degradation of alkoxyamine initiators for nitroxide‐mediated polymerization (NMP) was studied using styrene/acrylic acid and styrene/sodium acrylate random copolymers (20 mol% initial acrylate feed concentration) as macro‐initiators. The random copolymers were re‐initiated with fresh styrene in 1,4‐dioxane at 110 °C at SG1 mediator/BlocBuilder^® unimolecular initiator ratios of 5 and 10 mol%. RESULTS: The value of k_pK (k_p = propagation rate constant, K = equilibrium constant) was not significantly different for styrene/acrylic acid and styrene/sodium acrylate compositions at 110 °C (k_pK = 2.4 × 10^?6–4.6 × 10^?6 s^?1) and agreed closely with that for styrene homopolymerization at the same conditions (k_pK = 2.7 × 10^?6–3.0 × 10^?6 s^?1). All random copolymers had monomodal, narrow molecular weight distributions (polydispersity index M?_w/M?_n = 1.10–1.22) with similar number‐average molecular weights M?_n = 19.3–22.1 kg mol^?1. Re‐initiation of styrene/acrylic acid random copolymers with styrene resulted in block copolymers with broader molecular weight distributions (M?_w/M?_n = 1.37–2.04) compared to chains re‐initiated by styrene/sodium acrylate random copolymers (M?_w/M?_n = 1.33). CONCLUSIONS: Acrylic acid degradation of the alkoxyamines was prevented by neutralization of acrylic acid and allowed more SG1‐terminated chains to re‐initiate the polymerization of a second styrenic block by NMP. Copyright © 2008 Society of Chemical Industry     

Thiuram Disulfides as Pseudo‐irreversible Inhibitors of Lymphoid Tyrosine Phosphatase

We screened a small library of thiuram disulfides for inhibition of lymphoid tyrosine phosphatase (LYP) activity. The parent thiuram disulfide, disulfiram, inhibited LYP activity in vitro and in Jurkat T cells, whereas diethyldithiocarbamate failed to inhibit LYP at the concentrations tested. Compound 13 , an N‐(2‐thioxothiazolidin‐4‐one) analogue, was found to be the most potent LYP inhibitor in this series, with an IC₅₀ value of 3 μM . Compound 13 inhibits LYP pseudo‐irreversibly, as evidenced by the time‐dependence of inhibition, with a K_i value of 1.1 μM and a k_inact value of 0.004 s^?1. The inhibition of LYP by compound 13 could not be reversed significantly by incubation with glutathione or by prolonged dialysis, but could be partially reversed by incubation with dithiothreitol. Compound 13 also inhibited LYP activity in Jurkat T cells.     

Grain Size Effects on Piezoelectric Properties and Domain Structure of BaTiO3 Ceramics Prepared by Two‐Step Sintering

A series of highly dense barium titanate (BaTiO₃) ceramics with the average grain size (GS) from 0.29 to 8.61 μm are successfully prepared by two‐step sintering, and the GS effect on piezoelectric coefficient (d₃₃) is systematically discussed in this work. It is found that when GS above 1 μm, d₃₃ can be enhanced with decreasing GS, reaching a maximum value of 519 pC/N around 1 μm due to the high activity of domain wall mobility. Subsequently, d₃₃ rapidly drops with a further decrease in GS owing to the reduced domain density. The results suggest that it is possible to prepare high‐performance BaTiO₃ ceramics by controlling the GS and domain configuration properly, which brings great revitalization to the BaTiO₃‐based piezoceramics.