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A new Eu III β-diketonate complex [Eu(btfa)3(dmbpy)] containing the btfa ( 4,4,4-trifluoro-1-phenyl-1,3-butanedione ) and the p,p ′-disubstituted bipyridine ligand dmbpy ( 4,4′-dimethyl-2,2′-bipyridine ) have been synthesized and fully characterized. The X-ray crystal structure reveals that the compound crystallize in monoclinic system of space group P2 1 /n , with a classical structure observed in other similar compounds. The molecular structure of the Eu III complex was calculated using the Sparkle/PM6 model, and your optimized ground state geometry were used to calculated all details involved in the energy transfer process and compared with photoluminescence experimental data. These data shows that the triplet → 5 D 1 and triplet → 5 D 0 are the main energy transfer channels and that the photoluminescence mechanism in this complex is proposed to be a ligand sensitized luminescence process. Additionally, red organic light emitting diode (OLED) devices were fabricated using this complex, presenting the characteristic EL emission bands due to 5 D 0 → 7 F J ( J = 0–4) transitions, which gives evidence that the “ antenna effect ” is operative. Due to its intense red photo/electroluminescence emission, this complex have potential applications as light-conversion molecular devices (LCMDs), mainly to fabricate new OLEDs. [ABSTRACT FROM AUTHOR]

Six novel rare earth metal organic-frameworks with the general formula {[RE 2 (2,5-tdc) 3 (dmso) 2 ]·H 2 O} n ( RE = Y III , Pr III , Nd III , Sm III , Er III and Tm III ; 2,5-tdc 2− = 2,5-thiophenedicarboxylate anion; dmso = dimethylsulfoxide ) were synthesized and their complete characterization, including single crystal X-ray diffraction, FTIR spectroscopy and thermal analysis (TG/DTA) are reported. Structure analysis reveals that RE III ions show distorted capped trigonal – prismatic geometry. The 2,5-tdc 2− ligands connect four RE III centers, adopting (κ 1 – κ 1 ) – (κ 1 – κ 1 ) – μ 4 coordination mode, generating an interesting 3D network with potential application for gas adsorption. Photophysical properties were studied using excitation/emission spectra and the photoluminescence data show the near infrared (NIR) and visible (Vis) emission with the characteristic transitions: 1 D 2 → 3 F 2 for Pr III , 4 F 3/2 → 4 I J ( J = 9/2, 11/2 and 13/2) for Nd III , 4 G 5/2 → 6 H J ( J = 5/2, 7/2, 9/2 and 11/2) for Sm III and 4 I 13/2 → 4 I 15/2 for Er III . This study indicates that 2,5-tdc 2− ligand is able to act as a sensitizer for emission in NIR and Vis region in these ions. [ABSTRACT FROM AUTHOR]

In this work, DFT calculations were conducted to understand the interactions of two luminescent complexes series, named [Ln(cin) 3 (H 2 O) 3 ]·Hcin and the [Ln 2 (cin) 6 (bpy) 2 ] (where cin = hydrocinnamate anion and bpy = 2,2′-bipyridine). For the reduction of the computational cost in the geometry optimization calculations, the PBE-D2 and the GGA + U methodologies were tested, even as the 4f electrons treatment, in the core and in the valence shell of the lanthanide metals. As a result of the electronic structure calculations, the lattice parameters of these complexes was obtained and corroborated by a comparison between the simulated and experimental diffractograms. The projected density of states and the charge density analysis were made for a better understanding of the electronic structure and the stabilization of these complexes, like the importance of some ligands and the difference of the interaction between the rare-earth metals and the ligands. It could be concluded that there is no need to compute the spin polarization and to include the hubbard correction in order to conduct a structural analysis of these rare-earth metal complexes. The electronic density maps show that the structures are mainly stabilized by charge transfer between the ligands and the rare-earth cations. This result also corroborates the geometry optimizations performed with the DFT-D2 method, which indicate that the computation of the Van der Waals forces are negligible. [ABSTRACT FROM AUTHOR]

Abstract: The new europium binuclear complex [Eu2(dcpz)2(suc)(H2O)8]·(H2O)1.5 (dcpz=3,5-dicarboxypyrazolate and suc=succinate) has been synthesized and structurally characterized by single crystal X-ray diffraction methods. The binuclear complex crystallizes in the triclinic space group and consists of two lanthanide ions linked by two different bridging organic ligands. 3D supramolecular framework is constructed by hydrogen bonds. The compound shows strong red emission under UV excitation at room temperature associated to IL transitions indicating a ligand to metal energy transfer mechanism since the triplet energy level lies higher than that of europium 5D0 level. Magnetic susceptibility studies showed weak temperature dependence characteristic of the Van Vleck paramagnetism. [Copyright &y& Elsevier]

Abstract: Two new coordination polymers {[Co(μ-4,4′-dps)2(H2O)2](NO3)2·2(4,4′-dps)·4H2O} n (1) and {[Cu(μ-4,4′-dps)2(H2O)2](NO3)2·2H2O} n (2) [4,4′-dps=di(4-pyridyl)sulfide] have been synthesized by solvothermal reactions between the nitrate salts of cobalt(II) (1) and copper(II) (2) and the 4,4′-dps molecule. Compounds 1 and 2 have been characterized by elemental analysis, thermal analysis (TG/DTA), vibrational spectroscopy, single crystal X-ray diffraction analysis and variable-temperature magnetic measurements. Compounds 1 and 2 are cationic chain compounds of formula {[M(μ-4,4′-dps)2(H2O)2] n 2 n + [M=Co(II) (1) and Cu(II) (2)] with double 4,4′-dps bridges, uncoordinated nitrate anions, and crystallization water (1 and 2) and 4,4′-dps (1) molecules. Each metal ion in 1 and 2 is six-coordinated with two coordinated water molecules in trans position and four pyridyl-nitrogen atoms from four 4,4′-dps ligands building a distorted octahedral environment. The values of the intrachain metal–metal separation are 9.940(4) and 9.702(4)Å for 1 and 2, respectively. The magnetic properties of 1 and 2 correspond to those of magnetically isolated copper(II) and high-spin cobalt(II) centers, the extended 4,4′-dps bridge being a poor mediator of magnetic interactions. [Copyright &y& Elsevier]

Abstract: Two novel coordination polymers with the formula {[Ln2(2,5-tdc)3(dmso)2]·H2O} n (Ln=Tb(III) for (1) and Dy(III) for (2)), (2,5-tdc2− =2,5-thiophenedicarboxylate and dmso=dimethylsulfoxide) have been synthesized by the diffusion method and characterized by thermal analysis, vibrational spectroscopy and single crystal X-ray diffraction analysis. Structure analysis reveals that 2,5-tdc2− play a versatile role toward different lanthanide ions to form three-dimensional metal-organic frameworks (MOFs) in which the lanthanides ions are heptacoordinated. Photophysical properties were studied using excitation and emission spectra, where the photoluminescence data show the high emission intensity of the characteristic transitions 5D4 → 7F J (J =6, 5, 4 and 3) for (1) and 4F9/2 → 6HJ (J =15/2, 13/2 and 11/2) for (2), indicating that 2,5-tdc2− is a good sensitizer. [Copyright &y& Elsevier]

Purpose Expect Respect Support Groups (ERSGs) are a targeted 24-week dating abuse prevention program tailored to middle and high school students who have been exposed to violence. As part of a controlled evaluation, this qualitative study was designed to examine facilitators' experiences with program implementation and generate a deeper understanding of factors that enhance or challenge implementation and program outcomes. Methods Semistructured interviews with Expect Respect Support Group facilitators (three males and four females) were conducted at the midpoint and endpoint of the school year. Interview topics included working within the school system, strategies for establishing a productive group process, and individual- and group-level responses to the program. Results Facilitators indicated that school counselors' awareness of students' exposure to violence increased their ability to refer eligible students. Within a supportive school environment, successful groups harnessed the protective qualities of a positive peer group, supported members in questioning the normalcy of abuse, and provided opportunities for building healthy relationship skills. Challenges resulted from impediments to group cohesion including insufficient referrals, inconsistent attendance, and low levels of school support. Students who were frequently absent and disengaged from school were particularly challenging to engage in a school-based program. Conclusions This research demonstrates that successful implementation of a targeted school-based dating violence prevention program relies on building school support and awareness of teen dating violence, especially for appropriate identification and referral of at-risk students. High levels of school support enhance the development of a supportive group process and attitudinal and behavioral changes among participants. [ABSTRACT FROM AUTHOR]

Four series of disubstituted carbazole-1-carboxamides were designed and synthesised as inhibitors of Bruton’s tyrosine kinase (BTK). 4,7- and 4,6-disubstituted carbazole-1-carboxamides were potent and selective inhibitors of BTK, while 3,7- and 3,6-disubstituted carbazole-1-carboxamides were potent and selective inhibitors of Janus kinase 2 (JAK2). [ABSTRACT FROM AUTHOR]

Leveraging available technologies for high-throughput screening (HTS), to enable the rapid delivery of comprehensive data packages for drug discovery programs, is a primary goal in developing new molecular entities for clinical applications. Pharmaceutical companies like Bristol-Myers Squibb (BMS) must constantly evolve their assay methods to ensure an effective and timely impact to business. This article is focused on a novel three step approach, using Linguamatics I2E text analytics software to mine the full text of patents, to identify (1) kinase assay technology information, and (2) kinase group information that is associated with therapeutic areas for drug screening. [ABSTRACT FROM AUTHOR]

Kinases, accounting for 20% of the human genome, have been the focus of pharmaceutical drug discovery efforts for over three decades. Despite concerns surrounding the tractability of kinases as drug targets, it is evident that kinase drug discovery offers great potential, underscored by the US Food and Drug Administration (FDA) approval of 48 small-molecule kinase inhibitors. Despite these successes, it is challenging to identify novel kinome selective inhibitors with good pharmacokinetic/pharmacodynamic (PK/PD) properties, and resistance to kinase inhibitor treatment frequently arises. A new era of kinase drug discovery predicates the need for diverse and powerful tools to discover the next generation of kinase inhibitors. Here, we outline key tenets of the Bristol Meyers Squibb (BMS) kinase platform, to enable efficient generation of highly optimized kinase inhibitors. This review highlights the evolving kinase small-molecule drug discovery landscape, and key tenets of the kinase platform at Bristol Myers Squibb to discover the next generation of kinase inhibitors. [ABSTRACT FROM AUTHOR]

Abstract In this work, we present the synthesis, solid state characterization and complete photoluminescence study of new important homobimetallic lanthanide complexes containing the non - steroidal anti - inflammatory drug (NSAID) naproxen. The analytical and spectroscopic techniques reveals the formation of eight compounds of general formula [Ln 2 (nap) 6 (H 2 O) 4 ] (Eu 1 and Gd 2), [Ln 2 (nap) 6 (bpy) 2 ] (Eu 3 and Gd 4), [Ln 2 (nap) 6 (4,4' - dmbpy) 2 ] (Eu 5 and Gd 6) and [Ln 2 (nap) 6 (phen) 2 ] (Eu 7 and Gd 8), where: nap = naproxen ligand, bpy = 2,2' - bipyridine , 4,4' - dmbpy = 4,4' - dimethyl - 2,2' - bipyridine and phen = 1,10 - phenanthroline. Using the RM1 model, the molecular structures of the EuIII complexes were calculated, with your optimized ground state geometries used to obtain all details involved in the energy transfer process. From the respective GdIII complexes were obtained the lowest ligand triplet states, proving that the photoluminescence in the EuIII naproxen complexes is proposed to be a ligand sensitized luminescence process. On the other hand, the position of the triplet states also explains the non - effective energy transfer in the TbIII naproxen complexes. The presence of N,N - donors ligands (bpy , 4,4' - dmbpy and phen) results in an 3–4 - fold increase in the quantum efficiency when compared with the EuIII complex without nitrogen ligands. The high values of emission quantum efficiency (η ~ 70 - 98%) show the EuIII complexes can be potential candidates as emitters in biologic assays. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Three new Ln-β-diketonates have been synthesized and characterized. • Energy transfer mechanism for Yb and Nd compounds has been discussed. • In the Yb and Nd complexes, the NIR luminescence was observed. • Near-infrared electroluminescence of the Yb complex in OLEDs has been observed. • The complexes may be used as light-converters. Abstract Three new lanthanide(III) β-diketonate complexes [Ln(btfa) 3 (4,4′-dmbpy)] (Ln = Yb(III), Gd(III) and Nd(III); btfa = anionic 4,4,4-trifluoro-1-phenyl-1,3-butanedione and 4,4′-dmbpy = 4,4′-dimethyl-2,2′-bipyridine) were synthesized and their characterization, including elemental analysis, FTIR spectroscopy and thermal analysis (TG/DTA), is reported. The crystal description based on powder X-ray diffraction reveals that Gd(III) and Yb(III) compounds are isostructural and that lanthanide ion is eight-coordinated by oxygen and nitrogen atoms to give new tris- β-diketonates [Ln(btfa) 3 (4,4′-dmbpy)]. The cell parameters of Nd(III) complex are close to Gd(III) and Yb(III) ones. Phosphorescence data of Gd(III) complex shows that the triplet states (T 1) of the ligands have higher energy than the emitting states of Yb(III) and Nd(III), indicating the possibility of intramolecular energy transfer to these metal ions, which exhibit near-infrared (NIR) emission. We have used the Yb(III) complex as an emitting layer (EML) in a near infrared organic light emitting diode (NIR-OLED) with the structure: CuPc(15 nm)/XD-03(40 nm)/Yb(60 nm)/BCP(15 nm)/Alq 3 (10 nm)/Al(120 nm). OLEDs exhibit both visible electroluminescence and a NIR electroluminescence at 980 nm from the 2F 5/2 → 2F 7/2 transition of the Yb(III). [ABSTRACT FROM AUTHOR]

Incorporation of a suitably-placed electrophilic group transformed a series of reversible BTK inhibitors based on carbazole-1-carboxamide and tetrahydrocarbazole-1-carboxamide into potent, irreversible inhibitors. Removal of one ring from the core of these compounds provided a potent irreversible series of 2,3-dimethylindole-7-carboxamides having excellent potency and improved selectivity, with the additional advantages of reduced lipophilicity and molecular weight. [ABSTRACT FROM AUTHOR]

The TGFβ-TGFβR signaling pathway has been reported to play a protective role in the later stages of tumorigenesis via increasing immunosuppressive Treg cells and facilitating the epithelial to mesenchymal transition (EMT). Therefore, inhibition of TGFβR has the potential to enhance antitumor immunity. Herein we disclose the identification and optimization of novel heterobicyclic inhibitors of TGFβRI that demonstrate potent inhibition of SMAD phosphorylation. Application of structure-based drug design to the novel pyrrolotriazine chemotype resulted in improved binding affinity (Ki apparent = 0.14 nM), long residence time (T 1/2  > 120 min) and significantly improved potency in the PSMAD cellular assay (IC 50  = 24 nM). Several analogs inhibited phosphorylation of SMAD both in vitro and in vivo . Additionally, inhibition of TGFβ-stimulated phospho-SMAD was observed in primary human T cells. [ABSTRACT FROM AUTHOR]

A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described. [ABSTRACT FROM AUTHOR]

The discovery, synthesis, and characterization of 9 H -carbazole-1-carboxamides as potent and selective ATP-competitive inhibitors of Janus kinase 2 (JAK2) are discussed. Optimization for JAK family selectivity led to compounds 14 and 21 , with greater than 45-fold selectivity for JAK2 over all other members of the JAK kinase family. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase-3 (GSK-3) has been proposed to play a crucial role in the pathogenesis of many diseases including cancer, stroke, bipolar disorders, diabetes and neurodegenerative diseases. GSK-3 inhibition has been a major area of pharmaceutical interest over the last two decades. A plethora of reports appeared recently on selective inhibitors and their co-crystal structures in GSK-3β. We identified several series of promising new GSK-3β inhibitors from a coherent design around a pyrrolopyridinone core structure. A systematic exploration of the chemical space around the central spacer led to potent single digit and sub-nanomolar GSK-3β inhibitors. When dosed orally in a transgenic mouse model of Alzheimer’s disease (AD), an exemplary compound showed significant lowering of Tau phosphorylation at one of the GSK-3 phosphorylating sites, Ser396. X-ray crystallography greatly aided in validating the binding hypotheses. [ABSTRACT FROM AUTHOR]

A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified ( R )-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core ( 3b ). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors ( 4g – 4j ) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3–JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3–JAK1 pathway versus JAK2, and active in a human whole blood assay. [ABSTRACT FROM AUTHOR]

Abstract: A series of phenylacylsulfonamides has been prepared as antagonists of Bcl-2/Bcl-xL. In addition to potent binding affinities for both Bcl-2 and Bcl-xL, these compounds were shown to induce classical markers of apoptosis in isolated mitochondria. Overall weak cellular potency was improved by the incorporation of polar functionality resulting in compounds with moderate antiproliferative activity. [Copyright &y& Elsevier]

Abstract: 5-Butyl-1,4-diphenyl pyrazole and 2-amino-5-chloro pyrimidine acylsulfonamides were developed as potent dual antagonists of Bcl-2 and Bcl-xL. Compounds were optimized for binding to the I88, L92, I95, and F99 pockets normally occupied by pro-apoptotic protein Bim. An X-ray crystal structure confirmed the proposed binding mode. Observation of cytochrome c release from isolated mitochondria in MV-411 cells provides further evidence of target inhibition. Compounds demonstrated submicromolar antiproliferative activity in Bcl-2/Bcl-xL dependent cell lines. [Copyright &y& Elsevier]

Abstract: SAR studies of pyrrolo[1,2-f]triazines as JAK2 inhibitors is presented. Achieving JAK2 inhibition selectively over JAK3 is discussed. [Copyright &y& Elsevier]

Abstract: The synthesis and follow-up SAR studies of our development candidate 1 by incorporating 2-aryl-4-oxazolylmethoxy and 2-aryl-4-thiazolylmethoxy moieties into the oxybenzylglycine framework of the PPARα/γ dual agonist muraglitazar is described. SAR studies indicate that different substituents on the aryloxazole/thiazole moieties as well as the choice of carbamate substituent on the glycine moiety can significantly modulate the selectivity of PPARα versus PPARγ. Potent, highly selective PPARα activators 2a and 2l, as well as PPARα activators with significant PPARγ activity, such as 2s, were identified. The in vivo pharmacology of these compounds in preclinical animal models as well as their ADME profiles are discussed. [Copyright &y& Elsevier]

Abstract: The design, synthesis and structure–activity relationships of a novel series of N-phenyl-substituted pyrrole, 1,2-pyrazole and 1,2,3-triazole acid analogs as PPAR ligands are outlined. The triazole acid analogs 3f and 4f were identified as potent dual PPARα/γ agonists both in binding and functional assays in vitro. The 3-oxybenzyl triazole acetic acid analog 3f showed excellent glucose and triglyceride lowering in diabetic db/db mice. [Copyright &y& Elsevier]

Abstract: Several series of substituted dehydropiperidine and piperidine-4-carboxylic acid analogs have been designed and synthesized as novel, potent dual PPARα/γ agonists. The SAR of these series of analogs is discussed. A rare double bond migration occurred during the basic hydrolysis of the α,β-unsaturated dehydropiperidine esters 12, and the structures of the migration products were confirmed through a series of 2D NMR experiments. [Copyright &y& Elsevier]

Abstract: A novel class of azetidinone acid-derived dual PPARα/γ agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARα and PPARγ receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described. [Copyright &y& Elsevier]

Abstract: 2-Amino-5-(thioaryl)thiazoles are potent inhibitors of TrkA (e.g., 20h, TrkA IC50 =0.6nM) that show anti-proliferative effect in cellular assays. A proposed inhibitor binding mode to TrkA active site is consistent with key SAR observations. [Copyright &y& Elsevier]

• Huge refrigerant capacity in Fe(phen) 2 (NCS) 2. • Barocaloric effect in spin crossover materials. • Entropic caloric effect triggered from (LS)-(HS) phase transition. • Solid refrigerant materials. The next-generation of refrigerant materials should be based on solid materials with big entropy-driven conversion when submitted to an external stimulus change. We report the refrigerant capacity (RC = 2950 J kg−1, upon pressure change of ΔP = 1 kbar) in one of the most known and investigated spin-crossover material [Fe(phen) 2 (NCS) 2 ]. Our indirect obtained experimental data for the isothermal entropy change (ΔS T = 78 Jkg−1K−1) and the adiabatic temperature change (ΔT ad = 11 K) for ΔP = 1 kbar, agree with our theoretical calculations. From comparison between the thermodynamic and microscopic entropy descriptions, the origin of the barocaloric effect was ascribed to the pressure phonons activation in spin-crossover materials. Besides, a proper refrigeration thermodynamic cycle (Ericsson cycle) was quantitatively used for showing the refrigeration capacity of [Fe(phen) 2 (NCS) 2 ]. [ABSTRACT FROM AUTHOR]

We present a highly photoluminescent and thermally stable terbium(III) coordination network [TbHbtec] n CN 1 , exhibiting a cubic primitive network with topology pcu - α Po, uninodal and point symbol (412. 63). The results show that CN 1 is a good candidate for luminescent marker of gunshot residues (GSR). • New TbIII-coordination network with topology pcu - α Po uninodal and point symbol (412. 63). • 3-D coordination network of formula [TbHbtec] n , [H 4 btec = 1,2,4,5-benzenetetracarboxylic acid]. • High thermal stability (higher than 470 °C) and high photoluminescence. • Good candidate as luminescent marker for gunshot residues. • Stability of the structure after exposure to high temperature of detonation. A novel terbium(III) coordination network (CN) of formula [TbHbtec] n 1 , constructed from 1,2,4,5-benzenetetracarboxylic acid (H 4 Btec) and Tb3+ ions, has been obtained under hydrothermal conditions. Single crystal X-ray diffraction and topological studies revealed the crystal structure of CN 1 involves a cubic primitive network with topology pcu - α Po, uninodal and with point symbol (412. 63). In the crystal structure, the ligand is monoprotonated (Hbtec3−) with six Hbtec3− adopting the monodentate, bidentate chelating and bidentate chelating-bridging coordination modes, leading to the formation of a 3-D coordination network. Solid state luminescence spectrum showed the characteristic 5D 4 → 7F J (J = 6–2) transitions of the Tb3+ ion upon excitation in the Hbtec3− singlet levels, revealing that the ligand Hbtec3− is a good sensitizer for the intense green emission of Tb3+ ions. Thermogravimetric analysis (TGA) showed CN 1 has exceptional thermal stability decomposing at temperatures higher than 470 °C. Taking advantage of its excellent thermal and optical properties, the [TbHbtec] n was tested as luminescent marker for gunshot residues, opening the possibility of using this compound in forensic analysis of crime scenes. [ABSTRACT FROM AUTHOR]