- ORGANOMETALLIC COMPOUND, ORGANIC LIGHT-EMITTING DEVICE INCLUDING THE SAME
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The invention relates to an organometallic compound, an organic light-emitting device including the same. The organometallic compound is represented by Formula 1. The organic light-emitting device includes a first electrode, a second electrode, and an org
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Paragraph 0714-0719
(2021/05/29)
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- Azole-Based Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors
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The heme enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays an essential role in immunity, neuronal function, and aging through catalysis of the rate-limiting step in the kynurenine pathway of tryptophan metabolism. Many IDO1 inhibitors with different chemotypes have been developed, mainly targeted for use in anti-cancer immunotherapy. Lead optimization of direct heme iron-binding inhibitors has proven difficult due to the remarkable selectivity and sensitivity of the heme-ligand interactions. Here, we present experimental data for a set of closely related small azole compounds with more than 4 orders of magnitude differences in their inhibitory activities, ranging from millimolar to nanomolar levels. We investigate and rationalize their activities based on structural data, molecular dynamics simulations, and density functional theory calculations. Our results not only expand the presently known four confirmed chemotypes of sub-micromolar heme binding IDO1 inhibitors by two additional scaffolds but also provide a model to predict the activities of novel scaffolds.
- R?hrig, Ute F.,Majjigapu, Somi Reddy,Reynaud, Aline,Pojer, Florence,Dilek, Nahzli,Reichenbach, Patrick,Ascencao, Kelly,Irving, Melita,Coukos, George,Vogel, Pierre,Michielin, Olivier,Zoete, Vincent
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p. 2205 - 2227
(2021/03/01)
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- HERBICIDAL COMPOUNDS
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The present invention relates to compounds of Formula (I) or an agronomically acceptable salt of said compounds wherein Q, R1, R2, n and m are as defined herein. The invention further relates to herbicidal compositions which comprise a compound of Formula (I) and to the use of compounds of Formula (I) for controlling weeds, in particular in crops of useful plants.
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Page/Page column 28-29
(2020/06/01)
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- Fragment-Based Discovery of a Qualified Hit Targeting the Latency-Associated Nuclear Antigen of the Oncogenic Kaposi's Sarcoma-Associated Herpesvirus/Human Herpesvirus 8
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The latency-associated nuclear antigen (LANA) is required for latent replication and persistence of Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8. It acts via replicating and tethering the virus episome to the host chromatin and exerts other functions. We conceived a new approach for the discovery of antiviral drugs to inhibit the interaction between LANA and the viral genome. We applied a biophysical screening cascade and identified the first LANA binders from small, structurally diverse compound libraries. Starting from a fragment-sized scaffold, we generated optimized hits via fragment growing using a dedicated fluorescence-polarization-based assay as the structure-activity-relationship driver. We improved compound potency to the double-digit micromolar range. Importantly, we qualified the resulting hit through orthogonal methods employing EMSA, STD-NMR, and MST methodologies. This optimized hit provides an ideal starting point for subsequent hit-to-lead campaigns providing evident target-binding, suitable ligand efficiencies, and favorable physicochemical properties.
- Kirsch, Philine,Jakob, Valentin,Oberhausen, Kevin,Stein, Saskia C.,Cucarro, Ivano,Schulz, Thomas F.,Empting, Martin
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- Fragment-Based Discovery of a Qualified Hit Targeting the Latency-Associated Nuclear Antigen of the Oncogenic Kaposi's Sarcoma-Associated Herpesvirus/Human Herpesvirus 8
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The latency-associated nuclear antigen (LANA) is required for latent replication and persistence of Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8. It acts via replicating and tethering the virus episome to the host chromatin and exerts other functions. We conceived a new approach for the discovery of antiviral drugs to inhibit the interaction between LANA and the viral genome. We applied a biophysical screening cascade and identified the first LANA binders from small, structurally diverse compound libraries. Starting from a fragment-sized scaffold, we generated optimized hits via fragment growing using a dedicated fluorescence-polarization-based assay as the structure-activity-relationship driver. We improved compound potency to the double-digit micromolar range. Importantly, we qualified the resulting hit through orthogonal methods employing EMSA, STD-NMR, and MST methodologies. This optimized hit provides an ideal starting point for subsequent hit-to-lead campaigns providing evident target-binding, suitable ligand efficiencies, and favorable physicochemical properties.
- Kirsch, Philine,Jakob, Valentin,Oberhausen, Kevin,Stein, Saskia C.,Cucarro, Ivano,Schulz, Thomas F.,Empting, Martin
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p. 3924 - 3939
(2019/05/06)
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- Polyfunctional Imidazolium Aryloxide Betaine/Lewis Acid Catalysts as Tools for the Asymmetric Synthesis of Disfavored Diastereomers
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Enzymes are Nature's polyfunctional catalysts tailor-made for specific biochemical synthetic transformations, which often proceed with almost perfect stereocontrol. From a synthetic point of view, artificial catalysts usually offer the advantage of much broader substrate scopes, but stereocontrol is often inferior to that possible with natural enzymes. A particularly difficult synthetic task in asymmetric catalysis is to overwrite a pronounced preference for the formation of an inherently favored diastereomer; this requires a high level of stereocontrol. In this Article, the development of a novel artificial polyfunctional catalyst type is described, in which an imidazolium-aryloxide betaine moiety cooperates with a Lewis acidic metal center (here Cu(II)) within a chiral catalyst framework. This strategy permits for the first time a general, highly enantioselective access to the otherwise rare diastereomer in the direct 1,4-addition of various 1,3-dicarbonyl substrates to β-substituted nitroolefins. The unique stereocontrol by the polyfunctional catalyst system is also demonstrated with the highly stereoselective formation of a third contiguous stereocenter making use of a diastereoselective nitronate protonation employing α,β-disubstituted nitroolefin substrates. Asymmetric 1,4-additions of β-ketoesters to α,β-disubstituted nitroolefins have never been reported before in literature. Combined mechanistic investigations including detailed spectroscopic and density functional theory (DFT) studies suggest that the aryloxide acts as a base to form a Cu(II)-bound enolate, whereas the nitroolefin is activated by H-bonds to the imidazolium unit and the phenolic OH generated during the proton transfer. Detailed kinetic analyses (RPKA, VTNA) suggest that (a) the catalyst is stable during the catalytic reaction, (b) not inhibited by product and (c) the rate-limiting step is most likely the C-C bond formation in agreement with the DFT calculations of the catalytic cycle. The robust catalyst is readily synthesized and recyclable and could also be applied to a cascade cyclization.
- Willig, Felix,Lang, Johannes,Hans, Andreas C.,Ringenberg, Mark R.,Pfeffer, Daniel,Frey, Wolfgang,Peters, René
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supporting information
p. 12029 - 12043
(2019/08/16)
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- Correction to: Polyfunctional Imidazolium Aryloxide Betaine/Lewis Acid Catalysts as Tools for the Asymmetric Synthesis of Disfavored Diastereomers (Journal of the American Chemical Society (2019) 141 (12029-12043) DOI: 10.1021/jacs.9b04902)
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Page 12035 and Supporting Information pp S91-S94. It has come to our attention that the wrong initial concentration of 1a was erroneously used in two experiments of the "same excess" protocol.1 The experiments were thus repeated (0.055 rather than 0.06 mol/L of 1a was erroneously used before), and an excellent overlay of the "time-adjusted same excess" reaction profiles and the standard reaction profile, as previously presented, was found. This indicates that no significant catalyst deactivation takes place and that the active catalyst concentration remains constant during the catalytic reaction. The conclusions are thus not affected by the unintentional error. The corrected Figure 1 is shown below, and a corrected including Figures S1-S28 and Tables S1-S8 (corrected).(Figure Persented).Supporting Information file is available, in which pp S91?S94 have been replaced, in which the correct kinetic experiments are described, including raw data. We apologize for any inconvenience.
- Willig, Felix,Lang, Johannes,Hans, Andreas C.,Ringenberg, Mark R.,Pfeffer, Daniel,Frey, Wolfgang,Peters, René
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supporting information
p. 17022 - 17022
(2019/11/14)
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- Enhanced Catalytic Activity of Oxygen-Tethered IrIII NHC Complexes in Aqueous Transfer Hydrogenative Reductive Amination Reactions: Experimental Kinetic and Mechanistic Study
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The synthesis and characterization of seven new IrIII complexes containing o-phenoxide or o-naphthoxide chelated N-heterocyclic carbene ligands is reported herein. The crystal structures of six of the complexes have been determined. These complexes efficiently catalyze the transfer hydrogenative reductive amination (RA) of carbonyls and amines in water. Amongst the complexes tested, the introduction of o-naphthoxide on a nitrogen atom of imidazole based NHC ligand greatly increased the catalytic activity. The catalytic system has a broad substrate scope, which allows the synthesis of a variety of amines in excellent yields and with high turnover numbers up to 490 (for ketones) and 14800 (for aldehydes). The mechanism of aqueous RA reaction with an o-aryloxide chelated NHC-IrIII catalyst has been investigated by NMR spectroscopy and kinetic measurements. These studies suggest that the transfer hydrogenation (TH) is turnover-limited by the hydride formation step. As a result of the 1H NMR studies, the higher catalytic activity of o-naphthoxide chelated catalyst (3 g) over o-phenoxide chelated one (3 b) can be attributed partly due to the faster formation of an iridium hydride, the key intermediate in the RA reactions.
- ?zbozkurt, ?brahim Kayahan,Gülcemal, Derya,Günnaz, Salih,G?k?e, Ayta? Gürhan,?etinkaya, Bekir,Gülcemal, Süleyman
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p. 3593 - 3604
(2018/08/03)
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- Phenoxide chelated Ir(iii) N-heterocyclic carbene complexes: Synthesis, characterization, and evaluation of their in vitro anticancer activity
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Twelve novel half-sandwich IrIII-NHC complexes [(η5-Cpx)Ir(C^O)Cl] were synthesized and characterized. These complexes showed higher cytotoxic activity toward A549 cells and HeLa cells than cisplatin. An increase in the nu
- Zhang, Yujiao,Zhang, Shumiao,Tian, Zhenzhen,Li, Juanjuan,Xu, Zhishan,Li, Shanshan,Liu, Zhe
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supporting information
p. 13781 - 13787
(2018/10/20)
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- Formation of N-Heterocyclic Carbenes by Tautomerization of Mesomeric Betaines: Cyclic Boron Adducts and Palladium Complexes from 2-(Imidazolium-1-yl)phenolates
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2-(Imidazolium-1-yl)phenolates are conjugated heterocyclic mesomeric betaines in tautomeric equilibrium with the corresponding N-heterocyclic carbenes (NHCs), 3-(2-hydroxyphenyl)-imidazol-2-ylidenes. The carbene tautomers can be trapped as thiones (X-ray analysis). Moreover, bis(triphenylphosphine)palladium(II) dichloride in THF trapped the carbene tautomer as a palladium complex without participation of the phenolate group (X-ray analysis). The corresponding anionic NHCs, 2-phenolate-substituted imidazol-2-ylidenes, can be trapped by triethylborane or triphenylborane to form 4,4-diethyl- or 4,4-diphenyl-4H-benzo[e]imidazo[2,1-c][1,4,2]oxaza-borininium-4-ides, respectively (two X-ray analyses). These tricyclic systems are the first representatives of a new heterocyclic ring system. The results of DFT calculations concerning the HOMO/LUMO profiles and partial charges are also presented.
- Liu, Ming,Nieger, Martin,Hübner, Eike G.,Schmidt, Andreas
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p. 5416 - 5424
(2016/04/09)
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- PYRAZOLO[3,4-D]PYRIMIDIN-4(5H)-ONE DERIVATIVES AS PDE9 INHIBITORS
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A compound of the general formula (I) wherein R1 is selected from the group consisting of phenyl unsubstituted or substituted with 1 to 3 substituents selected from F, Cl, Br, I, CN, -O-C1-C3-alkyl, fluorinated -O-C1-C3-alkyl, -(CH2)mOH and 5-membered heterocyclic group with 1 or 2 heteroatoms selected from N, O and S; and 6- or 10-membered heteroaryl with 1 to 3 heteroatoms selected from O, N and S; R2 and R3 independently of each other represent H atom or straight or branched C1-C3 alkyl; R4 is selected from the group consisting of 4- to 6- membered cycloalkyl, wherein one of carbon atoms can be replaced by O atom, and which is unsubstituted or substituted with one or two halogen atoms,and straight or branched C1-C4 alkyl; Q represents a bond or C1-C3-alkylene, which can be optionally substituted by one to three C1-C3-alkyls; X is selected from the group consisting of O, NR5, and S(O)p; R5 represents H atom or C1-C3alkyl; m is 1, 2 or 3; p is 0, 1 or 2; and salts thereof, for use as a medicament, in particular for treating cognitive function disorders and neurodegenerative diseases.
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Page/Page column 31; 32
(2014/02/16)
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- 4,5-DIHYDROISOXAZOLE DERIVATIVES AS NAMPT INHIBITORS
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The present invention provides substituted 4,5-dihydroisoxazole derivatives of formula (I), which may be therapeutically useful, more particularly NAMPT inhibitors and in which R1 R2, Y, X, "Het" and "p" have the meanings given in the specification, and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention of diseases or disorder caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPT) in a mammal. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of the substituted 4,5-dihydroisoxazole derivatives of formula (I) or a pharmaceutically acceptable salts or stereoisomers or N-oxide thereof.
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Page/Page column 178
(2014/08/06)
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- A concept of supported amino acid ionic liquids and their application in metal scavenging and heterogeneous catalysis
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Novel supported task-specific ionic liquids have been developed for the first time via the ionic-pair coupling of imidazolium cation of the modified polystyrene support with L-proline. The materials have shown an efficient metal scavenging ability (e.g., Cul, Pd(OAc)2, Pd0, and IrCl3) without the aid of a nonimmobilized ionic liquid, which relies on the highly synergistic effect of the coordination with the nitrogen atom and the COO- group of the L-proline moiety, electrostatic forces, and steric protection. The resulting metal-soaked supported ionic liquids can be used as efficient heterogeneous catalysts. These materials have been investigated in the Cul-catalyzed N-arylation of nitrogen-containing heterocycles and exhibit much higher catalytic activity and a more extensive structural range of aryl and heteroaryl halides than those exhibited by free L-proline in combination with Cul both in the ionic liquid ([BMIM][BF 4]) and in the corresponding homogeneous reaction conditions. The Cul-soaked catalyst 4a-2 can be recycled for nine runs at least without any considerable loss of activity. To the best of our knowledge, our catalytic process is among the most efficient approaches to the N-arylation of imidazoles with aryl halides so far reported. Furthermore, the Pd-soaked material 4a-2 also shows higher catalytic activity in the solvent-free hydrogenation of styrene to ethylbenzene. This new concept is generally applicable and may easily be extended to other supported task-specific ionic liquids.
- Chen, Wen,Zhang, Yuanyuan,Zhu, Liangbo,Lan, Jingbo,Xie, Rugang,You, Jingsong
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p. 13879 - 13886
(2008/09/16)
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- Highly efficient copper-catalyzed N-arylation of nitrogen-containing heterocycles with aryl and heteroaryl halides
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(Chemical Equation Presented) New (S)-pyrrolidinylmethylimidazole ligands (4a-c) have been readily synthesized in a straightforward fashion from least expensive starting materials in short steps in high yields. Relatively mild and highly efficient Cul-catalyzed N-arylation procedures for imidazoles with aryl and heteroaryl bromides or chlorides have been developed in the presence of 4a and Cs2CO3. It is important to note that the protocol could tolerate functional groups such as ester, nitrile, nitro, ketone, free hydroxyl, and free primary amine on the aryl halide. The protocol could also be applicable to other π-electron-rich nitrogen heterocycles (pyrrole, pyrazole, indole, benzimidazole, and triazole), affording the N-arylazoles in good to excellent yields.
- Zhu, Liangbo,Cheng, Liang,Zhang, Yuxi,Xie, Rugang,You, Jingsong
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p. 2737 - 2743
(2008/02/05)
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- Model studies of the histidine-tyrosine cross-link in cytochrome c oxidase reveal the flexible substituent effect of the imidazole moiety
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(Chemical Equation Presented) Experimental and theoretical studies were carried out to interrogate the effect of an imidazole substituent in each of the ortho, meta, and para positions on the pKa, E°, and O-H BDE of phenol. The results reveal t
- Pratt, Derek A.,Pesavento, Russell P.,Van Der Donk, Wilfred A.
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p. 2735 - 2738
(2007/10/03)
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- Syntheses and pKa determination of 1-(o-hydroxyphenyl)imidazole carboxylic esters
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All three isomers of 1-(o-hydroxyphenyl)imidazole carboxylic esters (1-3) have been synthesized regioselectively via their methyl ether precursors. Methyl 1-(o-methoxyphenyl)imidazole-2-carboxylate (6) and the corresponding 1,4-isomer (11) were synthesized via Cu-catalyzed coupling of 2-iodoanisole with imidazole followed by methoxy-carbonylation, and by direct coupling of 2-iodoanisole with methyl imidazole-4-carboxylate (7), respectively. The 1,5-isomer (15) was prepared by annulation of an N-aryl glycine ester derivative (13). The boron tribromide mediated cleavage of methyl ethers gave the hydroxyphenyl compounds (1-3) in good to excellent yields. These compounds can serve as building blocks for synthesizing a new generation of active-site model compounds of cytochrome c oxidase (CcO). The pKa values have been determined by spectrophotometric measurements in order to provide a basis for the understanding of the proton transfer processes in CcO.
- Collman, James P.,Wang, Zhong,Zhong, Min,Zeng, Li
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p. 1217 - 1221
(2007/10/03)
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- Compounds enhancing antitumor activity of other cytotoxic agents
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This invention relates to certain heterocyclic compounds and their pharmaceutically acceptable salts, which are useful for sensitizing multidrug-resistant tumor cells to anticancer agents and multidrug resistant forms of malaria, tuberculosis, leishmania and amoebic dysentery to chemotherapeutants. The compounds and their pharmaceutically acceptable salts are also inhibitors of the active drug transport capability of P-glycoprotein which is encoded by the human MDR1 gene, as well as of certain other related ATP-binding-cassette transporters from eukaryotic and prokaryotic organisms (e.g., pfmdr from Plasmodium falciprum, and murine mdr1 and mdr3 gene products).
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