- π-Conjugated polymers with pendant coumarins: Design, synthesis, characterization, and interactions with carbon nanotubes
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A series of new fluorene-based π-conjugated polymers having coumarin derivatives as part of dendritic side chains were designed and prepared using the Suzuki-Miyaura cross-coupling reaction. A new coumarin derivative bearing a heptyl side chain for solubility was utilized to ensure solubility of the final polymers. It was found that fluorescence resonance energy transfer (FRET) from the coumrains to the polyfluorene backbone was efficient, especially for the polymers decorated with lower-generation dendrons. Each of the polymers was found to interact strongly with the surface of single-walled carbon nanotubes (SWNTs) in THF, and their ability to selectively disperse specific SWNT chiralities was investigated. Photoluminescence studies revealed that the strong polymer emission is efficiently quenched in the corresponding supramolecular complexes with SWNTs. This high quenching efficiency indicates that the coumarin-polymer FRET system can be supramolecularly bound to the surface of (SWNTs to produce an energy transfer system in which the energy absorbed by the donor coumarin chromophores is channeled to the SWNTs.
- Imit, Mokhtar,Imin, Patigul,Adronov, Alex
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- Design and Synthesis of 2-Alkylpyrimidine-4,6-diol and 6-Alkylpyridine-2,4-diol as Potent GPR84 Agonists
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A series of alkylpyrimidine-4,6-diol derivatives were designed and synthesized as novel GRP84 agonists based on a high-throughput screening (HTS) hit 1. 6-Nonylpyridine-2,4-diol was identified as the most potent agonist of GPR84 reported so far, with an EC50 of 0.189 nM. These novel GPR84 agonists will provide valuable tools for the study of the physiological functions of GPR84.
- Liu, Yang,Zhang, Qing,Chen, Lin-Hai,Yang, Hui,Lu, Wei,Xie, Xin,Nan, Fa-Jun
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- A Continuous, Fluorogenic Sirtuin 2 Deacylase Assay: Substrate Screening and Inhibitor Evaluation
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Sirtuins are important regulators of lysine acylation, which is implicated in cellular metabolism and transcriptional control. This makes the sirtuin class of enzymes interesting targets for development of small molecule probes with pharmaceutical potential. To achieve detailed profiling and kinetic insight regarding sirtuin inhibitors, it is important to have access to efficient assays. In this work, we report readily synthesized fluorogenic substrates enabling enzyme-economical evaluation of SIRT2 inhibitors in a continuous assay format as well as evaluation of the properties of SIRT2 as a long chain deacylase enzyme. Novel enzymatic activities of SIRT2 were thus established in vitro, which warrant further investigation, and two known inhibitors, suramin and SirReal2, were profiled against substrates containing ε-N-acyllysine modifications of varying length.
- Galleano, Iacopo,Schiedel, Matthias,Jung, Manfred,Madsen, Andreas S.,Olsen, Christian A.
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- Amide/Ester Cross-Coupling via C-N/C-H Bond Cleavage: Synthesis of β-Ketoesters
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Activated primary, secondary, and tertiary amides were coupled with enolizable esters in the presence of LiHMDS to obtain good yields of β-ketoesters at room temperature. Notably, this protocol provides an efficient, mild, and high chemoselectivity method
- Chen, Jiajia,Joseph, Devaneyan,Xia, Yuanzhi,Lee, Sunwoo
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p. 5943 - 5953
(2021/04/02)
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- Synthetic Scope of Br?nsted Acid-Catalyzed Reactions of Carbonyl Compounds and Ethyl Diazoacetate
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The comprehensive study of the reactions of carbonyl compounds and ethyl diazoacetate in the presence of a Br?nsted acid catalyst is described. In result, a broad range of 3-oxo-esters were synthesized from a variety of ketones and aliphatic aldehydes by 1,2-aryl/alkyl/hydride shift. Aryl-methyl ketones produced only aryl-migrated products, whereas other ketones yielded a mixture of products. For diaryl ketones, the identity of two inseparable migrated products was confirmed by two-dimensional NMR spectroscopy.
- Rahaman, Mizzanoor,Ali, M. Shahnawaz,Jahan, Khorshada,Hinz, Damon,Belayet, Jawad Bin,Majinski, Ryan,Hossain, M. Mahmun
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p. 6138 - 6147
(2021/05/06)
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- Synthesis and Pharmacological Evaluation of Triazolopyrimidinone Derivatives as Noncompetitive, Intracellular Antagonists for CC Chemokine Receptors 2 and 5
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CC chemokine receptors 2 (CCR2) and 5 (CCR5) are involved in many inflammatory diseases; however, most CCR2 and CCR5 clinical candidates have been unsuccessful. (Pre)clinical evidence suggests that dual CCR2/CCR5 inhibition might be more effective in the treatment of such multifactorial diseases. In this regard, the highly conserved intracellular binding site in chemokine receptors provides a new avenue for the design of multitarget ligands. In this study, we synthesized and evaluated the biological activity of a series of triazolopyrimidinone derivatives in CCR2 and CCR5. Radioligand binding assays first showed that they bind to the intracellular site of CCR2, and in combination with functional assays on CCR5, we explored structure-affinity/activity relationships in both receptors. Although most compounds were CCR2-selective, 39 and 43 inhibited β-arrestin recruitment in CCR5 with high potency. Moreover, these compounds displayed an insurmountable mechanism of inhibition in both receptors, which holds promise for improved efficacy in inflammatory diseases.
- Ortiz Zacarías, Natalia V.,Van Veldhoven, Jacobus P. D.,Den Hollander, Lisa S.,Dogan, Burak,Openy, Joseph,Hsiao, Ya-Yun,Lenselink, Eelke B.,Heitman, Laura H.,Ijzerman, Adriaan P.
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p. 11035 - 11053
(2019/12/24)
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- Screening, synthesis, crystal structure, and molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as novel AKR1C3 inhibitors
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AKR1C3 is a promising therapeutic target for castration-resistant prostate cancer. Herein, an evaluation of in-house library discovered substituted pyranopyrazole as a novel scaffold for AKR1C3 inhibitors. Preliminary SAR exploration identified its derivative 19d as the most promising compound with an IC50 of 0.160 μM among the 23 synthesized molecules. Crystal structure studies revealed that the binding mode of the pyranopyrazole scaffold is different from the current inhibitors. Hydroxyl, methoxy and nitro group at the C4-phenyl substituent together anchor the inhibitor to the oxyanion site, while the core of the scaffold dramatically enlarges but partially occupies the SP pockets with abundant hydrogen bond interactions. Strikingly, the inhibitor undergoes a conformational change to fit AKR1C3 and its homologous protein AKR1C1. Our results suggested that conformational changes of the receptor and the inhibitor should both be considered during the rational design of selective AKR1C3 inhibitors. Detailed binding features obtained from molecular dynamics simulations helped to finally elucidate the molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as AKR1C3 inhibitors, which would facilitate the future rational inhibitor design and structural optimization.
- Zheng, Xuehua,Jiang, Zan,Li, Xiaolin,Zhang, Chen,Li, Zhe,Wu, Yinuo,Wang, Xinhua,Zhang, Chao,Luo, Hai-bin,Xu, Jun,Wu, Deyan
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supporting information
p. 5934 - 5943
(2018/11/23)
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- Auto-Tandem Catalysis-Induced Synthesis of Trisubstituted Furans through Domino Acid-Acid-Catalyzed Reaction of Aliphatic Aldehydes and 1,3-Dicarbonyl Compounds by using N-Bromosuccinimide as Oxidant
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A simple aluminium(III) chloride-catalyzed synthesis of tri-substituted furans from aliphatic aldehydes and 1,3-dicarbonyl compounds was developed by using N-bromosuccinimide (NBS) as an oxidant. This method was effective for the synthesis of various furan derivatives. Some of the products were not accessible with the previously reported methods. Mechanically, this reaction involved an auto-tandem catalysis based on a newly reported acid-acid-catalyzed tandem reaction to ensure that furans were successfully synthesized. (Figure presented.).
- Huang, Wenbo,Liu, Changhui,Gu, Yanlong
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p. 1811 - 1818
(2017/06/09)
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- From in vitro to in cellulo: Structure-activity relationship of (2-nitrophenyl)methanol derivatives as inhibitors of PqsD in Pseudomonas aeruginosa
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Recent studies have shown that compounds based on a (2-nitrophenyl)methanol scaffold are promising inhibitors of PqsD, a key enzyme of signal molecule biosynthesis in the cell-to-cell communication of Pseudomonas aeruginosa. The most promising molecule displayed anti-biofilm activity and a tight-binding mode of action. Herein, we report on the convenient synthesis and biochemical evaluation of a comprehensive series of (2-nitrophenyl)methanol derivatives. The in vitro potency of these inhibitors against recombinant PqsD as well as the effect of selected compounds on the production of the signal molecules HHQ and PQS in P. aeruginosa were examined. The gathered data allowed the establishment of a structure-activity relationship, which was used to design fluorescent inhibitors, and finally, led to the discovery of (2-nitrophenyl)methanol derivatives with improved in cellulo efficacy providing new perspectives towards the application of PqsD inhibitors as anti-infectives. This journal is the Partner Organisations 2014.
- Storz, Michael P.,Allegretta, Giuseppe,Kirsch, Benjamin,Empting, Martin,Hartmann, Rolf W.
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supporting information
p. 6094 - 6104
(2014/08/05)
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- Structure optimization of 2-benzamidobenzoic acids as PqsD inhibitors for Pseudomonas aeruginosa infections and elucidation of binding mode by SPR, STD NMR, and molecular docking
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Pseudomonas aeruginosa employs a characteristic pqs quorum sensing (QS) system that functions via the signal molecules PQS and its precursor HHQ. They control the production of a number of virulence factors and biofilm formation. Recently, we have shown that sulfonamide substituted 2-benzamidobenzoic acids, which are known FabH inhibitors, are also able to inhibit PqsD, the enzyme catalyzing the last and key step in the biosynthesis of HHQ. Here, we describe the further optimization and characterization of this class of compounds as PqsD inhibitors. Structural modifications showed that both the carboxylic acid ortho to the amide and 3′-sulfonamide are essential for binding. Introduction of substituents in the anthranilic part of the molecule resulted in compounds with IC50 values in the low micromolar range. Binding mode investigations by SPR with wild-type and mutated PqsD revealed that this compound class does not bind into the active center of PqsD but in the ACoA channel, preventing the substrate from accessing the active site. This binding mode was further confirmed by docking studies and STD NMR.
- Weidel, Elisabeth,De Jong, Johannes C.,Brengel, Christian,Storz, Michael P.,Braunshausen, Andrea,Negri, Matthias,Plaza, Alberto,Steinbach, Anke,Müller, Rolf,Hartmann, Rolf W.
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supporting information
p. 6146 - 6155
(2013/09/02)
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- Validation of PqsD as an anti-biofilm target in pseudomonas aeruginosa by development of small-molecule inhibitors
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2-Heptyl-4-hydroxyquinoline (HHQ) and Pseudomonas quinolone signal (PQS) are involved in the regulation of virulence factor production and biofilm formation in Pseudomonas aeruginosa. PqsD is a key enzyme in the biosynthesis of these signal molecules. Using a ligand-based approach, we have identified the first class of PqsD inhibitors. Simplification and rigidization led to fragments with high ligand efficiencies. These small molecules repress HHQ and PQS production and biofilm formation in P. aeruginosa. This validates PqsD as a target for the development of anti-infectives.
- Storz, Michael P.,Maurer, Christine K.,Zimmer, Christina,Wagner, Nathalie,Brengel, Christian,De Jong, Johannes C.,Lucas, Simon,Muesken, Mathias,Haeussler, Susanne,Steinbach, Anke,Hartmann, Rolf W.
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p. 16143 - 16146
(2012/11/07)
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- AMIDE COMPOUND AND BACTERIAL DISEASE CONTROL AGENT FOR AGRICULTURAL AND HORTICULTURAL USE
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The present invention provides an amide compound having antibacterial activity, and a bacterial infection control agent for agricultural and horticultural use that contains the amide compound. The novel amide compound of the present invention is represented by General Formula (1): wherein R is a -CH(R1)(R2) or a -CO(R2) group, R1 is a hydrogen atom or a hydroxyl group, and R2 is a C1-12 alkyl group.
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Page/Page column 10
(2010/09/05)
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- Synthesis of 4-alkyl- and 4-(ω-chloroalkyl)-3-hydroxy-5- alkylidenebutenolides based on cyclizations of 4-alkyl- and 4-(ω- chloroalkyl)-1,3-bis(trimethylsilyloxy)buta-1,3-dienes with oxalyl chloride
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4-Alkyl- and 4-(ω-chloroalkyl)-1,3-bis(trimethylsilyloxy)buta-1,3- dienes were prepared from ethyl acetoacetate in three steps. Their cyclization with oxalyl chloride allowed an efficient synthesis of 4-alkyl- and 4-(ω-chloroalkyl)-5-alkylidenebutenolides. Georg Thieme Verlag Stuttgart.
- Nguyen, Van Thi Hong,Bellur, Esen,Appel, Bettina,Langer, Peter
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p. 2865 - 2872
(2008/02/07)
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- Substituted-4-quinolones
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Substituted-4-quinolones of the formula (I): wherein R1 is a straight or branched chain, saturated or ethylenically-unsaturated aliphatic hydrocarbyl group containing 1 to 18 carbon atoms which may optionally be substituted by one or more substituent groups selected from halo, 1-6C alkoxy, carboxy, 1-6C alkoxycarbonyl and NR6R7, wherein each of R6 and R7 is independently selected from H and 1-6C alkyl or R6 and R7 together with the N atom to which they are attached form a saturated heterocyclic group selected from piperidino, piperazino and morpholino. R2 is a group selected from H, —OH, halo, —CHO, —CO2H and CONHR8 wherein R8 is H or a 1-6C alkyl; each of R3, R4 and R1 is independently selected form H, —CH3, —OCH3 and halo; or a non-toxic pharmaceutically-acceptable salt thereof, have use in the manufacture of a medicament for the treatment of a disease of a living animal body, including a human, which disease is responsive to the activity of an immunosuppressant. The preferred compound of the formula 1 is 2-n-heptyl-3-hydroxy-4(1H)-quinolone.
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- Method for preparing chiral diphosphines
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The invention concerns a method for preparing a compound of formula (1) wherein: A represents naphthyl or phenyl optionally substituted; and Ar1, Ar2independently represent a saturated or aromatic carbocyclic group, optionally substituted.
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- Asymmetric hydrogenation method of a ketonic compound and derivative
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The present invention relates to a process for the asymmetric hydrogenation of a ketonic compound and derivative. The invention relates to the use of optically active metal complexes as catalysts for the asymmetric hydrogenation of a ketonic compound and derivative. The process for the asymmetric hydrogenation of a ketonic compound and derivative is characterized in that the asymmetric hydrogenation of said compound is carried out in the presence of an effective amount of a metal complex comprising as ligand an optically active diphosphine corresponding to one of the following formulae: STR1
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- Discovery of a series of pyrrolidine-based endothelin receptor antagonists with enhanced ET(A) receptor selectivity
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Endothelins, ET-1, ET-2, and ET-3 are potent vasoconstricting and mitogenic 21-amino acid bicyclic peptides, which exert their effects upon binding to the ET(A) and ET(B) receptors. The ET(A) receptor mediates vasoconstriction and smooth muscle cell proliferation, and the ET(B) receptor mediates different effects in different tissues, including nitric oxide release from endothelial cells, and vasoconstriction in certain vascular cell types. Selective antagonists of endothelin receptor subtypes may prove useful in determining the role of endothelin in various tissue types and disease states, and hence as therapeutic agents for such diseases. The pyrrolidine carboxylic acid A-127722 has been disclosed as a potent and ET(A)-selective antagonist, and is currently undergoing clinical trials. In our efforts to find antagonists with altered selectivity (ET(A)-selective, ET(B)-selective, or nonselective), we investigated the SAR of the 2-substituent on the pyrrolidine. Compounds with alkyl groups at the 2-position possessed ET(A) selectivity improved over A-127722 (1400-fold selective), with the best of these compounds showing nearly 19,000-fold selectivity. Copyright (C) 1999 Elsevier Science Ltd.
- Boyd, Steven A.,Mantei, Robert A.,Tasker, Andrew S.,Liu, Gang,Sorensen, Bryan K.,Henry Jr., Kenneth J.,Von Geldern, Thomas W.,Winn, Martin,Wu-Wong, Jinshyun R.,Chiou, William J.,Dixon, Douglas B.,Hutchins, Charles W.,Marsh, Kennan C.,Nguyen, Bach,Opgenorth, Terry J.
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p. 991 - 1002
(2007/10/03)
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- An efficient synthesis of novel N-acetyl-3-alkanoyl and 3-dienoyl tetramic acids
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A general synthesis of N-acetyl-3-alkanoyl- and 3-dienoyl-tetramic acids is presented. The condensation of N-(N-acetylglycyloxy)succinimide with β-keto esters bearing alkanoyl or dienoyl groups furnishes the new 3-substituted N-acetyltetramic acids 6-9 and 16 in good yields. The key intermediates 4 and 5 have been isolated and subsequently cyclized to the corresponding tetramic acids. Spectral data for and the physical characteristics of all compounds are reported.
- Petroliagi, Margarita,Igglessi-Markopoulou, Olga
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p. 3543 - 3548
(2007/10/03)
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