- Hydroxamic Acid-Piperidine Conjugate is an Activated Catalyst for Lysine Acetylation under Physiological Conditions
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Lysine acylation of proteins is an essential chemical reaction for posttranslational modification and as a means of protein modification in various applications. N,N-Dimethyl-4-aminopyridine (DMAP) derivatives are widely-used catalysts for lysine acylatio
- Mizumoto, Shinsuke,Xi, Siqi,Fujiwara, Yusuke,Kawashima, Shigehiro A.,Yamatsugu, Kenzo,Kanai, Motomu
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Read Online
- Metal complex, electroluminescent device containing metal complex and application of metal complex
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The invention provides a metal complex, an electroluminescent device containing the metal complex and application of the electroluminescent device, the metal complex has an M(La)m(Lb)n structure, the metal complex provided by the invention can more effectively finely adjust the luminescence color and adjust the luminescence peak width, so that the half-peak width is narrowed, the luminescence color is more saturated, the device efficiency is improved, and the current efficiency and the external quantum efficiency are relatively high.
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Paragraph 0154; 0161-0163
(2021/07/17)
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- Fungal Dioxygenase AsqJ Is Promiscuous and Bimodal: Substrate-Directed Formation of Quinolones versus Quinazolinones
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Previous studies showed that the FeII/α-ketoglutarate dependent dioxygenase AsqJ induces a skeletal rearrangement in viridicatin biosynthesis in Aspergillus nidulans, generating a quinolone scaffold from benzo[1,4]diazepine-2,5-dione substrates. We report that AsqJ catalyzes an additional, entirely different reaction, simply by a change in substituent in the benzodiazepinedione substrate. This new mechanism is established by substrate screening, application of functional probes, and computational analysis. AsqJ excises H2CO from the heterocyclic ring structure of suitable benzo[1,4]diazepine-2,5-dione substrates to generate quinazolinones. This novel AsqJ catalysis pathway is governed by a single substituent within the complex substrate. This unique substrate-directed reactivity of AsqJ enables the targeted biocatalytic generation of either quinolones or quinazolinones, two alkaloid frameworks of exceptional biomedical relevance.
- Einsiedler, Manuel,Jamieson, Cooper S.,Maskeri, Mark A.,Houk, Kendall N.,Gulder, Tobias A. M.
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supporting information
p. 8297 - 8302
(2021/03/01)
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- A Diverse Library of Chiral Cyclopropane Scaffolds via Chemoenzymatic Assembly and Diversification of Cyclopropyl Ketones
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Chiral cyclopropane rings are key pharmacophores in pharmaceuticals and bioactive natural products, making libraries of these building blocks a valuable resource for drug discovery and development campaigns. Here, we report the development of a chemoenzymatic strategy for the stereoselective assembly and structural diversification of cyclopropyl ketones, a highly versatile yet underexploited class of functionalized cyclopropanes. An engineered variant of sperm whale myoglobin is shown to enable the highly diastereo- and enantioselective construction of these molecules via olefin cyclopropanation in the presence of a diazoketone carbene donor reagent. This biocatalyst offers a remarkably broad substrate scope, catalyzing this reaction with high stereoselectivity across a variety of vinylarene substrates as well as a range of different α-aryl and α-alkyl diazoketone derivatives. Chemical transformation of these enzymatic products enables further diversification of these molecules to yield a collection of structurally diverse cyclopropane-containing scaffolds in enantiopure form, including core motifs found in drugs and natural products as well as novel structures. This work illustrates the power of combining abiological biocatalysis with chemoenzymatic synthesis for generating collections of optically active scaffolds of high value for medicinal chemistry and drug discovery.
- Nam, Donggeon,Steck, Viktoria,Potenzino, Robert J.,Fasan, Rudi
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p. 2221 - 2231
(2021/02/16)
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- Remote Directed Isocyanation of Unactivated C(sp3)-H Bonds: Forging Seven-Membered Cyclic Ureas Enabled by Copper Catalysis
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Reported herein is an unprecedented copper-catalyzed site-selective ?-C(sp3)-H bonds activation of aliphatic sulfonamides for constructing the synthetically useful seven-membered N-heterocycles. A key to success is the use of in-situ-formed amide radicals, to activate the inert C(sp3)-H bond, and inexpensive TMSNCO, as a coupling reagent under mild conditions. To the best of our knowledge, this represents the first use of alkylamine derivatives as a five-membered synthon to prepare a seven-membered N-heterocycles.
- Zhang, Hongwei,Tian, Peiyuan,Ma, Lishuang,Zhou, Yulu,Jiang, Cuiyu,Lin, Xufeng,Xiao, Xiao
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supporting information
p. 997 - 1002
(2020/02/15)
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- PRODRUGS OF 4-((1R,3S)-6-CHLORO-3-PHENYL-2,3-DIHYDRO-1H-INDEN-1-YL)-1,2,2-TRIMETHYLPIPERAZINE AND 4-((1/R,3S)-6-CHLORO-3-(PHENYL-D5)-2,3-DIHYDRO-1H-INDEN-1-YL)-2,2-DIMETHY-1-(METHYL-D3)PIPERAZINE
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The present invention relates to prodrugs of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)- 1,2,2-trimethylpiperazine in the form of 1a and 1b; and 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro- 1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d
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Page/Page column 14; 15
(2020/07/06)
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- Palladium-Catalyzed Distal C?H Selenylation of 2-Aryl Acetamides with Diselenides and Selenyl Chlorides
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A convenient and effective method of palladium-catalyzed C?H selenylation of the 2-aryl acetamides assisted with removable 8-aminoquinoline with readily available diselenides and selenyl chlorides has been developed. This selenylation reaction is scalable and tolerates a wide range of functional groups, providing a straightforward way of the preparing unsymmetrical diaryl selenides and dibenzoselene-pinone. Preliminary mechanistic studies indicated that a single-electron transfer type mechanism and facile C?H metalation are operative. (Figure presented.).
- Gu, Linghui,He, Meicui,Ma, Wenbo,Tan, Yuqiang,Wang, Yang,Wang, Yuchi,Zhang, Chunran
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supporting information
p. 5708 - 5715
(2020/12/01)
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- Copper-Catalyzed Amide Radical-Directed Cyanation of Unactivated Csp3-H Bonds
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A method for site-selective intermolecular δ/?-Csp3-H cyanation of aliphatic sulfonamides is developed using TsCN as the cyanating reagent, catalyzed by a Cu(I)/phenanthroline complex. The mild, expeditious, and modular protocol allows efficient remote Csp3-H cyanation with good functional group tolerance and high regioselectivity. Mechanistic studies indicate that the reaction might proceed through a Cu(I)-mediated N-F bond cleavage to generate an amidyl radical, 1,5-HAT, and cyano group transfer of the resulting carbon radical with TsCN.
- Zhang, Hongwei,Zhou, Yulu,Tian, Peiyuan,Jiang, Cuiyu
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supporting information
(2019/03/19)
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- Synthetic Utility of N-Benzoyloxyamides as an Alternative Precursor of Acylnitrenoids for γ-Lactam Formation
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Described herein is the development of a new entry of acylnitrenoid precursors for γ-lactam synthesis via an intramolecular C-H amidation reaction. Upon Ir catalysis, N-benzoyloxyamides serve as efficient substrates to afford 5-membered amides. Mechanistic studies revealed that the generation of a putative Ir-carbonylnitrenoid via N-O bond cleavage is facilitated by the chelation of countercations. This protocol offers a convenient and step-economic route to γ-lactams starting from the corresponding carboxylic acids.
- Huh, Soohee,Hong, Seung Youn,Chang, Sukbok
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supporting information
p. 2808 - 2812
(2019/04/17)
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- A General Approach to Site-Specific, Intramolecular C?H Functionalization Using Dithiocarbamates
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Intramolecular hydrogen atom transfer is an established approach for the site-specific functionalization of unactivated, aliphatic C?H bonds. Transformations using this strategy typically require unstable intermediates formed using strong oxidants and have mainly targeted C?H halogenations or intramolecular aminations. Herein, we report a site-specific C?H functionalization that significantly increases the synthetic scope and convergency of reactions proceeding via intramolecular hydrogen atom transfer. Stable, isolable N-dithiocarbamates are used as precursors to amidyl radicals formed via either light or radical initiation to efficiently deliver highly versatile alkyl dithiocarbamates across a wide range of complex structures.
- Na, Christina G.,Alexanian, Erik J.
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supporting information
p. 13106 - 13109
(2018/09/21)
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- Primary, Secondary, and Tertiary γ-C(sp3)-H Vinylation of Amides via Organic Photoredox-Catalyzed Hydrogen Atom Transfer
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An efficient strategy for primary, secondary and tertiary aliphatic γ-C(sp3)-H vinylation of amides with alkenylboronic acids is reported. These reactions are catalyzed by visible-light organic photoredox agents. Regioselective γ-C(sp3)-H vinylation of amides is controlled by a 1,5-hydrogen atom transfer of an amidyl radical generated in situ.
- Chen, Hui,Guo, Liangliang,Yu, Shouyun
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supporting information
p. 6255 - 6259
(2018/10/05)
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- Asymmetric radical addition of TEMPO to titanium enolates
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A mild method for a-hydroxylation of N-acyl oxazolidinones by asymmetric radical addition of the 2,2,6,6-tetramethylpiperidine N-oxy (TEMPO) radical to titanium enolates was developed. The high diastereoselectivity and broad scope of the reaction show synthetic utility for the a-hydroxylation of substrates that are not tolerant to strongly basic conditions.
- Mabe, Phillip J.,Zakarian, Armen
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supporting information
p. 516 - 519
(2014/04/03)
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- Protein kinase CK-1 inhibitors as new potential drugs for amyotrophic lateral sclerosis
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease where motor neurons in cortex, brain stem, and spinal cord die progressively, resulting in muscle wasting, paralysis, and death. Currently, effective therapies for ALS are lacking; however, identification of pathological TAR DNA-binding protein 43 (TDP-43) as the hallmark lesion in sporadic ALS suggests new therapeutic targets for pharmacological intervention. Pathological TDP-43 phosphorylation appears to drive the onset and progression of ALS and may result from upregulation of the protein kinase CK-1 in affected neurons, resulting in postranslational TDP-43 modification. Consequently, brain penetrant specific CK-1 inhibitors may provide a new therapeutic strategy for treating ALS and other TDP-43 proteinopathies. Using a chemical genetic approach, we report the discovery and further optimization of a number of potent CK-1δ inhibitors. Moreover, these small heterocyclic molecules are able to prevent TDP-43 phosphorylation in cell cultures, to increase Drosophila lifespan by reduction of TDP-43 neurotoxicity, and are predicted to cross the blood-brain barrier. Thus, N-(benzothiazolyl)-2-phenyl-acetamides are valuable drug candidates for further studies and may be a new therapeutic approach for ALS and others pathologies in which TDP-43 is involved.
- Salado, Irene G.,Redondo, Miriam,Bello, Murilo L.,Perez, Concepción,Liachko, Nicole F.,Kraemer, Brian C.,Miguel, Laetitia,Lecourtois, Magalie,Gil, Carmen,Martinez, Ana,Perez, Daniel I.
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p. 2755 - 2772
(2014/04/17)
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- SERINE RACEMASE INHIBITOR
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A novel serine racemase inhibitor exhibits sufficient activity and specificity. The serine racemase inhibitor includes one or more compounds selected from compounds respectively represented by the following general formulas [MM_1], [DR_1], [DR'_1], [LW_1], and [ED_1] as an active ingredient.
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Paragraph 0173
(2014/12/12)
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- Alkylsulfanyl-1,2,4-triazoles, a New Class of allosteric valosine containing protein inhibitors. Synthesis and structure-activity relationships
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Valosine containing protein (VCP), also known as p97, is a member of AAA ATPase family that is involved in several biological processes and plays a central role in the ubiquitin-mediated degradation of misfolded proteins. VCP is an ubiquitously expressed, highly abundant protein and has been found overexpressed in many tumor types, sometimes associated with poor prognosis. In this respect, VCP has recently received a great deal of attention as a potential new target for cancer therapy. In this paper, the discovery and structure-activity relationships of alkylsulfanyl-1,2,4-triazoles, a new class of potent, allosteric VCP inhibitors, are described. Medicinal chemistry manipulation of compound 1, identified via HTS, led to the discovery of potent and selective inhibitors with submicromolar activity in cells and clear mechanism of action at consistent doses. This represents a first step toward a new class of potential anticancer agents.
- Polucci, Paolo,Magnaghi, Paola,Angiolini, Mauro,Asa, Daniela,Avanzi, Nilla,Badari, Alessandra,Bertrand, Jay,Casale, Elena,Cauteruccio, Silvia,Cirla, Alessandra,Cozzi, Liviana,Galvani, Arturo,Jackson, Peter K.,Liu, Yichin,Magnuson, Steven,Malgesini, Beatrice,Nuvoloni, Stefano,Orrenius, Christian,Sirtori, Federico Riccardi,Riceputi, Laura,Rizzi, Simona,Trucchi, Beatrice,O'Brien, Tom,Isacchi, Antonella,Donati, Daniele,D'Alessio, Roberto
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p. 437 - 450
(2013/04/10)
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- Palladium-catalyzed allylic alkylation of carboxylic acid derivatives: N-acyloxazolinones as ester enolate equivalents
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Triple A: A general asymmetric allylic alkylation of ester enolate equivalents at the carboxylic acid oxidation state is reported. N-Acylbenzoxazolinone-derived enol carbonates were synthesized and employed in the palladium-catalyzed alkylation reaction. The imide products were readily converted into a series of carboxylic acid derivatives without loss of enantiopurity.
- Trost, Barry M.,Michaelis, David J.,Charpentier, Julie,Xu, Jiayi
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supporting information; experimental part
p. 204 - 208
(2012/02/16)
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- A simple method for asymmetric trifluoromethylation of N-acyl oxazolidinones via Ru-catalyzed radical addition to zirconium enolates
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A Ru-catalyzed direct thermal trifluoromethylation and perfluoroalkylation of N-acyloxazolidinones has been developed. The reaction is experimentally simple and requires inexpensive reagents while providing good yields of products with good levels of stereocontrol. Preliminary studies have shown notable compatibility with functional groups, aromatics, and certain heteroaromatic substituents. The described method provides a useful alternative for the synthesis of fluorinated materials in an experimentally convenient manner.
- Herrmann, Aaron T.,Smith, Lindsay L.,Zakarian, Armen
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supporting information; experimental part
p. 6976 - 6979
(2012/06/15)
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- Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties
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Structure-guided lead optimization of recently described benzimidazolyl acetamides addressed the key liabilities of the previous lead compound 1. These efforts culminated in the discovery of 4-{(S)-2-[2-(4-chloro-phenyl)-5,6- difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid 7g, a highly potent and selective FXR agonist with excellent physicochemical and ADME properties and potent lipid lowering activity after oral administration to LDL receptor deficient mice.
- Richter, Hans G.F.,Benson,Bleicher,Blum,Chaput,Clemann,Feng,Gardes,Grether,Hartman,Kuhn,Martin,Plancher,Rudolph,Schuler,Taylor
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scheme or table
p. 1134 - 1140
(2011/04/16)
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- Synthesis of α-CF3-substituted carbonyl compounds with relative and absolute stereocontrol using electrophilic CF3-transfer reagents
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Evans-type chiral lithium imide enolates undergo diastereoselective α-trifluoromethylation with a hypervalent iodine-CF3 reagent with up to 91% combined isolated yield and 97:3 dr. The resulting isolated diastereopure products can be further transformed into valuable products without racemization.
- Matousek, Vaclav,Togni, Antonio,Bizet, Vincent,Cahard, Dominique
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supporting information; experimental part
p. 5762 - 5765
(2012/01/06)
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- 2-AMINO-QUINOLINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE)
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The present invention is directed to 2-amino-quinoline derivatives, pharmaceutical compositions containing them and their use in the treatment of Alzheimer's disease (AD) and related disorders. The compounds of the invention are inhibitors of β-secretase, also known as β-site cleaving enzyme and BACE, BACE1, Asp2 and memapsin2.
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Page/Page column 37
(2008/12/07)
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- Affinity of 3-acyl substituted 4-quinolones at the benzodiazepine site of GABAA receptors
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The finding that alkyl 1,4-dihydro-4-oxoquinoline-3-carboxylate and N-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxamide derivatives may be high-affinity ligands at the benzodiazepine binding site of the GABAA receptor, prompted a study of 3-acyl-1,4-dihydro-4-oxoquinoline (3-acyl-4-quinolones). In general, the affinity of the 3-acyl derivatives was found to be comparable with the 3-carboxylate and the 3-carboxamide derivatives, and certain substituents (e.g., benzyl) in position 6 were again shown to be important. As it is believed that the benzodiazepine binding site is situated between an α- and a γ-subunit in the GABAA receptor, selected compounds were tested on the α1β2γ2s, α2β2γ2s and α3β2γ2s GABAA receptor subtypes. The 3-acyl-4-quinolones display various degrees of selectivity for α1- versus α2- and α3-containing receptors, and high-affinity ligands essentially selective for α1 over α3 were developed.
- Lager, Erik,Nilsson, Jakob,stergaard Nielsen, Elsebet,Nielsen, Mogens,Liljefors, Tommy,Sterner, Olov
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p. 6936 - 6948
(2008/12/21)
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- Potent platelet-derived growth factor-β receptor (PDGF-βR) inhibitors: Synthesis and structure-activity relationships of 7-[3-(cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl} quinoxalin-2(1H)-one derivatives
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We found previously that 7-[3-(cyclohexylmethyl)ureido]-3-{1-methyl-1H- pyrrolo[2,3-b]pyridin-3-yl}quinoxalin-2(1H)-one (7d-6) has considerable potency as a PDGF inhibitor. This compound showed potent inhibitory activity in a PDGF-induced CPA (Cell Proliferation Assay) and APA (Auto-Phosphorylation Assay) (IC50=0.05 μmol/l in CPA, 0.03 μmol/l in APA). Therefore, we tried to develop a novel and effective PDGF-βR inhibitor by optimizing a series of its derivatives. We found that trifluoroacetic acid (TFA)-catalyzed coupling of pyrrolo[2,3-b]pyridines with quinoxalin-2-ones proceeded efficiently under mild oxidation condition with manganese(IV) oxide (MnO2) in situ, so this method was applied to prepare a series of derivatives. Results of in vitro screening of newly synthesized derivatives identified compound 7d-9 as having potent (IC50=0.014 μmol/l in CPA, 0.007 μmol/l in APA) and selective [IC50 values against vascular endothelial growth factor receptor 2 (VEGFR2, kinase domain region, KDR), epidermal growth factor receptor (EGFR), c-Met (hepatocyte growth factor receptor) and insulin growth factor I receptor (IGF-IR)/IC50 against PDGFR were each >1000] inhibitory activity. Moreover, in this series of derivatives, 7b-2 showed potent inhibitory activity toward both PDGF- and VEGF-induced signaling (PDGFR: IC50=0.004 μmol/l in CPA, 0.0008 μmol/l in APA, KDR: IC 50=0.008 μmol/l in APA). Herein we report a new and convenient synthetic method for this series of derivatives and its SAR study.
- Aoki, Katsuyuki,Obata, Tatsuhiro,Yamazaki, Yosuke,Mori, Yoshikazu,Hirokawa, Hiroko,Koseki, Jun-Ichi,Hattori, Tomohisa,Niitsu, Kazuaki,Takeda, Shuichi,Aburada, Masaki,Miyamoto, Ken-Ichi
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p. 255 - 267
(2007/10/03)
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- 2-AMINO-3,4-DIHYDRO-QUINOLINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE)
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The present invention is directed to 2-amino-3,4-dihydro-quinoline derivatives, pharmaceutical compositions containing them and their use in the treatment of Alzheimer's disease (AD) and related disorders. The compounds of the invention are inhibitors of β-secretase, also known as β-site cleaving enzyme and BACE, BACE1, Asp2 and memapsin2.
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Page/Page column 28
(2010/11/28)
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- Improved replicon cellular activity of non-nucleoside allosteric inhibitors of HCV NS5B polymerase: From benzimidazole to indole scaffolds
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Benzimidazole-based allosteric inhibitors of the hepatitis C virus (HCV) NS5B polymerase were diversified to a variety of topologically related scaffolds. Replacement of the polar benzimidazole core by lipophilic indoles led to inhibitors with improved potency in the cell-based subgenomic HCV replicon system. Transposing the indole scaffold into a previously described series of benzimidazole-tryptophan amides generated the most potent inhibitors of HCV RNA replication in cell culture reported to date in this series (EC50 ~ 50 nM).
- Beaulieu, Pierre L.,Gillard, James,Bykowski, Darren,Brochu, Christian,Dansereau, Nathalie,Duceppe, Jean-Simon,Hache, Bruno,Jakalian, Araz,Lagace, Lisette,LaPlante, Steven,McKercher, Ginette,Moreau, Elaine,Perreault, Stephane,Stammers, Timothy,Thauvette, Louise,Warrington, Jeff,Kukolj, George
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p. 4987 - 4993
(2007/10/03)
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- Privileged structure based ligands for melanocortin-4 receptors-Aliphatic piperazine derivatives
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Aliphatic carbocyclic replacement of the benzyl group of compound 1 yielded compounds with high affinity for the melanocortin-4 receptor (MC4R). Compounds with a cyclohexyl group showed a consistent high affinity, while different polar groups with less basicity were good replacements for the original diethyl amines. Substitution of the polar group found in these privileged structures with an aliphatic moiety produced compounds with high affinity for MC4R.
- Briner, Karin,Collado, Iván,Fisher, Matthew J.,García-Paredes, Cristina,Husain, Saba,Kuklish, Steven L.,Mateo, Ana I.,O'Brien, Thomas P.,Ornstein, Paul L.,Zgombick, John,de Frutos, óscar
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p. 3449 - 3453
(2007/10/03)
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- α-Aminoalkylphosphonates as a tool in experimental optimisation of P1 side chain shape of potential inhibitors in S1 pocket of leucine- and neutral aminopeptidases
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The synthesis and biological activity studies of the series of structurally different α-aminoalkylphosphonates were performed in order to optimise the shape of the side chain of the potential inhibitors in S1 pocket of leucine aminopeptidase [E.C.3.4.11.1]. Analysis of a series of compounds with aromatic, aliphatic and alicyclic P1 side chains enabled to find out the structural features, optimal for that fragment of inhibitors of LAP. The most active among all investigated compounds were the phosphonic analogues of homo-tyrosine (Ki = 120:nM) and homo-phenylalanine (Ki = 140:nM), which even as racemic mixtures were better inhibitors in comparison with the best till now-phosphonic analogue of l-leucine (230 nM). Additional comparison of the inhibitory activity obtained for aminopeptidase N (APN, E.C.3.4.11.2) give insight into structural preferences of both enzymes.
- Drag, Marcin,Grembecka, Jolanta,Pawelczak, Malgorzata,Kafarski, Pawel
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p. 764 - 771
(2007/10/03)
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- COMPOUND LIBRARIES
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The present invention relates to compounds capable of binding to the active site of protein kinase enzymes. The invention further relates to libraries of compounds and a family of libraries of compounds for use in screening programmes against protein kinases as well as the individual compounds for use in hit to lead and lead optimisation projects, and similar stages in the drug discovery process. The invention also provides methods for making compounds and libraries.
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- NEW P2X7 RECEPTOR ANTAGONISTS AND THEIR USE
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The invention provides compounds of formula (IA), processes for their preparation, pharmaceutical compositions containing them, and their use in therapy. [Chemical formula should be inserted here. Please see paper copy] (IA)
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- Hepatitis C inhibitor peptides
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Disclosed herein are hepatitis C viral protease inhibitors of formula (I): wherein a is0or1; b is0or1; Y is H or C1-6alkyl; B is H, an acyl derivative or a sulfonyl derivative; R6, when present, is C1-6alkyl substituted wi
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- Synthesis and microbiological activity of some novel N-[2-(p-substitutedphenyl)-5-benzoxazolyl]-cyclohexyl carboxamide, -cyclohexyl acetamide and -cyclohexyl propionamide derivatives
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The synthesis and microbiological activity of a new series of N-[2-(p-substitutedphenyl)-5-benzoxazolyl]-cyclohexyl carboxamide, -cyclohexyl acetamide and -cyclohexyl propionamide derivatives (4-11) is described. The in vitro microbiological activity of the compounds was determined against Gram-positive, Gram-negative bacteria and the yeast Candida albicans in comparison with standard drugs. Microbiological results indicated that the synthesized compounds possessed a broad spectrum of activity against the tested microorganisms.
- Temiz Arpac, Oezlem,Ener, Esin Ak,Yalcn, Ismail,Altanlar, Nurten
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p. 771 - 775
(2007/10/03)
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- Non-thiol farnesyltransferase inhibitors: Structure-activity relationships of aralkylsubsituted benzophenones
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We describe a novel class of benzophenone-based farnesyltransferase inhibitors exploiting a novel aryl binding region in the farnesyltransferase's active site. The present study was mainly focussed on structural modifications of the trimethylene spacer of the 4-phenyl butyroyl residue of our lead structure (IC50 = 530 nM). These modifications turned out to have little effect on activity as had the replacement of the terminal aryl by cyclohexyl (IC50 = 440 nM vs. IC50 = 530 nM).
- Mitsch, Andreas,Wi, Pia,Sattler, Isabel,Schlitzer, Martin
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- 3-(Arylacetylamino)-N-methylbenzamides: A novel class of selective anti-Helicobacter pylori agents
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After chemical modification preceded by the random screening of our chemical library, a novel class of selective anti-Helicobacter pylori agents was generated. Consequently, the 3-(arylacetylamino)-N-methylbenzamides, which were quite easy to prepare, showed potent inhibitory activity against Helicobacter pylori but exhibited no inhibitory activity against other sorts of bacteria and fungi, e.g., Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Bacteroides fragilis, and Candida albicans. These compounds showed potent anti-H. pylori activity under acidic conditions, whereas amoxicillin and clarithromycin decreased activity. The 3-(3-arylpropionylamino)-N-methylbenzamides, 3-(aryloxyacetylamino)-N-methylbenzamides, and (3-methylcarbamoylphenyl)carbamic acid 1-arylmethyl esters also exhibited potent anti-H. pylori activity. Finally, we selected 7n (BAS-118) as a candidate compound for further evaluation.
- Ando,Kawamura,Chiba
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p. 4468 - 4474
(2007/10/03)
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- Diaryl-2-(5H)-furanones as Cox-2 inhibitors
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The invention encompasses the novel compound of Formula (I) as well as a method of treating cyclooxygenase-2 mediated diseases comprising administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of Formula (I). The invention also encompasses certain pharmaceutical compositions for treatment of cyclooxygenase-2 mediated diseases comprising compounds of Formula (I).
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- Arylalkanoyl derivatives, processes for their preparation, their use and pharmaceutical compositions containing them
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The present invention relates to new compounds for the inhibition of blood clotting proteins, and more particularly, to arylalkanoyl derivatives of the formula I, wherein R(1), R(2), R(3), R(4), R(5), R(6a) and R(6b) have the meanings indicated in the cla
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- THERAPEUTIC AGENT FOR DIABETES
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A therapeutic agent for diabetes, which comprises a compound of the formula [I] wherein Xis a group of the formula wherein R4and R5are the same or different and each is a hydrogen atom, an optionally substituted alkyl having 1 to 5 carbon atoms and the like, and R6is a hydrogen atom or an amino-protecting group; R1is an optionally substituted alkyl having 1 to 5 carbon atoms, an optionally substituted alkenyl having 2 to 6 carbon atoms and the like, R2is a hydrogen atom, an optionally substituted alkyl having 1 to 5 carbon atoms and the like, R2' is a hydrogen atom, and R3is an optionally substituted alkyl having 1 to 5 carbon atoms and the like, a prodrug thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof. The compound of the present invention shows superior blood sugar decreasing action on the state of hyperglycemia, but does not affect the blood sugar when it is in the normal range or in the hypoglycemic state, which means that it is free of serious side effects such as hypoglycemia. Therefore, the compound of the present invention is useful as a therapeutic drug for diabetes and also useful as a preventive of the chronic complications of diabetes.
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- Diastereoselectivity in the SE2″ reaction of chiral pentadienylsilanes: A test for the relative importance of steric and electronic effects
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The homochiral pentadienylsilanes (3Z,5E)-(hepta-3,5-dien-2-yl)dimethyl(phenyl)silane 9, (3Z,5E)-(hepta-3,5-dien-2-yl)trimethylsilane 13, (4Z,6E)-(2-methylocta-4,6-dien-3-yl)dimethyl(phenyl)silane 14 and (4Z,6E)-(2-methylocta-4,6-dien-3-yl)trimethylsilane 17 undergo Lewis acid catalysed reactions with isobutyraldehyde and its dimethyl acetal stereospecifically anti with surprisingly high levels of stereoselectivity, ca. 90:10. The pentadienylsilanes (3Z)-hexa-3,5-dien-2-yldimethyl(phenyl)silane 20aa, (4Z)-(2-methylhepta-4,6-dien-3-yl)dimethyl(phenyl)silane 20ab, (3Z)-(hexa-3,5-dien-2-yl)-trimethylsilane 20ba and (2Z)-(1-phenylpenta-2,4-dienyl)trimethylsilane 20bc undergo dipolar cycloadditions to 2,2-dimethylpropanenitrile oxide regioselectively at the terminal double bond and stereoselectively anti to the silyl group to a somewhat lower extent, ca. 70:30. The pentadienylsilane (3Z,5E)-(6-cyclohexylhexa-3,5-dien-2-yl)trimethylsilane 25 undergoes deuteriodesilylation stereospecifically anti to a lower extent still, ca. 55:45. The pentadienylsilane (3Z,5E)-(8-methyl-8-methoxyethoxymethoxynona-3,5-dien-2-yl)trimethylsilane 34 undergoes an intramolecular reaction stereospecifically anti again to the extent of about 60:40, whereas the reaction of the corresponding allylsilane (3Z)-(6-methyl-6-methoxyethoxymethoxyhept-3-en-2-yl)trimethylsilane 32 is essentially completely anti. These results show that SE2″ reactions can be highly stereoselective in the anti sense, that the high level is probably best accounted for by the steric effect of the silyl group, and that when the steric effect is minimised, the stereospecificity is low, but still measurable. The pentadienylsilanes were prepared by aldol reactions between β-silyl esters and the appropriate α,β-unsaturated aldehyde, followed by decarboxylative elimination. The products of the SE2″ reactions were identified and their stereochemistry determined by comparison with authentic materials or by degradation and synthesis, using chiral auxiliaries to determine the enantiomeric purity. The products of two of the dipolar cycloadditions were identified by degradation and stereospecific vinylogous Peterson elimination, but the vinylogous Peterson elimination taking place with (1RS,2Z,4SR,6SA)-(4,6-dihydroxy-7,7-dimethyl-1-phenyloct-2-enyl)trimethylsilane 67bc and its (1SR) diastereoisomer 68bc was not stereospecific, giving (5E,7E)-2,2-dimethyl-8-phenylocta-5,7-dien-3-ol 73 from both isomers. The stereochemistries of all the reactions are summarised.
- Fleming, Ian,Jones, Graeme R.,Kindon, Nicholas D.,Landais, Yannick,Leslie, Colin P.,Morgan, Ian T.,Peukert, Stefan,Sarkar, Achintya K.
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p. 1171 - 1196
(2007/10/03)
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- Pharmacologically active phenylalkanoyl substituted imidazo (4,5-C) pyridines
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This invention relates to substituted imidazopyridine dervatives having the following formula STR1 and isomers thereof; or a pharmaceutically acceptable acid addition salt thereof: wherein R1 and R2 are each independently selected fr
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- Novel class of acyl-derivatives of carnitine process for preparing same and therapeutic use thereof
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A novel class of acyl-derivatives of carnitine is disclosed wherein the acyl radical is either the radical of unsaturated organic acids (typically, acrylic acid) or the radical of saturated organic acids substituted with tert-alkyl, cycloalkyl, cycloalkenyl, alkoxyl, heterocyclic and carboalkoxylradicals, or with aldehyde or hydroxy groups. These acyl-derivatives of carnitine are useful therapeutical agents in the treatment of cardiac disorders, hyperlipidaemias and hyperlipoproteinaemias.
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- Peptide immunostimulants
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Peptide compounds of formula 1, pharmaceutically acceptable base salts thereof, pharmaceutical compositions and their use as antiinfective agents where R1 is alkyl, cycloalkyl or cycloalkylmethyl; R2 is hydrogen or alkyl and R3 is hydroxy or an amino acid residue of the formula where X is hydrogen, alkyl or hydroxymethyl and nis an integer of 0 to 4 and R4 and R5 are alkyl, hydrogen, benzyl or cyclohexylmethyl.
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- MESOMORPHOGENS. VI. CHOLESTERYL AND THIOCHOLESTERYL ESTERS OF CYCLOALKANECARBOXYLIC ACIDS
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The acylation of cholesterol and thiocholesterol by acid chlorides of ω-cycloalkane carboxylic acid gave the cholesteryl and thiocholesteryl esters of the corresponding acids.The mesogenic capacity of the ω-cycloalkanoates of cholesterol and thiocholesterol is largely a factor of the polarizability of these molecules and not their spatial configuration.A decrease in the geometric anisotropy and concurrent increase in polarizability impart instability to the meso phase of most ω-cycloalkanoates.
- Bogatskii, A. V.,Kondrat'eva, R. V.,Galatina, A. I.,Novikova, N. S.
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p. 1286 - 1290
(2007/10/02)
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- Cyclopentanone Synthesis by Intramolecular Carbon-Hydrogen Insertion of Diazo Ketones. A Diterpene-to-Steroid Skeleton Conversion
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Intramolecular carbon-hydrogen insertion on cupric sulfate assisted decomposition of diazomethyl ketones derived from four 1-methylcycloalkanecarboxylic acids and (hexahydrophenyl)acetic, homopivalic, and enanthic acids is shown to yield mostly cyclopentanones.The yields are appreciable in the conformationally favorable cases, and insertion in the solvent cyclohexane can be avoided by the use of Freon TF as the solvent.The conversion of a primaradienic diterpene into a 14-iso-16-androstanone derivative shows the power of the new method of cyclopentanone synthesis.
- Wenkert, Ernest,Davis, Linda L.,Mylari, Banavara L.,Solomon, Mary F.,Silva, Roberto R. da,et al.
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p. 3242 - 3247
(2007/10/02)
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- Type II Photoelimination from α-Cycloalkylacetophenones and a Polystyrene-Bound Analogue
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In order to evaluate the effects of polymer binding on photoreactivity and other photochemical properties, we have synthesized α-cyclohexyl-p-methylacetophenone (I), α-cyclopentylacetophenone (II), and an analogue bound to insoluble polystyrene beads (P-I).All undergo type II photoelimination and are effective in energy transfer to an added quencher, trans-stilbene.Quantitative comparisons show that the polymer binding has little effect upon the photoreactivity as long as the polymer is in a swelling solvent, such as pentane, which allows the necessary molecular flexibility.The efficiency of energy transfer is somewhat reduced upon polymer binding.
- Wamser, Carl C.,Wagner, William R.
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p. 7232 - 7234
(2007/10/02)
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- PHOTOCHEMISTRY OF N-ACYLAZOLES. VI). PHOTOREACTIVITIES OF 1-ACYL-1,2,4-TRIAZOLES AND OF 2-ACYLTETRAZOLES
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Contrary to the findings in the photolysis of N-acylimidazoles (2) irradiation of 1-acyl-1,2,4-triazoles afforded no photo-Fries product, but instead products formed via the corresponding acyl radicals and aldehydes.Photolysis of 2-acyltetrazoles gave in part the same products as those obtained from the irradiation of the corresponding acyl-triazoles as well as 2-alkyl-1,3,4-oxadiazoles.N-Acyltetrazoles didn't give any photo-Fries product neither.
- Murato, Kazuo,Yatsunami, Takashi,Iwasaki, Shigeo
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p. 588 - 605
(2007/10/02)
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