- Tuning transthyretin amyloidosis inhibition properties of iododiflunisal by combinatorial engineering of the nonsalicylic ring substitutions
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Two series of iododiflunisal and diflunisal analogues have been obtained by using a two step sequential reaction solution-phase parallel synthesis. The synthesis combined an aqueous Suzuki-Miyaura cross-coupling and a mild electrophilic aromatic iodination step using a new polymer-supported iodonium version of Barluengas reagent. From a selected set of 77 noniodinated and 77 iodinated diflunisal analogues, a subset of good transthyretin amyloid inhibitors has been obtained with improved turbidimetry inhibition constants, high binding affinity to transthyretin, and good selectivity for TTR compared to other thyroxine binding proteins.
- Vilar, Maria,Nieto, Joan,La Parra, Juan Ramn,Almeida, Maria Rosrio,Ballesteros, Alfredo,Planas, Antoni,Arsequell, Gemma,Valencia, Gregorio
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Read Online
- Enantioselective Lactonization by π-Acid-Catalyzed Allylic Substitution: A Complement to π-Allylmetal Chemistry
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Asymmetric allylic alkylation (AAA) is a powerful method for the formation of highly useful, non-racemic allylic compounds. Here we present a complementary enantioselective process that generates allylic lactones via π-acid catalysis. More specifically, a
- Kizhakkayil Mangadan, Arun Raj,Liu, Ji,Aponick, Aaron
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p. 22224 - 22229
(2021/09/09)
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- Iridium(III)-Catalyzed Intermolecular C(sp3)?H Insertion Reaction of Quinoid Carbene: A Radical Mechanism
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Described herein is an IrIII/porphyrin-catalyzed intermolecular C(sp3)?H insertion reaction of a quinoid carbene (QC). The reaction was designed by harnessing the hydrogen-atom transfer (HAT) reactivity of a metal-QC species with aliphatic substrates followed by a radical rebound process to afford C?H arylation products. This methodology is efficient for the arylation of activated hydrocarbons such as 1,4-cyclohexadienes (down to 40 min reaction time, up to 99 % yield, up to 1.0 g scale). It features unique regioselectivity, which is mainly governed by steric effects, as the insertion into primary C?H bonds is favored over secondary and/or tertiary C?H bonds in the substituted cyclohexene substrates. Mechanistic studies revealed a radical mechanism for the reaction.
- Wang, Hai-Xu,Richard, Yann,Wan, Qingyun,Zhou, Cong-Ying,Che, Chi-Ming
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p. 1845 - 1850
(2019/12/27)
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- Oxidative [3+3] Annulation of Atropaldehyde Acetals with 1,3-Bisnucleophiles: An Efficient Method of Constructing Six-Membered Aromatic Rings, Including Salicylates and Carbazoles
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An oxidative [3+3] annulation of atropaldehyde acetals with various 1,3-bisnucleophiles was developed using either N-bromosuccinimide or copper(II) bromide as oxidizing reagent and Br?nsted or Lewis acids as catalyst. The [3+3] annulations can be considered mechanistically as oxidizing reagent-induced acid-acid-catalyzed domino reactions established through the concept of auto-tandem catalysis. Alkyl acetoacetates, α-(indol-2-yl)acetate, anilines, 1-methyl-1H-pyrazol-3-amine, ethyl 5-amino-1H-pyrazole-3-carboxylate, and 3-amino-1H-indazole can all be used as 1,3-bisnucleophiles in this type of transformation. The established reactions can very efficiently construct six-membered aromatic rings, including salicylates and carbazoles. A four-step method of synthesizing the anti-inflammatory agent diflunisal was also developed based on the oxidative [3+3] annulation reaction, and the yield was high. (Figure presented.).
- Gu, Yanlong,Wu, Fengtian,Yang, Jian
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p. 2727 - 2741
(2018/07/29)
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- Palladium-Catalyzed Cross-Coupling of Arenediazonium Salts with Organoindium or Organobismuth Reagents
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Arylindium and isolated triarylbismuth compounds generated in situ react as nucleophiles with arenediazonium salts in palladium-catalyzed cross-coupling reactions to give substituted biphenyls.
- Riemer, Nastja,Coswig, Christin,Shipman, Mike,Schmidt, Bernd
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p. 2427 - 2431
(2018/11/23)
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- Rhodium(ii)-catalysed generation of cycloprop-1-en-1-yl ketones and their rearrangement to 5-aryl-2-siloxyfurans
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Donor-acceptor cyclopropenes formed from enoldiazoketones undergo catalytic rearrangement to 5-aryl-2-siloxyfurans via a novel mechanism that involves a nucleophilic addition of the carbonyl oxygen to the rhodium-activated cyclopropene.
- Marichev, Kostiantyn O.,Wang, Yi,Carranco, Alejandra M.,Garcia, Estevan C.,Yu, Zhi-Xiang,Doyle, Michael P.
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supporting information
p. 9513 - 9516
(2018/08/28)
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- Suzuki-Miyaura cross coupling reactions with Phenoldiazonium salts
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The Suzuki-Miyaura coupling of phenol diazonium salts and aryl trifluoroborates yields 4-hydroxybiaryls in a protecting group-free synthesis. The Royal Society of Chemistry 2011.
- Schmidt, Bernd,Hoelter, Frank
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supporting information; experimental part
p. 4914 - 4920
(2011/08/06)
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- Structure-guided design, synthesis, and evaluation of salicylic acid-based inhibitors targeting a selectivity pocket in the active site of human 20α-hydroxysteroid dehydrogenase (AKR1C1)
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The first design, synthesis, and evaluation of human 20α- hydroxysteroid dehydrogenase (AKR1C1) inhibitors based on the recently published crystal structure of its ternary complex with inhibitor are reported. While the enzyme-inhibitor interactions observ
- El-Kabbani, Ossama,Scammells, Peter J.,Gosling, Joshua,Dhagat, Urmi,Endo, Satoshi,Matsunaga, Toshiyuki,Soda, Midori,Hara, Akira
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experimental part
p. 3259 - 3264
(2010/06/16)
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- Mono- and disalicylic acid derivatives: PTP1B inhibitors as potential anti-obesity drugs
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A series of compounds containing one or two salicylic acid moieties were synthesized, and their efficacy to inhibit the phosphohydrolase activity of PTP1B examined. Some of the methylenedisalicylic acid derivatives were potent inhibitors of PTP1B. Of those derivatives, 3c exhibited about a 14-fold selectivity against TC-PTP, and this compound was tested in a mouse model for its efficacy to prevent diet-induced obesity. It effectively suppressed the increases in body weight and adipose mass, without any noticeable toxic effect. The compound also prevented increases in the plasma triglyceride, cholesterol, and nonesterified fatty acid concentrations; thus, expanding its therapeutic potential to other related metabolic diseases, such as hyperlipidemia and hypercholesterolemia.
- Shrestha, Suja,Bhattarai, Bharat Raj,Lee, Keun-Hyeung,Cho, Hyeongjin
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p. 6535 - 6548
(2008/04/12)
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- Synthesis of xanthones, thioxanthones, and acridones by the coupling of arynes and substituted benzoates
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The reaction of silylaryl triflates, CsF, and ortho-heteroatom-substituted benzoates affords a general and efficient way to prepare biologically interesting xanthones, thioxanthones, and acridones. This chemistry presumably proceeds by a tandem intermolecular nucleophilic coupling of the benzoate with an aryne and a subsequent intramolecular electrophilic cyclization.
- Zhao, Jian,Larock, Richard C.
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p. 583 - 588
(2007/10/03)
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- The discovery of fluoropyridine-based inhibitors of the Factor VIIa/TF complex
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The activated Factor VII/tissue factor complex (FVIIa/TF) plays a key role in the formation of blood clots. Inhibition of this complex may lead to new antithrombotic drugs. An X-ray crystal structure of a fluoropyridine-based FVIIa/TF inhibitor bound in the active site of the enzyme complex suggested that incorporation of substitution at the 5-position of the hydroxybenzoic acid side chain could lead to the formation of more potent inhibitors through interactions with the S1′/S2′ pocket.
- Kohrt, Jeffrey T.,Filipski, Kevin J.,Cody, Wayne L.,Cai, Cuiman,Dudley, Danette A.,Van Huis, Chad A.,Willardsen, J. Adam,Rapundalo, Stephen T.,Saiya-Cork, Kamlai,Leadley, Robert J.,Narasimhan, Lakshmi,Zhang, Erli,Whitlow, Marc,Adler, Marc,McLean, Kirk,Chou, Yuo-Ling,McKnight, Cecile,Arnaiz, Damian O.,Shaw, Kenneth J.,Light, David R.,Edmunds, Jeremy J.
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p. 4752 - 4756
(2007/10/03)
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- 2-ARYLOXYETHYL GLYCINE DERIVATIVES AND THEIR USE AS GLYCINE TRANSPORT INHIBITORS
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The present invention relates to certain 2-aryloxyethyl glycine derivatives that exhibit activity as inhibitors of the glycine type-1 transporter, to pharmaceutical compositions containing them and to their use in the treatment of neurological and neuropsychiatric disorder.
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Page/Page column 74
(2010/02/14)
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- Diflunisal Analogues Stabilize the Native State of Transthyretin. Potent Inhibition of Amyloidogenesis
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Analogues of diflunisal, an FDA-approved nonsteroidal antiinflammatory drug (NSAID), were synthesized and evaluated as inhibitors of transthyretin (TTR) aggregation, including amyloid fibril formation. High inhibitory activity was observed for 26 of the compounds. Of those, eight exhibited excellent binding selectivity for TTR in human plasma (binding stoichiometry > 0.50, with a theoretical maximum of 2.0 inhibitors bound per TTR tetramer). Biophysical studies reveal that these eight inhibitors dramatically slow tetramer dissociation (the rate-determining step of amyloidogenesis) over a duration of 168 h. This appears to be achieved through ground-state stabilization, which raises the kinetic barrier for tetramer dissociation. Kinetic stabilization of WT TTR by these eight inhibitors is further substantiated by the decreasing rate of amyloid fibril formation as a function of increasing inhibitor concentration (pH 4.4). X-ray cocrystal structures of the TTR·182 and TTR·202 complexes reveal that 18 and 20 bind in opposite orientations in the TTR binding site. Moving the fluorines from the meta positions in 18 to the ortho positions in 20 reverses the binding orientation, allowing the hydrophilic aromatic ring of 20 to orient in the outer binding pocket where the carboxylate engages in favorable electrostatic interactions with the ε-ammonium groups of Lys 15 and 15′. The hydrophilic aryl ring of 18 occupies the inner binding pocket, with the carboxylate positioned to hydrogen bond to the serine 117 and 117′ residues. Diflunisal itself appears to occupy both orientations based on the electron density in the TTR·12 structure. Structure-activity relationships reveal that para-carboxylate substitution on the hydrophilic ring and dihalogen substitution on the hydrophobic ring afford the most active TTR amyloid inhibitors.
- Adamski-Werner, Sara L.,Palaninathan, Satheesh K.,Sacchettini, James C.,Kelly, Jeffery W.
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p. 355 - 374
(2007/10/03)
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