- Synthesis of a coronene analogue containing an amide bond by Pd-mediated intramolecular C[sbnd]C bond formation of 2-halogenated 4-(alkylamino)benzoic acid cyclic trimer
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A coronene analogue containing amide linkage was synthesized from a halogenated cyclic triamide by palladium-mediated intramolecular C[sbnd]C bond formation. The cyclic triamide was formed from the condensation of 2-chloro-4-(isobutylamino)benzoic acid in
- Yokoyama, Akihiro,Ishii, Arisa,Ohishi, Tomoyuki,Kikkawa, Shoko,Azumaya, Isao
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Read Online
- In vitro and in vivo antimalarial activity of peptidomimetic protein farnesyltransferase inhibitors with improved membrane permeability
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A series of ester derivatives of 17 with increased lipophilicity were synthesized and tested against P. falciparum in red blood cells, where the benzyl ester derivative 16 exhibited the best inhibition activity (ED 50 = 150 nM). Compound 16 sho
- Carrico, Dora,Ohkanda, Junko,Kendrick, Howard,Yokoyama, Kohei,Blaskovich, Michelle A.,Bucher, Cynthia J.,Buckner, Frederick S.,Van Voorhis, Wesley C.,Chakrabarti, Debopam,Croft, Simon L.,Gelb, Michael H.,Sebti, Sa?d M.,Hamilton, Andrew D.
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Read Online
- An Activatable Lanthanide Luminescent Probe for Time-Gated Detection of Nitroreductase in Live Bacteria
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Herein we report the development of a turn-on lanthanide luminescent probe for time-gated detection of nitroreductases (NTRs) in live bacteria. The probe is activated through NTR-induced formation of the sensitizing carbostyril antenna and resulting energ
- Brennecke, Benjamin,Hu, Hai-Yu,Nazaré, Marc,Wang, Qinghua,Zhang, Qingyang
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supporting information
p. 8512 - 8516
(2020/04/24)
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- Scope and mechanism of a true organocatalytic beckmann rearrangement with a boronic acid/perfluoropinacol system under ambient conditions
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Catalytic activation of hydroxyl functionalities is of great interest for the production of pharmaceuticals and commodity chemicals. Here, 2-alkoxycarbonyl- and 2-phenoxycarbonyl-phenylboronic acid were identified as efficient catalysts for the direct and chemoselective activation of oxime N-OH bonds in the Beckmann rearrangement. This classical organic reaction provides a unique approach to prepare functionalized amide products that may be difficult to access using traditional amide coupling between carboxylic acids and amines. Using only 5 mol % of boronic acid catalyst and perfluoropinacol as an additive in a polar solvent mixture, the operationally simple protocol features mild conditions, a broad substrate scope, and a high functional group tolerance. A wide variety of diaryl, aryl-alkyl, heteroaryl-alkyl, and dialkyl oximes react under ambient conditions to afford high yields of amide products. Free alcohols, amides, carboxyesters, and many other functionalities are compatible with the reaction conditions. Investigations of the catalytic cycle revealed a novel boron-induced oxime transesterification providing an acyl oxime intermediate involved in a fully catalytic nonself-propagating Beckmann rearrangement mechanism. The acyl oxime intermediate was prepared independently and was subjected to the reaction conditions. It was found to be self-sufficient; it reacts rapidly, unimolecularly without the need for free oxime. A series of control experiments and 18O labeling studies support a true catalytic pathway involving an ionic transition structure with an active and essential role for the boronyl moiety in both steps of transesterification and rearrangement. According to 11B NMR spectroscopic studies, the additive perfluoropinacol provides a transient, electrophilic boronic ester that is thought to serve as an internal Lewis acid to activate the ortho-carboxyester and accelerate the initial, rate-limiting step of transesterification between the precatalyst and the oxime substrate.
- Mo, Xiaobin,Morgan, Timothy D. R.,Ang, Hwee Ting,Hall, Dennis G.
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p. 5264 - 5271
(2018/04/24)
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- Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines
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We present comprehensive testing of solvent representation in quantum mechanics (QM)-based scoring of protein-ligand affinities. To this aim, we prepared 21 new inhibitors of cyclin-dependent kinase 2 (CDK2) with the pyrazolo[1,5-a]pyrimidine core, whose
- Hylsová, Michaela,Carbain, Benoit,Fanfrlík, Jind?ich,Musilová, Lenka,Haldar, Susanta,K?prülüo?lu, Cemal,Ajani, Haresh,Brahmkshatriya, Pathik S.,Jorda, Radek,Kry?tof, Vladimír,Hobza, Pavel,Echalier, Aude,Paruch, Kamil,Lep?ík, Martin
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p. 1118 - 1128
(2017/01/03)
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- NOVEL COMPOUNDS AS CHLORIDE CHANNEL BLOCKING AGENT
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Disclosed is a novel compound to function as a calcium-dependent chloride channel blocking agent.
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Paragraph 0167; 0168; 0169; 0170; 0171; 0172; 0173-0175
(2015/06/03)
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- Novel pyrrolobenzoxaboroles: Design, synthesis, and biological evaluation against Trypanosoma brucei
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Human African trypanosomiasis is a fatal parasitic infection caused by the protozoan Trypanosoma brucei. The development of novel antitrypanosomal agents is urgently needed. Here we report the synthesis and structure-activity relationship of a new class of benzoxaboroles as antitrypanosomal agents. These compounds showed antiparasitic IC50 values ranging from 4.02 to 0.03 μg/mL and satisfactory cytotoxicity profile. Three of the lead compounds were demonstrated to cure the parasitic infection in a murine acute infection model. The structure-activity relationship of the pyrrolobenzoxaboroles are also discussed.
- Wu, Puhua,Zhang, Jiong,Meng, Qingqing,Nare, Bakela,Jacobs, Robert T.,Zhou, Huchen
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- AMPHIPATHIC AND OTHER DOUBLE-SIDED ALPHA-HELIX MIMETICS BASED ON A 1,2-DIPHENYLACETYLENE SCAFFOLD
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Small-molecule scaffolds based on 1,2-diphenylacetylene that accurately replicate the spatial and angular projections of several side chains on both faces of an α-helix, specifically the i and i+7 side chains on one face, and the i and i+2 side chains on the other. The amphipathic α-helix mimetic can be used to disrupt disease-promoting protein-protein interactions that are mediated by α-helices.
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(2014/09/29)
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- Monna, a potent and selective blocker for transmembrane protein with unknown function 16/anoctamin-1
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Transmembrane protein with unknown function 16/anoctamin-1 (ANO1) is a protein widely expressed in mammalian tissues, and it has the properties of the classic calcium-activated chloride channel (CaCC). This protein has been implicated in numerous major physiological functions. However, the lack of effective and selective blockers has hindered a detailed study of the physiological functions of this channel. In this study, we have developed a potent and selective blocker for endogenous ANO1 in Xenopus laevis oocytes (xANO1) using a drug screening method we previously established (Oh et al., 2008). We have synthesized a number of anthranilic acid derivatives and have determined the correlation between biological activity and the nature and position of substituents in these derived compounds. A structure-activity relationship revealed novel chemical classes of xANO1 blockers. The derivatives contain a-NO2 group on position 5 of a naphthyl group-substituted anthranilic acid, and they fully blocked xANO1 chloride currents with an IC 5050 of 0.08 μM for xANO1. Selectivity tests revealed that other chloride channels such as bestrophin-1, chloride channel protein 2, and cystic fibrosis transmembrane conductance regulator were not appreciably blocked by 10~30 μM MONNA. The potent and selective blockers for ANO1 identified here should permit pharmacological dissection of ANO1/CaCC function and serve as potential candidates for drug therapy of related diseases such as hypertension, cystic fibrosis, bronchitis, asthma, and hyperalgesia.
- Oh, Soo-Jin,Hwang, Seok Jin,Jung, Jonghoon,Yu, Kuai,Kim, Jeongyeon,Choi, Jung Yoon,Hartzell, H. Criss,Roh, Eun Joo,Justin Lee
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p. 726 - 735
(2013/11/06)
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- Regio- and chemoselective C-H chlorination/bromination of electron-deficient arenes by weak coordination and study of relative directing-group abilities
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It's all relative: A practical and efficient PdII-catalyzed regio- and chemoselective chlorination/bromination has been developed for the facile synthesis of a broad range of aromatic chlorides. The reaction demonstrates excellent reactivity, good functional-group tolerance, and high yields. A preliminary study was conducted to evaluate relative directing-group abilities of various functionalities. Copyright
- Sun, Xiuyun,Shan, Gang,Sun, Yonghui,Rao, Yu
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supporting information
p. 4440 - 4444
(2013/05/22)
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- PHENYL-UREA AND PHENYL-CARBAMATE DERIVATIVES AS INHIBITORS OF PROTEIN AGGREGATION
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The present invention relates to certain phenyl-urea and phenyl-carbamate derivatives, pharmaceutical compositions containing them, and methods of using them, including methods for preventing, reversing, slowing, or inhibiting protein aggregation, and methods of treating diseases that are associated with protein aggregation, including neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Lewy body disease, and multiple system atrophy.
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Paragraph 00101
(2013/10/21)
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- Amphipathic α-helix mimetics based on a 1,2-diphenylacetylene scaffold
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In order to mimic amphipathic α-helices, a novel scaffold based on a 1,2-diphenylacetylene was designed. NMR and computational modeling confirmed that an intramolecular hydrogen bond favors conformations of the 1,2-diphenylacetylene that allow for accurat
- Jung, Kwan-Young,Vanommeslaeghe, Kenno,Lanning, Maryanna E.,Yap, Jeremy L.,Gordon, Caryn,Wilder, Paul T.,Mackerell, Alexander D.,Fletcher, Steven
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supporting information
p. 3234 - 3237
(2013/07/26)
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- Synthesis of a novel pyrrolo-benzoxaborole scaffold and its derivatization via Friedel-Crafts reaction catalyzed by anhydrous stannic chloride
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A novel pyrrolo-benzoxaborole, 6-(pyrrol-1-yl)-1,3-dihydro-1-hydroxy-2,1- benzoxaborole, was synthesized with 27% overall yield over six steps from 2-bromo-1-methyl-4-nitrobenzene as starting material. Its derivatization was achieved via Friedel-Crafts re
- Wu, Pu Hua,Meng, Qing Qing,Zhou, Hu Chen
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p. 1411 - 1414
(2012/06/16)
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- New Ras CAAX mimetics: Design, synthesis, antiproliferative activity, and RAS prenylation inhibition
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Mimetics of the C-terminal CAAX tetrapeptide of Ras protein were designed replacing cysteine (C) by 2-hydroxymethylbenzodioxane or 2-aminomethylbenzodioxane, respectively etherified and amidified with 2′-methyl or 2′-methoxy substituted 2-carboxy-4-hydrox
- Bolchi, Cristiano,Pallavicini, Marco,Fumagalli, Laura,Ferri, Nicola,Corsini, Alberto,Rusconi, Chiara,Valoti, Ermanno
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scheme or table
p. 5500 - 5504
(2010/06/16)
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- Conception of myeloperoxidase inhibitors derived from flufenamic acid by computational docking and structure modification
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The development of myeloperoxidase (MPO) inhibitors has been conducted using flufenamic acid as a lead compound. Computational docking of the drug and its analogs in the MPO active site was first attempted. Several molecules were then synthesized and assessed using three procedures for the measurement of their inhibiting activity: (i) the taurine assay, (ii) the accumulation of compound II, and (iii) the LDL oxidation by ELISA. Most of the synthesized molecules had an activity in the same range as flufenamic acid but none of them were able to inhibit the MPO-dependent LDL oxidation. The experiments however gave some useful indications for a rational conception of MPO inhibitors.
- Van Antwerpen, Pierre,Prevost, Martine,Zouaoui-Boudjeltia, Karim,Babar, Sajida,Legssyer,Moreau, Patrick,Moguilevsky, Nicole,Vanhaeverbeek, Michel,Ducobu, Jean,Neve, Jean,Dufrasne, Francois
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p. 1702 - 1720
(2008/09/20)
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- 2-PHENYL-5-AMINO-1,3,4-OXADIAZOLES AND THEIR USE AS NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS
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The present invention relates to novel oxadiazole derivatives of formula (1) having pharmacological activity, processes for their preparation, compositions containing them and their use in the treatment of neurological, psychiatric disorders and gastrointestinal disorders through modulation of the nicotinic α7 receptor formula (I).
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Page/Page column 32-33
(2008/06/13)
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- Structure-based design of imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase
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A series of imidazole-containing peptidomimetic PFTase inhibitors and their co-crystal structures bound to PFTase and FPP are reported. The structures reveal that the peptidomimetics adopt a similar conformation to that of the extended CVIM tetrapeptide,
- Ohkanda, Junko,Strickland, Corey L.,Blaskovich, Michelle A.,Carrico, Dora,Lockman, Jeffrey W.,Vogt, Andreas,Bucher, Cynthia J.,Sun, Jiazhi,Qian, Yimin,Knowles, David,Pusateri, Erin E.,Sebti, Said M.,Hamilton, Andrew D.
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p. 482 - 492
(2008/02/04)
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- A new fluorogenic transformation: Development of an optical probe for coenzyme Q
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(Chemical Equation Presented) A new fluorogenic transformation based on a quinone reduction/lactonization sequence has been developed and evaluated as a tool for probing redox phenomena in a biochemical context. The probe presented herein is an irreversible redox probe and is reduced selectively by biologically relevant quinols such as ubiquinol but is inert to reduced nicotinamides (e.g., NADH). The ensuing cyclization is fast and quantitative and provides a measurable optical response.
- Tremblay, Matthew S.,Sames, Dalibor
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p. 2417 - 2420
(2007/10/03)
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- 3-Mercaptopyrrolidines as farnesyl protein transferase inhibitors
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The present invention relats to inhibitors of ras farnesylation of Formula (I) wherein: R1 is for example H and further values as defined in the specification; R2 is for example H and further values as defined in the specification; R
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Page/Page column 20
(2010/02/14)
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- Amino (oxo) acetic acid protein tyrosine phosphatase inhibitors
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Compounds of formula (I) or therapeutically acceptable salts thereof, are protein tyrosine kinase PTP1B inhibitors. Preparation of the compounds, compositions containing the compounds, and treatment of diseases using the compounds are disclosed.
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- 4-benzoyl isoxazoles derivatives and their use as herbicides
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4-Benzoylisoxazole derivatives of the formula wherein R is H or an ester; R1is alkyl, haloalkyl or optionally substituted cycloalkyl; R2is halogen, optionally halogenated alkyl, alkenyl or alkynyl; alkyl substituted with one or more —OR5; —NO2, —CN, —CO2R5, —S(O)pR6, —O(CH2)mOR5, —COR5, —NR5R6, —N(R8)SOqR7, —CONR9R10or —OR51; or optionally substituted phenyl; R3is —S(O)qR7; X is —N(R8)—; n is 0, 1, 2, 3, or 4; R5, R51and R6are independently H; optionally halogenated alkyl, alkenyl or alkynyl; optionally substituted phenyl; or cycloalkyl; R7is optionally halogenated alkyl, alkenyl or alkynyl; cycloalkyl; optionally substituted phenyl; or optionally substituted amino; R8is H; optionally halogenated alkyl, alkenyl or alkynyl; cycloalkyl; optionally substituted phenyl; or alkoxy; m is 1, 2 or 3; p is 0, 1 or 2; q is 0 or 2; and their use as herbicides are described.
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- Probing the hydrophobic pocket of farnesyltransferase: Aromatic substitution of CAAX peptidomimetics leads to highly potent inhibitors
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Cysteine farnesylation at the carboxylate terminal tetrapeptide CAAX of Ras protein is catalyzed by farnesyltransferase. This lipid modification is necessary for regulatory function of both normal and oncogenic Ras. The high frequency of Ras mutation in human cancers has prompted an intensive study on finding ways of controlling oncogenic Ras function. Inhibition of farnesyltransferase is among the most sought after targets for cancer chemotherapy. We report here the design, synthesis and biological characterization of a series of peptidomimetics as farnesyltransferase inhibitors. These compounds are extremely potent towards farnesyltransferase with IC50 values ranging from subnanomolar to low nanomolar concentrations. They have a high selectivity for farnesyltransferase over the closely related geranylgeranyltransferase-I. Structure-activity relationship studies demonstrated that a properly positioned hydrophobic group significantly enhanced inhibition potency, reflecting an improved complementarity to the large hydrophobic pocket in the CAAX binding site. Copyright (C) 1999 Elsevier Science Ltd.
- Qian, Yimin,Marugan, Juan Jose,Fossum, Renae D.,Vogt, Andreas,Sebti, Said M.,Hamilton, Andrew D.
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p. 3011 - 3024
(2007/10/03)
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