31767-14-3Relevant articles and documents
Dual acting oximes designed for therapeutic decontamination of reactive organophosphatesviacatalytic inactivation and acetylcholinesterase reactivation
Cannon, Jayme,Choi, Seok Ki,Harrison, Racquel,Tang, Shengzhuang,Yang, Kelly
, p. 1592 - 1603 (2021)
A conventional approach in the therapeutic decontamination of reactive organophosphate (OP) relies on chemical OP degradation by oxime compounds. However, their efficacy is limited due to their lack of activity in the reactivation of acetylcholinesterase (AChE), the primary target of OP. Here, we describe a set of α-nucleophile oxime derivatives which are newly identified for such dual modes of action. Thus, we prepared a 9-member oxime library, each composed of an OP-reactive oxime core linked to an amine-terminated scaffold, which varied through anN-alkyl functionalization. This library was screened by enzyme assays performed with human and electric eel subtypes of OP-inactivated AChE, which led to identifying three oxime leads that displayed significant enhancements in reactivation activity comparable to 2-PAM. They were able to reactivate both enzymes inactivated by three OP types including paraoxon, chlorpyrifos and malaoxon, suggesting their broad spectrum of OP susceptibility. All compounds in the library were able to retain catalytic reactivity in paraoxon inactivation by rates increased up to 5 or 8-fold relative to diacetylmonoxime (DAM) under controlled conditions at pH (8.0, 10.5) and temperature (17, 37 °C). Finally, selected lead compounds displayed superb efficacy in paraoxon decontamination on porcine skinin vitro. In summary, we addressed an unmet need in therapeutic OP decontamination by designing and validating a series of congeneric oximes that display dual modes of action.
Intermolecular cycloaddition of ethyl glyoxylate O-tert- butyldimethylsilyloxime with alkenes
Tamura, Osamu,Morita, Nobuyoshi,Takano, Yuu,Fukui, Kenji,Okamoto, Iwao,Huang, Xin,Tsutsumi, Yoshiyuki,Ishibashi, Hiroyuki
, p. 658 - 660 (2007)
Ethyl glyoxylate O-tert-butyldimethylsilyloxime, on treatment with various alkenes in the presence of BF3·OEt2, generated a C-ethoxycarbonyl N-boranonitrone intermediate, which underwent intermolecular cycloaddition to afford 3-(etho
Mechanistic rationalization of unusual sigmoidal kinetic profiles in the machetti-de sarlo cycloaddition reaction
Mower, Matthew P.,Blackmond, Donna G.
, p. 2386 - 2391 (2015)
Unusual sigmoidal kinetic profiles in the Machetti-De Sarlo base-catalyzed 1,3-dipolar cycloaddition of acrylamide to N-methylnitroacetamide are rationalized by detailed in situ kinetic analysis. A dual role is uncovered in which a substrate acts as a precursor to catalyze its own reaction. Such kinetic studies provide a general protocol for distinguishing among different mechanistic origins of induction periods in complex organic reactions.
COMPOUNDS AND USE THEREOF FOR THE TREATMENT OF INFECTIOUS DISEASES AND CANCER
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Page/Page column 35; 37; 39-40, (2021/02/26)
The invention provides the imidazole, oxazole and thiazole compounds and use thereof in methods for treating a disease or a disorder, such as infectious diseases and cancer, wherein inhibition of sphingosine-1-phosphate lyase is beneficial to treat the disease or the disorder.
Structure-property relationship study of n-(hydroxy)peptides for the design of self-assembled parallel β-sheets
Roche, Stéphane P.,Richaud, Alexis D.
, p. 12329 - 12342 (2020/11/10)
The design of novel and functional biomimetic foldamers remains a major challenge in creating mimics of native protein structures. Herein, we report the stabilization of a remarkably short β-sheet by incorporating N-(hydroxy)glycine (Hyg) residues into the backbone of peptides. These peptide- peptoid hybrids form unique parallel β-sheet structures by selfassembly upon hydrogenation. Our spectroscopic and crystallographic data suggest that the local conformational perturbations induced by N-(hydroxy)amides are outweighed by a network of strong interstrand hydrogen bonds.
Hydrophilic scaffolds of oxime as the potent catalytic inactivator of reactive organophosphate
Tang, Shengzhuang,Wong, Pamela T.,Cannon, Jayme,Yang, Kelly,Bowden, Sierra,Bhattacharjee, Somnath,O'Konek, Jessica J.,Choi, Seok Ki
, p. 67 - 79 (2018/11/02)
Despite its efficacy as a skin decontaminant of reactive organophosphates (OP), Dekon 139—a potassium salt of 2,3-butanedione monooxime (DAM)—is associated with adverse events related to percutaneous absorption largely due to its small size and lipophilicity. In order to address this physicochemical issue, we synthesized and evaluated the activity of a focused library of 14 hydrophilic oxime compounds, each designed with either a DAM or monoisonitrosoacetone (MINA) oxime tethered to a polar or charged scaffold in order to optimize the size, hydrophilicity, and oxime acidity. High-throughput colorimetric assays were performed with paraoxon (POX) as a model OP to determine the kinetics of POX inactivation by these compounds under various pH and temperature conditions. This primary screening led to the identification of 6 lead compounds, predominantly in the MINA series, which displayed superb catalytic activity by reducing the POX half-life (t1/2) by 2–3 fold relative to Dekon 139. Our mechanistic studies show that POX inactivation by the oxime compounds occurred faster at a higher temperature and in a pH-dependent manner in which the negatively charged oximate species is ≥ 10–fold more effective than the neutral oxime species. Lastly, using one of the lead compounds, we demonstrated its promising efficacy for POX decontamination in porcine skin ex vivo, and showed its potent ability to protect acetylcholine esterase (AChE) through POX inactivation. In summary, we report the rational design and chemical biological validation of novel hydrophilic oximes which address an unmet need in therapeutic OP decontamination.
In vitro and in silico evaluation of non-quaternary reactivators of AChE as antidotes of organophosphorus poisoning - A new hope or a blind alley?
Soukup, Ondrej,Korabecny, Jan,Malinak, David,Nepovimova, Eugenie,Pham, Ngoc L.,Musílek, Kamil,Hrabinova, Martina,Hepnarova, Vendula,Dolezal, Rafael,Pavek, Petr,Jost, Petr,Kobrlova, Tereza,Jankockova, Jana,Gorecki, Lukas,Psotka, Miroslav,Nguyen, Thuy D.,Box, Karl,Outhwaite, Breeze,Ceckova, Martina,Sorf, Ales,Jun, Daniel,Kuca, Kamil
, p. 281 - 292 (2018/05/17)
Background: In the last decade, the concept of uncharged reactivators potentially able to penetrate the CNS has been introduced as an alternative to the classic charged oxime reactivators. However, this concept brings with it several associated drawbacks
Water-Assisted Nitrile Oxide Cycloadditions: Synthesis of Isoxazoles and Stereoselective Syntheses of Isoxazolines and 1,2,4-Oxadiazoles
Kesornpun, Chatchai,Aree, Thammarat,Mahidol, Chulabhorn,Ruchirawat, Somsak,Kittakoop, Prasat
supporting information, p. 3997 - 4001 (2016/03/19)
Conventional methods generate nitrile oxides from oxime halides in organic solvents under basic conditions. However, the present work revealed that water-assisted generation of nitrile oxides proceeds under mild acidic conditions (pH 4-5). Cycloadditions of nitrile oxides with alkynes and alkenes easily occurred in water without using catalysts, thus yielding isoxazoles and isoxazolines, respectively, with excellent stereoselectivity toward five- and six-membered cyclic alkenes. A double stereoselective cycloaddition of two units of a nitrile oxide with cyclohexene was also achieved, thus yielding 1,2,4-oxadiazole derivatives having a unique hybrid isoxazoline-oxadiazole skeleton. Enantiomerically pure isoxazolines were prepared from monoterpenes with a ring strain. In one case, the isoxazoline with a butterfly-like structure was simply prepared, and it might be used as a ligand in asymmetric catalysis.
Enzyme-catalyzed cascade synthesis of hydroxyiminoacetamides
Kne?evi?, Anamarija,Vinkovi?, Vladimir,Marakovi?, Nikola,?inko, Goran
, p. 4338 - 4341 (2014/07/22)
In order to synthesize N-(3-azido-1-phenylpropyl)-2-hydroxyiminoacetamide, a key compound for the preparation of acetylcholinesterase (AChE) reactivators of the N-substituted 2-hydroxyiminoacetamide type, it was necessary to develop a method for forming a
Stereoselective 1,3-dipolar cycloadditions of nitrones derived from amino acids. Asymmetric synthesis of N-(alkoxycarbonylmethyl)-3-hydroxypyrrolidin-2- ones Dedicated to Professor Giovanni Romeo on occasion of his 70th birthday
Merino, Pedro,Greco, Graziella,Tejero, Tomás,Hurtado-Guerrero, Ramon,Matute, Rosa,Chiacchio, Ugo,Corsaro, Antonino,Pistarà, Venerando,Romeo, Roberto
, p. 9381 - 9390 (2013/10/08)
Diastereoselective asymmetric 1,3-dipolar cycloadditions of N-(alkoxycarbonylmethyl) nitrones derived from glycine, alanine and phenylalanine have been studied both experimentally and theoretically. Asymmetric induction is evaluated by either introducing
