cas 37858-07-4, anti-2-Acetoxyacetaldoxime

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COMPOUNDS AND USE THEREOF FOR THE TREATMENT OF INFECTIOUS DISEASES AND CANCER
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.
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Page/Page column 35; 37; 39-40

(2021/02/26)

Dual acting oximes designed for therapeutic decontamination of reactive organophosphatesviacatalytic inactivation and acetylcholinesterase reactivation
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.
Cannon, Jayme,Choi, Seok Ki,Harrison, Racquel,Tang, Shengzhuang,Yang, Kelly
p. 1592 - 1603
(2022/01/19)

Structure-property relationship study of n-(hydroxy)peptides for the design of self-assembled parallel β-sheets
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.
Roche, Stéphane P.,Richaud, Alexis D.
p. 12329 - 12342
(2020/11/10)

Hydrophilic scaffolds of oxime as the potent catalytic inactivator of reactive organophosphate
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.
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)

In vitro and in silico evaluation of non-quaternary reactivators of AChE as antidotes of organophosphorus poisoning - A new hope or a blind alley?
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
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)

Water-Assisted Nitrile Oxide Cycloadditions: Synthesis of Isoxazoles and Stereoselective Syntheses of Isoxazolines and 1,2,4-Oxadiazoles
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.
Kesornpun, Chatchai,Aree, Thammarat,Mahidol, Chulabhorn,Ruchirawat, Somsak,Kittakoop, Prasat
supporting information
p. 3997 - 4001
(2016/03/19)

Mechanistic rationalization of unusual sigmoidal kinetic profiles in the machetti-de sarlo cycloaddition reaction
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.
Mower, Matthew P.,Blackmond, Donna G.
supporting information
p. 2386 - 2391
(2015/03/04)

Enzyme-catalyzed cascade synthesis of hydroxyiminoacetamides
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
Kne?evi?, Anamarija,Vinkovi?, Vladimir,Marakovi?, Nikola,?inko, Goran
p. 4338 - 4341
(2014/07/22)

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
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
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)

MONOBACTAMS
The present invention is directed to a new class of monobactam derivatives and their use for treating bacterial infections.
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(2012/06/16)

HISTONE DEACETYLASE INHIBITORS
Provided herein are isoform selective histone deacetylase inhibitors of the formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, metabolites, prodrugs, solvates, pharmaceutically acceptable salts and compositions thereof. These compounds are isoform selective inhibitors of HDACs and are useful as a therapeutic or ameliorating agent for diseases that are involved in cellular growth such as cancer, malignant tumors, autoimmune diseases, skin diseases, fungal infections, protozoal infections, HIV, inflammation and CNS disorders.
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(2012/09/21)

Amidine-Oximes: Reactivators for organophosphate exposure
Figure Presented. Figure presented. A new class of amidine-oxime reactivators of organophosphate (OP)-inhibited cholinesterases (ChE) were designed, synthesized, and tested. These compounds represent a novel group of oximes with enhanced capabilities of crossing the blood-brain barrier. Lack of brain penetration is a major limitation for currently used oximes as antidotes of OP poisoning. The concept described herein relies on a combination of an amidine residue and oxime functionality whereby the amidine increases the binding affinity to the ChE and the oxime is responsible for reactivation. Amidine-oximes were tested in vitro and reactivation rates for OP-BuChE were greater than pralidoxime (2-PAM) or monoisonitrosoacetone (MINA). Amidine-oxime reactivation rates for OP-AChE were lower compared to 2-PAM but greater compared with MINA. After pretreatment for 30 min with oximes 15c and 15d (145 μmol/kg, ip) mice were challenged with a soman model compound. In addition, 15d was tested in a post-treatment experiment (145 μmol/kg, ip, administration 5 min after sarin model compound exposure). In both cases, amidine-oximes afforded 100% 24 h survival in an animal model of OP exposure.
Kalisiak, Jaros?aw,Ralph, Erik C.,Zhang, Jun,Cashman, John R.
experimental part
p. 3319 - 3330
(2011/06/24)

Synthesis and biological evaluation of novel GSK-3β inhibitors as anticancer agents
A series of isoxazol-indolin-2-one was designed for GSK-3β inhibitors as novel anticancer agents based on their binding mode analysis in GSK-3β crystal structure. Total 21 compounds were synthesized and evaluated for their inhibitory activity against two tumor cell lines (DU145 and HT29). Most of the synthesized compounds were potent with above 80% inhibitory activity at 100 μM, and several compounds were examined for inhibitory activity against GSK-3β. Among them, 15(Z) (R1=H, R2=3-Cl-phenyl) was most active with 78% inhibition of tumor cell line (HT29) at 20 μM and 72% inhibition of GSK-3β at 20 μM.
Choi, Min Jeong,Oh, Da Won,Jang, Jae Wan,Cho, Yong Seo,Seo, Seon Hee,Jeong, Kyu Sung,Ko, Soo Young,Pae, Ae Nim
scheme or table
p. 2015 - 2020
(2012/01/06)

Oxidation of α-oxo-oximes to nitrile oxides with hypervalent iodine reagents
Upon reaction with PhI(OAc)2, α-oxo-aldoximes are oxidized to α-oxo-nitrile oxides, while α-oxo-ketoximes are converted into nitrile oxides via the oxidative cleavage of the carbonyl-imino σ bond. The nitrile oxides thus formed were trapped wit
Jen, Tim,Mendelsohn, Brian A.,Ciufolini, Marco A.
supporting information; experimental part
p. 728 - 731
(2011/03/22)

High-yield synthesis of pyrrolidinyl PNA monomers
Two monomers for the syntheses of conformationally restricted peptide nucleic acids were synthesized through a simple procedure, involving an asymmetric 1,3-dipolar cycloaddition chemistry as a key step, from common starting materials in 3 and 5 steps, and 58.8% and 30.5% overall yields, respectively.
Merino, Pedro,Greco, Graziella,Tejero, Tomás,Chiacchio, Ugo,Corsaro, Antonino,Pistarà, Venerando,Romeo, Giovanni
scheme or table
p. 6003 - 6006
(2011/11/30)

New structural scaffolds for centrally acting oxime reactivators of phosphylated cholinesterases
We describe here the synthesis and activity of a new series of oxime reactivators of cholinesterases (ChEs) that contain tertiary amine or imidazole protonatable functional groups. Equilibration between the neutral and protonated species at physiological pH enables the reactivators to cross the blood-brain barrier and distribute in the CNS aqueous space as dictated by interstitial and cellular pH values. Our structure-activity analysis of 134 novel compounds considers primarily imidazole aldoximes and N-substituted 2- hydroxyiminoacetamides. Reactivation capacities of novel oximes are rank ordered by their relative reactivation rate constants at 0.67 mM compared with 2-pyridinealdoxime methiodide for reactivation of four organophosphate (sarin, cyclosarin, VX, and paraoxon) conjugates of3 human acetylcholinesterase (hAChE). Rank order of the rates differs for reactivation of human butyrylcholinesterase (hBChE) conjugates. The 10 best reactivating oximes, predominantly hydroxyimino acetamide derivatives (for hAChE) and imidazole-containing aldoximes (for hBChE) also exhibited reasonable activity in the reactivation of tabun conjugates. Reactivation kinetics of the lead hydroxyimino acetamide reactivator of hAChE, when analyzed in terms of apparent affinity (1/Kox) and maximum reactivation rate (k2), is superior to the reference uncharged reactivators monoisonitrosoacetone and 2,3-butanedione monoxime and shows potential for further refinement. The disparate pH dependences for reactivation of ChE and the general base-catalyzed oximolysis of acetylthiocholine reveal that distinct reactivator ionization states are involved in the reactivation of ChE conjugates and in conferring nucleophilic reactivity of the oxime group.
Sit, Rakesh K.,Radic, Zoran,Gerardi, Valeria,Zhang, Limin,Garcia, Edzna,Katalinic, Maja,Amitai, Gabriel,Kovarik, Zrinka,Fokin, Valery V.,Sharpless, K. Barry,Taylor, Palmer
experimental part
p. 19422 - 19430
(2012/04/10)

Intermolecular cycloaddition of N-boranonitrone with alkenes
(Chemical Equation Presented) Ethyl glyoxylate O-tert- butyldimethylsilyloxime (8), on treatment with 2.2 equiv of BF 3·OEt2, generated N-boranonitrone E, which underwent intermolecular cycloaddition with alkenes 18 to afford isoxazo
Morita, Nobuyoshi,Fukui, Kenji,Irikuchi, Jinshi,Sato, Hiroshi,Takano, Yuu,Okamoto, Iwao,Ishibashi, Hiroyuki,Tamura, Osamu
body text
p. 7164 - 7174
(2009/05/09)

Method for the synthesis of 4-hydroxyisoleucine and the derivatives thereof
The invention relates to a method for the synthesis of two isomers, at function OH, alone or in mixtures, of amino acids α or the derivatives thereof, having general formula (B), wherein: linkage C—O of the 4-position carbon (represented by symbol) denotes one or other of isomers III or IV, or mixtures thereof. Moreover, R1 and R2 represent: a hydrogen atom; or either R1 or R2 represents a hydrogen atom and the other substituent is a radical Ra, an acyl group —CORa, such as acetyl, or a functional group —COORa, —SO2Ra, —N (Ra, Rb), Ra and Rb, which are identical or different, representing a C1-C12 linear or branched alkyl radical, optionally substituted, an aryl group with one or more aromatic rings and heterocycles, comprising between 5 and 8C, optionally substituted, or aralkyl, the alkyl substituent and the aryl group being as defined above; or R1 and R2 both represent a substituent as defined above. R3 represents a hydrogen atom or Ra and R4 has the significance of Ra. The invention is characterised in that it comprises: the isomerisation of a compound having formula (I), wherein R1, R2, Ra, R3 and R4 are as defined above, such as to produce a compound having formula (II); and the reduction of the carbonyl function thereof which, depending on the catalytic system employed and the formula (I) compound used, produces one of the isomers having general formula (III) or (IV) or a mixture thereof having formula (B). The invention can be used for the synthesis of (2S, 3R, 4S)-4-hydroxyisoleucine.
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(2008/06/13)

Intermolecular cycloaddition of ethyl glyoxylate O-tert- butyldimethylsilyloxime with alkenes
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
Tamura, Osamu,Morita, Nobuyoshi,Takano, Yuu,Fukui, Kenji,Okamoto, Iwao,Huang, Xin,Tsutsumi, Yoshiyuki,Ishibashi, Hiroyuki
p. 658 - 660
(2007/10/03)

5-Hydroxy[1,2]oxazinan-3-ones as potential carbapenem and D-ala-D-ala surrogates
The title compounds are amino acids whose nitrogen atom is enclosed in a six-membered cyclic hydroxamate bearing a C5-hydroxyl group. They belong to a proposed new family of antibacterial agents targeted to the penicillin receptor. The glycine and alanine members of the family have been synthesized, as racemates, in seven steps from the four-carbon synthon diketene and the tert-butyl esters of N-hydroxyglycine and N-hydroxyalanine. Numerous alternatives to diketene have also been examined, but these lead mainly to five-membered cyclic hydroxamates. The theoretical considerations that have led to this synthetic programme are discussed in some detail. They include analysis of the structures of natural and unnatural penicillin surrogates, analysis of the penicillin pharmacophore, and a treatment of the chemical reaction with which penicillin blocks bacterial cell wall synthesis. The glycine derivative exhibits marginal but real activity vs. Micrococcus luteus. The alanine derivative, which more closely resembles D-ala-D-ala, is fifty times more active. Two five-membered structural isomers of the glycine derivative are inactive.
Wolfe, Saul,Akuche, Christiana,Ro, Stephen,Wilson, Marie-Claire,Kim, Chan-Kyung,Shi, Zheng
p. 915 - 936
(2007/10/03)

A method for the conversion of sulfoximines to sulfones: Application to polymer-bound sulfoximines and to the synthesis of chiral sulfones
Reaction of N-alkyl, N-aryl, and N-H sulfoximines with m- chloroperbenzoic acid cleanly gives the corresponding sulfones in high yield. In the case of the cleavage of N-alkyl and N-arylsulfoximines, formation of the corresponding nitroso compounds as the other reaction product was proven. Starting from enantio- and diastereopure sulfoximines, a number of chiral sulfones, including the axially chiral sulfone 6 and the sulfonyl- functionalized homoallylic alcohol 8, have been prepared. Reaction of the enantiopure sulfoximine 30 with Merrifield resin gave the polymer-bound sulfoximine 32. Oxidative cleavage of 32 afforded the sulfone 16 in high yield. Deprotonation of the sulfoximine resin 32 and reaction of Li-32 with benzaldehyde and propanal furnished the β-hydroxysulfoximine resins 33a and 33b, respectively. Oxidative cleavage of 33a and 33b readily afforded the β- hydroxy sulfones 14a and 14b, respectively.
Hachtel, Jochen,Gais, Hans-Joachim
p. 1457 - 1465
(2007/10/03)

Peripheral Mercuration of Metalloporphyrins: Novel Syntheses of Deoxophylloerythroetioporphyrin and Deoxophylloerythrin Methyl Ester
Zinc(II) porphyrins bearing unsubstituted β positions can be mercurated at the β position and at an adjacent meso position.Palladium / olefin reactions with the dimercurated porphyrins produce products possessing a five-membered isocyclic ring bridging the β and meso positions and resembling that found in chlorophyll derivatives.With use of this methodology, novel syntheses of deoxophylloerythroetioporphyrin (2) and deoxophylloerythrin methyl ester (3), two degradation products of chlorophyll, are described.
Smith, Kevin M.,Langry, Kevin C.,Minnetian, Ohannes M.
p. 4602 - 4609
(2007/10/02)

Nitrosoalkenes: Synthesis and Reactivity
Some α- and β-halonitrosoalkenes 1 have been synthesized and characterized.The halogen atoms of the oxime precursors 2 can be substituted by alkoxy groups.Two kinds of cycloaddition reaction of 1 have been observed: i) reaction of the NO group with dienes
Francotte, Eric,Merenyi, Robert,Vandenbulcke-Coyette, Brigitte,Viehe, Heinz-Guenther
p. 1208 - 1218
(2007/10/02)

Process for the production of lower alkyl 2-chloro-2-hydroxyiminoacetates
Lower alkyl 2-chloro-2-hydroxyiminoacetates are produced by (A) reacting chloral with a lower alkanol and a hydroxylamine salt in the presence of a Lewis acid or a metal oxide which is convertible into said Lewis acid during the course of the reaction to give a lower alkyl 2-hydroxyiminoacetate and then chlorinating the resulting product or (B) reacting chloral oxime with a lower alkanol in the presence of a base to give a lower alkyl 2-hydroxyiminoacetate and finally chlorinating the thus formed product.
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(2008/06/13)