- Substituted 2-hydroxy-1,2-dihydropyrrol-3-ones: Fluorescent markers pertaining to oxidative stress and aging
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Previous observations that the aging process correlates with occurrence of certain fluorescent biological pigments have led to numerous efforts in elucidating the chemical nature of the fluorophores generated through reactions of primary amines and various products of lipid peroxidation. In this study, model reactions of saturated aldehydes with aliphatic amines in the presence of peroxides were found to generate structurally unusual fluorescent compounds. Substitution of a lysine-containing peptide for simpler amines has also yielded similar fluorescence. The spectral excitation and emission maxima (around 360 and 430 nm, respectively) of these fluorophores match those widely reported in peroxidized biological objects. The fluorescent compounds in our model studies have been chromatographically isolated and their structures determined through mass spectrometry, NMR spectrometry, and Fourier-transform infrared spectroscopy. The spectrometric data indicate the fluorescent products to be alkylated 2- hydroxy-1,2-dihydropyrrol-3-ones, obtained by the action of 1,2,4-triketone intermediates upon the primary amines. Independent syntheses of several 1,2,4-triketones were carried out. One such triketone reacted with hexylamine to form a fluorescent compound spectroscopically identical to the fluorescent reaction product of hexanal, hydrogen peroxide, and hexylamine.
- Chen, Peng,Wiesler, Donald,Chmelik, Josef,Novotny, Milos
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Read Online
- An iron (II) dependent oxygenase performs the last missing step of plant lysine catabolism
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Despite intensive study, plant lysine catabolism beyond the 2-oxoadipate (2OA) intermediate remains unvalidated. Recently we described a missing step in the D-lysine catabolism of Pseudomonas putida in which 2OA is converted to D-2-hydroxyglutarate (2HG)
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Read Online
- Quinoxaline-benzimidazole rearrangements in the reactions of 3-alkanoylquinoxalin-2-ones with 1,2-phenylenediamines
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The interaction of 3-alkanoylquinoxalin-2-ones with 1,2-phenylenediamines in boiling acetic acid led to the contraction of the pyrazine ring as the result of a quinoxaline-benzimidiazole rearrangement with the formation of 2-benzimidazolyl-substituted quinoxalines.
- Kalinin,Isaikina,Mamedov
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Read Online
- Discovery and mechanistic study of thiazole-4-acylsulfonamide derivatives as potent and orally active ChemR23 inhibitors with a long-acting effect in cynomolgus monkeys
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Plasmacytoid dendritic cells (pDCs) are a subset of dendritic cells that can secrete large amounts of type I interferon. ChemR23, a G protein-coupled receptor (GPCR) expressed on the surface of pDCs, contributes to the recruitment of pDCs to inflamed tissues through chemotaxis signaling, and is therefore considered an attractive target for the treatment of autoimmune diseases. We previously reported benzoxazole-based compounds that can inhibit ChemR23 signaling through receptor internalization. Although these compounds showed ChemR23 internalization on pDCs in cynomolgus monkeys after oral administration, further improvement of the pharmacokinetics profile was needed for a clinical candidate and we therefore attempted scaffold-hopping from the benzoxazole core structure leading to novel thiazole derivatives. In this report, the design, synthesis, and biological evaluation of new thiazole-based ChemR23 inhibitors were described. Through sequential structure–activity relationship studies regarding (i) the side chain of the N-acylsulfonamide moiety, (ii) the 5-position of the thiazole ring, and (iii) the 1,2,4-oxadiazol-5-one moiety, we have succeeded in finding a potent thiazole-based ChemR23 inhibitor, 14f (IC80 = 12 nM). In addition, the oral administration of 14f at 30 mg/kg to cynomolgus monkeys demonstrated a sustained pharmacological effect of ChemR23 internalization on pDCs until 8 h after dosing, which was considered a longer effect in comparison to previously reported 2-aminobenzoxazole-based ChemR23 inhibitors. This report also shows the synthesis and evaluation of fluorescein-labeled compound 45c for a mechanistic study, and we could confirm the direct binding of our thiazole derivative to ChemR23. We believe that our research on small molecule ChemR23 inhibitors and chemical probe will contribute to the elucidation and analysis of the functions of ChemR23 as well as identifying novel therapeutics for autoimmune diseases.
- Imaizumi, Takamichi,Otsubo, Shigeki,Maemoto, Michihiro,Kobayashi, Atsuko,Komai, Masato,Takada, Hidenori,Sakaida, Yumi,Otsubo, Nobumasa
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- Asymmetric Transfer Hydrogenation of α-Keto Amides; Highly Enantioselective Formation of Malic Acid Diamides and α-Hydroxyamides
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The asymmetric transfer hydrogenation (ATH) of α-keto-1,4-diamides using a tethered Ru/TsDPEN catalyst was achieved in high ee. Studies on derivatives identified the structural elements which lead to the highest enantioselectivities in the products. The α-keto-amide reduction products have been converted to a range of synthetically valuable derivatives.
- Gediya, Shweta K.,Vyas, Vijyesh K.,Clarkson, Guy J.,Wills, Martin
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supporting information
p. 7803 - 7807
(2021/10/20)
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- Alkene Ozonolysis in the Presence of Diazo Functionality: Accessing an Intermediate for Squalestatin Synthesis
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Studies on both the propensity for intramolecular cycloaddition between diazo and alkene functionality, and the tolerance of α-substituted α-diazoesters towards ozone in the presence of an alkene, led to chemoselective alkene ozonolysis of an ?-unsaturated-α-diazoester to give a key racemic diazoketone for the synthesis of 6,7-dideoxysqualestatin H5.
- Almohseni, Hasanain A. A.,Arif, Tanzeel,Fegheh-Hassanpour, Younes,Hodgson, David M.
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p. 4231 - 4238
(2019/11/14)
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- Design, synthesis, and evaluation of alkyl-quinoxalin-2(1h)-one derivatives as anti-quorum sensing molecules, inhibiting biofilm formation in aeromonas caviae Sch3
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With the increasing antibiotic resistance of bacterial strains, alternative methods for infection control are in high demand. Quorum sensing (QS) is the bacterial communication system based on small molecules. QS is enables bacterial biofilm formation and pathogenic development. The interruption of QS has become a target for drug discovery, but remains in the early experimental phase. In this study, we synthesized a set of six compounds based on a scaffold (alkyl-quinoxalin-2(1H)-one), new in the anti-QS of Gram-negative bacteria Aeromonas caviae Sch3. By quantifying biofilm formation, we were able to monitor the effect of these compounds from concentrations of 1 to 100 μM. Significant reduction in biofilm formation was achieved by 3-hexylylquinoxalin-2(1H)-one (11), 3-hexylylquinoxalin-2(1H)-one-6-carboxylic acid (12), and 3-heptylylquinoxalin-2(1H)-one-6-carboxylic acid (14), ranging from 11% to 59% inhibition of the biofilm. This pilot study contributes to the development of anti-QS compounds to overcome the clinical challenge of resistant bacteria strains.
- Bl?cher, René,Ramírez, Ariel Rodarte,Castro-Escarpulli, Graciela,Curiel-Quesada, Everardo,Reyes-Arellano, Alicia
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- Synthesis of 3-alkylquinoxalin-2(1H)-ones via Grignard reaction
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A two-step procedure has been developed for the synthesis of 3-alkylquinoxalin-2(1H)-ones from o-phenylenediamine and ethyl 2-oxoalkanoates prepared by the Grignard reaction of diethyl oxalate with alkyl bromides. Analogous reaction with α,ω-dibromoalkanes instead of alkyl bromides leads to the formation of 3,3'-(alkane-α,ω-diyl)di[quinoxalin-2(1H) -ones].
- Kalinin,Mamedov
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experimental part
p. 1098 - 1101
(2011/02/26)
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- PYRIDAZINONE COMPOUNDS
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The invention is directed to pyridazinone compounds and pharmaceutical compositions containing such compounds that are useful in treating infections by hepatitis C virus.
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Page/Page column 23-24
(2010/11/30)
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- Preparation of α,α-disubstituted α-amino acid derivatives via alkyl addition to α-oxime esters with organozinc species
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An α-oxime ester derivative prepared via treatment of an acetylenedicarboxylate or an α-keto ester with hydroxylamine underwent C-alkylation to the C=N bond of the oxime group by a Lewis-acid-promoted reaction with a trialkylzincate or a dialkylzinc reagent. The O-N bond of the thus obtained adduct was reductively cleaved under hydrogenolysis in the presence of the Pd-C catalyst to afford an α-amino ester. Treatment of the oxime derivative prepared from methyl 5-bromo-2-oxopentanoate with the trialkylzincate gave an α-alkyl proline derivative via the addition reaction followed by the intramolecular attack upon a bromine-bearing carbon. The reaction of ethyl 4-oxo-2-pentynoate with hydroxylamine formed an isoxazole derivative by way of the intramolecular attack of an in situ-generated oxime to the carbonyl group. From this isoxazole derivative, ethyl 2-amino-4-oxo-2- pentenoate was given by the Pd-C-catalyzed hydrogenolysis. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Mitani, Michiharu,Tanaka, Yasunori,Sawada, Akihiko,Misu, Ayuko,Matsumoto, Yoshihiro
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body text
p. 1383 - 1391
(2009/04/04)
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- Studies on non-thiazolidinedione antidiabetic agents. 1. Discovery of novel oxyiminoacetic acid derivatives
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A novel series of oxyiminoacetic acid derivatives were synthesized in an effort to develop a potent antidiabetic agent, which does not contain the 2,4-thiazolidinedione moiety. These compounds were evaluated for glucose and lipid lowering effects in genetically obese and diabetic KKAy mice. Several of the compounds showed strong antidiabetic activity, including functional potency at peroxisome proliferator-activated receptor (PPAR)-γ. (Z)-2-[4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino]-2-(4- phenoxyphenyl)acetic acid (25) significantly reduced plasma glucose (33%, p0.01) and plasma triglycelide levels (43%, p0.01) even at a dosage of 0.001% in diet. Pharmacokinetic analyses of 25 are also reported.
- Imoto, Hiroshi,Imamiya, Eikoh,Momose, Yu,Sugiyama, Yasuo,Kimura, Hiroyuki,Sohda, Takashi
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p. 1349 - 1357
(2007/10/03)
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- Facile Synthesis of α-Ketocarbonyl Compounds from α-Hydroxycarbonyl Compounds
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Various α-ketocarbonyl compounds were obtained in excellent yields under mild condition from the reaction of the corresponding α-hydroxycarbonyl compounds with sodium hypobromite in the presence of HCl catalyst.
- Chang, Hae Sung,Woo, Jae Chun,Lee, Kyoung Mo,Ko, Young Kwan,Moon, Surk-Sik,Kim, Dae-Whang
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- Synthesis and reactivity of α and β-chloro-α-phenylselanyl esters
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Thermal decomposition of the dichloro-adducts derived from α-phenylselanylesters 1, 2 and 4 has been studied. N-Chloro-succinimide treatment of esters 2 was an efficient preparative method for α-chloro-α-phenylselanylesters 10 and α-chloro-α,β-unsaturated esters 11. Some transformations of esters 10 were achieved, α,β-Dichloro-α-phenylselanylesters 22 were prepared from β-chloro-α-phenylselanylesters 5 or by decomposition of the dichloroselenuranes 21 derived from esters 4. (C) 2000 Elsevier Science Ltd.
- Lebarillier, Loic,Outurquin, Francis,Paulmier, Claude
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p. 7495 - 7502
(2007/10/03)
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- Preparation process for alpha , beta -dicarbonylated compounds
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Preparation process for alpha , beta -dicarbonylated compounds of formula (I) in which R2=alkyl, phenyl or benzyl being able to be substituted in various ways on the cycle, or carboxylic ester, and R3=alkyl or alkoxy or carboxylic ester in which a compound of formula (II) in which R1=alkyl, or alkyl alpha -ketocarboxylate or carboxylic ester, and R2 and R3 have the same meanings as previously is reacted in a nitrile type solvent, with molecular oxygen in the presence of copperII nitrate or ferric chloride as catalyst, and use for obtaining ethyl alpha -ketobutyrate, ethyl phenyl pyruvate, ethyl pyruvate, ethyl phenylglyoxylate, butane-2,3-dione or diethyl mesoxalate.
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- A convenient preparation of α-keto esters by the Grignard reaction on N-acylpyrazoles
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The α-keto esters were prepared by the formation of N-acylpyrazole followed by the appropriate Grignard reaction. These short step reaction conveniently afforded various α-keto esters in good yields.
- Kashima, Choji,Shirahata, Yoshie,Tsukamoto, Yoshihiro
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p. 459 - 464
(2007/10/03)
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- Synthesis and reactivity of β-phenylselanyl α-oxoesters
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β-Phenylsetanyl α-oxoesters 2 were prepared by N-phenylselanyl morpholine treatment of α-oxoesters 1, oxidized into β-unsaturated α- oxoesters 5 and subjected to the Wittig-Horner olefination. The diethyl (l- phenylselanylalkyl)maleates 6 have led, after [2,3]sigmatropic rearrangement of the corrsponding selenoxides to the diethyl 3-alkylidene-2- hydroxysuccinates 7. The 2-(1-butoxycarbonylamino)-3-alkylidenesuccinates 8 were prepared in a similar way. The decomposition of halo-adducts derived from components 6 has the synthesis of the siethyl 3-alkylidene-2- halosuccinates 9 and 10.
- Boivin, Stephane,Outurquin, Francis,Paulmier, Claude
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p. 16767 - 16782
(2007/10/03)
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- Novel synthesis of 2-oxo-4-phenyl-3-butynoic acid, a new inhibitor and alternate substrate of pyruvate decarboxylase
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An improved method is reported for the synthesis of 2-oxo acids and is applied to the synthesis of 2-oxo-4-phenyl-3-butynoic acid. The compound is synthesized by reacting the N-methoxy-N-methylamide of monoethyloxalic acid with lithium phenylacetylide yielding ethyl 2-oxo-4-phenyl-3-butynoate (78% yield), followed by strictly pH-controlled hydrolysis to the free acid in nearly quantitative yield. The compound is shown to be a potent irreversible inhibitor of brewers' yeast pyruvate decarboxylase, in addition to producing both cis- and trans-cinnamic acids as products of turnover. The formation of these isomeric cinnamic acids can be rationalized if the thiamin diphosphate-bound α-carbanion/enamine intermediate resulting from decarboxylation is protonated at the side chain γ carbon to form two diastereomeric allenols, whose tautomerization and hydrolysis lead to the two products.
- Chiu,Jordan
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p. 5763 - 5766
(2007/10/02)
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- Facile Synthesis of α-Keto Carbonyl Compounds by Indirect Anodic Oxidation
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Secondary alcohols having a carbonyl group at the neighboring carbon atom were electrochemically oxidized to the corresponding α-keto carbonyl compounds in good yields.Thus, aromatic α-hydroxyl esters were easily transformed to arylglyoxylates in excellent yields using an undivided cell while efficient anodic oxidation of α-hydroxyl ketones and aliphatic α-hydroxyl esters successfully proceeded in a divided cell to give the corresponding α-keto carbonyl compounds.
- Maekawa, Hirofumi,Ishino, Yoshio,Nishiguchi, Ikuzo
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p. 1017 - 1020
(2007/10/02)
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- Tungsten complex induced dehydration of 2,3-dihydroxycarboxylic acids to α-keto acids
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In the absence of added base, WOCl4 induces rapid dehydration of the title compounds to give α-keto acids. A mechanism is suggested based on a neighboring group effect.
- Yu,Schwartz
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p. 6791 - 6794
(2007/10/02)
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- A Facile General Route to α-Keto Esters and α-Diketones
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A novel synthetic route to α-keto esters and α-diketones through ozonolytic fragmentation of α-substituted acetoacetic esters and α-substituted acetylacetones is described.
- Si, Zong-xing,Jiao, Xian-yun,Hu, Bing-fang
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p. 509 - 510
(2007/10/02)
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- Stereochemical Control on Yeast Reduction of α-Keto Esters. Reduction by Immobilized Bakers' Yeast in Hexane
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Ethyl 2-oxoheptanoate has been reduced by three methods: free bakers' yeast (FBY) in water, immobilized bakers' yeast (IMBY) in water, and IMBY in hexane.It has been found that the stereochemistry of reduction of α-keto esters by bakers' yeast is controlled by appropiate choice of reaction conditions.
- Nakamura, Kaoru,Inoue, Kiyoko,Ushio, Kazutoshi,Oka, Shinzaburo,Ohno, Atsuyoshi
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p. 2589 - 2593
(2007/10/02)
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- OXIDATION OF α-HYDROXY ESTERS TO α-KETO ESTERS USING THE DESS-MARTIN PERIODINANE REAGENT
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The oxidation of α-hydroxy esters, including peptidyl α-hydroxy esters, with the Dess-Martin periodinane reagent is a useful and general method for the preparation of α-keto esters.
- Burkhart, Joseph P.,Peet, Norton P.,Bey, Philippe
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p. 3433 - 3436
(2007/10/02)
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- Reaction of Singlet Oxygen with Enamino Carbonyl Systems. A General Method for the Synthesis of α-Keto Derivatives of Lactones, Esters, Amides, Lactams, and Ketones
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A general method for the introduction of a ketone α to the carbonyl group of a ketone, lactone. ester, substituted amide, or lactam has been developed involving the formation and dye-sensitized photooxygenation of enamino carbonyl intermediates.
- Wasserman, Harry H.,Ives, Jeffrey L.
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p. 3573 - 3580
(2007/10/02)
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- REACTION OF ORGANOMETALLIC REAGENTS WITH TRIETHOXYACETONITRILE. A NEW AND SHORT SYNTHESIS OF α-KETOESTERS.
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Grignard reagents react with triethoxyacetonitrile to give esters, while organolithium reagents provide α-ketoesters in excellent yields.
- Axiotis, Georges P.
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p. 1509 - 1510
(2007/10/02)
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