- Intermediate, synthesis and application of vaccine adjuvant MPLA
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The invention discloses an intermediate of a vaccine adjuvant MPLA, and synthesis and application thereof. The intermediate provided by the invention uses Nap as a protecting group, and can be conveniently removed in subsequent operation. The synthesis route is short, and the total yield is obviously increased. For synthesis and amplification MPLA, a foundation is provided.
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Paragraph 0121-0124
(2021/10/27)
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- Intermediate, synthesis and application of vaccine adjuvant MPLA
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The invention discloses an intermediate of a vaccine adjuvant MPLA, and synthesis and application thereof. The intermediate provided by the invention takes the allyl phosphate ligand as MPLA phosphate group source, Nap is a protecting group, and can be conveniently removed in subsequent operation. The synthesized intermediate route is short, and the total yield is obviously increased. For synthesis and amplification MPLA, a foundation is provided.
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Paragraph 0081-0086
(2021/10/27)
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- Intermediate, synthesis and application of vaccine adjuvant MPLA
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The invention discloses an intermediate of a vaccine adjuvant MPLA, and synthesis and application thereof. The intermediate provided by the invention takes the allyl phosphate ligand as MPLA phosphate group source, Nap is a protecting group, and can be conveniently removed in subsequent operation. The synthesized intermediate route is short, and the total yield is obviously increased. For synthesis and amplification MPLA, a foundation is provided.
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Paragraph 0262-0263; 0265-0268
(2021/10/27)
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- Intermediate, synthesis and application of vaccine adjuvant MPLA
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The invention discloses an intermediate of a vaccine adjuvant MPLA, and synthesis and application thereof. The intermediate provided by the invention takes the allyl phosphate ligand as MPLA phosphate group source, Nap is a protecting group, and can be conveniently removed in subsequent operation. The synthesized intermediate route is short, and the total yield is obviously increased. For synthesis and amplification MPLA, a foundation is provided.
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Paragraph 0247-0253
(2021/10/27)
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- Intermediate, synthesis and application of vaccine adjuvant MPLA
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The invention discloses an intermediate of a vaccine adjuvant MPLA, and synthesis and application thereof. The intermediate provided by the invention takes the allyl phosphate ligand as MPLA phosphate group source, Nap is a protecting group, and can be conveniently removed in subsequent operation. The synthesized intermediate route is short, and the total yield is obviously increased. For synthesis and amplification MPLA, a foundation is provided.
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Paragraph 0100-0106
(2021/10/27)
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- Intermediate, synthesis and application of vaccine adjuvant MPLA
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The invention discloses an intermediate of a vaccine adjuvant MPLA, and synthesis and application thereof. The intermediate provided by the invention takes the allyl phosphate ligand as MPLA phosphate group source, Nap is a protecting group, and can be conveniently removed in subsequent operation. The synthesized intermediate route is short, and the total yield is obviously increased. For synthesis and amplification MPLA, a foundation is provided.
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Paragraph 0080-0086
(2021/10/27)
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- Synthesis of monophosphorylated lipid A precursors using 2-naphthylmethyl ether as a protecting group
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Lipid A, the hydrophobic domain of lipopolysaccharide (LPS), is a strong immunostimulator and therefore a valuable target for the development of novel immunomodulators. Various lipid A derivatives have been chemically synthesized in order to reduce toxicity while retaining the immunostimulatory activity. In this work, we describe a novel approach to the frequently problematic synthesis of monophosphorylated mono- and disaccharide lipid X using a combination of established chemistry and a novel 2-naphthyl-methyl ether (Nap) protecting group for “permanent” protection of hydroxy groups. Of particular note is the fact that the key Nap protecting group is able to remain in the molecule until the final global deprotection step. Our synthetic strategy is not only efficient in regards to the yield of the various chemical transformations, but also robust in regards to the potential application of this route to the production of other lipid A analogs.
- Cai, Li,Emmanuel, Khalisha A.,Gao, Qi,Ge, Dongmian,Han, Ziyi,Li, Gen,McManus, Cynthia L.,Sui, Qiang,Xue, Jundi
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supporting information
p. 1955 - 1962
(2020/10/02)
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- Synthesis of monophosphoryl lipid A using 2-naphtylmethyl ethers as permanent protecting groups
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Lipid A, which is a conserved component of lipopolysaccharides of gram-negative bacteria, has attracted considerable interest for the development of immuno-adjuvants. Most approaches for lipid A synthesis rely on the use of benzyl ethers as permanent protecting groups. Due to the amphiphilic character of lipid A, these compounds aggregate during the hydrogenation step to remove benzyl ethers, resulting in a sluggish reaction and by-product formation. To address this problem, we have developed a synthetic approach based on the use of 2-naphtylmethyl ether (Nap) ethers as permanent protecting group for hydroxyls. At the end of a synthetic sequence, multiple of these protecting groups can readily be removed by oxidation with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ). Di-allyl N,N-diisopropylphosphoramidite was employed to install the phosphate ester and the resulting allyl esters were cleaved using palladium tetrakistriphenylphosphine. The synthetic strategy allows late stage introduction of different fatty acids at the amines of the target compound, which is facilitated by Troc and Fmoc as orthogonal amino-protecting groups.
- Verpalen, Enrico C.J.M.,Brouwer, Arwin J.,Boons, Geert-Jan
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supporting information
(2020/10/09)
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- Ruthenium catalyzes the synthesis of γ-butenolides fused with cyclohexanones
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Ruthenium(II)-catalyzed reactions of cyclic diazodicarbonyl compounds with β-ketoamides for chemo- and stereoselective construction of cyclohexanone-fused γ-butenolides are described. This study represents the first example of the addition of an enol substrate which is formed by the tautomerization of the β-ketoamides to the electrophilic carbene center for unusual cyclization through amide cleavage. The combined experimental and computational studies shed light on the mechanistic pathway favouring the unusual ring formation reaction instead of the involvement of the general carbonyl ylide intermediates for the product generation.
- Thombal, Raju S.,Kim, Seoung-Tae,Baik, Mu-Hyun,Lee, Yong Rok
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supporting information
p. 2940 - 2943
(2019/03/26)
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- An Unsaturated Quinolone N-Oxide of Pseudomonas aeruginosa Modulates Growth and Virulence of Staphylococcus aureus
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The pathogen Pseudomonas aeruginosa produces over 50 different quinolones, 16 of which belong to the class of 2-alkyl-4-quinolone N-oxides (AQNOs) with various chain lengths and degrees of saturation. We present the first synthesis of a previously proposed unsaturated compound that is confirmed to be present in culture extracts of P. aeruginosa, and its structure is shown to be trans-Δ1-2-(non-1-enyl)-4-quinolone N-oxide. This compound is the most active agent against S. aureus, including MRSA strains, by more than one order of magnitude whereas its cis isomer is inactive. At lower concentrations, the compound induces small-colony variants of S. aureus, reduces the virulence by inhibiting hemolysis, and inhibits nitrate reductase activity under anaerobic conditions. These studies suggest that this unsaturated AQNO is one of the major agents that are used by P. aeruginosa to modulate competing bacterial species.
- Szamosvári, Dávid,B?ttcher, Thomas
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supporting information
p. 7271 - 7275
(2017/06/13)
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- SYNTHETIC GLUCOPYRANOSYL LIPID ADJUVANTS
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PROBLEM TO BE SOLVED: To provide a novel glucopyranosyl lipid adjuvant (GLA) for inducing or enhancing immune responses, and a vaccine composition and a pharmaceutical composition comprising the GLA. SOLUTION: The present invention provides a GLA represented by a compound of the following formula, and a vaccine composition and a pharmaceutical composition comprising the GLA. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0171
(2016/11/24)
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- Preparation of the even-numbered 3-oxo fatty acid nicotinyl esters from C6:0 to C18:0
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Here, we report a systematic comparison of different methods for the transesterification of 3-oxo fatty acid alkyl esters to the corresponding nicotinyl esters. A simple method producing the target esters in high yields and purity has been developed. Nicotinyl esters are of interest for mass spectrometry analysis of fatty acids. Also, the hydrophilic head group of nicotinyl esters can be used as the basis for the preparation of liposome-building molecules.
- Sieben, Daniela,Santana, Alexander,Nowka, Paul,Weber, Sven,Funke, Kai,Hüttenhain, Stefan H.
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supporting information
p. 808 - 810
(2016/02/03)
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- Chiral Surfactant-Type Catalyst: Enantioselective Reduction of Long-Chain Aliphatic Ketoesters in Water
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A series of amphiphilic ligands were designed and synthesized. The rhodium complexes with the ligands were applied to the asymmetric transfer hydrogenation of broad range of long-chained aliphatic ketoesters in neat water. Quantitative conversion and excellent enantioselectivity (up to 99% ee) was observed for α-, β-, γ-, δ- and ε-ketoesters as well as for α- and β-acyloxyketone using chiral surfactant-type catalyst 2. The CH/π interaction and the strong hydrophobic interaction of long aliphatic chains between the catalyst and the substrate in the metallomicelle core played a key role in the catalytic transition state. Synergistic effects between the metal-catalyzed site and the hydrophobic microenvironment of the core in the micelle contributed to high stereoselectivity. (Chemical Equation Presented).
- Lin, Zechao,Li, Jiahong,Huang, Qingfei,Huang, Qiuya,Wang, Qiwei,Tang, Lei,Gong, Deying,Yang, Jun,Zhu, Jin,Deng, Jingen
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p. 4419 - 4429
(2015/05/13)
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- Synthesis of β-ketoesters from renewable resources and Meldrum's acid
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β-Ketoesters are valuable building blocks for the synthesis of compounds with different biological activities. In this study, a series of fatty β-ketoesters were obtained from fatty acids and Meldrum's acid using N,N-dicyclohexylcarbodiimide and dimethylaminopyridine. In addition, we demonstrate for the first time the synthesis of new fatty β-ketoesters from oleic (cis-C18:1), elaidic (trans-C18:1), ricinoleic (cis-C18:1, 12-OH), linoleic (cis,cis-C18:2), and linolenic (cis,cis,cis-C18:3) acids in good yields.
- Brinkerhoff, Rafael C.,Tarazona, Hernan F.,De Oliveira, Patrick M.,Flores, Darlene C.,Montes D'Oca, Caroline Da R.,Russowsky, Dennis,Montes D'Oca, Marcelo G.
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p. 49556 - 49559
(2014/12/10)
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- Robust routes for the synthesis of N-acylated-l-homoserine lactone (AHL) quorum sensing molecules with high levels of enantiomeric purity
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The ready availability of native quorum sensing molecules and related structural analogues is of significant biological interest in the development of methods to manipulate bacterial quorum sensing systems in a useful fashion. In this Letter we report robust routes for the synthesis of a range of N-acylated-l-homoserine lactone (AHL) quorum sensing molecules. Crucially, we have analysed the enantiopurity of the final AHLs and in all cases, excellent levels were observed.
- Hodgkinson, James T.,Galloway, Warren R.J.D.,Casoli, Mariangela,Keane, Harriet,Su, Xianbin,Salmond, George P.C.,Welch, Martin,Spring, David R.
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p. 3291 - 3294
(2011/06/28)
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- Asymmetric synthesis of tetrahydrolipstatin and valilactone
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The highly diastereoselective aldol reaction between acyl complexes of the iron chiral auxiliary [(η5-C5H5)Fe(CO)(PPh3)] and β-hydroxy aldehydes (obtained via a Noyori asymmetric hydrogenation), followed by a tandem oxidative decomplexation-cyclisation process gives access to β-substituted and α,β-disubstituted β-lactones in high ee. This methodology has been employed in the asymmetric syntheses of tetrahydrolipstatin and valilactone.
- Case-Green, Stephen C.,Davies, Stephen G.,Roberts, Paul M.,Russell, Angela J.,Thomson, James E.
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experimental part
p. 2620 - 2631
(2009/04/06)
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- Chemical synthesis of a glycolipid library by a solid-phase strategy allows elucidation of the structural specificity of immunostimulation by rhamnolipids
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The first synthesis of a glycolipid library by hydrophobically assisted switching phase (HASP) synthesis is described. HASP synthesis enables flexible switching between solution-phase steps and solid-supported reactions conducted with molecules attached to a hydrophobic silica support. A library of glycolipids derived from the lead compound 1 - a strongly immunostimulatory rhamnolipid - with variations in the carbohydrate part, the lipid components, and the stereochemistry of the 3-hydroxy fatty acids was designed and synthesized. The enantiose lective synthesis of the 3-hydroxy fatty acid building blocks was achieved by employing asymmetric hydrogenation of 3-oxo fatty acids. Glycolipids were prepared by this approach without any intermediary isolation steps, mostly in excellent yields. Final deprotection to the carboxylic acids was accomplished by enzymatic ester cleavage. All prepared rhamnolipids were tested for their immunostimulatory properties against human monocyte cells by assaying the secretion of the cytokine tumor necrosis factor α (TNFα) into the medium. The observed structure-activity relationships of rhamnolipids indicate a specific, recognition-based mode of action, with small structural variations in the rhamnolipids resulting in strong effects on the immunostimulatory activities of the rhamnolipids at low micromolar concentrations.
- Bauer, Joerg,Brandenburg, Klaus,Zaehringer, Ulrich,Rademann, Joerg
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p. 7116 - 7124
(2007/10/03)
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- Small molecule inhibitors of bacterial quorum sensing and biofilm formation
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Bacteria monitor their local population densities using small molecules (or autoinducers) in a process known as quorum sensing. Here, we report a new and efficient synthetic route to naturally occurring bacterial autoinducers [N-acyl L-homoserine lactones (AHLs)] that is readily amenable to the synthesis of analogues. This route has been applied in the first synthesis of a library of non-native AHLs. Evaluation of these compounds in bacterial reporter gene and biofilm assays has revealed a potent set of quorum sensing antagonists. These ligands will serve as valuable new tools to explore the role of quorum sensing in bacterial pathogenesis. Copyright
- Geske, Grant D.,Wezeman, Rachel J.,Siegel, Adam P.,Blackwell, Helen E.
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p. 12762 - 12763
(2007/10/03)
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- Analogues of thiolactomycin as potential anti-malarial and anti-trypanosomal agents
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A series of analogues of the naturally occurring antibiotic thiolactomycin (TLM) have been synthesised and evaluated for their ability to inhibit the growth of the malaria parasite, Plasmodium falciparum. Thiolactomycin is an inhibitor of Type II fatty acid synthase which is found in plants and most prokaryotes, but not an inhibitor of Type I fatty acid synthase in mammals. A number of the analogues showed inhibition equal to or greater than TLM. The introduction of hydrophobic alkyl groups at the C3 and C5 positions of the thiolactone ring lead to increased inhibition, the best showing a fourteenfold increase in activity over TLM. In addition, some of the analogues showed activity when assayed against the parasitic protozoa, Trypanosoma cruzi and Trypanosoma brucei.
- Jones, Simon M.,Urch, Jonathan E.,Brun, Reto,Harwood, John L.,Berry, Colin,Gilbert, Ian H.
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p. 683 - 692
(2007/10/03)
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- Structural requirements of dictyopyrones isolated from Dictyostelium spp. in the regulation of Dictyostelium development and in anti-leukemic activity
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Cellular slime molds are fascinating to the field of developmental biology, and have long been used as excellent model organisms for the study of various aspects of multicellular development. We have recently isolated α-pyronoids, named dictyopyrones A-D (1-4), from various species of Dictyostelium cellular slime molds, and it was shown that compound 3 may regulate Dictyostelium development. In this study, we synthesized dictyopyrones A-D (1-4) and their analogues, investigated the physiological role of the molecules in cell growth and morphogenesis in D. discoideum, and further verified their effects on human leukemia K562 cells. Nitrogen-containing compounds 22 and 37 strongly inhibited cell growth in K562 leukemia cells, indicating that these compounds may be utilized as novel lead compounds for anti-leukemic agents.
- Kikuchi, Haruhisa,Sasaki, Kazunori,Sekiya, Jun'ichi,Maeda, Yasuo,Amagai, Aiko,Kubohara, Yuzuru,Oshima, Yoshiteru
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p. 3203 - 3214
(2007/10/03)
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- Enantioselective synthesis of α-amino acids from N-tosyloxy β-lactams derived from β-keto esters
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A novel synthetic sequence has been developed to convert simple β-keto esters into enantiomerically enriched α-amino acids. The key features of this sequence include the addition of azide to the C3 position of β-keto ester derived N-tosyloxy-β-lactams through a concomitant nucleophilic addition/N-O bond reduction reaction, a mild CsF-induced N1 benzylation of α-azido monocyclic β-lactams, the preparation of α-keto-β-lactams through a novel four-step sequence from the corresponding 3-azido-1-benzyl-β-lactams, and TEMPO-mediated ring expansion of these compounds to the corresponding N-carboxy anhydrides (NCAs). In addition, the synthesis, isolation, and characterization of unusual 3-imino and 3-chloramino-β-lactams is reported.
- Durham, Timothy B.,Miller, Marvin J.
-
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- Enantioselective Hydrogenation of β-Keto Esters using Chiral Diphosphine-Ruthenium Complexes: Optimization for Academic and Industrial Purposes and Synthetic Applications
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Enantioselective hydrogenation using chiral complexes between atropisomeric diphosphines and ruthenium is a powerful tool for producing chiral compounds. Using a simple and straightforward in situ catalyst preparation, the conditions were optimized using molecular hydrogen for both academic and industrial purposes. This led to the best conditions and the lowest catalytic ratio required for the pressure used. Hydrogenation of various β-keto esters was efficiently performed at atmospheric and higher pressures, leading to the use of very low catalyst-substrate ratios up to 1/20,000. Asymmetric hydrogenations were used in key-steps towards the total synthesis of corynomycolic acid, Duloxetine and Fluoxetine.
- Ratovelomanana-Vidal,Girard,Touati,Tranchier,Ben Hassine,Genet
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p. 261 - 274
(2007/10/03)
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- Process for producing 3-oxocarboxylic acid esters
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A novel process for producing 3-oxocarboxylic acid esters, which are useful as intermediates in the synthesis of ceramides to be used as a humectant, biodegradable polymers, drugs, etc., at a high purity and a high yield without requiring any troublesome procedure, is disclosed. The process comprises reacting an acetoacetic ester with a calcium compound, a barium compound or a strontium compound in the presence of an organic solvent at a temperature of 10 to 120° C., further reacting the obtained product with a carboxylic acid chloride to thereby acylate it, and then adding thereto an alcohol in an amount 1 to 5 times by mol as much as the calcium compound, barium compound or strontium compound to thereby deacetylate the same.
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- New potential immunoenhancing compounds. Synthesis and pharmacological evaluation of new long-chain 2-amido-2-deoxy-D-glucose derivatives
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A series of long-chain fatty acids and the corresponding 2-hydroxy, 2-oxo, 3-hydroxy acid glucosamides were evaluated as immunomodulating compounds. In a preliminary screening, 2-[(2-ethoxycarbonyloxy)tetradecanoyl-amino]-2-deoxy-D-glucose (2b) and 2-(3-hydroxydodecanoyl-amino)-2-deoxy-D-glucose (5a) resulted to be the most effective in enhancing the glucosamine activity. The findings of in vitro-ex vivo tests (unidirectional mixed lymphocyte culture reaction and primary antibody production) and in vivo tests (delayed type hypersensitivity, protection against bacterial or fungal infection and against Sarcoma 180 or Lewis lung carcinoma transplants) were very encouraging and allowed to assume for the two substances a protective activity, presumably through the ability of activating phagocytic and NK cells.
- Valcavi,Albertoni,Brandt,Corsi,Farina,Foresta,Pascucci,Ramacci
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p. 1190 - 1195
(2007/10/02)
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- Meerwein Saponification of Alkyl 3-Oxoalkanoates in the Gas Chromatograph
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Alkyl 3-oxoalkanoates decompose by unevitable traces of water in the gas chromatograph to yield the corresponding methyl ketones and alcohols (Meerwein saponification).Decomposition occurs in the hot injector (T= 270 deg C) of the gas chromatograph and also on glass capillary columns (T> 160 deg C).Decomposition in routine work can be avoided by preparing the corresponding 3-trimethylsilyl enol ethers.
- Thoma, Heinz,Spiteller, Gerhard
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p. 1237 - 1248
(2007/10/02)
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- The Preparation of Optically Pure 3-Hydroxyalkanoic Acid. The Enantioface-differentiating Hydrogenation of the C=O Double Bond with Modified Raney Nickel. XXXVII
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The enantioface-differentiating hydrogenation of methyl 3-oxoalkanoate (CH3(CH2)nCOCH2COOCH3, n=0, 6, 8, 10, 12) over the (R,R)-tartaric acid-NaBr-modified Raney nickel catalyst ((R,R)-TA-NaBr-MRNi) gave methyl (R)-3-hydroxyalkanoate (CH3(CH2)nCH(OH)CH2COOCH3, n=0, 6, 8, 10, 12) in an average optical yield of 85percent.After the methyl ester had been converted to dicyclohexylammonium salt of 3-hydroxyalkanoic acid, the salt was recrystallized three times from acetonitrile and then treated with acid to give optically pure (R)-3-hydroxyalkanoic acid (CH3(CH2)nCH(OH)CH2COOH, n=0, 6, 8, 10, 12) in a reasonable yield.From the hydrogenation product with (S,S)-TA-NaBr-MRNi, optically pure (S)-3-hydroxyalkanoic acid was obtained by the same process as above.
- Nakahata, Masaaki,Imaida, Motomasa,Ozaki, Hiroshi,Harada, Tadao,Tai, Akira
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p. 2186 - 2189
(2007/10/02)
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