- Zirconium-Catalyzed Hydroalumination of C=O Bonds: Site-Selective De- O-acetylation of Peracetylated Compounds and Mechanistic Insights
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An unprecedented hydroalumination of C = O bonds catalyzed by zirconocene dichloride is reported herein and applied to the site-selective deprotection of peracetylated functional substrates. A mixed metal hydride, with 1:1 zirconium/aluminum stoichiometry
- Courant, Thibaut,Gavel, Marine,Renard, Romain M. Q.,Gandon, Vincent,Joosten, Antoine Y. P.,Lecourt, Thomas
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p. 9280 - 9288
(2021/06/30)
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- Aryloxy Triester Phosphoramidates as Phosphoserine Prodrugs: A Proof of Concept Study
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The specific targeting of protein-protein interactions by phosphoserine-containing small molecules has been scarce due to the dephosphorylation of phosphoserine and its charged nature at physiological pH, which hinder its uptake into cells. To address these issues, we herein report the synthesis of phosphoserine aryloxy triester phosphoramidates as phosphoserine prodrugs that are enzymatically metabolized to release phosphoserine. This phosphoserine-masking approach was applied to a phosphoserine-containing inhibitor of 14-3-3 dimerization, and the generated prodrugs exhibited improved pharmacological activity. Collectively, this provided a proof of concept that the masking of phosphoserine with biocleavable aryloxy triester phosphoramidate masking groups is a viable intracellular delivery system for phosphoserine-containing molecules. Ultimately, this will facilitate the discovery of phosphoserine-containing small-molecule therapeutics.
- Dhiani, Binar A.,James, Edward,Kadri, Hachemi,Lambourne, Olivia A.,Mehellou, Youcef,Miccoli, Ageo,Thornton, Peter J.
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supporting information
(2020/03/30)
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- Non-naturally Occurring Regio Isomer of Lysophosphatidylserine Exhibits Potent Agonistic Activity toward G Protein-Coupled Receptors
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Lysophosphatidylserine (LysoPS), an endogenous ligand of G protein-coupled receptors, consists of l-serine, glycerol, and fatty acid moieties connected by phosphodiester and ester linkages, respectively. An ester linkage of phosphatidylserine can be hydrolyzed at the 1-position or at the 2-position to give 2-acyl lysophospholipid or 1-acyl lysophospholipid, respectively. 2-Acyl lysophospholipid is in nonenzymatic equilibrium with 1-acyl lysophospholipid in vivo. On the other hand, 3-acyl lysophospholipid is not found, at least in mammals, raising the question of whether the reason for this might be that the 3-acyl isomer lacks the biological activities of the other isomers. Here, to test this idea, we designed and synthesized a series of new 3-acyl lysophospholipids. Structure-activity relationship studies of more than 100 "glycol surrogate"derivatives led to the identification of potent and selective agonists for LysoPS receptors GPR34 and P2Y10. Thus, the non-natural 3-acyl compounds are indeed active and appear to be biologically orthogonal with respect to the physiologically relevant 1-and 2-acyl lysophospholipids.
- Nakamura, Sho,Sayama, Misa,Uwamizu, Akiharu,Jung, Sejin,Ikubo, Masaya,Otani, Yuko,Kano, Kuniyuki,Omi, Jumpei,Inoue, Asuka,Aoki, Junken,Ohwada, Tomohiko
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p. 9990 - 10029
(2020/10/18)
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- Regio- A nd chemoselective deprotection of primary acetates by zirconium hydrides
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A combination of DIBAL-H and Cp2ZrCl2 is shown to promote the regioselective cleavage of primary acetates on a broad scope of substrates, ranging from carbohydrates to terpene derivatives, with a high tolerance toward protecting groups and numerous functionalities found in natural products and bioactive compounds. Apart from providing highly valuable building blocks in only two steps from biosourced raw materials, this selective de-O-acetylation should also be strongly helpful to solve selectivity issues in organic synthesis.
- Gavel, Marine,Courant, Thibaut,Joosten, Antoine Yvan Philippe,Lecourt, Thomas
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supporting information
p. 1948 - 1952
(2019/04/10)
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- L-Type amino acid transporter 1 activity of 1,2,3-triazolyl analogs of L-histidine and L-tryptophan
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A series of 1,2,3-triazole analogs of the amino acids L-histidine and L-tryptophan were modeled, synthesized and tested for L-type amino acid transporter 1 (LAT1; SLC7A5) activity to guide the design of amino acid-drug conjugates (prodrugs). These triazol
- Hall, Colton,Wolfe, Hannah,Wells, Alyssa,Chien, Huan-Chieh,Colas, Claire,Schlessinger,Giacomini, Kathleen M.,Thomas, Allen A.
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supporting information
p. 2254 - 2258
(2019/06/27)
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- Synthesis of l-[4-11C]Asparagine by Ring-Opening Nucleophilic 11C-Cyanation Reaction of a Chiral Cyclic Sulfamidate Precursor
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The development of a convenient and rapid method to synthesize radiolabeled, enantiomerically pure amino acids (AAs) as potential positron emission tomography (PET) imaging agents for mapping various biochemical transformations in living organisms remains
- Xu, Youwen,Cankaya, Aylin Sibel,Hoque, Ruma,Lee, So Jeong,Shea, Colleen,Kersting, Lena,Schueller, Michael,Fowler, Joanna S.,Szalda, David,Alexoff, David,Riehl, Barbara,Gleede, Tassilo,Ferrieri, Richard A.,Qu, Wenchao
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p. 6848 - 6853
(2018/04/25)
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- Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1)
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The L-type amino acid transporter 1 (LAT1, SLC7A5) transports essential amino acids across the blood-brain barrier (BBB) and into cancer cells. To utilize LAT1 for drug delivery, potent amino acid promoieties are desired, as prodrugs must compete with millimolar concentrations of endogenous amino acids. To better understand ligand-transporter interactions that could improve potency, we developed structural LAT1 models to guide the design of substituted analogues of phenylalanine and histidine. Furthermore, we evaluated the structure-activity relationship (SAR) for both enantiomers of naturally occurring LAT1 substrates. Analogues were tested in cis-inhibition and trans-stimulation cell assays to determine potency and uptake rate. Surprisingly, LAT1 can transport amino acid-like substrates with wide-ranging polarities including those containing ionizable substituents. Additionally, the rate of LAT1 transport was generally nonstereoselective even though enantiomers likely exhibit different binding modes. Our findings have broad implications to the development of new treatments for brain disorders and cancer.
- Chien, Huan-Chieh,Colas, Claire,Finke, Karissa,Springer, Seth,Stoner, Laura,Zur, Arik A.,Venteicher, Brooklynn,Campbell, Jerome,Hall, Colton,Flint, Andrew,Augustyn, Evan,Hernandez, Christopher,Heeren, Nathan,Hansen, Logan,Anthony, Abby,Bauer, Justine,Fotiadis, Dimitrios,Schlessinger, Avner,Giacomini, Kathleen M.,Thomas, Allen A.
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supporting information
p. 7358 - 7373
(2018/08/06)
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- Optimized syntheses of Fmoc azido amino acids for the preparation of azidopeptides
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The rise of CuI-catalyzed click chemistry has initiated an increased demand for azido and alkyne derivatives of amino acid as precursors for the synthesis of clicked peptides. However, the use of azido and alkyne amino acids in peptide chemistry is complicated by their high cost. For this reason, we investigated the possibility of the in-house preparation of a set of five Fmoc azido amino acids: β-azido l-alanine and d-alanine, γ-azido l-homoalanine, δ-azido l-ornithine and ω-azido l-lysine. We investigated several reaction pathways described in the literature, suggested several improvements and proposed several alternative routes for the synthesis of these compounds in high purity. Here, we demonstrate that multigram quantities of these Fmoc azido amino acids can be prepared within a week or two and at user-friendly costs. We also incorporated these azido amino acids into several model tripeptides, and we observed the formation of a new elimination product of the azido moiety upon conditions of prolonged couplings with 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate/DIPEA. We hope that our detailed synthetic protocols will inspire some peptide chemists to prepare these Fmoc azido acids in their laboratories and will assist them in avoiding the too extensive costs of azidopeptide syntheses. Experimental procedures and/or analytical data for compounds 3–5, 20, 25, 26, 30 and 43–47 are provided in the supporting information.
- Pícha, Jan,Budě?ínsky, Milo?,Machá?ková, Kate?ina,Collinsová, Michaela,Jirá?ek, Ji?í
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p. 202 - 214
(2017/04/06)
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- LYSOPHOSPHATIDYLSERINE DERIVATIVE
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PROBLEM TO BE SOLVED: To provide a lysophosphatidylserine derivative or salt thereof. SOLUTION: The present invention provides a lysophosphatidylserine derivative or salt thereof, or a pharmaceutical composition or lysophosphatidylserine receptor function modulator including the compound or salt thereof. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT
- -
-
Paragraph 0265-0266
(2016/10/07)
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- LYSOPHOSPHATIDYLSERINE DERIVATIVE COMPRISING FATTY ACID SURROGATE
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PROBLEM TO BE SOLVED: To provide a lysophosphatidylserine derivative to serve as a lysophosphatidylserine receptor function modulator or salt thereof, and a fatty acid surrogate which can be used as a synthetic intermediate of these compounds. SOLUTION: The present invention relates to, for example, a lysophosphatidylserine derivative of the following formula that is obtained by the condensation of the synthetic intermediate 3-(2-((3-(o-tolyloxy)benzil)oxy)phenyl)propanoic acid induced from o-cresol with a corresponding serine phosphoester compound having a hydroxy group. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT
- -
-
Paragraph 0354
(2016/10/08)
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- 3-Alkyl-1,2-cyclopentanediones by Negishi cross-coupling of a 3-bromo-1,2-cyclopentanedione silyl enol ether with alkylzinc reagents: An approach to 2-substituted carboxylic acid γ-lactones, homocitric and lycoperdic acids
-
Negishi cross-coupling of the silyl-protected 3-bromoenol of 1,2-cyclopentanedione with primary and secondary alkylzinc reagents using Pd-catalysts affords 3-alkyl substituted 1,2-cyclopentanediones in good yield. The method was applied to obtain 3-methyl
- Paju, Anne,Kostomarova, Diana,Matkevit?, Katharina,Laos, Marit,Pehk, T?nis,Kanger, T?nis,Lopp, Margus
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p. 9313 - 9320
(2015/11/27)
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- COMPOUND EXHIBITING REGULATORY ACTIVITY ON LYSOPHOSPHATIDYLSERINE RECEPTOR FUNCTION
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The object of the present invention is to provide a compound having a lysophosphatidylserine receptor function modulation activity or a salt thereof. A compound having a lysophosphatidylserine receptor function modulation activity or a salt thereof, or a pharmaceutical composition or a lysophosphatidylserine receptor function moderator containing such compound or salt is provided by the present invention.
- -
-
Paragraph 0217
(2015/12/19)
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- Structure-activity relationships of lysophosphatidylserine analogs as agonists of G-protein-coupled receptors GPR34, P2Y10, and GPR174
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Lysophosphatidylserine (LysoPS) is an endogenous lipid mediator generated by hydrolysis of membrane phospholipid phosphatidylserine. Recent ligand screening of orphan G-protein-coupled receptors (GPCRs) identified two LysoPS-specific human GPCRs, namely, P2Y10 (LPS2) and GPR174 (LPS3), which, together with previously reported GPR34 (LPS1), comprise a LysoPS receptor family. Herein, we examined the structure-activity relationships of a series of synthetic LysoPS analogues toward these recently deorphanized LysoPS receptors, based on the idea that LysoPS can be regarded as consisting of distinct modules (fatty acid, glycerol, and l-serine) connected by phosphodiester and ester linkages. Starting from the endogenous ligand (1-oleoyl-LysoPS, 1), we optimized the structure of each module and the ester linkage. Accordingly, we identified some structural requirements of each module for potency and for receptor subtype selectivity. Further assembly of individually structure-optimized modules yielded a series of potent and LysoPS receptor subtype-selective agonists, particularly for P2Y10 and GPR174.
- Ikubo, Masaya,Inoue, Asuka,Nakamura, Sho,Jung, Sejin,Sayama, Misa,Otani, Yuko,Uwamizu, Akiharu,Suzuki, Keisuke,Kishi, Takayuki,Shuto, Akira,Ishiguro, Jun,Okudaira, Michiyo,Kano, Kuniyuki,Makide, Kumiko,Aoki, Junken,Ohwada, Tomohiko
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p. 4204 - 4219
(2015/06/08)
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- C-Glycosyl amino acids through hydroboration-cross-coupling of exo-glycals and their application in automated solid-phase synthesis
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O-Glycosylation is one of the most important post-translational modifications of proteins. The attachment of carbohydrates to the peptide backbone influences the conformation as well as the solubility of the conjugates and can even be essential for binding to specific ligands in cell-cell interactions or for active transport over membranes. This makes glycopeptides an interesting class of compounds for medical applications. To enhance the long-term availability of these molecules in vivo, the stabilization of the glycosidic bond between the amino acid residue and the carbohydrate is of interest. The described modular approach affords β-linked C-glycosyl amino acids by a sequence of Petasis olefination of glyconolactones, stereoselective hydroboration and a mild B-alkyl-Suzuki coupling reaction. The coupling products were transformed to C-glycosyl amino acid building-blocks suitable for solid-phase synthesis and successfully incorporated into a partial sequence of the tumor-associated MUC1-glycopeptide. The resulting C-glycopeptides are candidates for the development of long-term stable mimics of O-glycopeptide vaccines. Copyright
- Koch, Stefan,Schollmeyer, Dieter,L?we, Holger,Kunz, Horst
-
supporting information
p. 7020 - 7041
(2013/07/05)
-
- Total synthesis of the elastin crosslinker (+)-desmopyridine
-
Desmopyridine, isolated from the acid hydrolysates of bovine ligamentum nuchae, is an elastin crosslinker and an amino acid that has a 3,4,5-trisubstituted pyridine skeleton. Herein we report the first total synthesis of (+)-desmopyridine in 10% yield over six steps starting from 4-aminopyridine via chemo- and regioselective palladium-catalyzed Sonogashira and Negishi cross-coupling reactions.
- Murakami, Yuko,Yanuma, Hiroto,Usuki, Toyonobu
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p. 1557 - 1563
(2013/02/23)
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- PRODRUGS OF FUSED HETEROCYCLIC INHIBITORS OF D-AMINO ACID OXIDASE
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The invention relates to prodrugs of fused heterocyclic inhibitors of D-amino oxidase (DAAO) and methods of treating diseases and conditions, wherein modulation of D-amino acid oxidase activity, D-serine levels, D-serine oxidative products and NMDA receptor activity in the nervous system of a mammalian subject is effective.
- -
-
Page/Page column 79; 88
(2011/02/26)
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- PRODRUGS OF FUSED HETEROCYCLIC INHIBITORS OF D-AMINO ACID OXIDASE
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The invention relates to prodrugs of fused heterocyclic inhibitors of D-amino oxidase (DAAO) and methods of treating diseases and conditions, wherein modulation of D- amino acid oxidase activity, D-serine levels, D-serine oxidative products and NMDA receptor activity in the nervous system of a mammalian subject is effective.
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Page/Page column 99; 109
(2010/04/03)
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- Access to enantioenriched α-amino esters via rhodium-catalyzed 1,4-addition/enantioselective protonation
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Conjugate addition of potassium trifluoro(organo)borates 2 to dehydroalanine derivatives 1, mediated by a chiral rhodium catalyst and in situ enantioselective protonation, afforded straightforward access to a variety of protected α-amino esters 3 with high yields and enantiomeric excesses up to 95%. Among the tested chiral ligands and proton sources, Binap, in combination with guaiacol (2-methoxyphenol), an inexpensive and nontoxic phenol, afforded the highest asymmetric inductions. Organostannanes have also shown to participate in this reaction. By a fine-tuning of the ester moiety, and using Difluorophos as chiral ligand, increased levels of enantioselectivity, generally close to 95%, were achieved. Deuterium labeling experiments revealed, and DFT calculation supported, an unusual mechanism involving a hydride transfer from the amido substituent to the α carbon explaining the high levels of enantioselectivity attained in controlling this α chiral center.
- Navarre, Laure,Martinez, Remi,Genet, Jean-Pierre,Darses, Sylvain
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p. 6159 - 6169
(2008/12/20)
-
- CIDOFOVIR PEPTIDE CONJUGATES AS PRODRUGS
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Cidofovir-based compounds having an amino acid, dipeptide or tripeptide attached to a cidofovir or cyclic cidofovir framework. The compounds show enhanced oral bioavailability and increased binding to the PepT1 transporter. The present invention also provides compositions and methods for treating virus infections, and a method of preparing cidofovir.
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Page/Page column 13-14
(2008/06/13)
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- Chemical investigations in the synthesis of O-serinyl aminoribosides
-
Glycosylation involving d-ribose derivatives and various N-protected tert-butyl l-serinates can be achieved efficiently by careful choice of the activation method at the anomeric position and of the Lewis acid promoter. The conditions described allow the major formation of the β-anomer required for further elaboration to liposidomycin and caprazamycin analogues.
- Ginisty, Maryon,Gravier-Pelletier, Christine,Le Merrer, Yves
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p. 142 - 150
(2007/10/03)
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- Access to any site-directed isotopomer of methionine, selenomethionine, cysteine, and selenocysteine - Use of simple, efficient modular synthetic reaction schemes for isotope incorporation
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Simple modular reaction schemes that allow access to any isotopomer of protected serine and homoserine have been worked out. These systems could be simply converted into cysteine, selenocysteine, homocysteine, homoselenocysteine, the essential amino acid methionine, and selenomethionine by Mitsunobu chemistry. These sulfur- and selenium-containing amino acids fulfil many essential roles in the living organism. In addition, homoserine could be converted in a few steps into optically active L-vinylglycine. As well as the stable isotopes 13C, 15N, 17O, and 18O, the radioactive isotopes of sulfur, selenium and carbon can also be easily introduced in a site-directed fashion. In view of the wide scope of the Mitsunobu reaction, we feel that many more important systems with the carbon skeleton of serine and homoserine should be preparable through this basic chemistry in any site-directed isotopically labeled form. Wiley-VCH Verlag GmbH & Co, KGaA, 69451 Weinheim, Germany, 2004.
- Siebum, Arjan H. G.,Woo, Wei Sein,Raap, Jan,Lugtenburg, Johan
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p. 2905 - 2913
(2007/10/03)
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- A versatile scaffold for a library of liposidomycins analogues: A crucial and potent glycosylation step
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A key step for the synthesis of a diazepanone scaffold dedicated to a library of MraY inhibitors is described. It involves the O-glycosylation of a conveniently protected L-serine by a D-ribofuranose derivative. High yield and selectivity were obtained.
- Gravier-Pelletier, Christine,Ginisty, Maryon,Le Merrer, Yves
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p. 189 - 193
(2007/10/03)
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- Synthesis and pharmacological activity of O-(5-isoxazolyl)-L-serine
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A novel isoxazole derivative, O-(5-isoxazolyl)-L-serine (OIS, 1), was synthesized by a Mitsunobu reaction of isoxazolin-5-one (4) with N-Boc-L- serine tert-butyl ester (5) and subsequent deprotection of the coupling product. Its structure was elucidated by spectroscopic analyses. The pharmacological activity of 1 was also examined with cloned glutamate receptors and transporters using a Xenopus oocyte-expressing system showing substrate activity on an excitatory amino acid carrier 1 (EAAC 1) as a glutamate transporter.
- Ikegami, Fumio,Yamamoto, Akemi,Sekine, Toshikazu,Ishikawa, Tsutomu,Kusamae-Eguchi, Kuniko,Kusama, Tadashi,Watanabe, Kazuko
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p. 278 - 280
(2007/10/03)
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- A novel and efficient route towards α-GalNAc-Ser and α-GalNAc-Thr building blocks for glycopeptide synthesis
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Michael addition of serine and threonine derivatives 4a-4c to 3,4,6-tri- O-benzyl-2-nitro-D-galactal (1) afforded the corresponding 2-deoxy-2-nitro- α-D-galactopyranosides 5a-5c in good yield and stereoselectivity. 2-deoxy-2- nitroglycosides 5a and 5b were reduced to the 2-acetamido compounds by platinized Raney nickel T4. Manipulation of the protecting groups afforded known N-Fmoc-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D- galactopyranosyl)-L-serine (8a) and -threonine (8b), valuable building blocks for O-glycopeptide synthesis.
- Winterfeld, Gottfried A.,Ito, Yukishige,Ogawa, Tomoya,Schmidt, Richard R.
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p. 1167 - 1171
(2007/10/03)
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- Synthesis of lysophosphatidylserine with 19:4 acyl group, as a novel sodium-potassium ATPase inhibitor, in relation to DLIS-2, an endogenous digoxin-like substance
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A lysophosphatidylserine with 19:4 acyl group proposed as a candidat of DLIS-2, an endogenous digoxin-like substance was chemically synthesized. The synthetic compound showed a significant activity of Na+,K+-ATPase inhibition, which has been accepted as a major indicator activity for the essential hypertension.
- Inami,Teshima,Emura,Shiba
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p. 4033 - 4036
(2007/10/02)
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