- A remarkable enhancement of selectivity towards versatile analytes by a strategically integrated H-bonding site containing phase
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A double β-alanylated l-glutamide-derived organic phase has been newly designed and synthesized in such a way that integrated H-bonding (interaction) sites make it very suitable for the separation of versatile analytes, including shape-constrained isomers, and nonpolar, polar and basic compounds. The β-alanine residues introduced into two long-chain alkyl group moieties provide ordered polar groups through H-bonding among the amide groups.
- Mallik, Abul K.,Qiu, Hongdeng,Kuwahara, Yutaka,Takafuji, Makoto,Ihara, Hirotaka
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Read Online
- GLUCOPYRANOSYL DERIVATIVE AND USE THEREOF
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The present invention relates to a glucopyranosyl derivative and a use thereof. In particular, the present invention relates to a glucopyranosyl derivative that is used as an inhibitor of sodium-dependent glucose transporters (SGLTs), particularly being used as an inhibitor of sodium-dependent glucose transporter-1 (SGLT1), and a pharmaceutically acceptable salt or stereoisomer thereof, further relating to a pharmaceutical composition containing the derivative. The present invention further relates to a use of the compound and a pharmaceutical composition thereof in the preparation of a drug for treating diabetes and diabetes-related diseases.
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Paragraph 0293-0295
(2020/12/16)
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- Dioxygen activation with molybdenum complexes bearing amide-functionalized iminophenolate ligands
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Two novel iminophenolate ligands with amidopropyl side chains (HL2 and HL3) on the imine functionality have been synthesized in order to prepare dioxidomolybdenum(VI) complexes of the general structure [MoO2L2] featuring pendant internal hydrogen bond donors. For reasons of comparison, a previously published complex featuring n-butyl side chains (L1) was included in the investigation. Three complexes (1-3) obtained using these ligands (HL1-HL3) were able to activate dioxygen in an in situ approach: The intermediate molybdenum(IV) species [MoO(PMe3)L2] is first generated by treatment with an excess of PMe3. Subsequent reaction with dioxygen leads to oxido peroxido complexes of the structure [MoO(O2)L2]. For the complex employing the ligand with the n-butyl side chain, the isolation of the oxidomolybdenum(IV) phosphino complex [MoO(PMe3)(L1) 2] (4) was successful, whereas the respective Mo(IV) species employing the ligands with the amidopropyl side chains were found to be not stable enough to be isolated. The three oxido peroxido complexes of the structure [MoO(O2)L2] (9-11) were systematically compared to assess the influence of internal hydrogen bonds on the geometry as well as the catalytic activity in aerobic oxidation. All complexes were characterized by spectroscopic means. Furthermore, molecular structures were determined by single-crystal X-ray diffraction analyses of HL3, 1-3, 9-11 together with three polynuclear products {[MoO(L2) 2]2 (μ-O)} (7), {[MoO(L2)] 4 (μ-O) 6} (8) and [C9H13N2O]4 [Mo8O26] 6OPMe3 (12) which were obtained during the synthesis of reduced complexes of the type [MoO(PMe3)L2] (4-6).
- Zwettler, Niklas,Ehweiner, Madeleine A.,Schachner, J?rg A.,Dupé, Antoine,Belaj, Ferdinand,M?sch-Zanetti, Nadia C.
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- Combined inhibition of the EGFR/AKT pathways by a novel conjugate of quinazoline with isothiocyanate
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Epidermal growth factor receptor inhibitors (EGFR-TKIs) represent a class of compounds widely used in anticancer therapy. An increasing number of studies reports on combination therapies in which the block of the EGFR-TK activity is associated with inhibition of its downstream pathways, as PI3K-Akt. Sulforaphane targets the PI3K-Akt pathway whose dysregulation is implicated in many functions of cancer cells. According to these considerations, a series of multitarget molecules have been designed by combining key structural features derived from an EGFR-TKI, PD168393, and the isothiocyanate sulforaphane. Among the obtained molecules 1-6, compound 6 emerges as a promising lead compound able to exert antiproliferative and proapoptotic effects in A431 epithelial cancer cell line by covalently binding to EGFR-TK, and reducing the phosphorylation of Akt without affecting the total Akt levels.
- Tarozzi, Andrea,Marchetti, Chiara,Nicolini, Benedetta,D'Amico, Massimo,Ticchi, Nicole,Pruccoli, Letizia,Tumiatti, Vincenzo,Simoni, Elena,Lodola, Alessio,Mor, Marco,Milelli, Andrea,Minarini, Anna
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p. 283 - 291
(2016/05/10)
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- Chloroperoxidase-catalyzed amino alcohol oxidation: Substrate specificity and novel strategy for the synthesis of N-Cbz-3-aminopropanal
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The ability of chloroperoxidase (CPO) to catalyze amino alcohol oxidations was investigated. The oxidations of compounds with different configurations with respect to the amine position towards hydroxyl – using H2O2 and tert-butyl hydroperoxide (t-BuOOH) – were analyzed in terms of the initial reaction rate, substrate conversion, and CPO operational stability. It was observed that the further the amino group from the hydroxyl, the lower the initial reaction rate. The effect of the amino-protecting group and other substituents (i.e., methyl and hydroxyl) was also examined, revealing an increase in steric hindrance due to the effect of bulky substituents. The observed reaction rates were higher with t-BuOOH, whereas CPO was more stable with H2O2. Moreover, CPO stability had to be determined case by case as the enzyme activity was modulated by the substrate. The oxidation of N-Cbz-3-aminopropanol (Cbz, carboxybenzyl) to N-Cbz-3-aminopropanal was investigated. Main operational conditions such as the reaction medium, initial amino alcohol concentration, and peroxide nature were studied. The reaction kinetics was determined, and no substrate inhibition was observed. By-products from a chemical reaction between the formed amino aldehyde and the peroxide were identified, and a novel reaction mechanism was proposed. Finally, the biotransformation was achieved by reducing side reactions and identifying the key factors to be addressed to further optimize the product yield.
- Masdeu, Gerard,Pérez-Trujillo, Míriam,López-Santín, Josep,álvaro, Gregorio
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p. 1204 - 1211
(2016/08/09)
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- A new concept for production of (3S,4R)-6-[(benzyloxycarbonyl)amino]-5,6-dideoxyhex-2-ulose, a precursor of d-fagomine
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A novel cascade reaction for the production of aldol adduct (3S,4R)-6-[(benzyloxycarbonyl)amino]-5,6-dideoxyhex-2-ulose was studied in this work. The strategy combines three enzymes in one pot: (i) horse liver alcohol dehydrogenase for the oxidation of N-Cbz-3-aminopropanol to the corresponding aldehyde, (ii) NADH oxidase for the regeneration of coenzyme NAD+ and (iii) d-fructose-6-phosphate aldolase from E. coli A129S variant for the aldol addition of dihydroxyacetone to N-Cbz-3-aminopropanal. On the basis of preliminary experiments, optimization of the initial reaction conditions was done using statistical methods, i.e. factorial design of experiments. 79% yield of aldol adduct was achieved in the batch reactor after optimization.
- Sudar, Martina,Findrik, Zvjezdana,Vasi-Raki, Durda,Soler, Anna,Claps, Pere
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p. 69819 - 69828
(2015/09/01)
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- Photoinduced release of neurotransmitter amino acids from coumarin-fused julolidine ester cages
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The photoinduced release of several neurotransmitter amino acids (glycine, alanine, glutamic acid, β-alanine and γ-aminobutyric acid) was accomplished from ester cages based on a new photoremovable protecting group consisting of a coumarin built on the julolidine nucleus, namely a (11-oxo-2,3,5,6,7,11-hexahydro-1H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-9-yl) methyl group. Photolysis and steady-state sensitization studies revealed that release of the active molecule occurred in short irradiation times at long wavelengths, with a very promising performance at 419 nm. Given the interest in the development of novel protecting groups that are cleavable with UV A or even visible radiation, it was found that a structural modification in the coumarin ring by assembly of a fused julolidine leads to a promising photolabile protecting group for organic synthesis and also for bioapplications. Photolysis and steady-state sensitization studies of several neurotransmitter amino acids from ester cages based on a new photoremovable protecting group consisting of a coumarin-fused julolidine nucleus, revealed that the release of the active molecule occurred in short irradiation times at long wavelengths, especially at 419 nm. Copyright
- Piloto, Ana M.,Hungerford, Graham,Costa, Susana P. G.,Goncalves, M. Sameiro T.
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p. 7715 - 7723
(2013/12/04)
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- One-pot efficient synthesis of N α-urethane-protected β- And γ-amino acids
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1-[(4-Methylphenyl)oxy]pyrrolidine-2,5-dione and 1-[(4-methylphenyl)oxy] piperidine-2,6-dione react in a Lossen-type reaction with primary alcohols in the presence of triethylamine to furnish corresponding N α- urethane-protected β-alanine and γ-aminopropionic acid (GABA), respectively, with excellent yields and purities, in an essentially "one-pot" procedure.
- Cal, Marta,Jaremko, Mariusz,Jaremko, Lukasz,Stefanowicz, Piotr
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p. 1085 - 1091
(2013/07/05)
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- Molecular-shape selectivity by molecular gel-forming compounds: Bioactive and shape-constrained isomers through the integration and orientation of weak interaction sites
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A molecular gel system was assembled on carrier particles and the integrated effect of weak interaction sites enabled highly efficient separation of the bioactive and shape-constrained isomers of tocopherols, β-carotene, and polycyclic aromatic hydrocarbons (PAHs) by multiple interaction mechanisms.
- Mallik, Abul K.,Qiu, Hongdeng,Sawada, Tsuyoshi,Takafuji, Makoto,Ihara, Hirotaka
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supporting information; experimental part
p. 10341 - 10343
(2011/10/31)
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- Papain-catalyzed peptide bond formation: Enzyme-specific activation with guanidinophenyl esters
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The substrate mimetics approach is a versatile method for small-scale enzymatic peptide-bond synthesis in aqueous systems. The protease-recognized amino acid side chain is incorporated in an ester leaving group, the substrate mimetic. This shift of the specific moiety enables the acceptance of amino acids and peptide sequences that are normally not recognized by the enzyme. The guanidinophenyl group (OGp), a known substrate mimetic for the serine proteases trypsin and chymotrypsin, has now been applied for the first time in combination with papain, a cheap and commercially available cysteine protease. To provide insight in the binding mode of various Z-XAA-OGp esters, computational docking studies were performed. The results strongly point at enzyme-specific activation of the OGp esters in papain through a novel mode of action, rather than their functioning as mimetics. Furthermore, the scope of a model dipeptide synthesis was investigated with respect to both the amino acid donor and the nucleophile. Molecular dynamics simulations were carried out to prioritize 22 natural and unnatural amino acid donors for synthesis. Experimental results correlate well with the predicted ranking and show that nearly all amino acids are accepted by papain.
- de Beer, Roseri J.A.C.,Zarzycka, Barbara,Amatdjais-Groenen, Helene I.V.,Jans, Sander C.B.,Nuijens, Timo,Quaedflieg, Peter J.L.M.,van Delft, Floris L.,Nabuurs, Sander B.,Rutjes, Floris P.J.T.
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experimental part
p. 2201 - 2207
(2012/05/05)
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- Amphiphilic molecular gels from ω-aminoalkylated L-glutamic acid derivatives with unique chiroptical properties
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Self-assembling amphiphiles with unique chiroptical properties were derived from L-glutamic acid through ω-aminoalkylation and double long-chain alkylation. These amphiphiles can disperse in various solvents ranging from water to n-hexane. TEM and SEM observations indicate that the improvement in dispersity is induced by the formation of tubular and/or fibrillar aggregates with nanosized diameters, which makes these amphiphiles similar to aqueous lipid membrane systems. Spectroscopic observations, such as UV-visible and CD spectroscopies indicate that the aggregates are constructed on the basis of S-and R-chirally ordered structures through interamide interactions in water and organic media, respectively, and that these chiroptical properties can be controlled thermotropically and lyotropically. It is also reported that the chiral assemblies provide specific binding sites for achiral molecules and then induce chirality for the bonded molecules. Further, the applicability of the amphiphiles to template polymerization is discussed. Springer-Verlag 2010.
- Kira, Yoshiko,Okazaki, Yutaka,Sawada, Tsuyoshi,Takafuji, Makoto,Ihara, Hirotaka
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experimental part
p. 587 - 597
(2010/11/17)
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- Oxazole light triggered protecting groups: Synthesis and photolysis of fused heteroaromatic conjugates
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Fused oxazole derivatives were synthesized and evaluated as new light triggered protecting groups by using amino acids as model bifunctional molecules. The photosensitivity of ester conjugates was tested under irradiation at 254, 300, and 350 nm. Oxazole
- Soares, Ana M.S.,Costa, Susana P.G.,Gonalves, M. Sameiro T.
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experimental part
p. 8189 - 8195
(2010/11/04)
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- 2-Oxo-2H-benzo[h]benzopyran as a new light sensitive protecting group for neurotransmitter amino acids
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Aiming at the development of new benzopyran-based photocleavable protecting groups, novel chloromethylated and hydroxymethylated 2-oxo-2H-benzo[h] benzopyran derivatives bearing a methoxy substituent were designed and used in the synthesis of a series of fluorescent bioconjugates, by linking through an ester or urethane bond to several model neurotransmitter amino acids (glycine, alanine, β-alanine and γ-aminobutyric acid, GABA). The resulting fluorescent bioconjugates with emission in the visible range and high fluorescent quantum yields, were subjected to photocleavage reaction in methanol/HEPES buffer (80:20) solution at different wavelengths of irradiation (250, 300, 350 and 419 nm) and photocleavage kinetic data were obtained.
- Soares, Ana M. S.,Costa, Susana P. G.,Goncalves, M. Sameiro T.
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experimental part
p. 121 - 133
(2010/09/07)
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- A novel synthesis of N-but-3-enyl-α- and β-amino acids
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N-But-3-enyl-α- and β-amino acids can be prepared by cleaving 1,3-oxazolidin-5-ones and 1,3-oxazinan-6-ones in the presence of allylsilanes and boron trifluoride etherate at room temperature in good to excellent yields. Georg Thieme Verlag Stuttgart.
- Van Nguyen,Brownlee, Robert T. C.,Hughes, Andrew B.
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experimental part
p. 1991 - 1998
(2010/03/24)
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- 2-Phenyl-tetrahydropyrimidine-4(1H)-ones - Cyclic benzaldehyde aminals as precursors for functionalised β2-amino acids
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Novel procedures have been developed to condense benzaldehyde effectively with β-amino acid amides to cyclic benzyl aminals. Double carbamate protection of the heterocycle resulted in fully protected chiral β-alanine derivatives. These serve as universal precursors for the asymmetric synthesis of functionalised β2-amino acids containing acid-labile protected side chains. Diastereoselective alkylation of the tetrahydropyrimidinone is followed by a chemoselective two step degradation of the heterocycle to release the free β2-amino acid. In the course of this study, an L-asparagine derivative was condensed with benzaldehyde and subsequently converted to orthogonally protected (R)-β2-homoaspartate.
- Nahrwold, Markus,Stoncius, Arvydas,Penner, Anna,Sewald, Norbert,Neumann, Beate,Stammler, Hans-Georg
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supporting information; experimental part
(2010/04/22)
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- Inhibitors interacting with the magnesium binding site of reverse transcriptase: Synthesis and biological activity studies of 3′-(Ω- amino-acyl) amino-3′-deoxy-thymidine
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Active site of reverse transcriptase contains carboxylate groups involved in the magnesium binding. We prepared some nucleoside analogs which could bind to these carboxylates preventing the binding of nucleotides. To the 3′-amino-3′-deoxy-thymidine, different N-protected ω-amino-acids were bound, the protection removed to give the 3′-(ω-amino-acyl-) amino-3′-deoxy-thymidines in good yield. Some showed moderate to low activity in HIV 1 replication test. Copyright Taylor & Francis Group, LLC.
- Goud, Thirumani Venkateshwar,Aubertin, Anne-Marie,Biellmann, Jean-Francois
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p. 495 - 505
(2008/09/21)
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- Synthesis and self-association properties of flexible guanidiniocarbonylpyrrole-carboxylate zwitterions in DMSO: Intra- versus intermolecular ion pairing
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(Chemical Equation Presented) We have synthesized a new class of flexible zwitterions 6a-e, in which a carboxylate is linked via an alkyl chain with variable length (one to five methylene groups) to a guanidiniocarbonylpyrrole cation. The self-association properties of these zwitterions were determined by NMR dilution studies in DMSO and by ESI-MS experiments. The stability and hence also the size of the aggregates formed via self-assembly is critically dependent on the length and therefore flexibility of the spacer. Whereas the smallest zwitterion 6a forms large aggregates already at low concentrations, the more flexible zwitterions only form small oligomers (6b) or dimers (6c-e) at much larger concentrations. The differences between the five zwitterions can be explained based on the different extent of intramolecular ion pairing within the monomers. Any intramolecular ion pairing, which becomes possible with increasing linker length, stabilizes the monomer and therefore destabilizes any oligomer.
- Schmuck, Carsten,Rehm, Thomas,Geiger, Lars,Schaefer, Mathias
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p. 6162 - 6170
(2008/02/10)
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- Effective methods for the synthesis of N-methyl β-amino acids from all twenty common α-amino acids using 1,3-oxazolidin-5-ones and 1,3-oxazinan-6-ones
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N-Methyl β-amino acids are generally required for application in the synthesis of potentially bioactive modified peptides and other oligomers. Previous work highlighted the reductive cleavage of 1,3-oxazolidin-5-ones to synthesise N-methyl α-amino acids. Starting from α-amino acids, two approaches were used to prepare the corresponding N-methyl β-amino acids. First, α-amino acids were converted to N-methyl α-amino acids by the so-called '1,3-oxazolidin-5-one strategy', and these were then homologated by the Arndt-Eistert procedure to afford N-protected N-methyl β-amino acids derived from the 20 common α-amino acids. These compounds were prepared in yields of 23-57% (relative to N-methyl α-amino acid). In a second approach, twelve N-protected α-amino acids could be directly homologated by the Arndt-Eistert procedure, and the resulting β-amino acids were converted to the 1,3-oxazinan-6-ones in 30-45% yield. Finally, reductive cleavage afforded the desired N-methyl β-amino acids in 41-63% yield. One sterically congested β-amino acid, 3-methyl-3-aminobutanoic acid, did give a high yield (95%) of the 1,3-oxazinan-6-one (65), and subsequent reductive cleavage gave the corresponding AIBN-derived N-methyl β-amino acid 61 in 71% yield (Scheme 2). Thus, our protocols allow the ready preparation of all N-methyl β-amino acids derived from the 20 proteinogenic α-amino acids.
- Hughes, Andrew B.,Sleebs, Brad E.
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p. 2611 - 2637
(2007/10/03)
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- Synthesis and pharmacological evaluation of glycine-modified analogues of the neuroprotective agent glycyl-L-prolyl-L-glutamic acid (GPE)
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The synthesis of 10 G*PE analogues, wherein the glycine residue has been modified, is described by coupling readily accessible dibenzyl-l-prolyl-l- glutamate 2 with various analogues of glycine. Pharmacological evaluation of the novel compounds was undertaken to further understand the role of the glycine residue on the observed neuroprotective properties of the endogenous tripeptide GPE.
- Lai, Michelle Y.H.,Brimble, Margaret A.,Callis, David J.,Harris, Paul W.R.,Levi, Mark S.,Sieg, Frank
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p. 533 - 548
(2007/10/03)
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- Preparation of both enantiomers of β2-(3,4-dihydroxybenzyl) -β-alanine, higher homologues of Dopa
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β2-(3,4-Dihydroxybenzyl)-β-alanine [β2-Homo-Dopa, 1] is a novel β-amino acid homologue of Dopa, the most successful therapeutic agent in the treatment of Parkinson's disease. Enantioenriched (R)-1 and (S)-1 were obtained via the diastereoselective alkylation of enantiopure pyrimidinone (R)- and (S)-3, chiral derivatives of β-alanine, with veratryl iodide. The major diastereomeric products (2S,5R)-4 and (2R,5S)-4 were hydrolyzed with 57% HBr, and the desired β-amino acids were purified by silica gel chromatography. Alternatively, enantioenriched (R)- and (S)-1 were prepared by means of the highly diastereoselective alkylation (3,4-dimethoxybenzyl iodide) of open-chain β-aminopropionic acid derivatives (R,R,S)-8 and (S,S,R)-8 containing the chiral auxiliary α-phenylethylamine. Finally, nearly enantiopure (R)- and (S)-1 were obtained by resolution of racemic N-benzyloxycarbonyl-2-(3,4- dibenzyloxybenzyl)-3-aminopropionic acid, rac-12, with (R)- or (S)-α-phenylethylamine, followed by catalytic hydrogenolysis.
- Avila-Ortiz, Claudia G.,Reyes-Rangel, Gloria,Juaristi, Eusebio
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p. 8372 - 8381
(2007/10/03)
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- Phospholipid prodrugs of anti-proliferative drugs
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The invention discloses prodrugs comprising anti-proliferative drugs covalently linked, via bridging group, to a phospholipid moiety such that the active species is preferentially released, preferably by enzymatic cleavage, at the required site of action. The invention further discloses pharmaceutical compositions said prodrugs and the uses thereof for the treatment of diseases and disorders related to inflammatory, to degenerative or atrophic conditions, and to uncontrolled cell growth. FIG.1depicts a graph of animal survival during the course of an experiment wherein mice were i.p. transplanted with 11210 mouse leukemia cells and then treated with vehicle only (squares), MTX (triangles) or molar equivalent dose of DP-MTX071 (circles) according to the regiment described example in Example 11.
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Page/Page column 10-11
(2010/02/08)
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- PHOSPHOLIPID DERIVATIVES OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
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Disclosed are compounds having non-steroidal anti-inflammatory drugs (NSAIDS) covalently linked to a phospholipid moiety via a bridging group. Also disclosed are a process for the synthesis of the compounds, pharmaceutical compositions comprising the compounds and the use thereof for the treatment of diseases and disorders related to inflammatory conditions.
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- The use of cellulose (chromatography paper) as a cheap, versatile and non-covalent support for organic molecules during multi-step synthesis
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Cellulose chromatography paper provides a novel non-covalent support for synthesis and in-situ purification of multi-dimensional arrays.
- Shanahan, Stephen E.,Byrne, Douglas D.,Inglis, Graham G. A.,Alam, Mahbub,Macdonald, Simon J. F.
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p. 2554 - 2555
(2007/10/03)
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- Enantioselective synthesis of β-amino acids. Part 11: Diastereoselective alkylation of chiral derivatives of β-aminopropionic acid containing the α-phenethyl group
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Several novel, chiral derivatives of β-aminopropionic acid were studied as potentially useful precursors of enantiopure α-substituted-β-amino acids. In particular, the diastereoselectivity of alkylation of (R,R)-2-Li enolate showed substantial stereoinduction by the bis[α-phenylethyl]amide auxiliary, leading to 80% ds in the methylation reaction. No appreciable effect upon diastereoselectivity was observed by the presence of additives (LiCl, HMPA, DMPU) in the reaction. On the other hand, stereoinduction by the α-phenylethylamino group in the methylation of ester enolate (S)-3-Li was lower (65% ds) under standard conditions (THF, -78°C) but improved to 81% ds in the presence of 3 equiv. of HMPA as cosolvent. 'Matched' and 'mismatched' derivatives, (R,R,S)-11 and (R,R,R)-11, respectively, were methylated via their corresponding lithium enolates. Observed diastereoselectivities generally followed the anticipated tendencies based on double stereoinduction. Thus diastereoselectivity reached 89% ds in the methylation of the matched isomer, (R,R,S)-11-Li.
- Gutiérrez-García, Víctor Manuel,López-Ruiz, Heraclio,Reyes-Rangel, Gloria,Juaristi, Eusebio
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p. 6487 - 6496
(2007/10/03)
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- A novel concept in combinatorial chemistry in solution with the advantages of solid-phase synthesis: Formation of N-betaines by multicomponent domino reactions
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Advantages of solid-phase and liquid-phase synthesis are combined in a new concept of combinatorial chemistry: a domino sequence comprising Knoevenagel and hetero-Diels-Alder reactions, with subsequent hydrogenation starting from protected aminoaldehydes, 1.3-dicarbonyl compounds, and enol ethers leads to N-heterocycles of high diversity with a betaine structure, which are isolated in highly pure form by precipitation with diethyl ether (see scheme), Cbz = benzylocycarbonyl, Bn = benzyl.
- Tietze, Lutz F.
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p. 903 - 905
(2007/10/03)
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- Expanding the utility of proteases in synthesis: Broadening the substrate acceptance in non-coded amide bond formation using chemically modified mutants of subtilisin
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The strategy of combined site directed mutagenesis and chemical modification creates chemically modified mutants (CMMs) with greatly broadened substrate specificities. We have previously reported that the CMMs of subtilisin Bacillus lentus (SBL) are efficient catalysts for the coupling of both L- and D-amino acids. We now report that these powerful catalysts also allow amide bond formation between a variety of non-coded carboxylic acids, including β-alanine and β-amino homologues of phenylalanine, with both L- and D-amino acid nucleophiles. As a guide to enzyme efficiency, a hydrolysis assay indicating pH change has been employed. CMMs selected by this screen furnished higher yields of coupling products compared to the wild-type enzyme (WT). Furthermore, both WT and CMM enzymes allow highly stereoselective aminolysis of a meso diester with an amino acid amine. These results highlight the utility of CMMs in the efficient formation of non-coded amides as potential peptide isosteres.
- Khumtaveeporn, Kanjai,Ullmann, Astrid,Matsumoto, Kazutsugu,Davis, Benjamin G.,Jones
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p. 249 - 261
(2007/10/03)
-
- Urethane N-carboxyanhydrides from β-amino acids
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A general method has been developed for the synthesis of N-tert-butyloxycarbonyl N-carboxyanhydrides from β-amino acids using Vilsmeier complex. These β-UNCA are stable, and the reactivity with different nucleophiles (alcohol, amine, lithium enolate) was studied.
- McKiernan,Huck,Fehrentz,Roumestant,Viallefont,Martinez
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p. 6541 - 6544
(2007/10/03)
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- β-Secondary Kinetic Isotope Effects in the Clavaminate Synthase-Catalyzed Oxidative Cyclization of Proclavaminic Acid and in Related Azetidinone Model Reactions
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Clavaminate synthase is an Fe(II)/α-ketoglutarate-dependent oxygenase that catalyzes three mechanistically distinct reactions in the course of clavulanic acid biosynthesis. Clavulanic acid is of significant chemical importance as a potent inhibitor/inactivator of β-lactamase enzymes, a prominent means of bacterial resistance to, for example, penicillin. Primary and α-secondary T(V/K) kinetic isotope effects have been determined in earlier work for the clavaminate synthase-catalyzed oxidative cyclization of proclavaminic acid, one of the three reactions mediated by this enzyme. In this paper the β-secondary deuterium kinetic isotope effect for this reaction has been determined using remote 3H and 14C labels in an attempt to distinguish between radical or cationic intermediates in the reaction as suggested by the magnitudes of the primary and secondary α-effects. The presence of the adjacent azetidinone nitrogen and the intervention of an azetinone intermediate, formally antiaromatic in the resonance form of the amide, make interpretation of the low β-secondary effect (1.056 ± 0.002 for dideuteriation at C-3′) problematic. To assist interpretation of this result, a 4-chloroazetidinone model system has been constructed dideuteriated at C-3 identically to proclavaminic acid and bearing remote radiolabels. Reaction of this substrate at 25°C under both radical and solvolysis conditions afforded β-secondary kinetic isotope effect data for direct comparison to the enzymic reaction. The measured effects are similarly small but strongly dependent on the polarity/acidity of the reaction medium. These results are discussed in terms of the commitment to catalysis and the extent to which amide resonance may be favored in the transition state of the oxidative cyclization.
- Iwata-Reuyl, Dirk,Basak, Amit,Townsend, Craig A.
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p. 11356 - 11368
(2007/10/03)
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- A total synthesis of arenastatin A, an extremely potent cytotoxic depsipeptide, from the Okinawan marine sponge dysidea arenaria
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An asymmetric synthesis of a cyclic depsipeptide arenastatin A (1), which was isolated from the marine sponge Dysidea arenaria and exhibited extremely potent cytotoxicity with IC50 5 pg/ml for KB cells, has been accomplished.
- Kobayashi,Kurosu,Wang,Kitagawa
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p. 2394 - 2396
(2007/10/02)
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- Synthetic Analogues of Low-Molecular-Weight Acyl-polyamine Spider Toxins
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Low-molecular-weight spider and wasp toxins are selective inhibitors of glutamate receptors of the central nervous system and consist of a polyamine backbone and one or several carboxylic acids and/or amino acids linked by a peptide-like bond.The syntheses of twelve analogues of spider and wasp toxins are described (10a-c, 15a-c, 20a-c, 25a-c) having the general structure of acyl, arylacyl, or heteroarylacyl -> DL-alanyl -> ω-aminoacyl -> N1-spermidine, with variation in the acyl and the ω-aminoacyl part.
- Fiedler, Wolfgang J.,Guggisberg, Armin,Hesse, Manfred
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p. 1167 - 1181
(2007/10/02)
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- Regioselective functionalization of chiral nickelacycles derived from N-protected aspartic and glutamic anhydrides
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The electrophilic cleavage of the nickelacycles resulting from oxidative addition of Ni(o) complexes to N-protected aspartic and glutamic anhydrides, followed by decarbonylation, gives rise regioselectively to derivatives of α- and β-alanine or α- and γ-aminobutyric acid, respectively.
- Castano,Echavarren
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p. 4783 - 4786
(2007/10/02)
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- Composition containing a penem or carbapenem antibiotic and the use of the same
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Administration of an N-acylated amino acid in association with a penem or carbapenem antibiotic relieves or eliminates the renal problems associated with administration of the antibiotic alone. The amino acid derivative and antibiotic may be formulated together as a composition or administered separately, either simultaneously or sequentially.
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- Composition containing a penem or carbapenem antibiotic
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Administration of an N-acylated amino acid in association with a penem or carbapenem antibiotic relieves or eliminates the renal problems associated with administration of the antibiotic alone. The amino acid derivative and antibiotic may be formulated together as a composition or administered separately, either simultaneously or sequentially. The composition may be prepared by simple mixing.
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- Substituted tetrapeptides
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Tetrapeptides of the formula I, STR1 in which R 1 represents hydrogen or acyl, R 2 represents alkyl or aralkyl, R 3 represents free or functionally modified hydroxy, R 4 represents free or substituted amino or free or etherified hydroxy, and -Pro-, -Phe- and -His- respectively represent the bivalent radicals of the amino acids proline, phenylalanine and histidine or the (D)-isomers thereof, salts of such compounds having salt-forming groups, and processes for their manufacture.The compounds inhibit the action of the enzyme renin and can be used as antihypertensives and for the treatment of cardiac insufficiency.
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- MECHANISM OF HYDROLYSIS OF p-NITROPHENYL ESTERS OF N-BENZYLOXYCARBONYLAMINO ACIDS CATALYZED BY IMIDAZOLE
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The kinetics of the imidazole hydrolysis of the p-nitrophenyl esters of some N-benzyloxycarbonylamino acids (glycine, phenylalanine, β-alanine), acetic acid, and chloroacetic acid in ethanol-water solutions at 25 deg C were studied.For all the above-menti
- Alebyan, G.P.,Topuzyan, V.O.,Mndzhoyan, O.L.
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p. 1712 - 1715
(2007/10/02)
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- STUDIES ON LACTAMS IX. A CONVENIENT SYNTHESIS OF LACTAM RINGS
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The auto-cyclization reaction has been employed for the synthesis of lactam rings by means of reduction from ω-carbobenzoxyamino acid active esters in high dilution method.
- Ogura, Haruo,Takeda, Kazuyoshi
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p. 467 - 468
(2007/10/02)
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