- Aza-peptidyl michael acceptor and epoxide inhibitors - Potent and selective inhibitors of Schistosoma mansoni and Ixodes ricinus legumains (asparaginyl endopeptidases)
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Aza-peptide Michael acceptors and epoxides with the general structure of YCO-Ala-Ala-AAsn-trans-CH=CHCOR and YCO-Ala-Ala-AAsn-EP-COR, respectively, are shown to be potent inhibitors of asparaginyl endopeptidases (legumains) from the bloodfluke, Schistosoma mansoni (SmAE), and the hard tick, Ixodes ricinus (IrAE). Structure-activity relationships (SARs) were determined for a set of 41 aza-peptide Michael acceptors and eight aza-peptide epoxides. Both enzymes prefer disubstituted amides to monosubstituted amides in the P10 position, and potency increased as we increased the hydrophobicity of the inhibitor in this position. Extending the inhibitor to P5 resulted in increased potency, especially against IrAE, and both enzymes prefer small over large hydrophobic residues at P2. Aza-peptide Michael acceptor inhibitors are more potent than aza-peptide epoxide inhibitors, and for some of these compounds, second-order inhibiton rate constants are the fastest yet discovered. Given the central functions of these enzymes in both parasites, the data presented here may facilitate the eventual design of selective antiparasitic drugs.
- Ovat, Asli,Muindi, Fanuel,Fagan, Crystal,Brouner, Michelle,Hansell, Elizabeth,Dvo?ák, Jan,Sojka, Daniel,Kopá?ek, Petr,McKerrow, James H.,Caffrey, Conor R.,Powers, James C.
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experimental part
p. 7192 - 7210
(2010/07/05)
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- Supramolecular bidentate ligands by metal-directed in situ formation of antiparallel β-sheet structures and application in asymmetric catalysis
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The principles of protein structure design, molecular recognition, and supramolecular and combinatorial chemistry have been applied to develop a convergent metal-ion-assisted self-assembly approach that is a very simple and effective method for the de novo design and the construction of topologically predetermined antiparallel β-sheet structures and self-assembled catalysts. A new concept of in situ generation of bidentate P-ligands for transition-metal catalysis, in which two complementary, monodentate, peptide-based ligands are brought together by employing peptide secondary structure motif as constructing tool to direct the self-assembly process, is achieved through formation of stable β-sheet motifs and subsequent control of selectivity. The supramolecular structures were studied by 1H, 31P, and 13C NMR spectroscopy, ESI mass spectrometry, X-ray structure analysis, and theoretical calculations. Our initial catalysis results confirm the close relationship between the self-assembled sheet conformations and the catalytic activity of these metallopeptides in the asymmetric rhodium-catalyzed hydroformylation. Good catalyst activity and moderate enantioselectivity were observed for the selected combination of catalyst and substrate, but most importantly the concept of this new methodology was successfully proven. This work presents a perspective interface between protein design and supramolecular catalysis for the design of β-sheet mimetics and screening of libraries of self-organizing supramolecular catalysts.
- Laungani, Andy C.,Slattery, John M.,Krossing, Ingo,Breit, Bernhard
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experimental part
p. 4488 - 4502
(2009/05/07)
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- The role of protecting groups in the formation of organogels through a nano-fibrillar network formed by self-assembling terminally protected tripeptides
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A series of eight synthetic self-assembling terminally blocked tripeptides have been studied for gelation. Some of them form gels in various aromatic solvents including benzene, toluene, xylene, and chlorobenzene. It has been found that the protecting groups play an important role in the formation of organogels. It has been observed that, if the C-terminal has been changed from methyl ester to ethyl ester the gelation property does not change significantly (keeping the N-terminal protecting group same), while the change of the protecting group from ethyl ester to isopropyl ester completely abolishes the gelation property. Similarly, keeping the identical C-terminal protecting group (methyl ester) the results of the gelation study indicate that the substitution of N-terminal protection Boc- (tert-butyloxycarbonyl) to Cbz- (benzyloxycarbonyl) does change the gelation property insignificantly, while the change from Boc- to pivaloyl (Piv-) or acetyl (Ac-) group completely eliminates the gelation property. Morphological studies of the dried gels of two of the peptides indicate the presence of an entangled nano-fibrillar network that might be responsible for gelation. FTIR studies of the gels demonstrate that an intermolecular hydrogen bonding network is formed during gelation. Results of X-ray powder diffraction studies for these gelator peptides in different states (dried gels, gel, and bulk solids) reflected that the structure in the wet gel is distinctly different from the dried gel and solid state structures. Single crystal X-ray diffraction studies of a non-gelator peptide, which is structurally similar to the gelator molecules reveal that the peptide forms an antiparallel β-sheet structure in crystals.
- Das, Apurba K.,Bose, Partha Pratim,Drew, Michael G.B.,Banerjee, Arindam
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p. 7432 - 7442
(2008/02/05)
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- Method for synthesis of C2-symmetric diamino diol mediated by titanium complexes
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A method for synthesis of C2-symmetric diamino diol mediated by titanium complexes is provided. A substituted-L-phenylalaninal undergoes pinacol coupling to yield the corresponding C2-symmetric (1S,2R,3R,4S)-1,4-diamino 2,3-diol in the presence of Cp2TiCl2/ZnCl2 and zinc metal, mediated in good yield and highly selective. This titanium-catalyzed reaction yields diaminodiol, offering a convenient alternative method to the synthesis of C2-symmetric peptidic protease inhibitors. Consequently, the method allows to synthesize TL-3 via titanium complex in moderate yield.
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Page/Page column 2; 3
(2008/06/13)
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- Structures, sensory activity, and dose/response functions of 2,5-diketopiperazines in roasted cocoa nibs (Theobroma cacao)
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The taste compounds inducing the blood-like, metallic bitter taste sensation reported recently for a dichloromethane extract prepared from roasted cocoa nibs were identified as a series of 25 diketopiperazines by means of HPLC degustation, LC-MS/MS, and i
- Stark, Timo,Hofmann, Thomas
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p. 7222 - 7231
(2007/10/03)
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- Scavenging of fluorinated N,N′-dialkylureas by hydrogen binding: A novel separation method for fluorous synthesis
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(matrix presented) A dramatic solubility increase in fluorous solvents is observed for N,N′-di(polyfluoroalkyl)ureas when hydrogen binding complexes are formed with commercially available perfluoroalkanoic acid scavengers. As a case example, analytically pure peptides and esters are obtained using this novel separation method.
- Palomo, Claudio,Aizpurua, Jesus M.,Loinaz, Iraida,Fernandez-Berridi, Maria Jose,Irusta, Lourdes
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p. 2361 - 2364
(2007/10/03)
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- Tandem deprotection-coupling of N(α)-Alloc-amino acids by use of ternary systems Pd cat./PhSiH3/carboxy-activated amino acid
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N(α)-allyloxycarbonyl derivatives of amino acids undergo smooth coupling with various carboxy-activated partners when treated with phenylsilane (PhSiH3) in the presence of catalytic amounts of tetrakis- (triphenylphosphine) palladium.
- Thieriet, Nathalie,Gomez-Martinez, Paloma,Guibe, Francois
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p. 2505 - 2508
(2007/10/03)
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- A novel kinetically-controlled peptide synthesis - Dramatic increase of chemical yield with retention of chiral integrity
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Peptide synthesis employing the highly selective reaction of isobutyl chloroformate at the carboxyl group of the N-protected amino acid, almost to the exclusion of the amino group of the C-protected amino acid, is described. This one-stage, kinetically-controlled strategy remarkably affords peptides with excellent optical purity in high chemical yields.
- Shieh, Wen-Chung,Carlson, John A.,Shore, Michael E.
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p. 7167 - 7170
(2007/10/03)
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- Carboxylic sulfonic mixed anhydrides: General utility and application to the synthesis of ceftazidime
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A high-yielding acylation process which utilizes a mixed anhydride of the type RCO2SO2CH3 for the synthesis of the cephalosporin ceftazidime is detailed. The mixed anhydride is conveniently prepared by addition of methanesulfonyl chloride to the triethylammonium salt of the acid 2a. Although known for some time, these anhydrides have not been used often in acylations. This lack of general utility is explained by side reactions, especially formation of the carboxylic symmetric anhydride in sterically unhindered systems.
- Wirth
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p. 1535 - 1540
(2007/10/02)
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- Comparative study of selected coupling reagents in dipeptide synthesis
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A comparative study of the effectiveness of selected coupling reagents in dipeptide synthesis was conducted. Included in the study were a new coupling agent, pentafluorophenyl diphenylphosphinate (FDPP, 1), benzotriazol-1-yl-oxytris(dimethylamino)phosphon
- Dudash Jr.,Jiang,Mayer,Joullie
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p. 349 - 356
(2007/10/02)
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- SYNTHESES VIA ANODICALLY PRODUCED PHENOXENIUM IONS. APPLICATIONS IN THE FIELD OF PEPTIDES AND CARBOHYDRATES
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Sterically hindered phenols are anodically oxidized to the corresponding phenoxenium ions which react with O- and N-nucleophiles to give cyclohexadienyl-protected nucleophiles. 4-Acyloxy substituted phenoxenium ions can transfer the acyl group to nucleoph
- Rieker, Anton,Beisswenger, Rudolf,Regier, Klaus
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p. 645 - 654
(2007/10/02)
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- A NEW CONVENIENT APPROACH TO PEPTIDE SYNTHESIS
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A new and highly efficient method based on a redox reaction using diphenyl diselenide and tributylphosphine for the general synthesis of peptides is described.The side reaction due to selenophenol formation is overcome by using chalcone as a scavenger or
- Singh, Usha,Ghosh, Sunil K.,Chadha, Mohindra S.,Mamdapur, Vasant R.
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p. 255 - 258
(2007/10/02)
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- KINETICS OF THE ALKALINE HYDROLYSIS OF SEVERAL N-BENZYLOXYCARBONYLDIPEPTIDE METHYL AND ETHYL ESTERS
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The reaction rates of the alkaline hydrolysis of synthesized N-protected dipeptide methyl and ethyl esters were studied systematically.From the kinetic data the energies of activation, the pre-exponential factors and the reference values at 40 deg C were calculated.The rate of hydrolysis shows to be strongly dependent on the C-terminal amino acid in the sequence Gly >> Ala/Met/Phe > Leu >> Val/Pro.Surprisingly the N-terminal amino acid also exerts an effect, but in a different sequence.N-Terminal Phe in particular shows a relative accelerating effect.Remarkable is the significantly faster ester hydrolysis of glycine containing dipeptide ethyl esters in ethanol/water compared to the corresponding methyl esters in methanol/water.
- Hoogwater, D. A.,Peereboom, M.
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p. 5325 - 5332
(2007/10/02)
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- 1,1'-Carbonylbis(3-methylimidazolium) Triflate: An Efficient Reagent for Aminoacylations
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Amino acid carboxyl activation and subsequent coupling with nucleophiles frequently suffer from uncertain risks of racemization, complex reagent preparation, or troublesome side-product removal.All of these difficulties are eliminated with a new, simple reagent, 1,1'-carbonylbis(3-methylimidazolium) triflate (CBMIT), obtainable readily by bis-alkylation of carbonyldiimidazole with methyl triflate.Via a highly reactive acyl imidazolium intermediate, CBMIT couples amino acid components or amino acids and alcohols to give peptides and esters, easily isolated in high yield.The reaction medium remains free of any base, and no loss of optical activity is observed.
- Saha, Ashis K.,Schultz, Peter,Rapoport, Henry
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p. 4856 - 4859
(2007/10/02)
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- 2(1H)-Pyridone as Leaving Group in Acylation Reactions - Applications in Peptide Synthesis
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Alkyl 2-pyridyl carbonates 3 or mixtures of 3 and the isomeric N-(alkoxycarbonyl)-2-pyridones 3' are useful for the introduction of urethane protective groups into amino acids.The N-protected amino acids 7 - 10 react with 2(1H)-pyridone (1a) using the carbodiimide method to yield 2-pyridyl active esters 11, which easily undergo coupling reactions with amino acid esters 12 with elimination of 1a to give peptides 13 in good yields as well as high optical purities.
- Effenberger, Franz,Brodt, Werner
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p. 468 - 482
(2007/10/02)
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- 3,3'-(Phenylphosphinylidene)bis and 3,3'-(Phenylphosphinylidene)bis. New Activating Agents
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New activating agents, 3,3'-(phenylphophinylidene)bis (4) and 3,3'-(phenylphosphinylidene)bis (5), were readily prepared by the reaction of phenylphosphonic dichloride (3) with 2(3H)-benzoxazolone (1) and 2(3H)-benzothiazolone (2) respectively in the presence of triethylamine at room temperature.The new activating agents 4 and 5 were found to be useful for the preparation of amides, esters, and dipeptides under mild conditions.Furthemore, the direct polycondensation of isophthalic acid with aromatic diamines using the activating agent 4 in the presence of pyridine proceeded fast at room temperature to produce polyamides with inherent viscosities up to 0.80 dL/g.
- Ueda, Mitsuru,Mochizuki, Amane,Hiratsuka, Ichiro,Oikawa, Hideaki
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p. 3291 - 3297
(2007/10/02)
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- 1,2-Benzisoxazol-3-yl Diphenyl Phosphate: A New, Reactive Activating Agent for the Synthesis of Amides, Esters, and Peptides via Condensation
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A new activating agent for condensations, 1,2-benzisoxazol-3-yl diphenyl phosphate (1), was readily prepared in high yield by the reaction of 1,2-benzisoxazol-3-ol (2) with diphenyl phosphorochloridate (3) in the presence of triethylamine in benzene.The reaction of the carboxylic acids with the amines in the presence of 1 was investigated by two procedures, a two-step method and a one-step procedure.Both methods gave the corresponding amides and esters in high yields under mild conditions, but the one-step procedure was found to be superior to the two-step procedure because of its simplicity and speed.Furthermore, the activating agent 1 was shown to be a useful peptide forming reagent.
- Ueda, Mitsuru,Oikawa, Hideaki
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p. 760 - 763
(2007/10/02)
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- RATES OF PEPTIDE FORMATION INVOLVING IMINO ACID RESIDUES
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The determination of the rates for peptide coupling in tetrahydrofuran between Z-Aaa-OPcp (Aaa = Ala, (NMe)Ala, Pro, Thz, Pip and (S)Pip) and H-Bbb-OMe (Bbb = (NMe)Ala, Pro, Thz, Pip and (S)Pip) allowed us to evaluate the relative reactivities between these members, either as active components or as amino components.The reactivity of Pro (either as the active species or the amino component) equals that of (NMe)Ala.The reactivity of Pip and (S)Pip as imino components is low while the activation energy is raised by an amount that roughly equals the energy increment needed for bringing the carboxylate grouping from the equatorial to the axial position The reactivities of these six-membered residues are also appreciably low when being the active components during peptide coupling.The presence of a ring-sulfur atom at γ-position of nitrogen additionally decreases the rate for peptidation, especially if (S)Pip is the imino component.
- Wante, Dirk P. M.,Anteunis, Marc J. O.
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