- Specificity of transglutaminase-catalyzed peptide synthesis
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Biocatalytic methods for peptide synthesis are of high value due to the rapidly increasing approval of peptide-based therapeutics and the need to develop new analogs. Guinea pig liver transglutaminase (gTG2) catalyzes the cross-linking of peptides and proteins via the formation of γ-glutamyl-ε-lysyl isopeptide bonds. In this study, we investigate gTG2-catalyzed peptide bond formation between various amino acid-derived donor and acceptor substrates. Using LC-MS analysis, we demonstrate that gTG2 forms Gly-Xaa and d-Ala-Gly dipeptide products, confirming that its natural transamidation activity can be co-opted for peptide synthesis. An aromatic ester of Gly was the most efficient acyl-donor substrate tested; aromatic esters of d-Ala and l-Ala showed 50-fold lower reactivity or no reactivity, respectively. A computational strategy combining computational protein design algorithms and molecular dynamics simulations was developed to model the binding modes of donor substrates in the gTG2 active site. We show that the inability of gTG2 to efficiently catalyze peptide synthesis from donors containing alanine results from the narrow substrate binding tunnel, which prevents bulkier donors from adopting a catalytically productive binding mode. Our observations pave the way to future protein engineering efforts to expand the substrate scope of gTG2 in peptide synthesis, which may lead to useful biocatalysts for the synthesis of desirable bioactive molecules.
- St-Jacques, Antony D.,Rachel, Natalie M.,Curry, Dan R.,Gillet, Steve M.F.G.,Clouthier, Christopher M.,Keillor, Jeffrey W.,Pelletier, Joelle N.,Chica, Roberto A.
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- UREA DERIVATIVES AS PYRUVATE KINASE ACTIVATORS
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The subject matter described herein is directed to pyruvate kinase activating compounds of Formula I and pharmaceutical salts thereof, methods of preparing the compounds, pharmaceutical compositions comprising the compounds and methods of administering the compounds for the treatment of diseases associated with PKR and/or PKM2, such as pyruvate kinase deficiency, sickle cell disease, and beta-thalassemia.
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Paragraph 505-507
(2022/02/15)
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- N-Alkenylation of hydroxamic acid derivatives with ethynyl benziodoxolone to synthesizecis-enamides through vinyl benziodoxolones
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The stereoselective synthesis ofcis-β-N-alkoxyamidevinyl benziodoxolones (cis-β-N-RO-amide-VBXs) fromO-alkyl hydroxamic acids in the presence of an ethynyl benziodoxolone-acetonitrile complex (EBX-MeCN) is reported herein. The reaction was performed under mild conditions including an aqueous solvent, a mild base, and room temperature. The reaction tolerated variousO-alkyl hydroxamic acids derived from carboxylic acids, such as amino acids, pharmaceuticals, and natural products. Vinyl dideuteratedcis-β-N-MeO-amide-VBXs were also synthesized using deuterium oxide as the deuterium source. Valine-derivedcis-β-N-MeO-amide-VBX was stereospecifically derivatized to hydroxamic acid-derivedcis-enamides without the loss of stereoselectivity or reduction in the deuterium/hydrogen ratio.
- Shimbo, Daisuke,Maruyama, Toshifumi,Tada, Norihiro,Itoh, Akichika
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supporting information
p. 2442 - 2447
(2021/04/02)
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- SN38-containing antibody-drug conjugate
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The invention discloses an SN38-containing antibody-drug conjugate. A series of SN-38-containing ADC molecules are designed on the basis of comprehensive understanding of ADC drugs, and it is shown through experiments that the designed ADC molecules have good antitumor activity.
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Paragraph 0119-0121
(2020/10/04)
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- Hydration of nitriles to amides by a chitin-supported ruthenium catalyst
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Chitin-supported ruthenium (Ru/chitin) promotes the hydration of nitriles to carboxamides under aqueous conditions. The nitrile hydration can be performed on a gram-scale and is compatible with the presence of various functional groups including olefins, aldehydes, carboxylic esters and nitro and benzyloxycarbonyl groups. The Ru/chitin catalyst is easily prepared from commercially available chitin, ruthenium(III) chloride and sodium borohydride. Analysis of Ru/chitin by high-resolution transmission electron microscopy indicates the presence of ruthenium nanoparticles on the chitin support.
- Matsuoka, Aki,Isogawa, Takahiro,Morioka, Yuna,Knappett, Benjamin R.,Wheatley, Andrew E. H.,Saito, Susumu,Naka, Hiroshi
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p. 12152 - 12160
(2015/02/19)
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- Polythiazole linkers as functional rigid connectors: A new RGD cyclopeptide with enhanced integrin selectivity
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Polythiazole amino acids clasp linear peptides to generate cyclic derivatives, however, the resulting species are not merely stapled peptides but bear a complex heterocyclic moiety displaying its intrinsic set of interactions. As a proof of concept, a bisthiazole moiety has been grafted onto an RGD sequence to deliver a new cilengitide analogue with improved integrin selectivity and remarkable in vivo antiangiogenic activity.
- Ruiz-Rodriguez,Miguel,Preciado,Acosta,Adan,Bidon-Chanal,Luque,Mitjans,Lavilla,Albericio
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p. 3929 - 3935
(2014/11/27)
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- One-pot synthesis of orthogonally protected dipeptide selenazoles employing Nα-amino selenocarboxamides and α-bromomethyl ketones
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A simple and efficient protocol for the synthesis of selenazole containing dipeptidomimetics using Nα-amino selenocarboxamides and α-bromomethyl ketones is described. All the compounds made were isolated in good yields and fully characterized.
- Madhu, Chilakapati,Panguluri, Nageswara Rao,Narendra,Panduranga,Sureshbabu, Vommina V.
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p. 6831 - 6835
(2015/01/09)
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- Synthesis of gem-diamino acid derivatives by a Hofmann rearrangement
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Starting from commercially available N-protected l-α-amino acids, N,N′-protected gem-diaminic units were obtained by a two-step methodology. A Hofmann reaction performed using a primary alcohol as the solvent to trap the isocyanate intermediate represents the key step of the new synthetic procedure. Then, the methodology was applied to α-carbamoyl α′-carboxyl aziridines, also functionalized with l-α-amino esters and stable gem-diaminic units characterized by an aziridine ring and by a retro-peptide modification were obtained. The use of the latter units in the retro-peptide chemistry allows to obtain modified peptides containing an aziridine ring able to behave as an electrophilic site and as a biomimetic structural analog of proline.
- Aresu, Emanuele,Fioravanti, Stefania,Gasbarri, Simona,Pellacani, Lucio,Ramadori, Federico
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p. 977 - 982
(2013/07/05)
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- Core refinement toward permeable β-secretase (BACE-1) inhibitors with low hERG activity
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By use of iterative design aided by predictive models for target affinity, brain permeability, and hERG activity, novel and diverse compounds based on cyclic amidine and guanidine cores were synthesized with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease. Since synthesis feasibility had low priority in the design of the cores, an extensive synthesis effort was needed to make the relevant compounds. Syntheses of these compounds are reported, together with physicochemical properties and structure-activity relationships based on in vitro data. Four crystal structures of diverse amidines binding in the active site are deposited and discussed. Inhibitors of BACE-1 with 3 μM to 32 nM potencies in cells are shown, together with data on in vivo brain exposure levels for four compounds. The results presented show the importance of the core structure for the profile of the final compounds.
- Ginman, Tobias,Viklund, Jenny,Malmstr?m, Jonas,Blid, Jan,Emond, Rikard,Forsblom, Rickard,Johansson, Anh,Kers, Annika,Lake, Fredrik,Sehgelmeble, Fernando,Sterky, Karin J.,Bergh, Margareta,Lindgren, Anders,Johansson, Patrik,Jeppsson, Fredrik,F?lting, Johanna,Gravenfors, Ylva,Rahm, Fredrik
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p. 4181 - 4205
(2013/07/19)
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- Enzymatic C-terminal amidation of amino acids and peptides
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Herein, we describe two versatile and high yielding enzymatic approaches for the conversion of semi-protected amino acid and peptidyl C-terminal α-carboxylic acids into their corresponding amides. In the first approach, the lipase Candida antarctica lipase-B (Cal-B), and in the second approach, the protease Subtilisin A, are used, respectively. We found that by using the ammonium salt of the α-carboxylic acid instead of separate ammonia sources, the enzymatic amidation reactions proceeded much faster without side reactions and gave near to quantitative yields of products.
- Nuijens, Timo,Piva, Elena,Kruijtzer, John A.W.,Rijkers, Dirk T.S.,Liskamp, Rob M.J.,Quaedflieg, Peter J.L.M.
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experimental part
p. 3777 - 3779
(2012/09/22)
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- Parallel synthesis of an oligomeric imidazole-4, 5-dicarboxamide library
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A library of oligomeric compounds was synthesized based on the imidazole-4, 5-dicarboxylic acid scaffold along with amino acid esters and chiral diamines derived from amino acids. The final compounds incorporate nonpolar amino acids (Leu, Phe, Trp), polar amino acids (Ser, Asp, Arg), and neutral amino acids (Gly, Ala), and were designed to be useful in screening for inhibitors of protein-protein interactions. Many of the protected and deprotected oligomers show evidence of conformational isomers persistent at room temperature in aqueous solution. A total of 317 final oligomers, out of 441 targeted compounds, were obtained in high analytical purity and of sufficient quantity to submit them for high-throughput screening as part of the NIH Roadmap.
- Xu, Zhigang,DiCesare, John C.,Baures, Paul W.
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supporting information; experimental part
p. 248 - 254
(2010/08/19)
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- Direct synthesis of phosphinopeptides containing C-terminal α-aminoalkylphosphinic acids
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A series of phosphinopeptides containing C-terminal α- aminoalkylphosphinic acids were prepared in good yields directly in one-pot reactions of 2-(N-benzoxycarbonylamino)alkanamides/peptide amides, aldehydes, and aryldichlorophosphines, followed by hydrolysis. In the current method, the peptide bond was formed in a Mannichtype reaction. Springer-Verlag 2010.
- Meng, Fanhua,Xu, Jiaxi
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experimental part
p. 533 - 538
(2010/11/04)
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- Heterocyclic Compounds Useful as RAF Kinase Inhibitors
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The present invention provides compounds useful as inhibitors of Raf protein kinase. The present invention also provides compositions thereof, and methods of treating Raf-mediated diseases.
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Page/Page column 32
(2009/01/24)
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- COMPOUNDS USEFUL AS RAF KINASE INHIBITORS
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The present invention provides compounds useful as inhibitors of Raf protein kinase. The present invention also provides compositions thereof, and methods of treating Raf-mediated diseases.
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Page/Page column 77
(2009/03/07)
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- Dihydroxypyrimidine-4-carboxamides as novel potent and selective HIV integrase inhibitors
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Human immunodeficiency virus type-1 (HIV-1) integrase, one of the three constitutive viral enzymes required for replication, is a rational target for chemotherapeutic intervention in the treatment of AIDS that has also recently been confirmed in the clinical setting. We report here on the design and synthesis of N-benzyl-5,6-dihydroxypyrimidine-4-carboxamides as a class of agents which exhibits potent inhibition of the HIV-integrase-catalyzed strand transfer process. In the current study, structural modifications on these molecules were made in order to examine effects on HIV-integrase inhibitory potencies. One of the most interesting compounds for this series is 2-[1-(dimethylamino)-1-methylethyl]-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine- 4-carboxamide 38, with a CIC95 of 78 nM in the cell-based assay in the presence of serum proteins. The compound has favorable pharmacokinetic properties in preclinical species (rats, dogs, and monkeys) and shows no liabilities in several counterscreening assays, highlighting its potential as a clinically useful antiviral agent.
- Pace, Paola,Di Francesco, M. Emilia,Gardelli, Cristina,Harper, Steven,Muraglia, Ester,Nizi, Emanuela,Orvieto, Federica,Petrocchi, Alessia,Poma, Marco,Rowley, Michael,Scarpelli, Rita,Laufer, Ralph,Paz, Odalys Gonzalez,Monteagudo, Edith,Bonelli, Fabio,Hazuda, Daria,Stillmock, Kara A.,Summa, Vincenzo
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p. 2225 - 2239
(2007/10/03)
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- 4,5-Dihydroxypyrimidine carboxamides and N-alkyl-5-hydroxypyrimidinone carboxamides are potent, selective HIV integrase inhibitors with good pharmacokinetic profiles in preclinical species
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The dihydroxypyrimidine carboxamide 4a was discovered as a potent and selective HIV integrase strand transfer inhibitor. The optimization of physicochemical properties, pharmacokinetic profiles, and potency led to the identification of 13 in the dihydroxypyrimidine series and 18 in the N-methylpyrimidinone series having low nanomolar activity in the cellular HIV spread assay in the presence of 50% normal human serum and very good pharmacokinetics in preclinical species.
- Summa, Vincenzo,Petrocchi, Alessia,Matassa, Victor G.,Gardelli, Cristina,Muraglia, Ester,Rowley, Michael,Paz, Odalys Gonzalez,Laufer, Ralph,Monteagudo, Edith,Pace, Paola
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p. 6646 - 6649
(2007/10/03)
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- Synthesis of functionalised oxazoles and bis-oxazoles
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A new method for the synthesis of oxazoles, and in particular chiral non-racemic oxazoles derived from amino acids, has been developed. Thus, rhodium(II) catalysed reaction of diazocarbonyl compounds 6 and 11 in the presence of amides 8 and 10 results in regioselective insertion of the carbenoid into the amide N-H bond with formation of the β-carbonyl amides 9 and 12. Cyclodehydration of amides 9 and 12 using triphenylphosphine-iodine-triethylamine gives functionalised oxazoles 7 and 13. The oxazoles 13c and 13f were converted into the bis-oxazoles 17a and 17b by a second rhodium(II) catalysed regioselective N-H insertion reaction on the amides 15, followed by cyclodehydration.
- Bagley, Mark C.,Buck, Richard T.,Hind, S. Lucy,Moody, Christopher J.
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p. 591 - 600
(2007/10/03)
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- Synthesis and characterization of β-O-Tosyldehydroserine as a precursor of dehydroamino acids
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β-O-Tosyldehydroserine 3 is prepared directly by the oxidation of the corresponding serine derivative 1 with dimethyl sulfoxide which is activated by p-toluenesulfonyl chloride. The enol tosylate 3 retains reactivities characteristic of aldehydes like those expected for the corresponding dehydroserine derivative 2. A typical reaction of 3 includes substitution of the tosyl group with nucleophiles such as primary and secondary amines, leading to other dehydroamino acids.
- Nakazawa, Takashi,Suzuki, Tomiko,Ishii, Masako
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p. 8951 - 8954
(2007/10/03)
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- Total synthesis of nosiheptide. Synthesis of thiazole fragments
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The preparation of three new thiazole derivatives from natural products is described, as well as improvements in the synthesis of ethyl 2-aminomethyl-4-thiazolecarboxylate.
- Koerber-Ple,Massiot
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p. 1309 - 1315
(2007/10/03)
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- Inverse Electron Demand Diels-Alder Reactions of Indole IV. A New Route to β-Carbolines
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β-Carbolines have been prepared by the intramolecular cycloaddition of indole with 1,2,4-triazines tethered from C3 with the indolyl nitrogen using a thiourea linkage.Subsequent to the cycloaddition, reductive cleavage of the thiourea subunit provides the β-carboline.
- Fan, Wen-Hong,Parikh, Mamta,Snyder, John K.
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p. 6591 - 6594
(2007/10/02)
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- Activation of carboxylic acids by pyrocarbonates. Application of di-tert-butyl pyrocarbonate as condensing reagent in the synthesis of amides of protected amino acids and peptides
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Amides formation from protected amino acids and peptides was achieved in an easy and convenient one-pot procedure using di-tert-butyl pyrocarbonate as activating agent in the presence of pyridine and ammonium hydrogencarbonate. The method gave good yields and did not induce racemization during the amidation of urethane protected amino acids.
- Pozdnev, Vladimir F.
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p. 7115 - 7118
(2007/10/02)
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- Protein backbone modification by novel C(α)-C side-chain scission
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α-Ketoamide (-NH-CO-CO-) units in intact peptides are generated from Ser/Thr residues via Ru(VIII)-catalyzed C(α)-C side-chain scission. Facets associated with this novel α-carbon modification have been probed with 75 peptides chosen to represent every possible peptide environment. The reactions were carried out at room temperature with in situ generated Ru(VIII) in biphasic (CH3CN/CCl4/pH 3 phosphate buffer, 1:1:2 v/v) medium. Whereas Ser/Thr residues placed at the C-terminal end in peptides undergo N-C bond scission leading to des-Ser/Thr peptide amides - thus acting as Gly equivalents in simulating the α-amidating action of pituitary enzymes - those located at the N-terminal or nonterminal or even at the C-terminal position (protected as amide) were found to undergo oxidative C-C bond scission (involving C(α) and C side-chain bond), resulting in the generation of α-ketoamide (-NH-CO-CO-) units in the intact peptide backbone. The difference in the products arising from C(α)-C side-chain scission of Ser/Thr esters and amides is rationalized on the basis of a common mechanism involving either oxaloesters [PeP-NH-CO-COX; X = OMe] or oxalamides [X = NH2 or NH-Pep] arising from the oxidation of initially formed carbinolamide intermediates [Pep-NH-CH(OH)-COX], wherein, while the former are shown to undergo hydrolysis to terminal amides [Pep-NH2], the oxalamides are found to be stable to hydrolysis. Ancillary noteworthy findings are those of peptide bond scission when contiguous Ser-Ser/Thr-Thr residues are present and the oxidative cleavage at C-terminal Tyr/Trp sites generating des amides. The oxidative methodology presented here is mild, simple, and practical and proceeds with chiral retention. The insensitivity of a large number of amino acid residues, such as Gly, Ala, Leu, Asn, Gln, Asp, Glu, Pro, Arg, Phe, Lys, Val, and Aib, and N-protecting groups, such as Boc, Z, and Bz, toward Ru(VIII) under the experimental conditions should make this methodology practical and useful. Sulfur-containing amino acids Cys and Met get oxidized to sulfones in the products.
- Ranganathan,Vaish,Shah
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p. 6545 - 6557
(2007/10/02)
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- Enol esters as intermediates for the facile conversion of amino acids into amides and dipeptides
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N-Protected amino enol esters are easily transformed at room temperature into amino amides, and in the presence of potassium cyanide as catalyst, into tertiary amides and dipeptides.
- Kabouche,Bruneau,Dixneuf
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p. 5359 - 5362
(2007/10/02)
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- A Simple Method for Amide Formation from Protected Amino Acids and Peptides
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Amide formation from protected amino acids and peptides is directly and simply achieved by using 1-hydroxybenzotriazole as activating agent and treating the intermediate O-(benzotriazol-1-yl) derivative ("active ester") in situ with 25percent ammonium hydroxide solution.
- Chen, Shui-Tein,Wu, Shih-Hsiung,Wang, Kung-Tsung
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- Synthese et reactions de N-acylphosphoramides apparentes aux ceto-4 diaza-1,3 phospholanes-2
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A new, general method, more efficient than previous ones, for the synthesis of N-acylphosphoramides 3, by reacting the silylated primary phosphoramides 2 with carboxylic chlorides is described (Figure 2).It is applied to the synthesis of precursors B and C and acyclic analogs D and E of the 4-keto 1,3-diaza, 2-phospholanes A (Figure 1). 3c (B) and 3a (C) lead to 15 (A) (Figure 5) and 17 (Figure 6) (A) in presence of sodium hydride, and hydrogen with palladium on charcoal as catalyst, respectively.Phosphorane 19 is formed from 3a and triphenylphosphine (Figure 6).D and E are not phosphorylating reagents but acylating ones.
- Mulliez, Michel
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p. 1211 - 1218
(2007/10/02)
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- Dichlorotris(dimethylamino)phosphorane as a Dehydratisation Reagent for the Preparation of N-Protected Amino Acid Amides
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Besides for the synthesis of peptides and activated esters dichlorotris(dimethylamino)phosphorane (2) now proved to be an excellent reagent for the preparation of N-protected amino acid amides.
- Appel, Rolf,Hiester, Ernst
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p. 2037 - 2040
(2007/10/02)
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- Studies on 2-Aziridinecarboxylic Acid.III. Reaction of 1-Acyl-2-aziridinecarboxylic Acid Peptide with Amines
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The reaction of Z-Gly-Azy-Gly-OBzl with amines was studied.With primary amines, the 1-acyl group (Z-Gly) of the aziridine peptide mainly migrated to the reactant amine with cleaving of the amide bond between glycine and aziridine, whereas aniline and diethylamine gave diaminopropionic acid derivatives via the ring opening reaction.
- Nakajima, Kiichiro,Tanaka, Takumi,Morita, Kaoru,Okawa, Kenji
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p. 283 - 284
(2007/10/02)
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