- Direct Hydroxylation of Benzene to Phenol by Cytochrome P450BM3 Triggered by Amino Acid Derivatives
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The selective hydroxylation of benzene to phenol, without the formation of side products resulting from overoxidation, is catalyzed by cytochrome P450BM3 with the assistance of amino acid derivatives as decoy molecules. The catalytic turnover rate and the total turnover number reached 259 min?1 P450BM3?1 and 40 200 P450BM3?1 when N-heptyl-l-proline modified with l-phenylalanine (C7-l-Pro-l-Phe) was used as the decoy molecule. This work shows that amino acid derivatives with a totally different structure from fatty acids can be used as decoy molecules for aromatic hydroxylation by wild-type P450BM3. This method for non-native substrate hydroxylation by wild-type P450BM3 has the potential to expand the utility of P450BM3 for biotransformations.
- Shoji, Osami,Yanagisawa, Sota,Stanfield, Joshua Kyle,Suzuki, Kazuto,Cong, Zhiqi,Sugimoto, Hiroshi,Shiro, Yoshitsugu,Watanabe, Yoshihito
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supporting information
p. 10324 - 10329
(2017/08/22)
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- Convenient green preparation of dipeptides using unprotected α-amino acids
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Dipeptides and amides were obtained in high yields from N-carbobenzyloxy α-amino acids and 3-phenylpropanoic acid with unprotected α-amino acids via the corresponding mixed carbonic carboxylic anhydrides using ethyl chloroformate and triethylamine by an ecological and convenient method in which the protection of C-terminals is not needed.
- Ezawa, Tetsuya,Jung, Seunghee,Kawashima, Yuya,Noguchi, Takuya,Imai, Nobuyuki
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- One-step C-terminal deprotection and activation of peptides with peptide amidase from stenotrophomonas maltophilia in neat organic solvent
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Chemoenzymatic peptide synthesis is a rapidly developing technology for cost effective peptide production on a large scale. As an alternative to the traditional C→N strategy, which employs expensive N-protected building blocks in each step, we have investigated an N→C extension route that is based on activation of a peptide C-terminal amide protecting group to the corresponding methyl ester. We found that this conversion is efficiently catalysed by Stenotrophomonas maltophilia peptide amidase in neat organic media. The system excludes the possibility of internal peptide cleavage as the enzyme lacks intrinsic protease activity. The produced peptide methyl ester was used for peptide chain extension in a kinetically controlled reaction by a thermostable protease.
- Arif, Muhammad I.,Toplak, Ana,Szymanski, Wiktor,Feringa, Ben L.,Nuijens, Timo,Quaedflieg, Peter J. L. M.,Wu, Bian,Janssen, Dick B.
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p. 2197 - 2202
(2014/07/21)
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- Kinetically controlled peptide synthesis mediated by papain using the carbamoylmethyl ester as an acyl donor
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A series of dipeptides were synthesized generally in good yields with carbamoylmethyl (Cam) esters as acyl donors in the presence of a cysteine protease, papain, immobilized on Celite. Several segment condensations were also achieved generally in high yields without danger of racemization and formation of the secondary-hydrolysis product. Moreover, partial sequences of some bioactive peptides were prepared through segment condensations, and aimed-at peptides were obtained generally in high yields without the racemization of C-terminal residues of the carboxyl components. Thus, the superiority of the Cam ester in the kinetically controlled peptide synthesis was once again ascertained in couplings mediated by the cysteine protease as in those catalyzed by the serine proteases reported earlier.
- Miyazawa, Toshifumi,Horimoto, Takao,Tanaka, Kayoko
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p. 371 - 376
(2014/08/18)
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- Synthesis and antimalarial bioassay of quinine - peptide conjugates
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Amino acid and peptide conjugates of quinine were synthesized using microwave irradiation in 52-95% yields using benzotriazole methodology. The majority of these conjugates retain in vitro antimalarial activity with IC50 values below 100 nm, similar to quinine.
- Panda, Siva S.,Ibrahim, Mohamed A.,Kuecuekbay, Hasan,Meyers, Marvin J.,Sverdrup, Francis M.,El-Feky, Said A.,Katritzky, Alan R.
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p. 361 - 366
(2013/10/08)
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- Enzyme-Specific Activation versus Leaving Group Ability
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Enzyme-specific activation and the substrate mimetics strategy are effective ways to circumvent the limited substrate recognition often encountered in protease-catalyzed peptide synthesis. A key structural element in both approaches is the guanidinophenyl (OGp) ester, which enables important interactions for affinity and recognition by the enzyme-at least, this is usually the explanation given for its successful application. In this study we show that leaving group ability is of equal or even greater importance. To this end we used both experimental and computational methods: 1) synthesis of close analogues of OGp, and their evaluation in a dipeptide synthesis assay with trypsin, 2) molecular docking studies to provide insights into the binding mode, and 3) ab initio calculations to evaluate their electronic properties.
- de Beer, Roseri J.A.C.,Boegels, Berry,Schaftenaar, Gijs,Zarzycka, Barbara,Quaedflieg, Peter J.L.M.,van Delft, Floris L.,Nabuurs, Sander B.,Rutjes, Floris P.J.T.
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experimental part
p. 1785 - 1790
(2012/09/22)
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- Enzymatic synthesis of activated esters and their subsequent use in enzyme-based peptide synthesis
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Chemoenzymatic peptide synthesis is potentially the most cost-efficient technology for the synthesis of short and medium-sized peptides. However, there are still some limitations when challenging peptides, e.g. containing sterically demanding acyl donors, non-proteinogenic amino acids or proline residues, are to be synthesized. To remedy these limitations, special ester moieties have been used that are specifically recognized by the enzyme, e.g. guanidinophenyl, carboxamidomethyl (Cam) or trifluoroethyl (Tfe) esters, which, unfortunately, are notoriously difficult to synthesize chemically. Herein, we demonstrate that Cam and Tfe esters are very useful for Alcalase-CLEA mediated peptide synthesis using sterically demanding and non-proteinogenic acyl donors as well as poor nucleophiles, and combinations thereof. Furthermore, these esters can be efficiently synthesized by using the lipase Cal-B or Alcalase-CLEA. Finally, it is shown that the ester synthesis by Cal-B and subsequent peptide synthesis by Alcalase-CLEA can be performed simultaneously using a two-enzyme-one-pot approach with glycolamide or 2,2,2-trifluoroethanol as additive.
- Nuijens, Timo,Cusan, Claudia,Schepers, Annette C.H.M.,Kruijtzer, John A.W.,Rijkers, Dirk T.S.,Liskamp, Rob M.J.,Quaedflieg, Peter J.L.M.
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- Condensation between isocyanates and carboxylic acids in the presence of 4-dimethylaminopyridine (DMAP), a mild and efficient synthesis of amides
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A mild and convenient method for the preparation of amides from carboxylic acids and isocyanates is described. By using DMAP as a catalyst milder reaction conditions are realised which also allow the conversion of α-chiral isocyanates, as well as α-chiral carboxylic acids without racemisation.
- Schuemacher,Hoffmann
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p. 243 - 246
(2007/10/03)
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- Inhibitors of tripeptidyl peptidase II. 2. Generation of the first novel lead inhibitor of cholecystokinin-8-inactivating peptidase: A strategy for the design of peptidase inhibitors
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The cholecystokinin-8 (CCK-8)-inactivating peptidase is a serine peptidase which has been shown to be a membrane-bound isoform of tripeptidyl peptidase II (EC 3.4.14.10). It cleaves the neurotransmitter CCK-8 sulfate at the Met-Gly bond to give Asp-Tyr(SO3H)-Met-OH + Gly-Trp-Met-Asp-Phe-NH2. In seeking a reversible inhibitor of this peptidase, the enzymatic binding subsites were characterized using a fluorimetric assay based on the hydrolysis of the artificial substrate Ala-Ala-Phe-amidomethylcoumarin. A series of di- and tripeptides having various alkyl or aryl side chains was studied to determine the accessible volume for binding and to probe the potential for hydrophobic interactions. From this initial study the tripeptides Ile-Pro-Ile-OH (K(i) = 1 μM) and Ala-Pro-Ala-OH (K(i) = 3 μM) and dipeptide amide Val-Nvl-NHBu (K(i) = 3 μM) emerged as leads. Comparison of these structures led to the synthesis of Val-Pro-NHBu (K(i) = 0.57 μM) which served for later optimization in the design of butabindide, a potent reversible competitive and selective inhibitor of the CCK-8-inactivating peptidase. The strategy for this work is explicitly described since it illustrates a possible general approach for peptidase inhibitor design.
- Ganellin, C. Robin,Bishop, Paul B.,Bambal, Ramesh B.,Chan, Suzanne M. T.,Law, James K.,Marabout, Benoit,Luthra, Pratibha Mehta,Moore, Andrew N. J.,Peschard, Olivier,Bourgeat, Pierre,Rose, Christiane,Vargas, Froylan,Schwartz, Jean-Charles
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p. 664 - 674
(2007/10/03)
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- Superiority of the carbamoylmethyl ester as an acyl donor for the protease-catalyzed kinetically controlled peptide synthesis in organic media: Application to segment condensations
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The superiority of the carbamoylmethyl ester as an acyl donor for the α-chymotrypsin-catalyzed kinetically controlled peptide synthesis was demonstrated in several segment condensations carried out in organic media with low water content. Then this approach was successfully applied to the construction of the Leuenkephalin sequence via the 4 + 1 segment condensation.
- Miyazawa, Toshifumi,Ensatsu, Eiichi,Tanaka, Kayoko,Yanagihara, Ryoji,Yamada, Takashi
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p. 1013 - 1014
(2007/10/03)
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- An Effective Water-Free Aprotic System for Dissolving Free Amino Acids
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An effective water-free system was proposed for dissolution and subsequent use in peptide synthesis of free amino acids and their derivatives. It consists of dimethylformamide, a tertiary base, and inorganic additives. Neutral salts (CF3COONa, Ba(ClO4)2, Ca(ClO4)2, NaClO4, BaI2, or Ca(NO3)2) serve as the inorganic additives that increase the solubility of free amino acids in dimethylformamide and provide true 0.2-3 M amino acid solutions. Triethylamine and N-methylmorpholine are most suitable as the tertiary bases. This system was used in reactions with acylating agents: Boc2O, ZOSu, FmocOSu, and activated derivatives of Nα-protected amino acids or peptides. The corresponding amino acid derivatives or Nα-protected di-, tri-, and tetrapeptides were obtained in yields of 80-99 percent at the reaction times of 30-240 min.
- Raydnov, M. G.,Klimenko, L. V.,Mitin, Yu. V.
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p. 283 - 287
(2007/10/03)
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- Cross-linked crystals of subtilisin: Versatile catalyst for organic synthesis
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Cross-linked enzyme crystals (CLECs) of subtilisin exhibit excellent activity in aqueous and various organic solvents. This catalyst is more stable than the native enzyme in both aqueous and mixed aqueous/organic solutions. Subtilisin-CLEC was shown to be a versatile catalyst. It was used for the syntheses of peptides and peptidomimetics, mild hydrolysis of amino acid and peptide amides, enantio- and regioselective reactions, and transesterifications.
- Wang, Yi-Fong,Yakovlevsky, Kirill,Zhang, Bailing,Margolin, Alexey L.
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p. 3488 - 3495
(2007/10/03)
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- A new water-compatible dehydrating agent DPTF
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The dehydration of a carboxylic acid and an amine to form an amide linkage was performed by the use of a new water-compatible dehydrating agent, 2,2-dichloro-5-(2-phenylethyl)-4-(trimethylsilyl)-3-furanone (DPTF). The application of this new agent to the peptide bond formation is also described.
- Murakami, Masahiro,Hayashi, Minoru,Tamura, Noriyasu,Hoshino, Yujiro,Ito, Yoshihiko
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p. 7541 - 7544
(2007/10/03)
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- Protecting group for carboxyl function: Mild and facile cleavage of 2- cyanoethyl ester under non-hydrolytic conditions
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The use of the 2-cyanoethyl group for carboxyl-protection is described. This group was readily introduced by esterification using ethylene cyanohydrin and the deprotection was carried out under mild conditions using tetrabutylammonium fluoride in dimethylformamide-tetrahydrofuran.
- Kita,Maeda,Takahashi,Fukui,Ogawa,Hatayama
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p. 147 - 150
(2007/10/02)
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- A One-Pot Peptide Synthesis via Se-phenyl Carboselenoate in Mixed Aqueous/Organic Solvent System
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A one pot synthesis of peptides with free C-terminal residues has been accomplished via the active Se-phenyl carboselenoate using diphenyl diselenide, tributylphosphine, and N-methylmorpholine N-oxide in an acetonitrile- water mixed solvent system.Free amino acids and peptides have been used as the amine component without pH adjustment.
- Ghosh, Sunil Kumar,Singh, Usha,Chandha, Mohindra S.,Mamdapur, Vasant R.
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p. 1566 - 1568
(2007/10/02)
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- PROTECTION DES ACIDES PAR LES GROUPEMENTS ABz. UTILISATION EN SYNTHESE PEPTIDIQUE
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The novel azidomethoxybenzyl esters (ABz esters) of various acids are easily obtained and are cleanly cleaved in very mild reductive conditions.Such esters serve to protect the carboxyl group in peptide synthesis without any racemisation.
- Loubinoux, Bernard,Gerardin, Philippe
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p. 239 - 248
(2007/10/02)
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- USE OF 4-CHLOROBUTYL ESTERS IN PEPTIDE SYNTHESIS
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Ho and Wong synthesised 4-chlorobutyl esters of simple carboxylic acids and removed the ester group by the action of sodium sulfide under reflux conditions.We describe here the synthesis of the 4-chlorobutyl esters of glycine and L-phenylalanine and its use in the synthesis of six new N-protected dipeptides 4-chlorobutyl esters (XHNCH2CO-HNCHRCO2(CH2)4Cl; R = H, CH2Ph; X = Z, Boc, Trt).The selective removal of the 4-chlorobutyl group can be achieved by the action of the sulfide anion in aqueous acetonitrile (room temperature, 1.5 to 5 h).The conditions are milder than those described, but similar to the conditions used with the dipeptides 2-bromoethyl esters.The N-protected dipeptides were isolated in 50 to 80percent yield.
- Trigo, M. Joaquina S. A. Amaral,Santos, M. Isabel A. Oliveira
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p. 2357 - 2359
(2007/10/02)
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- NOUVELLE METHODE DE PROTECTION DU CARBOXYLE DES ACIDES a-AMINES: ESTERS 9-FLUORENYLIQUES
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The novel 9-fluorenyl esters of various L-a-aminoacids (N-protected or N-free) are easily obtained by the action of 9-diazofluorene on the aminoacid in the appropriate organic solvent.Such esters are cleanly cleaved by mild acidolysis or hydrogenolysis and can serve as amino-components in peptide synthesis.
- Proussios, Cleanthis,Kolovos, Miltiadis
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p. 3413 - 3414
(2007/10/02)
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- Amino alcohols as C-Terminal Protecting Groups in Peptide Synthesis
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The synthesis of peptides using amino alcohols as C-terminal protecting groups is described.C-Terminal protection of amino acid could be accomplished by reduction of the terminal carboxyl group to a hydroxymethyl group, and regeneration of the carboxyl group could be achieved by Jones' oxidation.This method was applied to the formation of di- and tripeptides.
- Kashima, Choji,Harada, Kazuo,Fujioka, Yoko,Maruyama, Tatsuya,Omote, Yoshimori
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p. 535 - 540
(2007/10/02)
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- NEW APPROACH TO THE USE OF 2-BROMOETHYL ESTERS IN PEPTIDE SYNTHESIS
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The synthesis of six fully protected dipeptides 2-bromoethyl esters and a new method for the removal of the C-protection by the action of the sulphide anion, at room temperature, are described.
- Amaral Trigo, M. Joaquina S. A.,Oliveira Santos, M. Isabel A.
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p. 2787 - 2790
(2007/10/02)
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- An Improvment of the Anderson Test by the Use of High Performance Liquid Chromatography
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The replacement of the N-benzyloxycarbonyl (Z) group in the Anderson peptide (Z-Gly-L/D-Phe-Gly-OEt) by Z-L-Ala and the subsequent separation of the diastereomers of the resulting tetrapeptide by reversed-phase HPLC offer a more convenient version with higher accuracy to the original Anderson test for studying racemization in peptide synthesis.
- Miyazawa, Toshifumi,Yamada, Takashi,Kuwata, Shigeru
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p. 606 - 608
(2007/10/02)
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- SYNTHESIS OF MESOIONIC TRIAZOLOPYRIDINE. III. APPLICATIONS OF N-ACYL MESOIONIC TRIAZOLOPYRIDINES AS ACYLATING REAGENTS.
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Utility of N-acyl mesoionic triazolopyridines as acylating reagents was investigated concerning with peptide synthesis. Several dipeptides and N-alkoxycarbonyl amino acids were prepared by use of these reagents.
- Saito,Shimizu
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p. 2974 - 2980
(2007/10/02)
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- Glycopeptide Synthesis: Selective C-terminal Deblocking and Peptide Chain Elongation of Glucosylserine Derivatives
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Benzyloxycarbonyl-(Z-)serine 2-bromoethyl ester (3b) reacts with 2,3,4,6-tetra-O-benzoyl-α-D-glucopyranosyl bromide (14) to give the glucosylserine ester 15.After conversion into the corresponding 2-iodoethyl ester 23 the carboxylic group is deblocked selectively by reductive elimination using zinc.In this procedure the Z and the carbohydrate protective functions as well as the sensitive O-glycoside bond remain unaffected.The glycosylserine 24 is condensed with amino acid 2-bromoethyl esters 2 to form protected glycodipeptide 2-bromoethyl esters 18 which are extended to give glycotripeptide esters 25 after selective carboxyl deblocking.Whereas protected serine dipeptides 5 are glycosylated with 14 to form the conjugates 18, the glycosylation of the serine tripeptides 10 was not successful.
- Buchholz, Michael,Kunz, Horst
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p. 1859 - 1885
(2007/10/02)
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- THE OXAZOLE-TRIAMIDE REARRANGEMENT. APPLICATION TO PEPTIDE SYNTHESIS
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The carboxyl group of a N-acylated amino acid may be protected by conversion to an oxazole derivative which, on photooxygenation, regenerates the carboxyl group in activated (triamide) form for peptide synthesis.
- Wasserman, H. H.,Lu, T.-J.
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p. 3831 - 3834
(2007/10/02)
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- 3-AMINOACYL-TETRAHYDROTHIAZOLE-2-THIONE AS AN ACTIVE AMIDE FOR PEPTIDE SYNTHESIS (I)
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3-Aminoacyl-tetrahydrothiazole-2-thione can be used as an active amide for peptide synthesis.A series of peptides have been synthesized with satisfactory yields by this methods.
- Chung-hsi, Li,Yuen-hwa, Yieh,Yao, Lin,Yong-jun, Lu,Ai-hsueh, Chi,Chi-yi, Hsing
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p. 3467 - 3470
(2007/10/02)
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- Preparation of dehydropeptides
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A preparation of azlactones represented by the formula STR1 wherein R is a substituted or unsubstituted alkyl, aryl or nitrogen containing heterocyclic group, and R1 is an N-blocked amino acid residue or peptide chain, and stereoisomers thereof, by oxidizing the corresponding saturated azlactone with a benzoquinone oxidizing agent in the presence of a base is disclosed. The unsaturated azlactones, some of which are novel, can be converted to dehydro peptides, which are useful as intermediates for preparing novel biologically active compounds, or themselves have biological activity.
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- 5-Nitro-3H-1,2-benzoxathiole SS-Dioxide, a New Reagent for Coupling in Peptide Synthesis
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Peptides are rapidly prepared and isolated by a two-step, one-pot reaction using 5-nitro-3H-1,2-benzoxathiole SS-dioxide (1), a strained sultone, as a condensation agent.
- Wakselman, Michel,Acher, Francine
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p. 632 - 634
(2007/10/02)
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