- Tripeptide analogues of MG132 as protease inhibitors
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The 26S proteasome and calpain are linked to a number of important human diseases. Here, we report a series of analogues of the prototypical tripeptide aldehyde inhibitor MG132 that show a unique combination of high activity and selectivity for calpains over proteasome. Tripeptide aldehydes (1–3) with an aromatic P3 substituent show enhanced activity and selectivity against ovine calpain 2 relative to chymotrypsin-like activity of proteasome. Docking studies reveal the key contacts between inhibitors and calpain to confirm the importance of the S3 pocket with respect to selectivity between calpains 1 and 2 and the proteasome.
- Pehere, Ashok D.,Nguyen, Steven,Garlick, Sarah K.,Wilson, Danny W.,Hudson, Irene,Sykes, Matthew J.,Morton, James D.,Abell, Andrew D.
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p. 436 - 441
(2019/01/04)
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- Design and synthesis of novel hydroxypyridinone derivatives as potential tyrosinase inhibitors
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Two groups of novel hydroxypyridinone derivatives 6(a-e) and 12(a-c), were designed as potential tyrosinase inhibitors, and synthesized using kojic acid as a starting material. The tyrosinase inhibitory activity of these two groups was demonstrated to be potent, especially compounds 6e and 12a, whose IC50 values for monophenolase activity were 1.95 μM and 2.79 μM, respectively. Both of these values are lower than that of kojic acid (IC50 = 12.50 μM). Compounds 6e and 12a were investigated for the inhibitory effect on diphenolase activity. The results showed that the inhibitory mechanism of these two compounds was reversible and that the inhibitory type was a competitive-uncompetitive mixed-type. The values of IC50 of 6e and 12a on the diphenolase activity of tyrosinase were determined to be 8.97 μM and 26.20 μM, respectively. The inhibitory constants (KI and KIS) of 6e were determined as 17.17 μM and 22.09 μM, respectively; and the KI and KIS values of 12a were 34.41 μM and 79.02 μM, respectively. Compound 6e showed a greater ability to reduce copper and a stronger copper chelating ability than kojic acid.
- Zhao, De-Yin,Zhang, Ming-Xia,Dong, Xiao-Wu,Hu, Yong-Zhou,Dai, Xiao-Yan,Wei, Xiaoyi,Hider, Robert C.,Zhang, Jin-Chao,Zhou, Tao
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p. 3103 - 3108
(2016/06/13)
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- α-N-Protected dipeptide acids: A simple and efficient synthesis via the easily accessible mixed anhydride method using free amino acids in DMSO and tetrabutylammonium hydroxide
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The importance of dipeptides both in medicinal and pharmacological fields is well documented and many efforts have been made to find simple and efficient methods for their synthesis. For this reason, we have investigated the synthesis of α-N-protected dipeptide acids by reacting the easily accessible mixed anhydride of α-N-protected amino acids with free amino acids under different reaction conditions. The combination of TBA-OH and DMSO has been found to be the best to overcome the low solubility of amino acids in organic solvents. Under these experimental conditions, the homogeneous phase condensation reaction occurs rapidly and without detectable epimerization. The present method is also applicable to side-chain unprotected Tyr, Trp, Glu, and Asp but not Lys. This latter residue is able to engage two molecules of mixed anhydride giving the corresponding isotripeptide. Moreover, the applicability of this protocol for the synthesis of tri- and tetrapeptides has been tested. This approach reduces the need for protecting groups, is cost effective, scalable, and yields dipeptide acids that can be used as building blocks in the synthesis of larger peptides.
- Verardo,Gorassini
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p. 315 - 324
(2013/06/05)
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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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experimental part
p. 79 - 84
(2012/02/03)
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- Enzymatic synthesis of C-terminal arylamides of amino acids and peptides
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(Chemical Equation Presented) A mild and cost-efficient chemo-enzymatic method for the synthesis of C-terminal arylamides of amino acid and peptides is described. Using the industrial serine protease Alcalase under near-anhydrous conditions, C-terminal arylamides of N-Cbz-protected amino acids and peptides could be obtained from the corresponding C-terminal carboxylic acids, methyl (Me) or benzyl (Bn) esters, in high chemical and enantio- and diastereomeric purities. Yields ranged between 50% and 95% depending on the size of the aryl substituents and the presence of electron-withdrawing substituents. Complete α-C-terminal selectivity could be obtained even in the presence of various unprotected side-chain functionalities such as β/γ-carboxyl, hydroxyl, and guanidino groups. In addition, the use of the cysteine protease papain and the lipase Cal-B gave anilides in high yields. The chemo-enzymatic synthesis of arylamides proved to be completely free of racemization, in contrast to the state-of-the-art chemical methods.
- Nuijens, Timo,Cusan, Claudia,Kruijtzer, John A. W.,Rijkers, Dirk T. S.,Liskamp, Rob M. J.,Quaedflieg, Peter J. L. M.
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supporting information; experimental part
p. 5145 - 5150
(2009/12/06)
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- Enzymatic removal of carboxyl protecting groups. 2. Cleavage of the benzyl and methyl moieties
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Enzymes are versatile reagents for the efficient removal of methyl and benzyl protecting groups. An esterase from Bacillus subtilis (BS2) and a lipase from Candida antarctica (CAL-A) allow a mild and selective removal of these moieties in high yields without affecting other functional groups.
- Barbayianni, Efrosini,Fotakopoulou, Irene,Schmidt, Marlen,Constantinou-Kokotou, Violetta,Bornscheuer, Uwe T.,Kokotos, George
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p. 8730 - 8733
(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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- Diastereoselective specificity for the hydrolysis of dipeptide esters in aqueous media
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The diastereoselectivity for the hydrolysis of p-methoxycarbonylphenyl N-(benzyloxycarbonyl)-D(L)-phenylalanyl-L-leucinate in aqueous solution was inverted by changing concentrations of the substrates or the reaction temperature. The monomer-aggregate transition operated on the LL-substrate, which was suggested by the spectroscopic measurements, seems to be responsible for such behavior.
- Ueoka, Ryuichi,Goto, Kouichi,Tanoue, Osamu,Miki, Atsushi,Yoshimitsu, Shinya,Imamura, Chikara,Ihara, Yasuji,Murakami, Yukito
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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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- Efficient 1,4-Asymetric Induction Utilizing Electrostatic Interaction between Ligand and Substrate in the Asymmetric Hydrogenation of Didehydrodipeptides
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Electrostatic interaction between the amino group of the achiral 3-dimethylaminopropylidenebismethylenebis(diphenylphosphine) (1) and the carboxy group of the substrate enable an effective 1,4-asymmetric induction in the RhI-catalysed hydrogenation of didehydrodipeptides, to give (S,S)-or (R,R)-products selectively.The selectivity reached up to 94percent diastereoisomeric excess with acetyl didehydrodipeptides and 92percent with benzyloxycarbonyl substrates.
- Yamagishi, Takamichi,Ikeda, Satoru,Yatagai, Masanobu,Yamaguchi, Motowo,Hida, Mitsuhiko
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p. 1787 - 1790
(2007/10/02)
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- ENZYMIC SYNTHESIS OF OLIGOPETIDE - VI. THE MECHANISTIC FEATURES OF PEPSIN-CATALYSED PEPTIDE SYNTHESIS
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The dipeptide Z-Phe-Phe-OBzl and tripeptide Z-Phe-Phe-Phe-OBzl were synthesized by pepsin catalysis from the incubation of Z-Phe and Phe-OBzl in the reaction solution.The yield ratio of two peptides in relation to reaction time was investigated by HPLC.Another example: The tripeptide Z-Phe-Leu-Phe-OBzl and tetrapeptide Z-Phe-Leu-Phe-Phe-OBzl were also synthesized concurrently from Z-Phe-Leu and Phe-OBzl by pepsin catalysis.These results may have important implication for the transpeptidation of pepsin.But, according to the report of Pellegrini and Luisi, the dipeptide, Z-Ph-Phe-OBzl, synthesized by pepsin catalysis was not contaminated with the tripeptide,Z-Phe-Phe-Phe-OBzl, and the yield was high.In order to investigate the discrepancies between our observation and those reported by Pellegrini and Luisi, a mechanism by which pepsin synthesizes the dipeptide, Z-Phe-Phe-OBzl, and tripeptide, Z-Phe-Phe-Phe-OBzl, is proposed and supporting data demonstrated by HPLC analysis.
- Tseng, Min-Jen,Wu, Shih-Hsiung,Wang, Kung-Tsung
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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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- Synthesis of Amides of Dipeptides and Kinetics of Papain-catalysed Hydrolysis of These Amides
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The N-benzyloxycarbonylated amides of the dipeptides L-alanyl-L-phenylalanine, L-leucylleucine, L-leucyl-L-phenylalanine, L-phenylalanyl-L-alanine and L-phenylalanyl-L-leucine have been synthesised and the kinetic parameters for the papain-catalysed hydrolysis of these substrates and their ester analogs have been determined at pH 8 and 9.All the amide substrates are hydrolysed at the amide linkage except N-benzyloxycarbonyl-L-alanyl-L-phenylalanine amide which hydrolyses to the extent of 45percent at the amide linkage and 55percent at the peptide linkage.For amide hydrolysis acetylation and deacetylation rate constants are approximately equal.
- Zaher, M. R.,El-Sharief, A. M. Sh.
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p. 740 - 743
(2007/10/02)
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