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1.
The development of a multigram synthesis of the orthogonally protected amino acid‐derived Phaol [2‐{[(2S)‐2‐amino‐3‐phenylpropyl]amino}ethanol] is described. The goal of this work is to synthesize an orthogonally protected Phaol in a multigram scale up to 10 g (Cbz‐Phaol), so it can be used in solution‐based peptide synthesis of peptaibols. Two synthetic schemes were proposed and examined. Between the reduction‐coupling and the coupling‐reduction scheme, the latter gave the best results. A two‐step synthesis affords easily purifiable products. Several analogs were synthesized using this methodology. All the molecules were orthogonally protected, so that they can be used in peptide synthesis. Deprotection posed no problems. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.  相似文献   

2.
(S-2-amino-5-(aminooxy)pentanoic acid (L -homocanaline, HCan), a structural analogue of lysine, contains a reactive alkyloxyamine side chain and is therefore considered to react chemoselectively with carbonyl compounds by forming a kinetically stable oxime bond. The chemical synthesis of L -homocanaline starting from protected glutamic acid derivatives is described. Two orthogonally protected homocanaline derivatives were synthesized and their use in standard SPPS procedures was exemplified for the synthesis of a chemoselectively addressable cyclic peptide for use in TASP design. Moreover, the wide range of applications of this unique building block was demonstrated for the chemoselective ligation of an unprotected disaccharide to a HCan containing model peptide resulting in a chimeric glycopeptide structure. © 1998 European Peptide Society and John Wiley & Sons, Ltd.  相似文献   

3.
4.
Bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg; BK) occupies a special place in the history of the development of solid-phase peptide synthesis (SPPS). It was the first biologically-active peptide to be synthesized by Merrifield using the new method. Since that time many hundreds of BK analogs have been synthesized by SPPS. Certain of these analogs show potential as drug candidates. Dedicated to the memory of Bruce Merrifield. John Stewart (left) and RB Merrifield (right) with the first automatic peptide synthesizer.   相似文献   

5.
The 4‐methoxybenzyloxymethyl (MBom) group was introduced at the Nπ‐position of the histidine (His) residue by using a regioselective procedure, and its utility was examined under standard conditions used for the conventional and the microwave (MW)‐assisted solid phase peptide synthesis (SPPS) with 9‐fluorenylmethyoxycarbonyl (Fmoc) chemistry. The Nπ‐MBom group fulfilling the requirements for the Fmoc strategy was found to prevent side‐chain‐induced racemization during incorporation of the His residue even in the case of MW‐assisted SPPS performed at a high temperature. In particular, the MBom group proved to be a suitable protecting group for the convergent synthesis because it remains attached to the imidazole ring during detachment of the protected His‐containing peptide segments from acid‐sensitive linkers by treatment with a weak acid such as 1% trifluoroacetic acid in dichloromethane. We also demonstrated the facile synthesis of Fmoc‐His(π‐MBom)‐OH with the aid of purification procedure by crystallization to effectively remove the undesired τ‐isomer without resorting to silica gel column chromatography. This means that the present synthetic procedure can be used for large‐scale production without any obstacles. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.  相似文献   

6.
The Cu(I) catalyzed Huisgen 1,3‐dipolar azide‐alkyne cycloaddition (CuAAC) was applied for a nucleoside‐peptide bioconjugation. Systemin (Sys), an 18‐aa plant signaling peptide naturally produced in response to wounding or pathogen attack, was chemically synthesized as its N‐propynoic acid functionalized analog (Prp‐Sys) using the SPPS. Next, CuAAC was applied to conjugate Prp‐Sys with 3′‐azido‐2′,3′‐dideoxythymidine (AZT), a model cargo molecule. 1,4‐Linked 1,2,3‐triazole AZT‐Sys conjugate was designed to characterize the spreading properties and ability to translocate of cargo molecules of systemin. CuAAC allowed the synthesis of the conjugate in a chemoselective and regioselective manner, with high purity and yield. The presence of Cu(I) ions generated in situ drove the CuAAC reaction to completion within a few minutes without any by‐products. Under typical separation conditions of phosphate ‘buffer’ at low pH and uncoated fused bare‐silica capillary, an increasing peak intensity assigned to triazole‐linked AZT‐Sys conjugate was observed using capillary electrophoresis (CE) during CuAAC. CE analysis showed that systemin peptides are stable in tomato leaf extract for up to a few hours. CE‐ESI‐MS revealed that the native Sys and its conjugate with AZT are translocated through the tomato stem and can be directly detected in stem exudates. The results show potential application of systemin as a transporter of low molecular weight cargo molecules in tomato plant and of CE method to characterize a behavior of plant peptides and its analogs. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.  相似文献   

7.
Novel N‐(ureidoethyl)amides of cyclic enkephalin analogs have been synthesized. The p‐nitrophenyl carbamate of 1‐Boc‐1,2‐diaminoethane was coupled with 4‐methylbenzhydrylamine (MBHA) resin. The Boc group was removed by treatment with HCl/dioxane, and the peptide chain was assembled using Boc strategy. For deprotection of amino function, HCl/dioxane was used. D ‐Lys or D ‐Orn were incorporated in position 2, and the side chains of Lys, Orn, Dab, or Dap in position 5 were protected with Fmoc group. Side chain protection was removed by treatment with 55% piperidine in DMF, and cyclization was achieved by treatment with bis‐(4‐nitrophenyl)carbonate to form a urea bridge. The peptide was cleaved from the resin by treatment with 45% TFA in DCM. The peptides were tested in the guinea‐pig ileum (GPI) and mouse vas deferens (MVD) assays. Divers opioid activities were observed, depending on the size of the ring. In comparison with [Leu5]enkephalin, all peptides were more active in the GPI assay (between 125 and 12 times), and some of them were also more potent in the MVD assay. The conformational propensities of each peptide were determined using the EDMC method in conjunction with NMR experiments. This approach allows treating the dynamical behavior of small peptides properly. The results were compared with those obtained previously for corresponding nonsubstituted amides and are in agreement with the biologically active conformation proposed by us earlier. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd.  相似文献   

8.
The relationship between the conformation and biological activity of the peptide allosteric modulator of the interleukin‐1 receptor 101.10 (D ‐Arg‐D ‐Tyr‐D ‐Thr‐D ‐Val‐D ‐Glu‐D ‐Leu‐D ‐Ala‐NH2) has been studied using (R)‐ and (S)‐Bgl residues. Twelve Bgl peptides were synthesized using (R)‐ and (S)‐cyclic sulfamidate reagents derived from L ‐ and D ‐aspartic acid in an optimized Fmoc‐compatible protocol for efficient lactam installment onto the supported peptide resin. Examination of these (R)‐ and (S)‐Bgl 101.10 analogs for their potential to inhibit IL‐1β‐induced thymocyte cell proliferation using a novel fluorescence assay revealed that certain analogs exhibited retained and improved potency relative to the parent peptide 101.10. In light of previous reports that Bgl residues may stabilize type II′β‐turn‐like conformations in peptides, CD spectroscopy was performed on selected compounds to identify secondary structure necessary for peptide biological activity. Results indicate that the presence of a fold about the central residues of the parent peptide may be important for activity. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.  相似文献   

9.
Peptide p-nitroanilides (peptide p> NAs) have found wide application as chromogenic substrates. An improved SPPS method to synthesize rapidly and in good yield a broad range of peptide pNAs under mild conditions will be presented here. To obtain a suitable carrier, the (4-aminophenyl)aminocarbonyloxy derivatives of Wang resin and Sasrin were synthesized. SPPS employing Fmoc/tBu-based protection followed by acidolytic cleavage yielded the (protected) peptide p-aminoanilide which was oxidized with sodium perborate in acetic acid to yield the(protected) peptide pNA. Side-chain protectionproved to be advantageous. Acid-labile peptide pNAs such as the proteasome substrate Z-Glu(OtBu)-Ala-Leu-pNA thus can be obtaineddirectly. The behavior of Cys, Met, Tyr and Trp being susceptible towards oxidation was studied more closely.  相似文献   

10.
Two analogs of the ten‐amino acid residue, membrane‐active lipopeptaibiotic trichogin GA IV, mono‐labeled with 4‐cyano‐α‐methyl‐L ‐phenylalanine, a potentially useful fluorescence and IR absorption probe of the local microenvironment, were synthesized by the solid‐phase methodology and conformationally characterized. The single modification was incorporated either at the N‐terminus (position 1) or near the C‐terminus (position 8) of the peptide main chain. In both cases, the replaced amino acid was the equally helicogenic α‐aminoisobutyric acid (Aib) residue. We performed a solution conformational analysis by use of FT‐IR absorption, CD, and 2D‐NMR spectroscopies. The results indicate that both labeled analogs essentially maintain the overall helical propensity of the naturally occurring lipopeptaibiotic. Peptide? membrane interactions were assessed by fluorescence and ATR‐IR absorption techniques. Analogies and differences between the two peptides were highlighted. Taken together, our data confirm literature results that some of the spectroscopic parameters of the 4‐cyanobenzyl chromophore are sensitive markers of the local microenvironment.  相似文献   

11.
The oral bacterium Streptococcus mutans, strain JH1140, produces the antibiotic mutacin 1140. Mutacin 1140 belongs to a group of antibiotics called lanthipeptides. More specifically, mutacin 1140 is related to the epidermin type A(I) lanthipeptides. Mutagenesis experiments of this group of lanthipeptides have been primarily restricted to the posttranslationally modified meso-lanthionine and 3-methyllanthionine residues. Site-directed mutagenesis of the core peptide of mutacin 1140 was performed using the suicide vector pVA891. Substitutions of the N-terminal residue, the charged residue in the hinge region, and residues in ring A and intertwined rings C and D were investigated. A truncation and insertion of residues in ring A and intertwined rings C and D were also performed to determine whether or not they would alter the antimicrobial activity of the producing strain. Bioassays revealed that five of 14 mutants studied had improved antimicrobial activity against the indicator strain Micrococcus luteus ATCC 10240. MICs against Streptococcus mutans UA159, Streptococcus pneumoniae ATCC 27336, Staphylococcus aureus ATCC 25923, Clostridium difficile UK1, and Micrococcus luteus ATCC 10240 were determined for three mutacin 1140 variants that had the most significant increases in bioactivity in the M. luteus bioassay. This mutagenesis study of the epidermin group of lanthipeptides shows that antimicrobial activity can be significantly improved.  相似文献   

12.
We have been engaged in the microwave‐solid phase peptide synthesis (SPPS) synthesis of the phenylglycine (Phg)‐containing pentapeptide H‐Ala‐Val‐Pro‐Phg‐Tyr‐NH2 (1) previously demonstrated to bind to the so‐called BIR3 domain of the anti‐apoptotic protein XIAP. Analysis of the target peptide by a combination of RP‐HPLC, ESI‐MS, and NMR revealed the presence of two diastereoisomers arising out of the racemisation of the Phg residue, with the percentage of the LLLDL component assessed as 49%. We performed the synthesis of peptide (1) using different microwave and conventional stepwise SPPS conditions in attempts to reduce the level of racemisation of the Phg residue and to determine at which part of the synthetic cycle the epimerization had occurred. We determined that racemisation occurred mainly during the Fmoc‐group removal and, to a much lesser extent, during activation/coupling of the Fmoc‐Phg‐OH residue. We were able to obtain the desired peptide with a 71% diastereomeric purity (29% LLLDL as impurity) by utilizing microwave‐assisted SPPS at 50 °C and power 22 Watts, when the triazine‐derived coupling reagent DMTMM‐BF4 was used, together with NMM as an activator base, for the incorporation of this residue and 20% piperidine as an Fmoc‐deprotection base. In contrast, the phenylalanine analogue of the above peptide, H‐Ala‐Val‐Pro‐Phe‐Tyr‐NH2 (2), was always obtained as a single diastereoisomer by using a range of standard coupling and deprotection conditions. Our findings suggest that the racemisation of Fmoc‐Phg‐OH, under both microwave‐SPPS and stepwise conventional SPPS syntheses conditions, is very facile but can be limited through the use of the above stated conditions. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.  相似文献   

13.
The non-codable amino acid O-amino-serine, Ams, has been prepared in both L- and D-forms as the orthogonally protected derivative, Fmoc-Ams(Boc)-OH (1 and 2). This new amino acid derivative is useful for chemoselective ligations. Under acidic conditions and in the presence of all other common amino acid functionalities, the oxyamine function selectively forms oxime linkages with aldehydes. The Ams residue has been incorporated into both ends of the peptide sequence Asp-Leu-Trp-Gln-Lys using standard SPPS. The deprotected peptide has been used for chemical ligation to afford a peptide dimer as well as a glycopeptide. Ams racemization was found to be negligible, as monitored by HPLC separation of Ams dipeptide diastereomers.  相似文献   

14.
As part of our efforts to design constrained peptide mimics and introduce them in peptide sequences, we set up the synthesis of racemic N-Fmoc protected hydroxypyrrolidine by reduction of the corresponding oxopyrroline. Hydroxypyrrolidines are synthesized using amino acid building block and β-ketoester via a 4-steps solid supported route on Wang resin beads. The hydroxypyrrolidine template can be seen as a constrained mimic of statine. As proof of concept, the pseudopeptide JMV 2776, incorporating this new statine mimic has been synthesized. We replaced the phenyl statine building block in the sequence of known BACE 1/2 inhibitors by 5-benzyl 2-methyl 4-hydroxypyrrolidine, using conventional Fmoc SPPS on Rink amide PS resin. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.  相似文献   

15.
Cancer metastasis, including cell invasion, is a major cause of poor clinical outcomes and death in numerous cancer patients. In recent years, many efforts have been made to develop potent therapeutic molecules from naturally derived peptides. Sungsanpin is a naturally derived lasso peptide that inhibits A549 cell invasion. We aimed to evaluate the potential of sungsanpin derivatives as candidates for anti-invasion drugs. We synthesized an analog of sungsanpin (Sun A) using a solid-phase peptide synthesis strategy (SPPS) and further modified its structure to improve its anti-invasion activity. All peptides were tested for their proliferative inhibition and anti-invasion activities in the A549 cell lines. Octapeptide S3 and cyclooctapeptide S4 upregulated the expression of TIMP-1 and TIMP-2 mRNA effectively and thus improved the inhibitory effect on the invasion of A549 cells. The two peptides can inhibit the invasion of A549 cells by up to 60 %, suggesting that they have potential as lead molecules for the development of peptide inhibitors.  相似文献   

16.
Various organic solvents are routinely used in peptide synthesis, safe disposal of which are now an important environmental problem. To circumvent this problem, during the last few years we focused on developing an organic solvent-free SPPS method using aqueous solvents. For the SPPS in water, we designed protected amino acids that could be used in the aqueous media. Here we described development of several types of water-soluble protected amino acids and their application to the SPPS in water, and a novel technology that uses water-dispersible protected amino acids for in-water peptide synthesis.  相似文献   

17.
We prepared, by solution‐phase methods, and fully characterized three analogs of the membrane‐active peptaibiotic alamethicin F50/5, bearing a single trifluoroacetyl (Tfa) label at the N‐terminus, at position 9 (central region) or at position 19 (C‐terminus), and with the three Gln at positions 7, 18, and 19 replaced by Glu(OMe) residues. To add the Tfa label at position 9 or 19, a γ‐trifluoroacetylated α,γ‐diaminobutyric acid (Dab) residue was incorporated as a replacement for the original Val9 or Glu(OMe)19 amino acid. We performed a detailed conformational analysis of the three analogs (using FT‐IR absorption, CD, 2D‐NMR, and X‐ray diffraction), which clearly showed that Tfa labeling does not introduce any dramatic backbone modification in the predominantly α‐helical structure of the parent peptaibiotic. The results of an initial solid‐state 19F‐NMR study on one of the analogs favor the conclusion that the Tfa group is a very promising reporter for the analysis of peptaibiotic? membrane interactions. Finally, we found that the antimicrobial activities of the three newly synthesized analogs depend on the position of the Tfa label in the peptide sequence.  相似文献   

18.
La1 is a 73‐residue cysteine‐rich peptide isolated from the scorpion Liocheles australasiae venom. Although La1 is the most abundant peptide in the venom, its biological function remains unknown. Here, we describe a method for efficient chemical synthesis of La1 using the native chemical ligation (NCL) strategy, in which three peptide components of less than 40 residues were sequentially ligated. The peptide thioester necessary for NCL was synthesized using an aromatic N‐acylurea approach with Fmoc‐SPPS. After completion of sequential NCL, disulfide bond formation was carried out using a dialysis method, in which the linear peptide dissolved in an acidic solution was dialyzed against a slightly alkaline buffer to obtain correctly folded La1. Next, we determined the disulfide bonding pattern of La1. Enzymatic and chemical digests of La1 without reduction of disulfide bonds were analyzed by liquid chromatography/mass spectrometry (LC/MS), which revealed two of four disulfide bond linkages. The remaining two linkages were assigned based on MS/MS analysis of a peptide fragment containing two disulfide bonds. Consequently, the disulfide bonding pattern of La1 was found to be similar to that of a von Willebrand factor type C (VWC) domain. To our knowledge, this is the first report of the experimental determination of the disulfide bonding pattern of peptides having a single VWC domain as well as their chemical synthesis. La1 synthesized in this study will be useful for investigation of its biological role in the venom. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.  相似文献   

19.
Evaluating the stability of coupling reagents, quality control (QC), and surface functionalization metrology are all critical to the production of high quality peptide microarrays. We describe a broadly applicable screening technique for evaluating the fidelity of solid phase peptide synthesis (SPPS), the stability of activation/coupling reagents, and a microarray surface metrology tool. This technique was used to assess the stability of the activation reagent 1‐{[1‐(Cyano‐2‐ethoxy‐2‐oxo‐ethylidenaminooxy)dimethylamino‐morpholinomethylene]}methaneaminiumHexafluorophosphate (COMU) (Sigma‐Aldrich, St. Louis, MO, USA) by SPPS of Leu‐Enkephalin (YGGFL) or the coupling of commercially synthesized YGGFL peptides to (3‐aminopropyl)triethyoxysilane‐modified glass surfaces. Coupling efficiency was quantitated by fluorescence signaling based on immunoreactivity of the YGGFL motif. It was concluded that COMU solutions should be prepared fresh and used within 5 h when stored at ~23 °C and not beyond 24 h if stored refrigerated, both in closed containers. Caveats to gauging COMU stability by absorption spectroscopy are discussed. Commercial YGGFL peptides needed independent QC, due to immunoreactivity variations for the same sequence synthesized by different vendors. This technique is useful in evaluating the stability of other activation/coupling reagents besides COMU and as a metrology tool for SPPS and peptide microarrays. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.  相似文献   

20.
Azetidine-2-carboxylic acid (Aze) analogs possessing various heteroatomic side chains at the 3-position have been synthesized by modification of 1-9-(9-phenylfluorenyl) (PhF)-3-allyl-Aze tert-butyl ester (2S,3S)-1. 3-Allyl-Aze 1 was synthesized by regioselective allylation of alpha-tert-butyl beta-methyl N-(PhF)aspartate 13, followed by selective omega-carboxylate reduction, tosylation, and intramolecular N-alkylation. Removal of the PhF group and olefin reduction by hydrogenation followed by Fmoc protection produced nor-leucine-Aze chimera 2. Regioselective olefin hydroboration of (2S,3S)-1 produced primary alcohol 23, which was protected as a silyl ether, hydrogenated and N-protected to give 1-Fmoc-3-hydroxypropyl-Aze 26. Enantiopure (2S,3S)-3-(3-azidopropyl)-1-Fmoc-azetidine-2-carboxylic acid tert-butyl ester 3 was prepared as a Lys-Aze chimera by activation of 3-hydroxypropyl-Aze 26 as a methanesulfonate and displacement with sodium azide. Moreover, orthogonally protected azetidine dicarboxylic acid 4 was synthesized as an alpha-aminoadipate-Aze chimera by oxidation of alcohol 26. These orthogonally protected amino acid-Aze chimeras are designed to serve as tools for studying the influence of conformation on peptide activity.  相似文献   

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