- Tetrahydropyranyl: A Non-aromatic, Mild-Acid-Labile Group for Hydroxyl Protection in Solid-Phase Peptide Synthesis
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The use of the tetrahydropyranyl (Thp) group for the protection of serine and threonine side-chain hydroxyl groups in solid-phase peptide synthesis has not been widely investigated. Ser/Thr side-chain hydroxyl protection with this acid-labile and non-aromatic moiety is presented here. Although Thp reacts with free carboxylic acids, it can be concluded that to introduce Thp ethers at the hydroxyl groups of N-protected Ser and Thr, protection of the C-terminal carboxyl group is unnecessary due to the lability of Thp esters. Thp-protected Ser/Thr-containing tripeptides are synthesized and the removal of Thp studied in low concentrations of trifluoroacetic acid in the presence of cation scavengers. Given its general stability to most non-acidic reagents, improved solubility of its conjugates and ease with which it can be removed, Thp emerges as an effective protecting group for the hydroxyl groups of Ser and Thr in solid-phase peptide synthesis.
- Sharma, Anamika,Ramos-Tomillero, Iván,El-Faham, Ayman,Rodríguez, Hortensia,de la Torre, Beatriz G.,Albericio, Fernando
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Read Online
- O-SUBSTITUTED SERINE DERIVATIVE PRODUCTION METHOD
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It was discovered that a cyclic sulfamidate can be produced by reacting an amino acid derivative with a cyclization reagent. In addition, it was discovered that an O-substituted serine derivative can be produced by reacting a cyclic sulfamidate with an alcohol.
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- Synthesis of xylose-binding cyclic octalipopeptides burkholdine-1213 analogues
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The synthesis of xylose-bearing cyclic octalipopeptides burkholdine-1213 analogues is described. Sugar-containing lipopeptides are generally highly amphiphilic and often exhibit potent antifungal activities, but a synthesis of a xylose-bearing burkholdine analogue has never been reported. We prepared burkholdine-1213 analogues by solution-phase macrolactamization of xylose-bearing linear peptides obtained by incorporating the bespoke Fmoc-Ser(β-O-xyloseAc3)-OH building block into a Fmoc-solid phase peptide synthesis protocol. All analogues synthesized exhibited similar properties and moderate antifungal activities.
- Sasaki, Mio,Kadowaki, Toma,Kato, Seiya,Chida, So,Yano, Shigekazu,Nosaka, Kazuto,Konno, Hiroyuki
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supporting information
(2021/11/27)
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- Scope and limitations of pseudoprolines as individual amino acids in peptide synthesis
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Protected 4-carboxyoxazolidines and thiazolidines (pseudoprolines) are derivatives of serine, threonine or cysteine amino acids. Such compounds are used in peptide synthesis among the other protected amino acids. They are usually practiced when a peptide sequence is readily aggregating during synthesis due to their ability to disrupt secondary structure formation. Such compounds are usually applied as dipeptides. In present work Fmoc-protected pseudoprolines were synthesized and applied in peptide synthesis not as dipeptides but as individual amino acids. Different acylation protocols and amino acids were tested to acylate pseudoprolines. Several “difficult” peptides were synthesized to confirm the efficacy of such constructions. It was shown that pseudoprolines could be easily synthesized and used in automated or manual synthesis not as dipeptides but as ordinary amino acids.
- Senko, Dmitry A.,Timofeev, Nikita D.,Kasheverov, Igor E.,Ivanov, Igor A.
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p. 665 - 671
(2021/04/09)
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- Synthesis method and application of 1-aza -5-germanium-5-alkyl bicyclic [3.3.3] undecane compound.
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The invention provides a 1-aza-5-germanium hetero-5-alkyl bicyclic [3.3.3] hendecane compound having a structure shown in the formula I, and the types of the 1-aza-5-germanium hetero-5-alkyl bicyclic[3.3.3] hendecane compound are expanded. The provided compound can serve as a nucleophilic reagent, the air and humidity conditions of the nucleophilic reagent are stable, and the efficiency of the Ge-Stille coupling reaction of aryl halogen and the 1-aza-5-germanium hetero-5-alkyl bicyclic [3.3.3] hendecane compound is high.
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Paragraph 0207; 0212; 0242; 0247
(2020/05/11)
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- Novel chiral stationary phases based on 3,5-dimethyl phenylcarbamoylated β-cyclodextrin combining cinchona alkaloid moiety
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Novel chiral selectors based on 3,5-dimethyl phenylcarbamoylated β-cyclodextrin connecting quinine (QN) or quinidine (QD) moiety were synthesized and immobilized on silica gel. Their chromatographic performances were investigated by comparing to the 3,5-dimethyl phenylcarbamoylated β-cyclodextrin (β-CD) chiral stationary phase (CSP) and 9-O-(tert-butylcarbamoyl)-QN-based CSP (QN-AX). Fmoc-protected amino acids, chiral drug cloprostenol (which has been successfully employed in veterinary medicine), and neutral chiral analytes were evaluated on CSPs, and the results showed that the novel CSPs characterized as both enantioseparation capabilities of CD-based CSP and QN/QD-based CSPs have broader application range than β-CD-based CSP or QN/QD-based CSPs. It was found that QN/QD moieties play a dominant role in the overall enantioseparation process of Fmoc-amino acids accompanied by the synergistic effect of β-CD moiety, which lead to the different enantioseparation of β-CD-QN-based CSP and β-CD-QD-based CSP. Furthermore, new CSPs retain extraordinary enantioseparation of cyclodextrin-based CSP for some neutral analytes on normal phase and even exhibit better enantioseparation than the corresponding β-CD-based CSP for certain samples.
- Zhu, Lunan,Zhu, Junchen,Sun, Xiaotong,Wu, Yaling,Wang, Huiying,Cheng, Lingping,Shen, Jiawei,Ke, Yanxiong
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p. 1080 - 1090
(2020/05/25)
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- Determination of Chemical and Enantiomeric Purity of α-Amino Acids and their Methyl Esters as N-Fluorenylmethoxycarbonyl Derivatives Using Amylose-derived Chiral Stationary Phases
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Liquid chromatographic enantiomer separation and simultaneous determination of chemical and enantiomeric purity of α-amino acids and their methyl esters as N-fluorenylmethoxycarbonyl (FMOC) derivatives was performed on three covalently bonded type chiral stationary phases (CSPs) derived from amylose derivatives. The enantiomer separation of α-amino acid esters as N-FMOC derivatives was better than that of the corresponding acids, especially for CSP 1 and 2. Chemical impurities as the corresponding racemic acids present in several commercially available racemic amino acid methyl esters were observed to be 0.49–17.50%. Enantiomeric impurities of several commercially available L-amino acid methyl esters were found to be 0.03–0.58%, whereas chemical impurities as the corresponding racemic acids present in the same analytes were found to be 0.13–13.62%. This developed analytical method will be useful for the determination of chemical and enantiomeric purity of α-amino acids and/or esters as N-FMOC derivatives using amylose-derived CSPs.
- Islam, Md. Fokhrul,Adhikari, Suraj,Paik, Man-Jeong,Lee, Wonjae
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p. 332 - 338
(2019/04/13)
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- Supramolecular Platform Stabilizing Growth Factors
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High concentrations of supplemented growth factors can cause oversaturation and adverse effects in in vitro and in vivo studies, though these supraphysiological concentrations are often required due to the low stability of growth factors. Here we demonstrate the stabilization of TGF-β1 and BMP4 using supramolecular polymers. Inspired by heparan sulfate, sulfonated peptides were presented on a supramolecular polymer to allow for noncovalent binding to growth factors in solution. After mixing with excipient molecules, both TGF-β1 and BMP4 were shown to have a prolonged half-life compared to the growth factors free in solution. Moreover, high cellular response was measured by a luciferase assay, indicating that TGF-β1 remained highly active upon binding to the supramolecular assembly. The results demonstrate that significant lower concentrations of growth factors can be used when supramolecular polymers bearing growth factor binding moieties are implemented. This approach can also be exploited in hydrogel systems to control growth factor release.
- Hendrikse, Simone I. S.,Spaans, Sergio,Meijer,Dankers, Patricia Y. W.
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p. 2610 - 2617
(2018/05/14)
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- MgI2-chemoselective cleavage for removal of amino acid protecting groups: A fresh vision for peptide synthesis
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In the field of peptide synthesis, the key to a successful access to synthetic targets lies on a pertinent combination of protecting groups. Their choice is directed by their selective removal conditions. We present here the behavior of some of the most used protecting groups in peptide chemistry under experimental cleavage conditions, combining MgI2 with MW irradiation, using 2-Me-THF as a green solvent. In these experimental conditions, the benzyloxycarbonyl protecting group as well as the Merrifield resin can be re-considered in peptide chemistry.
- Berthet, Mathéo,Martinez, Jean,Parrot, Isabelle
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- Fmoc-OPhth, the reagent of Fmoc protection
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Fmoc-OSu has been widely used for Fmoc protection of amino groups, especially amino acids, in solid phase peptide synthesis. However, it has been recognized that Fmoc-βAla-OH is formed as a by-product via the Lossen rearrangement during the reaction. Since we reconfirmed the formation of Fmoc-βAla-OH during the preparation of Fmoc-AA-OH by Fmoc-OSu, Fmoc-OPhth was designed and synthesized as a new Fmoc reagent to avoid the formation of Fmoc-βAla-OH. Furthermore, Fmoc protection by Fmoc-OPhth and Fmoc-SPPS were evaluated. The various Fmoc-amino acids prepared by Fmoc-OPhth were carried out in good yields and these are applicable in Fmoc-SPPS.
- Yoshino, Ryo,Tokairin, Yoshinori,Kikuchi, Mari,Konno, Hiroyuki
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supporting information
p. 1600 - 1603
(2017/04/03)
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- Improved synthetic routes to the selenocysteine derivatives useful for Boc-based peptide synthesis with benzylic protection on the selenium atom
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Selenocysteine (Sec) derivatives, i.e., Boc-Sec(MBn)-OH (1) and Boc-Sec(MPM)-OH (2), which are useful for chemical synthesis of selenopeptides, were obtained from L-serine in five steps with total yields of 73% and 74%, respectively. The enantiomeric excesses were confirmed to be >99% e.e. by optical resolution using a chiral column on HPLC. On the other hand, for the case of a Fmoc-protected Sec derivative, i.e., Fmoc-Sec(MPM)-OH, similar reactions resulted in low yields and partial racemization taking place. [PRESENTED EQUATION]
- Shimodaira, Shingo,Iwaoka, Michio
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p. 260 - 271
(2017/03/09)
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- Caged xanthones: Potent inhibitors of global predominant MRSA USA300
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Total of 22 caged xanthones were subjected to susceptibility testing of global epidemic MRSA USA300. Natural morellic acid showed the strongest potency (MIC of 12.5 μM). However, its potent toxicity diminishes MRSA therapeutic potential. We synthetically modified natural morellic acid to yield 13 derivatives (3a-3m). Synthetically modified 3b retained strong potency in MRSA growth inhibition, yet the toxicity was 20-fold less than natural morellic acid, permitting the possibility of using caged xanthones for MRSA therapeutic.
- Chaiyakunvat, Pongkorn,Anantachoke, Natthinee,Reutrakul, Vichai,Jiarpinitnun, Chutima
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supporting information
p. 2980 - 2983
(2016/06/13)
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- Synthesis of the antimicrobial S-Linked glycopeptide, glycocin F
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The first total synthesis of glycocin F, a uniquely diglycosylated antimicrobial peptide bearing a rare S-linked N-acetylglucosamine (GlcNAc) moiety in addition to an O-linked GlcNAc, has been accomplished using a native chemical ligation strategy. The synthetic and naturally occurring peptides were compared by HPLC, mass spectrometry, NMR and CD spectroscopy, and their stability towards chymotrypsin digestion and antimicrobial activity were measured. This is the first comprehensive structural and functional comparison of a naturally occurring glycocin with an active synthetic analogue.
- Brimble, Margaret A.,Edwards, Pat J.,Harris, Paul W. R.,Norris, Gillian E.,Patchett, Mark L.,Wright, Tom H.,Yang, Sung-Hyun,Carley, Sarah E.
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supporting information
p. 3556 - 3561
(2015/03/04)
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- MgI2-Mediated Chemoselective Cleavage of Protecting Groups: An Alternative to Conventional Deprotection Methodologies
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The scope of MgI2 as a valuable tool for quantitative and mild chemoselective cleavage of protecting groups is described here. This novel synthetic approach expands the use of protecting groups, widens the concept of orthogonality in synthetic processes, and offers a facile opportunity to release compounds from solid supports. Amazing MgI2: Protecting groups have had a tremendous positive impact on the art of biomolecule synthesis. In a context in which the use of attractive protecting groups is often limited by harsh deprotection conditions and low chemoselective flexibility, MgI2 offers, by the execution of a very simple protocol, a fresh vision with extensive perspectives.
- Berthet, Mathéo,Davanier, Florian,Dujardin, Gilles,Martinez, Jean,Parrot, Isabelle
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supporting information
p. 11014 - 11016
(2015/11/10)
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- Influence of steric parameters on the synthesis of tetramates from α-amino-β-alkoxy-esters and Ph3PCCO
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α-Aminoesters react with Ph3PCCO in a domino addition-Wittig cyclization sequence affording enantiomerically pure tetramates. In the case of β-oxo functionalized α-aminoesters, e.g., esters of serine, threonine or β-hydroxyornithine the yields of this reaction depend heavily on the bulkiness of the β-OR group and on the configuration of β-carbon atom C-3. Smaller residues and 2R/3R-configured aminoesters give better yields. The alkoxycarbonyl group of the ester moiety and the residue on the N-atom are less important. These findings can be accounted for by assuming an early puckered transition state for the intramolecular ring-closing Wittig reaction. The addition of sub-stoichiometric amounts of benzoic acid or N-hydroxysuccinimide (for acid-sensitive compounds) is advantageous in some cases as it accelerates the formation of the intermediate amide ylides.
- Loke, Inga,Park, Natja,Kempf, Karl,Jagusch, Carsten,Schobert, Rainer,Laschat, Sabine
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supporting information; experimental part
p. 697 - 704
(2012/01/05)
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- New TFA-free cleavage and final deprotection in Fmoc solid-phase peptide synthesis: Dilute HCl in fluoro alcohol
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A novel method for cleaving from resin and removing acid-labile protecting groups for the Fmoc solid-phase peptide synthesis is described. 0.1 N HCl in hexafluoroisopropanol or trifluoroethanol cleanly and rapidly removes the tert-butyl ester and ether, Boc, trityl, and Pbf groups and cleaves the common resin linkers: Wang, HMPA, Rink amide, and PAL. Addition of just 5-10% of a hydrogen-bonding solvent considerably retards or even fully inhibits the reaction. However, a non-hydrogen-bonding solvent is tolerated.
- Palladino, Pasquale,Stetsenko, Dmitry A.
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supporting information
p. 6346 - 6349
(2013/02/25)
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- Benzotriazole reagents for the syntheses of Fmoc-, Boc-, and Alloc-protected amino acids
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Stable Fmoc-, Boc-, and Alloc-benzotriazoles react with various amino acids including unprotected serine and glutamic acid, in the presence of triethylamine at 20° as reagents to introduce -amino protecting groups to afford Fmoc-, Boc-, and Alloc-protected amino acids (77-94%) free of dipeptide and tripeptide impurities. Fmoc-, and Alloc-Gly-Gly-OH dipeptides were prepared in 90% yields by N-acylation of glycylglycine with Fmoc- and Alloc-benzotriazoles in the presence of triethylamine. Synthesized N-protected amino acids were greater than 99% pure, analyzed by HPLC. Georg Thieme Verlag Stuttgart - New York.
- Ibrahim, Tarek S.,Tala, Srinivasa R.,El-Feky, Said A.,Abdel-Samii, Zakaria K.,Katritzky, Alan R.
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p. 2013 - 2016
(2011/10/08)
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- Liquid-chromatography quantitative analysis of 20 amino acids after derivatization with FMOC-CI and its application to different origin Radix isatidis
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We developed a simple, rapid and reliable method for determination of 20 common amino acids based on derivatization with 9-fluorenylmethyl chloroformate (FMOC-CI) and RP-LC/UV, this method was first introduced into quantitative analysis of amino acids. The amino groups of amino acids were trapped with FMOC-CI to form amino acid-FMOC-Cl adducts which can be suitable for LC-UV. Chromatographic separation was performed on a C18 column with a mobile phase gradient consisting of acetonitrile and sodium acetate solution. This method was shown to be sensitive for 20 common amino acids. In the intra-day precisions assay, the range of RSDs was 3.21-7.67% with accuracies of 92.34-102.51%; for the inter-day precisions assay, the range of RSDs was 5.82-9.19% with accuracies of 90.25-100.63%. The results also indicated that solutions of amino acids-FMOC-Cl can be kept at room temperature for at least 24 h without showing significant losses in the quantified values. The validated method was successfully applied to the determination of major four kinds of amino acids in R. isatidis samples (Arg, Pro, Met and Val). The total content of amino acids in different origin R. isatidis was 13.32-19.16 mg/g. The differences between R. isatidis samples were large using HCA.
- Zhou, Wei,Zhang, Xiao-Yan,Duan, Geng-Li
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experimental part
p. 509 - 515
(2012/01/04)
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- Synthesis of Tn/T antigen MUC1 glycopeptide BSA conjugates and their evaluation as vaccines
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The tumor-associated mucin MUC1 over-expressed in most epithelial tumor tissues is considered a promising target for immunotherapy. The extracellular part of MUC1 contains a domain of numerous tandem repeats of the amino acid sequence HGVTSAPDTRPAPGSTAPPA, including five potential O-glycosylation sites. In this study, T9 and S15 have been chosen as the positions of glycosylation. The glycopeptides N-terminally equipped with a triethylene glycol spacer were synthesized by microwave-assisted Fmoc solid-phase peptide synthesis. After detachment from the resin and deprotection, the MUC1 glycopeptides were conjugated to bovine serum albumin (BSA). To evaluate the immunological properties, balb/c mice were immunized with these BSA vaccines. Copyright
- Cai, Hui,Huang, Zhi-Hua,Shi, Lei,Zou, Peng,Zhao, Yu-Fen,Kunz, Horst,Li, Yan-Mei
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scheme or table
p. 3685 - 3689
(2011/09/21)
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- Evidences for supramolecular organization of nucleopeptides: Synthesis, spectroscopic and biological studies of a novel dithymine l-serine tetrapeptide
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This work concerns a dithymine tetrapeptide, which can be seen as a new analogue of a dinucleoside monophosphate, made of both unfunctionalized and thymine-containing l-serine units alternated in the sequence. The new nucleopeptide was obtained on the solid phase by two different synthetic strategies. The first one is suitable to easily realize nucleopeptides with homonucleobase sequences, obtained by assembling an oligoserine backbone and then simultaneously coupling the free serine hydroxyl groups with the carboxymethylated nucleobase. The other strategy, which makes use of a Fmoc-protected nucleo-l-serine monomer, allows for the obtainment of nucleopeptides with mixed nucleobase sequences. CD spectroscopic studies and laser light scattering experiments, performed on solutions of the novel nucleopeptide, suggested the formation of supramolecular networks based on the self-assembly of the dithymine tetrapeptide molecules. Furthermore, CD binding studies with natural nucleic acids revealed a very weak interaction between the nucleopeptide and DNA (but not RNA). Molecular networks based on this biodegradable and water-soluble nucleopeptide, which is more resistant in plasma than standard tetrapeptides (and oligopeptides), contain a hydrophobic core which could provide the necessary environment to incorporate poorly water-soluble drugs, as evidenced by fluorescence spectroscopy. Furthermore, our studies evidenced that the structure of the tetrapeptide-based supramolecular assembly can be modified by metal ions as evidenced by UV interaction studies with Cu2+. The Royal Society of Chemistry.
- Roviello, Giovanni N.,Musumeci, Domenica,Bucci, Enrico M.,Pedone, Carlo
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experimental part
p. 1073 - 1080
(2012/03/10)
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- Lanthanide(III) complexes with two hexapeptides incorporating unnatural chelating amino acids: Secondary structure and stability
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Unnatural metal-chelating amino acids bearing aminodiacetate side-chains have been introduced into two hexapeptides to obtain efficient lanthanide-binding peptides. The synthesis of the enantiopure Fmoc-Ada.,(tBu)2-OH synthons is described with overall yields of 32 and 50% for n = 2 and n = 3 side-chain carbon atoms, respectively. The two peptides AcWAdanPGAdanGNH2 (Pn) were synthesized from the protected synthons by standard solid-phase peptide synthesis. Studies of the lanthanide complexes of the two peptides P" by luminescence titrations, mass spectrometry, circular dichroism, and solution NMR spectroscopy demonstrate that the Ada., chain length has a dramatic effect on the complexation properties. Indeed, the flexible compound P3 forms a mononuclear complex of moderate stability (β11 = 10 9.9), which tends to transform into a binuclear species in the presence of excess of the metal ion. Interestingly, the more compact peptide P2 provides stable Ln3+ complexes with the exclusive formation of the mononuclear LnP2 adduct. The stability constant of TbP2 is two orders of magnitude higher (β11 = 10 12.1) than that measured for P3. The 800 MHz NMR spectrum of the La3+ complex of P2 evidences a well-defined type II ss-turn as well as a hydrophobic Trp(indole)-Pro interaction. These interactions exemplify the non-innocent character of the peptide spacer in the complex LaP2 as well as the role of a peptide secondary structure in the stabilization of metal complexes.
- Cisnetti, Federico,Gateau, Christelle,Lebrun, Colette,Delangle, Pascale
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scheme or table
p. 7456 - 7469
(2010/03/24)
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- Efficient procedure for the preparation of oligomer-free N-fmoc amino acids
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A two-step method is presented for the peptide-free, high-purity, and high-yield synthesis of N-Fmoc amino acids. The first step involves the preparation of stable dicyclohexylammonium-amino acid ionic adduct in acetone. Subsequently, the ionic adducts, on reaction with Fmoc-Nosu under mild alkaline conditions, give dipeptide-free N-Fmoc amino acids. The positive charge of the dicyclohexylammonium counterion in the ionic salt has a longer radius, moderating the nucleophilicity of the carboxylate ion of the amino acid and preventing by-products by arresting the formation of mixed anhydrides, the precursors of oligopeptide impurities.
- Nowshuddin, Shaik,Rao,Reddy, A. Ram
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experimental part
p. 2022 - 2031
(2009/11/30)
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- Low-concentration 12-trans β-selective glycosylation strategy and its applications in oligosaccharide synthesis
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This study develops an operationally easy, efficient, and general 1,2-trans β-selective glycosylation reaction that proceeds in the absence of a C2 acyl function. This process employs chemically stable thioglycosyl donors and low substrate concentrations to achieve excellent β-selectivities in glycosylation reactions. This method is widely applicable to a range of glycosyl substrates irrespective of their structures and hydroxyl-protecting functions. This low-concentration 1,2-trans β-selective glycosylation in carbohydrate chemistry removes the restriction of using highly reactive thioglycosides to construct 1,2-trans β-glycosidic bonds. This is beneficial to the design of new strategies for oligosaccharide synthesis, as illustrated in the preparation of the biologically relevant β-(1-6)-glucan trisaccharide, β-linked Gb3 and isoGb3 derivatives.
- Chao, Chin-Sheng,Li, Chen-Wei,Chen, Min-Chun,Chang, Shih-Sheng,Mong, Kwok-Kong Tony
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supporting information; experimental part
p. 10972 - 10982
(2010/04/30)
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- Oxathiocoraline: Lessons to be learned from the synthesis of complex N-methylated depsipeptides
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Investigations into the synthesis of oxathiocoraline, a bicyclic depsipeptide with C2 symmetry, revealed a number of unexpected side-reactions that: could not be circumvented by classical or standard means. This cyclodepsipeptide has a large nu
- Bayo-Puxan, Nuria,Tulla-Puche, Judit,Albericio, Fernando
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scheme or table
p. 2957 - 2974
(2009/12/05)
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- Synthesis of fluorescein-labelled O-mannosylated peptides as components for synthetic vaccines: Comparison of two synthetic strategies
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Mannose-binding proteins on the surface of antigen-presenting cells (APCs) are capable of recognizing and internalizing foreign agents in the early stages of immune response. These receptors offer a potential target for synthetic vaccines, especially vaccines designed to stimulate T cells. We set out to synthesize a series of fluorescein-labelled O-mannosylated peptides using manual solid phase peptide synthesis (SPPS) on pre-loaded Wang resin, in order to test their ability to bind mannose receptors on human APCs in vitro. A flexible and reliable method for the synthesis of fluorescein-labelled O-mannosylated glycopeptides was desired in order to study their lectin-binding properties using flow cell cytometry. Two synthetic strategies were investigated: incorporation of a fluorescein label into the peptide chain via a lysine side chain ε-amino group at the final stage of standard Fmoc solid phase peptide synthesis or attachment of the fluorescein label to the Nα- amino group of a lysine with further incorporation of a mannosylated peptide unit through the side chain Nε-amino group. The latter strategy proved more effective in that it facilitated SPPS by positioning the growing mannosylated peptide chain further removed from the fluorescein label. The Royal Society of Chemistry 2008.
- Brimble, Margaret A.,Kowalczyk, Renata,Harris, Paul W. R.,Dunbar, P. Rod,Muir, Victoria J.
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p. 112 - 121
(2008/09/20)
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- Fluorescence-based detection of single nucleotide permutation in DNA via catalytically templated reaction
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Templated reduction of low fluorescence azidocoumarin-PNA conjugate to high fluorescence aminocoumarin was achieved using a catalytic amount of DNA with single nucleotide resolution. The Royal Society of Chemistry.
- Pianowski, Zbigniew L.,Winssinger, Nicolas
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p. 3820 - 3822
(2008/03/14)
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- Stereospecific synthesis of a carbene-generating angiotensin II analogue for comparative photoaffinity labeling: Improved incorporation and absence of methionine selectivity
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A stereospecific convergent synthesis of N-[(9-fluorenyl)methoxycarbonyl]- p-[3-(trifluoromethyl)-3H-diazirin-3-yl]-L-phenylalanine (Fmoc-12, Fmoc-Tdf) and its incorporation into the C-terminal position of the angiotensin II (AngII) peptide to form 125I[Sar1,Tdf8]AngII ( 125I-13) is presented. This amino acid photoprobe is a highly reactive carbene-generating diazirine phenylalanine derivative that can be used for photoaffinity labeling. Using model receptors, we compared the reactivity and the Met selectivity of 12 to that of the widely used and reputedly Met-selectivep-benzoyl-L-phenylalanine (Bpa) photoprobe. Wild-type and mutant AngII type 2 receptors, a G protein-coupled receptors, were photolabeled with 125I-13 as well as with 125I-[Sar1,Bpa 8]AngII (125I-14), and the respective incorporation yields were assessed. The carbene-generating 12 was more reactive toward inert residues and was not Met-selective compared to the biradical ketone-generating Bpa, allowing for more precise determination of ligand contact points in peptidergic receptors.
- Pillion, Dany,Dera?t, Maud,Holleran, Brian J.,Escher, Emanuel
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p. 2200 - 2209
(2007/10/03)
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- Enzyme-cleavable linkers for peptide and glycopeptide synthesis
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Hydroxymethylphenoxy linkers that are commonly used in solid phase peptide synthesis are surprisingly susceptible to efficient cleavage by the protease chymotrypsin with a broad range of amino acid residues being tolerated at the scissile bond; this enzyme-cleavable linker system has been applied to peptide and glycopeptide synthesis. The Royal Society of Chemistry 2005.
- Maltman, Beatrice A.,Bejugam, Mallesham,Flitsch, Sabine L.
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p. 2505 - 2507
(2007/10/03)
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- Cationic lipids with serine backbone
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The present invention provides cationic lipids with serine backbone, a composition for transferring biologically active molecules into cells and/or tissues comprising said cationic lipids, a process for the manufacture of said lipids, the use of said lipids as constituent of a transfection agent and a method for transferring biologically active molecules into cells and/or into tissues or for gene therapy.
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- Antiangiogenic peptides
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Mammalian kringle 5 fragments and kringle 5 fusion proteins are disclosed as a compounds for treating angiogenic diseases. Methods and compositions for inhibiting angiogenic diseases are also disclosed.
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- Alternative and chemoselective deprotection of the α-amino and carboxy functions of N-Fmoc-amino acid and N-Fmoc-dipeptide methyl esters by modulation of the molar ratio in the AlCl3/N,N-dimethylaniline reagent system
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The amino and carboxy functions in N-Fmoc-α-amino acid and N-Fmoc-peptide methyl esters can be alternatively and chemoselectively deprotected by treatment with the reagent system AlCl3/N,N- dimethylaniline (DMA). The chemoselectivity of the process is controlled by modulating the relative molar ratio of the Lewis acid and DMA. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
- Di Gioia, Maria Luisa,Leggio, Antonella,Le Pera, Adolfo,Liguori, Angelo,Perri, Francesca,Siciliano, Carlo
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p. 4437 - 4441
(2007/10/03)
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- A new polymer-supported reagent for the Fmoc-protection of amino acids
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A new polymer-supported Fmoc-OSu (Fmoc-P-OSu) has been prepared from polymer-bound N-hydroxysuccinimide (P-HOSu), and used as a solid-supported reagent for the Fmoc-protection of amino groups. The residual P-HOSu generated after the protection reaction can be separated by simple filtration and reused.
- Chinchilla, Rafael,Dodsworth, David,Nájera, Carmen,Soriano, José
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p. 7579 - 7581
(2007/10/03)
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- A mild and selective method for the cleavage of tert-butyl esters
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A method for the cleavage of t-butyl esters using silica gel in refluxing toluene is reported. Good yields of the corresponding carboxylic acids are obtained, and the reaction is selective for t-butyl esters over t-butyl ethers and trimethylsilylethyl (TMSE) esters.
- Jackson, Randy W
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p. 5163 - 5165
(2007/10/03)
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- Facile solid-phase synthesis of sulfated tyrosine-containing peptides: Total synthesis of human big gastrin-II and cholecystokinin (CCK)-39
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Chemical synthesis of tyrosine O-sulfated peptides is still a laborious task for peptide chemists because of the intrinsic acid-lability of the sulfate moiety. An efficient cleavage/deprotection procedure without loss of the sulfate is the critical difficulty remaining to be solved for fluoren-9-ylmethoxycarbonyl (Fmoc)-based solid-phase synthesis of sulfated peptides. To overcome the difficulty, TFA-mediated solvolysis rates of a tyrosine O-sulfate [Tyr(SO3H)] residue and two protecting groups, tBu for the hydroxyl group of Ser and 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) for the guanidino group of Arg, were examined in detail. The desulfation obeyed first-order kinetics with a large entropy (59.6 J·K-1·mol-1) and enthalpy (110.5 kJ·mol-1) of activation. These values substantiated that the desulfation rate of the rigidly solvated Tyr(SO3H) residue was strongly temperature-dependent. By contrast, the SN1-type deprotections were less temperature-dependent and proceeded smoothly in TFA of a high ionizing power. Based on the large rate difference between the desulfation and the SN1-type deprotections in cold TFA, an efficient deprotection protocol for the sulfated peptides was developed. Our synthetic strategy for Tyr(SO3H)containing peptides with this effective deprotection protocol is as follows: (i) a sulfated peptide chain is directly constructed on 2-chlorotrityl resin with Fmoc-based solid-phase chemistry using Fmoc-Tyr(SO3Na)-OH as a building block; (ii) the protected peptide-resin is treated with 90% aqueous TFA at 0 °C for an appropriate period of time for the cleavage and deprotection. Human cholecystokinin (CCK)-12, mini gastrin-II (14 residues), and little gastrin-II (17 residues) were synthesized with this method in 26-38% yields without any difficulties. This method was further applied to the stepwise synthesis of human big gastrin-II (34 residues), CCK-33 and -39. Despite the prolonged acid treatment (15-18 h at 0 °C), the ratios of the desulfated peptides were less than 15%, and the pure sulfated peptides were obtained in around 10% yields.
- Kitagawa,Aida,Fujiwara,Yagami,Futaki,Kogire,Ida,Inoue
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- Synthesis of a chiral precursor for no-carrier-added (NCA) PET tracer 6- [18F]fluoro-L-dopa based on regio- and enantioselective alkylation of 2,4- bis(chloromethyl)-5-iodoanisole
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(2S,5S)-5-(3-Formyl-6-iodo-4-methoxybenzyl)-1-t-butoxycarbonyl-2-t- butyl-3-methyl-4-imidazolidinone (11), a chiral intermediate towards NCA PET tracer 6-[18F]fluoro-L-dopa (1), was synthesized from 3-iodoanisole in four steps. 3-Iodoanisole was first bischloromethylated to 2,4-bis(chloromethyl)- 5-iodoanisole (14). Regio- and enantio-selective alkylation of 14 with (S)-1- (t-butoxycarbonyl)-2-t-butyl-3-methyl-4-imidazolidinone (12) afforded 33, which was then hydrolyzed and oxidized to the desired intermediate 11.
- Kuroda, Chiaki,Ochi, Atsushi,Nakane, Noritoshi,Umeyama, Takashi,Muto, Nobuko,Niimura, Nami,Teramoto, Yoshiki,Nogami, Hiroyuki,Reddy, Guvvala N.
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p. 417 - 422
(2007/10/03)
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- Cyclohexyl ether as a new hydroxy-protecting group for serine and threonine in peptide synthesis
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A new hydroxy-protecting group for Ser and Thr, cyclohexyl (Chx), has been developed, and its application to peptide synthesis is described. The Chx group is introduced to the hydroxy functions of Boc-Ser-OH and Boc-Thr-OH in two steps; Boc-Ser-OH and Boc-Thr-OH are treated with Nail and then allowed to react with 3-bromocyclohexene to afford N-Boc-O-(cyclohex-2-enyl)-Ser and N-Boc-O-(cyclohex-2-enyl)-Thr in satisfactory yields, which are hydrogenated in the presence of PtO2 to give Boc-Ser(Chx)-OH and Boc-Thr(Chx)-OH in good yields. The O-Chx group is stable to various acidic and basic conditions including TFA and 20% piperidine in DMF. It is not removed with catalytic hydrogenation over Pd-charcoal. The Chx group is, however, removed quantitatively with 1 mol dm-3 trifluoromethanesulfonic acid-thioanisole in TFA over a short period. These results indicate that the Chx group is suitable for the hydroxy-protection of Ser and Thr in peptide synthesis based on Boc-chemistry and can be used also in combination with either Nα-Fmoc or Nα-Z-protection. The apparent rate constant for removal of the Chx group with 50% TFA in CH2Cl2 (kChx) is found to be less than a twentieth of that of the Bzl group (kBzl), confirming the substantial stability of the Chx group under common Boc-deprotection conditions. Simulations of solid-phase peptide syntheses using kChx and kBzl indicate that the Chx group would be adequate for solid-phase synthesis of large peptides and proteins. Solid-phase synthesis of a peptide and conventional solution synthesis of a protected peptide segment using Chx protection are also demonstrated.
- Nishiyama, Yasuhiro,Shikama, Suguru,Morita, Ken-Ichi,Kurita, Keisuke
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p. 1949 - 1954
(2007/10/03)
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- Apparatus and methods for detecting antibodies
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A single, unitary, solid phase support apparatus having a planar surface divided into a plurality of separate zone functions to detect antibodies. Each zone has bonded to it, a different peptide through its C-terminal end. The zones are incubated with the analyte sample and observed for reaction, indicating the virus-specific or bacteria specific presence or absence.
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- Synthesis of a chiral serine aldehyde equivalent and its conversion to chiral α-Amino acid derivatives
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We report a new methodology for the synthesis of chiral nonproteinaceous α-amino acids, which involves protection of the carboxyl group of serine as a cyclic ortho ester. This reduces the acidity of the α-proton, allowing for oxidation of the side chain of serine to an aldehyde without racemization. A variety of carbonyl addition reactions, such as Grignard, Reformatsky, and Wittig additions, can then be carried out, leading to a wide range of amino acids. Very good stereocontrol is achieved, allowing for the selective synthesis of all four diastereomers of β-hydroxy-α-amino acids. The method readily allows for stereospecific incorporation of both C and H isotopes in amino acid side chains.
- Blaskovich, Mark A.,Lajoie, Gilles A.
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p. 5021 - 5030
(2007/10/02)
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- Application of t-Butyldimethylsilyl Ethers of Serine, Threonine and Tyrosine in Peptide Synthesis
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The utility of Tbdms (t-butyldimethylsilyl) ethers, prepared conveniently in a one pot procedure from Nα-Fmoc (9-fluorenylmethoxycarbonyl) and Nα-Z (benzyloxycarbonyl) hydroxyamino acids, is demonstrated: peptide bond formation and esterification to 4-alkoxybenzylalcohol resin are achieved readily with these derivatives.The lability of the Tbdms ethers to various reagents enables selective deprotection of the hydroxyl side-chains assembly, desirable, e.g., for phosphorylation of glycosylation.
- Fischer, Peter M.
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p. 7605 - 7608
(2007/10/02)
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- Improved efficiency and selectivity in peptide synthesis: Use of triethylsilane as a carbocation scavenger in deprotection of t-butyl esters and t-butoxycarbonyl-protected sites
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The use of triethylsilane as a carbocation scavenger in the presence of trifluoroacetic acid in dichloromethane leads to increased yields, decreased reaction times, simple work-up and improved selectivity for the deprotection of t-butyl ester and t-butoxycarbonyl sites in protected amino-acids and peptides in the presence of other acid-sensitive protecting groups such as the benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, O- and S-benzyl and t-butylthio groups.
- Mehta, Anita,Jaouhari, Rabih,Benson, Timothy J.,Douglas, Kenneth T.
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p. 5441 - 5444
(2007/10/02)
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- α-chlorinated carbonates, their method of manufacture and application in the protection of the amine functions of amino acids
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The invention relates to carbonates of formula: STR1 in which X is a fluorine, chlorine or bromine atom and R1 is different from the STR2 group and represents: a substituted or non-substituted, saturated or unsaturated, aliphatic, araliphatic, primary, secondary, tertiary or cycloaliphatic radical. These α-chlorinated carbonates are prepared by the action of a compound of formula R1 OH on a chloroformate of formula: STR3 in a solvent medium in the presence of an acid scavenger which is added after the two preceding compounds. They are used to block the amine function of amino acids. The α-chlorinated carbonate and amino acid are reacted in a solvent medium at a temperature of -5° to 100° C. in the presence of an acid scavenger. Blocked amines are very useful in peptide synthesis.
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- α-Chlorinated carbonates
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The invention relates to new α-chlorinated carbonates characterized in that their formula is: STR1 in which X is a fluorine, chlorine or bromine atom and R1 is different from the STR2 group and represents; a substituted or non-substituted, saturated or unsaturated, aliphatic, araliphatic, primary, secondary, tertiary or cycloaliphatic radical. These α-chlorinated carbonates are prepared by the action of a compound of formula R1 OH on a chloroformate of formula: STR3 in a solvent medium in the presence of an acid scavenger which is added after the two preceding compounds. They are used to block the amine function of amino acids. The α-chlorinated carbonate and amino acid are reacted in a solvent medium at a temperature of -5° to 100° C. in the presence of an acid scavenger. Blocked amines are very useful in peptide synthesis.
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- 9-Fluorenylmethyl Pentafluorophenyl Carbonate as a Useful Reagent for the Preparation of N-9-Fluorenylmethyloxycarbonylamino Acids and their Pentafluorophenyl Esters
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9-Fluorenylmethyl pentafluorophenyl carbonate is a useful reagent for the efficient, side reaction-free introduction of N-9-fluorenylmethyloxycarbonyl protecting group into amino acids and for the subsequent preparation of their pentafluorophenyl esters.Some new compounds of both types are described.
- Schoen, Istvan,Kisfaludy, Lajos
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p. 303 - 305
(2007/10/02)
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- Introduction of 9-fluorenylmethyloxycarbonyl, trichloroethoxycarbonyl, and benzyloxycarbonyl amine protecting groups into O-unprotected hydroxyamino acids using succinimidyl carbonates
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9-Fluorenylmethyl succinimidyl, pentachlorophenyl, and benzotriazole-1-yl carbonates were prepared and their reactivity with L-serine and L-serine benzyl ester was compared.The most efficient reagent, 9-fluorenylmethyl succinimidyl carbonate, was used for the preparation of 9-flourenylmethyloxycarbonyl derivatives of other hydroxyamino acids and hydroxyamino acid esters in high yields.The use of trichloroethyl and benzyl succinimidyl carbonates for an efficient conversion of hydroxyamino acids and their esters into the corresponding N-trichloroethoxycarbonyl and benzyloxycarbonyl derivatives is described.
- Paquet, Alenka
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p. 976 - 980
(2007/10/02)
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