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MeOOMeHN8OOOa -fH 2 NH 2 NOHX'NHNHOHNX''O NHOH OX''' NHONH 29 X'= Phe; Phe X''= D-Trp X'''= Thr;10 X'= Phe; Phe X''= D-2-NaI X'''= Thr;11* X'= Phe; Tyr X''= D-2-NaI X'''= Thr;*D-Gly-AllReagents and conditions: (a) Swelling in DMF; (b) 20% piperidine inDMF (2 x 10 min); (c) Coupling with 8 aminoacids , DMF; (d)catalyst 7 (10% mmol), DCM; (e) 20% piperidine in DMF (2 x 10min.); (f) Cleavage: [TFA/H 2O/EDT/Phenol (94:2:2:2)].Scheme 2. Synthesis of 8-membered ringSomatostatin dicarba-analogues.the efficacy of the MW technique forobtaining cyclooctapeptides dicarbaanalogues(9-11) (Scheme 2) impossibleto be obtained with normal heatingmethods (data not shown).We applied different MW methodsin order to clarify which parameters (MWpower, time, and temperature) couldinfluence RCM reaction. Differencesamong the available methods are due tothe possibility of setting temperature andpower as a function one of each other,while pressure had a fixed upper limitthreshold. Its value was correlated totemperature and power. We succeded to<strong>com</strong>plete the RCM cyclization step foralmost all the linear peptides in 1 h(instead of 24-48 h required with conventional heating) applying 300 W, 100 °C and 70-90psi pressure (main parameter for obtianing the cyclization reaction). Reaction timeextended to 2 h increased yield in RCM. There is evidence that different amino acidsconfiguration (L/D) in the sequence can favour or disfavour the RCM, even under MWirradiation.Table 1. Comparison in cyclic/linear yield and reaction time (h) between conventionalheating (50 °C) and microwave assisted irradiation (100 °C, 300 W, 70-90 psi) for thesynthesis of Somatostatin dicarba-analoguesDicarbaanalogueHeating method Time (hours) Yield (HPLC cyclic/linear ratio)4 Oil bath 48 90:104 MW 1 86:142 Oil bath 48 50:502 MW 1 84:165 Oil bath 24 90:105 MW 1 75:256 Oil bath 24 90:109 Oil bath 48 5:959 MW 1 75:2510 Oil bath 48 5:9510 MW 1 70:3011 Oil bath 48 5:9511 MW 2 98:2AcknowledgmentsSupported by Ente Cassa di Risparmio di Firenze and Advanced Accelerator Applications S. p. a..References1. Maemoto, A., et al. J. Biol. Chem. 279, 44188-44196 (2004).2. Weckbecker, G., Lewis I., Albert, R., et al. Nat. Rev. Drug Discovery 2, 999-1018 (2003).3. Williams, R.M., Liu, J. J. Org. Chem. 63, 2130-2132 (1998).4. Miller, S.J., et al. J. Am. Chem. Soc. 118, 9606-9614 (1996).5. Grubbs, R.H. Tetrahedron 60, 7117-7140 (2004).6. Carotenuto, A., et al. Lett. Org. Chem. 2, 274-279 (2005).7. D’Addona, D., et al. J. Med. Chem. 51, 512-520 (2008).8. Rizzolo, F., et al. Int. J. Pept. Res. Ther. 13, 203-208 (2007).9. Kappe, C.O. Angew. Chem. Int. Ed. Engl. 43, 6250-6284 (2004).185
<strong>Proceedings</strong> of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Microwave-Assisted Solid Phase Synthesis of[Asn 641 (Glc)]FAN(635-655): A New Case Study for Optimisationof Glycopeptide SynthesisFabio Rizzolo 1,2 , Francesca Nuti 1,2 , Shashank Pandey 1,2 ,Mario Chelli 1,2 , Paolo Rovero 1,3 , and Anna Maria Papini 1,21 Laboratory of Peptide & Protein Chemistry & Biology, University of Florence, PoloScientifico e Tecnologico, Sesto Fiorentino (Fi), I-50019, Italy; 2 Department of Chemistry‘‘Ugo Schiff’’ and CNR-ICCOM, Via della Lastruccia 3/13, University of Florence, PoloScientifico e Tecnologico, Sesto Fiorentino (Fi), I-50019, Italy; 3 Department ofPharmaceutical Sciences, Via Ugo Schiff 6, University of Florence, Polo Scientifico eTecnologico, Sesto Fiorentino (Fi), I-50019, ItalyIntroductionFactor associated with neutral sphingomyelinase activation (FAN) represents a member of theWD-repeat family of proteins that includes mainly regulatory proteins [1]. A preliminarybioinformatic study revealed high sequence homology of the fragment 635-655 of this proteinwith CSF114(Glc), the synthetic glycopeptide developed to detect antibodies in MultipleSclerosis (MS) patients’ sera [2]. As FAN(635-655) is characterized by the minimumconsensus pattern for N-glycosylation of asparagine residues (Asn-Xaa-Ser/Thr, where Xaa isany amino acid except Pro), we investigated a possible involvement of this peptide as linearnatural epitope of antibodies in MS.The bottleneck of this study was to obtain by Solid-Phase Peptide Synthesis (SPPS)[Asn 641 (Glc)]FAN(635-655) in high purity and good yield to be tested in immuneenzymaticassays on sera. In fact conventional SPPS protocol failed during the coupling of the stericallyhindered building block Asn 641 (GlcOAc 4 ) and of other bulky amino acid residues. Finally wesucceeded in the synthesis of this glycopeptide using microwave irradiations [3].Results and DiscussionThe main difficulty associated with high-throughput glycopeptide synthesis resides in theextremely low coupling efficiency of sterically hindered, sugar-bound amino acid derivatives.Solid-Phase Glycopeptides Synthesis (SPGS) could be improved by employing a largeexcess of Fmoc-Asn(GlcOAc 4 )-OH, but considering the non trivial protocol to achieve thisproduct, it is important to optimize glycopeptides synthetic strategy in order to obtain them inhigh yield and purity.[Asn 641 (Glc)]FAN(635-655) sequence is the following: H-Gly-Ile-Thr-Val-Ser-Arg-Asn(Glc)-Gly-Ser-Ser-Val-Phe-Thr-Thr-Ser-Gln-Asp-Ser-Thr-Leu-Lys-OH.The glycopeptide synthesis was performed on Liberty Microwave Peptide Synthesizer(CEM), a monomode microwave system, starting from a Fmoc-Lys(Boc)-Wang resin (0.67mmol/g, 0.150 g) using the following protocols: N -Fmoc deprotection with a 20% piperidinesolution in DMF; coupling reactions using a 0.2 M solution of amino acid in DMF (5 eq), 0.5M solution of TBTU in DMF (5 eq) and a 2 M solution of DIEA in NMP (10 eq); buildingblock coupling reaction with a 0.25M solution of HOBt/DIPCDI in DMF (3 eq) and 0.1 Msolution of Fmoc-Asn(GlcOAc 4 )-OH in NMP (3 eq).MW-SPPS cycle consists in two deprotection steps performed at 75 °C using 35 W for30 sec and 60 W for 180 sec respectively. Coupling steps were performed at 75 °C, using 30W for 300 sec, while Fmoc-Asn(GlcOAc 4 )OH coupling was performed at 55°C, 15 W for 900sec. The synthesis ongoing was monitored by microwave-assisted micro-cleavages usingTFA/water/TIS solution (95:2.5:2.5 v/v/v). Final cleavage of the peptide from the resin andside-chain deprotections were performed with ad hoc cleavage cocktail TFA/water/TISsolution (95:2.5:2.5 v/v/v), in 3 hours at room temperature.The application of microwaves to SPGS allowed us to synthesize glycopeptidescontaining sterically hindered building blocks, which are not easily accessible by conventionalsynthetic methods. In order to facilitate the coupling reactions and deprotections, wesuccessfully used microwave irradiation to synthesize [Asn 641 (Glc)]FAN(635-655).Microwaves were also applied to perform micro-cleavages of peptide fragments to monitorthe elongation of the chain, and in particular, during the Fmoc-Asn(GlcOAc 4 )-OH coupling.186
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Peptides 2010Tales of PeptidesProce
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Peptides 2010Tales of PeptidesProce
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IntroductionWe had the distinct hon
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Scientific programIn planning the 3
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31 st EUROPEAN PEPTIDE SYMPOSIUMSep
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published by John Wiley & Sons as a
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The Josef Rudinger AwardThis award
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Young Investigators' SymposiumThe y
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xxiv
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Design of Peptidyl-Inhibitors for G
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Synthetic Antifreeze Glycopeptide A
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Synthesis and Oxidative Folding of
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Convergent Syntheses of Huprp106-12
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Bactericidal Activity of Small Beta
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Bradykinin Analogues Acylated on Th
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Antimicrobial Activity of Small 3-(
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Interaction of Curcumin with A-Synu
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Fluorescent and Luminescent Fusion
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Cellular Expression of the Human An
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2D IR Spectroscopy of Oligopeptides
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large, non-redundant subset of prot
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The aberrantly glucosylated peptide
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Table 1. Proline cis/trans ratios o
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Table 1. Yields, UV-vis absorption
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Table 1. Purity of the targeted tri
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processes are blocked. Interestingl
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(tb4 n ,1 m )MTII(tb1 n ,4 m )MTIIF
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Once printed, the amino acid partic
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A) PSA, few seconds73B) PSA, 45 min
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short β strands. In contrast, nume
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neg. control Cs9-Rhd MM-218Fig. 2.
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Table 1. The general structure of t
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% ID in the liver 1 h p.i.100908070
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Peptidyl phosphoranes were first re
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obtained from the same sardines and
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MccJ25 variants were produced by si
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Fig. 2. Proposed signaling mechanis
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Table 1. mCD4-HS12 antiviral activi
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Subject index(S)-2-(1-adamantyl)gly
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chip 18chiral triazine condensing r
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heat stress 348helical conformation
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O-acyl isopeptide method 112obesity
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SH2-ligands 210short collagen-relat
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Author indexAboye, Teshome Leta 142
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Chi, Hongfang 480Chiche, Laurent 6C
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Geronikaki, Athina 444Gessmann, Ren
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Kostova, Kalina 528Kotzia, Georgia
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Nagata, Koji 162Nagayev, Igor Yu. 5
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Salvarese, Nicola 518Sammet, Benedi
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Vauquelin, Georges 138Veiga, Ana Sa
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