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Fig. 2. 3D-Representation of the 54 structures with energy < 147 kcal/mole resultingfrom the MD calculations of heptaibin (2·10 -3 M, 600 MHz, 313K, 100mM SDS-d 25 in 9:1H 2 O/D 2 O) with the backbone atoms superimposed. The Hyp 10 kink residue is highlighted.Average kink angle: 25.2° (+/- 3°).References1. Toniolo, C., Brückner, H. Peptaibiotics: Fungal Peptides Containing -Dialkyl Amino-Acids,Verlag Helvetica Chimica Acta, Zürich, Switzerland, and Wiley-VCH, Weinheim, Germany, 2009.2. Ishiyama, D., Satou, T., Senda, H., Fujimaki, T., Honda, R., Kanazawa, S. J. Antibiot. (Tokyo) 53,728-732 (2000).3. Hjørringgaard, C.U., Pedersen, J.M., Vosegaard, T., Nielsen, N.C., Skrydstrup, T. J. Org. Chem. 74,1329-1332 (2009).393
<strong>Proceedings</strong> of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Synthesis, Characterization and Cytostatic Effect ofNew Pemetrexed-Peptide ConjugatesErika Orbán 1 , Zsanett Miklán 1 , Zoltán Bánóczi 1 , andFerenc Hudecz 1,21 Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös LorándUniversity, Budapest, H-1117, Hungary; 2 Department of Organic Chemistry, EötvösLoránd University, 1518, Budapest, 112 POB 32, H-1518, HungaryIntroductionPemetrexed is used as a folate-antimetabolite in the treatment of pleural mesothelioma andnon-small cell lung carcinoma. This drug inhibits at least three enzymes (thymidylatesynthase, dihydrofolate reductase and glycinamide-ribonucleotide formyl transferase)involved in purine- and pyrimidine synthesis. Pemetrexed (Pem) treatment could beac<strong>com</strong>panied by various side-effects like nausea, vomiting, diarrhea, etc. Conjugation ofanticancer drug (e.g. daunomycin, methothrexate) with peptide carrier could decrease oreven eliminate side effects [1,2]. Oligoarginines are de novo designed cell penetratingpeptides capable to translocate covalently attached cargoes [2]. Oligoarginine and otheroligopeptides were conjugated with Pem in our group earlier [3]. It was observed thatpeptide IELLQAR used as selective inhibitor could inhibit the attachment of E-selectin tothe cell surface-carbohydrates and thus limit the risk of metastases formation [4].Results and DiscussionIn this study we report on the synthesis and characterization of novel Pem – peptideconjugates containing cell-penetrating octaarginine and/or E-selectin binding IELLQARpeptide and thioether bond between the moieties. The conjugates were characterized by RP-HPLC and ESI MS. The cytostatic effect of Pem derivatives and conjugates was studied onNCI-H358 non-small cell lung carcinoma and on HL-60 human leukemia cell lines.For the synthesis of these conjugates, we first prepared Pem dimethylester by thereaction between Pem disodium salt and thionyl chloride in methanol, based on publishedprocedure [5]. Pure Pem(OMe) 2 was obtained by crystallization from ethanol. In the nextstep ClAc-Pem(OMe) 2 was synthesized by the reaction of chloroacetic acid anhydride andPem(OMe) 2 in the presence of DIEA in DMF.C-terminally modified octaarginine and peptide IELLQAR as well as the conjugatepeptide, IELLQARGGCGGR 8 was prepared on solid phase by Fmoc-strategy using in situactive ester coupling strategy. Cysteine amino acid was incorporated into the sequence toprovide an appropriate site for thioether bond formation with the chloroacetyl group ofpemetrexed.Peptide conjugates of Pem(OMe) 2 were prepared by the reaction between chloroacetylgroup of Pem(OMe) 2 and thiol group of Cys, present in the peptide sequence, underalkaline conditions (pH 8). Finally, peptide conjugates of Pem were prepared by removingthe methylester protecting groups from the carboxylic groups of Pem. Removal of theprotecting groups is indispensable because these carboxylic groups are essential for thebiological activity of Pem, as demonstrated in in vitro experiments (Table 1). To removethe protecting groups three times molar excess of 0.1 M NaOH and acetone (1:1, v/v) wasused as cleavage mixture at 5°C for 60-90 min. The progress of the reaction was monitoredby analytical RP-HPLC and terminated by adding of 0. 1M HCl solution to the mixture.394
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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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Fig. 2. a) Part of the 400 MHz HR-M
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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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Proceedings of the 31 st European P
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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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