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Fig. 1. Antitumor activity against the A20 and RAMOS cell lines and toxicity against theMRC-5 cell line of compounds 6a-h correlated to retention time on a C 18 -RP-HPLCcolumn. Linear regression is displayed for the three different cell lines, as well as thecoefficients of determination (R 2 ).compounds with retention times between 4.5 and 6 min, while it was low, or notmeasurable, for compounds with the longest and shortest retention times. This might implythat the selectivity for cancer cells was more dependent on structural differences, and noton overall lipophilicity, as opposed to the anticancer potency of the beta-peptidomimetics.ConclusionWe have designed and synthezised a total of eight higly potent and selectivebeta-peptidomimetics resembeling AMPs, and their antitumoral activity correlated wellwith their retention times on a RP-HPLC column. At the same time the selectivity of thecompounds did not correlate with the retention times in the same way, but seemed to bemore dependent on structureal differences. Further studies are in progress to elucidate apharmacophore model for short anticancer beta-peptidomimetics.AcknowledgmentsThe project was supported by KOSK II grant 185141/V30 (Norwegian Research Council).References1. Smith, L.L., et al. Critical Reviews in Toxicology 30, 571-594 (2000).2. Pérez-Tomás, R. Current Medicinal Chemistry 13, 1859-1865 (2006).3. Ellis, L.M., Hicklin, D.J. Clin. Cancer Res. 15, 7471-7478 (2009).4. Hoskin, D.W., Ramamoorthy, A. Biochimica et Biophysica Acta (BBA) – Biomembranes 1778, 357-375 (2008).5. Leuschner, C., Hansel, W. Current Pharmaceutical Design 10, 2299-2310 (2004).6. Papo, N., Shai, Y. Cellular and Molecular Life Sciences 62, 784-790 (2005).7. Mader, J.S., Hoskin, D.W. Expert Opin. Investig. Drugs 15, 933-946 (2006).8. Schweizer, F. European Journal of Pharmacology 625, 190-194 (2009).9. Eliassen L.T., et al. International Journal of Cancer 119, 493-500 (2006).10. Kim, Y., Varki, A. Glycoconjugate Journal 14, 569-576 (1997).11. Utsugi, T., et al. Cancer Res. 51, 3063-3066 (1991).12. Schröder-Borm, H., Bakalova, R., Andrä, J. FEBS Letters 579, 6128-6134 (2005).13. Dobrzynska, I., et al. Molecular and Cellular Biochemistry 276, 113-119 (2005).14. Iwasaki, T., et al. Peptides 30, 660-668 (2009).263
Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Bactericidal Activity of Small Beta-PeptidomimeticsTerkel Hansen, Dominik Ausbacher, Martina Havelkova, andMorten B. Strøm *Department of Pharmacy, Faculty of Health Sciences, University of Tromsø, 9018,Tromsø, Norway; *Corresponding author, e-mail: morten.strom@uit.noIntroductionThe number of causalities reported in the US by methicillin resistant Staphylococcusaureus (MRSA) infections is currently higher than the number of both HIV/AIDS andtuberculosis together; hence the need for novel antimicrobial agents is urgent [1,2].Cationic antimicrobial peptides (AMP’s) have since their discovery during the 1980’s beenheavily investigated for their antimicrobial properties. AMP’s show a unique mode ofaction by targeting the bacterial cytoplasmic membrane in a non-receptor specific manner,and thereby have a much lower risk of inducing resistance compared to conventionalantimicrobial drugs [3-5].A pharmacophore model for short AMP’s was reported in 2003. In this model activityagainst both E. coli and S. aureus necessitates an amphipathic peptide with a net positivecharge of +2 [6]. To obtain antimicrobial activity against the Gram-negative bacterium E.coli three bulky/lipophilic groups is also a necessity, whereas for activity against the Grampositivebacteria Staphylococcus aureus, MRSA and methicillin resistant Staphylococcusepidermidis (MRSE), only two bulky/lipophilic groups are needed [6].The objective of the current project was to investigate if a scaffold based on an achirallipophilic 3-amino-2,2-disubstituted propionic acid (beta 2,2 -amino acid) coupled to aC-terminal amidated L-arginine residue could confine all the elements of the pharmacophoremodel for anti-staphylococcal activity. The minimal inhibitory concentration(MIC) of the compounds was determined against S. aureus, MRSA, MRSE and E. coli. Atoxicity assessment was performed using human erythrocytes by measuring the hemolyticactivity of the beta-peptidomimetics. Plating of treated bacterium suspensions at differenttime intervals and at different concentrations was used to investigate if the main mechanismof action was bactericidal or bacteriostatic.Results and DiscussionSynthesis:The beta-peptidomimetics were prepared in a seven-step synthesis in which only the threeintermediates shown in Scheme 1 were isolated, as previously reported by our group [7].The total yields for synthesis of the crude Boc-beta 2,2 -amino acids (3a-n) ranged thereforefrom 30-71%, depending on the bulkiness of the lipophilic side-chains. For detailsregarding structures and synthesis, see Hansen, et al [7].Scheme 1. Overview of synthesis.264
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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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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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