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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Cellular Binding and Internalization by Water-SolubleAromatic Amide FoldamersJone Iriondo-Alberdi 1 , Katta Laxmi-Reddy 1 , Aissa Bouguerne 1 ,Cathy Staedel 2 , and Ivan Huc 11 Université de Bordeaux – CNRS UMR5248, Institut Européen de Chimie et Biologie,2 rue Robert Escarpit, Pessac, 33607, France; 2 Affiliation Université de Bordeaux –INSERM U869, 16 rue Léo Saignat, Bordeaux, 33076, FranceIntroductionAromatic foldamers constitute a new subclass of non-natural oligomers that possess greatadvantages over their natural counterparts [1], such as their stability, robustness, thepredictability of their conformation and the diversity of precursor monomers. Additionally,even though they display linear or helical structures that are considerably different to thoseof α-peptides [2], several aromatic foldamers have been shown to exhibit peptide-likebiological activity (e.g. antimicrobial activity [3] and an ability to inhibit protein-proteininteractions [4]).We report here the synthesis of three fluorescein-tagged oligomers of 8-amino-2-quinolinecarboxylic acid (Figure 1) and their cellular uptake in HeLa, Jurkat lymphocyteand Huh-7 hepatocyte cells. These studies were designed to assess the effect of structuralfeatures such as oligomer length (and therefore the number of charges) on the ability ofthese compounds to cross the cell membrane [5].Results and DiscussionThe synthesis of the aromatic amide foldamers was carried out via a segment-doublingstrategy [5], where a dimer was obtained from two monomers, a tetramer from two dimers,the hexamer from a tetramer and a dimer, and so on. The introduction of the watersolubilizingaminopropoxy side-chain was achievedvia a Mitsunobu reaction at an early stage in theroute, whereas the fluorescent probe was attached tothe foldamers in the last step of the synthesis.Foldamer toxicity was evaluated by means ofthe MTS assay, and the results indicated that thelongest oligomer Q8 led to a 80% decrease in thecell viability only at the highest dose of 200 mg/mL,whereas Q4 and Q6 remained non-toxic up to thisFig. 1. Water soluble aromaticfoldamers. Q8= octamer, Q6=hexamer, Q4= tetramer.concentration. Such an increase in the relativetoxicity of the longer oligomer is expected to resultfrom the higher number of charges in the molecule[6].IFig. 2. Fluorescence microscopy images of Huh-7 cells incubated for 1 h with Q6, Q8 andFITC at 100 μM concentration at 37 ºC (A and D) and 0 ºC (B and E).270