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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, 2010Anticancer Activity of Short Cationic Beta-PeptidomimeticsVeronika Tørfoss 1 , Dominik Ausbacher 1 , Terkel Hansen 1 ,Martina Havelkova 1 , and Morten B. Strøm 11 Institute of Pharmacy, Department of Health Sciences, University of Tromsø,Tromsø, N-9037, NorwayIntroductionCurrent anticancer chemotherapy is based on alkylating agents, antimetabolites anddifferent natural products. However, these compounds show poor selectivity for tumor cellsand cause severe side-effects, resulting in troublesome therapeutic regimes and low patientcompliance [1]. Tumor cells are also notorious for developing resistance to currenttherapies by evolving efflux pumps that transport the chemotherapeutics out of the tumorcells, or by other mutations that prevent efficient drug-target interactions [2,3]. There istherefore an urgent demand for developing anticancer drugs with new targets and modes ofaction to improve anticancer selectivity, diminish induction of resistance, and improvepatient compliance.In the search for new types of anticancer drugs there is an increasing interest forcationic antimicrobial peptides (AMPs), or host defense peptides belonging to the innateimmunity of mammals, amphibians and insects [4-8]. Cationic AMPs that displayanticancer activity show a unique mode of action by targeting the cell membrane of tumorcells. The AMPs can destabilize the cytoplasmic membrane to cause lysis or translocateacross the cell membrane and attack the mitochondria, inducing apoptosis [9]. Theselectivity of cationic AMPs for cancer cells compared to non-malignant cells is thought toreside in a small excess of phosphatidylserine (PS) and other anionic cell membraneconstituents on the tumor surface, which are not present on the outer leaflet of the cellmembrane of healthy cells, giving the tumor cells a slightly more negative membranesurface than healthy cells [10-14].We have in the present study synthesized and tested the toxicity and antitumoralpotency of eight cationic beta-peptidomimetics that were designed to mimic theamphipathic properties of Lactoferricin B (LfcinB). LfcinB is a well-known antitumoralpeptide, and the basis of its antitumoral properties is assumed to reside in its content ofaromatic residues, a net positive charge, and an overall strong amphipathic structure. Thebeta-peptidomimetics were designed to mimic the structural properties of LfcinB byintroducing a bulky, lipophilic beta-amino acid into a palindromic model heptamericpeptide (H-Lys-Lys-Trp-‘beta-amino acid’-Trp-Lys-Lys-NH 2 ). By changing the bulkinessand lipophilicity of the substituents of the beta-amino acids, we have investigated how thebulk of the beta-amino acid could influence the antitumoral potency and toxicity of thebeta-peptidomimetics.Results and DiscussionThe beta-peptidomimetics displayed high anticancer potency against RAMOS cells (humanBurkit´s lymphoma) and the murine A20 cancer cell line, with IC 50 values from 8-24microMolar for the three most potent compounds. The beta-peptidomimetics displayedfurthermore up to 6-fold selectivity for cancer cells compared to non-malignant humanMRC-5 fibroblasts, and were basically non-hemolytic.Using retention times on a C 18 -RP-HPLC column as a measurement of overalllipophilicity, and correlating the retention times with biological data, we were able tovisualize important trends in our results (Figure 1).In general, the anticancer potency increased with increasing retention time, andthereby increasing lipophilicity of the beta-peptidomimetics. However, when consideringthe selectivity of the different beta-peptidomimetics, there was no apparent linearcorrelation with the retention times. But as we looked at the distribution of thebeta-peptidomimetics with respect to retention times, three clusters of compounds wereevident (Figure 1). Since the only difference between the beta-peptidomimetics was thesubstituent of the beta-amino acid, and since the retention times did not correlate with thecalculated logPs of the compounds, this clustering might reflect different types of structuralconformations of the peptide chains. The selectivity for A20 over MRC-5 was highest for262