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In the present study, we have further investigated the effects of increasing the rigidity and amphipathicity of two of our lead heptapeptides by preparing a series of seven to five residue cyclic peptides containing the two most promising <jats:italic>\u03b2<\/jats:italic><jats:sup>2,2<\/jats:sup>\u2010amino acid derivatives as part of the central lipophilic core. The peptides were tested for anticancer activity against human Burkitt's lymphoma (Ramos cells), haemolytic activity against human red blood cells (RBC) and cytotoxicity against healthy human lung fibroblast cells (MRC\u20105). The results demonstrated a considerable increase in anticancer potency following head\u2010to\u2010tail peptide cyclization, especially for the shortest derivatives lacking a tryptophan residue. High\u2010resolution NMR studies and molecular dynamics simulations together with an annexin\u2010V\u2010FITC and propidium iodide fluorescent assay showed that the peptides had a membrane disruptive mode of action and that the more potent peptides penetrated deeper into the lipid bilayer. The need for new anticancer drugs with novel modes of action is demanding, and development of short cyclic anticancer peptides with an overall rigidified and amphipathic structure is a promising approach to new anticancer agents. Copyright \u00a9 2012 European Peptide Society and John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/psc.2441","type":"journal-article","created":{"date-parts":[[2012,8,30]],"date-time":"2012-08-30T04:35:25Z","timestamp":1346301325000},"page":"609-619","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Improved anticancer potency by head\u2010to\u2010tail cyclization of short cationic anticancer peptides containing a lipophilic <i>\u03b2<\/i><sup>2,2<\/sup>\u2010amino acid"],"prefix":"10.1002","volume":"18","author":[{"given":"Veronika","family":"T\u00f8rfoss","sequence":"first","affiliation":[{"name":"Natural Products and Medicinal Chemistry Research Group, Department of Pharmacy, Faculty of Health Sciences University of Troms\u00f8  NO\u20109037 Troms\u00f8 Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Isaksson","sequence":"additional","affiliation":[{"name":"Drug Discovery and Design, Department of Chemistry, Faculty of Science and Technology University of Troms\u00f8  NO\u20109037 Troms\u00f8 Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Ausbacher","sequence":"additional","affiliation":[{"name":"Natural Products and Medicinal Chemistry Research Group, Department of Pharmacy, Faculty of Health Sciences University of Troms\u00f8  NO\u20109037 Troms\u00f8 Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f8rn\u2010Olav","family":"Brandsdal","sequence":"additional","affiliation":[{"name":"Drug Discovery and Design, Department of Chemistry, Faculty of Science and Technology University of Troms\u00f8  NO\u20109037 Troms\u00f8 Norway"},{"name":"Centre of Theoretical and Computational Chemistry, Department of Chemistry, Faculty of Science and Technology University of Troms\u00f8  NO\u20109037 Troms\u00f8 Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00f8ril E.","family":"Flaten","sequence":"additional","affiliation":[{"name":"Drug Transport and Delivery Research Group, Department of Pharmacy, Faculty of Health Sciences University of Troms\u00f8  NO\u20109037 Troms\u00f8 Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trude","family":"Anderssen","sequence":"additional","affiliation":[{"name":"Natural Products and Medicinal Chemistry Research Group, Department of Pharmacy, Faculty of Health Sciences University of Troms\u00f8  NO\u20109037 Troms\u00f8 Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiane de A.","family":"Cavalcanti\u2010Jacobsen","sequence":"additional","affiliation":[{"name":"Natural Products and Medicinal Chemistry Research Group, Department of Pharmacy, Faculty of Health Sciences University of Troms\u00f8  NO\u20109037 Troms\u00f8 Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Havelkova","sequence":"additional","affiliation":[{"name":"Natural Products and Medicinal Chemistry Research Group, Department of Pharmacy, Faculty of Health Sciences University of Troms\u00f8  NO\u20109037 Troms\u00f8 Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard T.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Biochemistry Research Group, Department of Biological Sciences University of Calgary  Calgary Alberta Canada T2N 1N4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans J.","family":"Vogel","sequence":"additional","affiliation":[{"name":"Biochemistry Research Group, Department of Biological Sciences University of Calgary  Calgary Alberta Canada T2N 1N4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten B.","family":"Str\u00f8m","sequence":"additional","affiliation":[{"name":"Natural Products and Medicinal Chemistry Research Group, Department of Pharmacy, Faculty of Health Sciences University of Troms\u00f8  NO\u20109037 Troms\u00f8 Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,8,30]]},"reference":[{"key":"e_1_2_6_2_1","volume-title":"Cancer Facts & Figures\u20092011","author":"AmericanCancerSociety","year":"2011"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/10408440008951120"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2007.11.008"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2009.08.043"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chemphyslip.2011.09.004"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0966-842X(00)01823-0"},{"key":"e_1_2_6_8_1","first-page":"151","article-title":"In vitro characterization of the anticancer activity of membrane\u2010active cationic peptides. 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