title: Improved anticancer potency by head-to-tail cyclization of short cationic anticancer peptides containing a lipophilic β(2,2) -amino acid.
abstract: We have recently reported a series of synthetic anticancer heptapeptides (H-KKWβ(2,2) WKK-NH(2) ) containing a central achiral and lipophilic β(2,2) -amino acid that display low toxicity against non-malignant cells and high proteolytic stability. 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 β(2,2) -amino 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-5). The results demonstrated a considerable increase in anticancer potency following head-to-tail peptide cyclization, especially for the shortest derivatives lacking a tryptophan residue. High-resolution NMR studies and molecular dynamics simulations together with an annexin-V-FITC 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.
authors.affiliation: Natural Products and Medicinal Chemistry Research Group, Department of Pharmacy, Faculty of Health Sciences, University of Tromsø, NO-9037, Tromsø, Norway.
authors.forename: Veronika
authors.initials: V
authors.lastname: Tørfoss
authors.forename: Johan
authors.initials: J
authors.lastname: Isaksson
authors.forename: Dominik
authors.initials: D
authors.lastname: Ausbacher
authors.forename: Bjørn-Olav
authors.initials: BO
authors.lastname: Brandsdal
authors.forename: Gøril E
authors.initials: GE
authors.lastname: Flaten
authors.forename: Trude
authors.initials: T
authors.lastname: Anderssen
authors.forename: Cristiane de A
authors.initials: Cde A
authors.lastname: Cavalcanti-Jacobsen
authors.forename: Martina
authors.initials: M
authors.lastname: Havelkova
authors.forename: Leonard T
authors.initials: LT
authors.lastname: Nguyen
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Vogel
authors.forename: Morten B
authors.initials: MB
authors.lastname: Strøm
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004912:Erythrocytes / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D010456:Peptides, Cyclic