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Publications (35)

  • Elizaveta M. Igumnova · Ekaterina Mishchenko · Tor Haug · [...] · Morten B. Strøm
    [Show abstract] [Hide abstract] ABSTRACT: A library of small aminobenzamide derivatives was synthesised to explore a cationic amphipathic motif found in marine natural antimicrobials. The most potent compound E23 displayed minimal inhibitory concentrations (MICs) of 0.5 – 2 μg/ml against several Gram-positive bacterial strains, including methicillin resistant Staphylococcus epidermidis (MRSE). E23 was also potent against 275 clinical isolates including Staphylococcus aureus, Enterococcus spp., Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae, as well as methicillin-resistant S. aureus (MRSA), vancomycin-resistant enterococci (VRE), and ESBL-CARBA multi-resistant Gram-negative bacteria. The study demonstrates how structural motifs found in marine natural antimicrobials can be a valuable source for making novel antimicrobial lead-compounds.
    Article · Sep 2016
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    [Show abstract] [Hide abstract] ABSTRACT: A practical and efficient methodology for the preparation of 2-aminoethyl α,α-disubstituted β-amino amides in three steps from methyl cyanoacetate has been developed. The key step in the synthesis was the chemoselective reduction of the nitrile group in presence of an amide and aryl halide functionalities. Reduction with RANEY® Nickel catalyst, either with molecular hydrogen (8-10 bar) or under transfer hydrogenation conditions, necessitated in situ protection of the resulting amines with Boc2O, whereas aryl bromide containing nitriles could be chemoselectively reduced with ZnCl2/NaBH4 without debromination. The developed protocol involved only one chromatographic purification step and can be performed at gram scale.
    Full-text available · Article · Jul 2016 · Organic & Biomolecular Chemistry
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    [Show abstract] [Hide abstract] ABSTRACT: We demonstrate in the current work that small cationic antimicrobial β2,2-amino acid derivatives (Mw < 500 Da) are highly potent against Chlamydia pneumoniae at clinical relevant concentrations (< 5 μM, i.e. < 3.4 μg/mL). C. pneumoniae is an atypical respiratory pathogen associated with frequent treatment failures and persistent infections. This gram-negative bacterium has a biphasic life cycle as infectious elementary bodies and proliferating reticulate bodies, and efficient treatment is challenging because of its long and obligate intracellular replication cycle within specialized inclusion vacuoles. Chlamydicidal effect of the β2,2-amino acid derivatives in infected human epithelial cells was confirmed by transmission electron microscopy. Images of infected host cells treated with our lead derivative A2 revealed affected chlamydial inclusion vacuoles 24 hours post infection. Only remnants of elementary and reticulate bodies were detected at later time points. Neither the EM studies nor resazurin-based cell viability assays showed toxic effects on uninfected host cells or cell organelles after A2 treatment. Besides the effects on early intracellular inclusion vacuoles, the ability of these β2,2-amino acid derivatives to suppress Chlamydia pneumoniae infectivity upon treatment of elementary bodies suggested also a direct interaction with bacterial membranes. Synthetic β2,2-amino acid derivatives that target C. pneumoniae represent promising lead molecules for development of antimicrobial agents against this hard-to-treat intracellular pathogen.
    Full-text available · Article · Jun 2016 · PLoS ONE
  • Annfrid Sivertsen · Veronika Tørfoss · Johan Isaksson · [...] · Morten B Strøm
    [Show abstract] [Hide abstract] ABSTRACT: We have in the present study explored the anticancer activity against human Burkitt's lymphoma cells (Ramos) of a series of small linear and cyclic tetrapeptides containing a β(2,2) -amino acid with either two 2-naphthyl-methylene or two para-CF3 -benzyl side chains, along with their interaction with the main plasma protein human serum albumin (HSA). The cyclic and more amphipathic tetrapeptides revealed a notably higher anticancer potency against Ramos cells [50% inhibitory concentration (IC50 ) 11-70 μM] compared to the linear tetrapeptide counterparts (IC50 18.7 to >413 μM). The most potent cyclic tetrapeptide c3 had a 16.5-fold preference for Ramos cells compared to human red blood cells, whereas the cyclic tetrapeptide c1 both showed low hemolytic activity and displayed the overall highest (2.9-fold) preference for Ramos cells (IC50 23 μM) compared to healthy human lung fibroblast cells (MRC-5). Investigating the interaction of selected tetrapeptides and recently reported hexapeptides with HSA revealed that the peptides bind to drug site II of HSA in the 22-28 μM range, disregarding size and overall structure. NMR and in silico molecular docking experiments identified the lipophilic residues as responsible for the interaction, but in vitro studies showed that the anticancer potency of the peptides varied in the presence of HSA and that c3 remained the most potent peptide. Based on our findings, we call for implementing serum albumin binding in development of anticancer peptides, as it may have implications for future administration and systemic distribution of peptide-based cancer drugs. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.
    Article · Apr 2014 · Journal of Peptide Science
  • [Show abstract] [Hide abstract] ABSTRACT: Small antimicrobial β(2,2)-amino acid derivatives (Mw < 500 Da) are reported to display high antibacterial activity against suspended Gram-positive strains combined with low hemolytic activity. In the present study, the anti-biofilm activity of six β(2,2)-amino acid derivatives (A1-A6) against Staphylococcus aureus (ATCC 25923) was investigated. The derivatives displayed IC50 values between 5.4 and 42.8 μM for inhibition of biofilm formation, and concentrations between 22.4 and 38.4 μM had substantial effects on preformed biofilms. The lead derivative A2 showed high killing capacity (log R), and it caused distinct ultrastructural changes in the biofilms as shown by electron and atomic force microscopy. The anti-biofilm properties of A2 was preserved under high salinity conditions. Extended screening showed also high activity of A2 against Escherichia coli (XL1 Blue) biofilms. These advantageous features together with high activity against preformed biofilms make β(2,2)-amino acid derivatives a promising class of compounds for further development of anti-biofilm agents.
    Article · Nov 2013 · Biofouling
  • Terkel Hansen · Dominik Ausbacher · Zack G Zachariassen · [...] · Morten B Strøm
    [Show abstract] [Hide abstract] ABSTRACT: We report the anticancer activity from screening of a series of synthetic β(2,2)-amino acid derivatives that were prepared to confirm the pharmacophore model of short cationic antimicrobial peptides with high anti-Staphylococcal activity. The most potent derivatives against human Burkitt's lymphoma (Ramos) cells displayed IC(50) values below 8 μM, and low toxicity against human red blood cells (EC(50) > 200 μM). A more than 5-fold preference for Ramos cancer cells compared to human lung fibroblasts (MRC-5 cells) was also obtained for the most promising β(2,2)-amino acid derivative 3-amino-N-(2-aminoethyl)-2,2-bis(naphthalen-2-ylmethyl)propanamide (5c). Screening of 5c at the National Cancer Institute (NCI, USA) confirmed its anticancer potency and revealed a very broad range of anticancer activity with IC(50) values of 0.32-3.89 μM against 59 different cancer cell lines. Highest potency was obtained against the colon cancer cell lines, a non-small cell lung cancer, a melanoma, and three leukemia cell lines included in the NCI screening panel. The reported β(2,2)-amino acid derivatives constitute a promising new class of anticancer agents based on their high anticancer potency, ease of synthesis, mode-of-action, and optimized pharmacokinetic properties compared to much larger antimicrobial peptides.
    Article · Oct 2012 · European Journal of Medicinal Chemistry
  • Veronika Tørfoss · Johan Isaksson · Dominik Ausbacher · [...] · Morten B Strøm
    [Show abstract] [Hide abstract] 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. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.
    Article · Oct 2012 · Journal of Peptide Science
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    [Show abstract] [Hide abstract] ABSTRACT: We have recently discovered that small antimicrobial β(2,2)-amino acid derivatives (Mw<500) also display activity against cancer cells. To explore their drug potential, we have presently investigated the mechanisms of action of two derivatives BAA-1 (IC(50) 8.1μg/ml) and BAA-2 (IC(50) 3.8μg/ml) on Ramos human Burkitt's lymphoma cells. Studies using annexin-V-FITC/propidium iodide staining and flow cytometry revealed essential mechanistic differences, which was confirmed by screening for active caspases, investigation of mitochondrial membrane potential, and electron microscopy studies. Our results indicated that BAA-1 killed Ramos cells by destabilizing the cell membrane, whereas BAA-2 caused apoptosis by the mitochondrial-mediated pathway.
    Full-text available · Article · Jul 2012 · Biochimica et Biophysica Acta
  • Terkel Hansen · Morten K Moe · Trude Anderssen · Morten B Strøm
    [Show abstract] [Hide abstract] ABSTRACT: We have investigated the in vitro metabolism of three small antimicrobial β(2,2)-amino acid derivatives (M (w) < 500) that are highly potent against methicillin resistant Staphylococcus aureus, and are among the first compounds designed from small cationic antimicrobial peptides with potential for oral administration. The β(2,2)-amino acid derivatives are virtually completely resistant against degradation by proteases, and to further explore their drug potential, we have investigated the hepatic Phase I metabolism of this class of antimicrobial compounds. The β(2,2)-amino acid derivatives were incubated with murine liver microsomes and the metabolites analyzed semi-quantitatively by HPLC-MS and qualitatively by ultra performance liquid chromatography coupled to a tandem mass spectrometer which enabled identification of the metabolites by careful interpretation of the collision activated dissociation spectra. The study shows that sterically hindered β(2,2)-amino acid derivatives that otherwise are stable against proteolytic degradation underwent Phase I metabolism and were oxidized to a number of different metabolites depending on the structure of the β(2,2)-amino acid side-chains.
    Article · Mar 2012 · European Journal of Drug Metabolism and Pharmacokinetics
  • [Show abstract] [Hide abstract] ABSTRACT: We report a series of synthetic anticancer heptapeptides (H-KKWβ(2,2) WKK-NH(2)) containing eight different central lipophilic β(2,2) -amino acid building blocks, which have demonstrated high efficiency when used as scaffolds in small cationic antimicrobial peptides and peptidomimetics. The most potent peptides in the present study had IC(50) values of 9-23 µm against human Burkitt's lymphoma and murine B-cell lymphoma and were all nonhaemolytic (EC(50)  > 200 µm). The most promising peptide 10e also demonstrated low toxicity against human embryonic lung fibroblast cells and peripheral blood mononuclear cells and exceptional proteolytic stability.
    Article · Mar 2012 · Journal of Peptide Science
  • Margey Tadesse · Morten B. Strøm · Johan Svenson · [...] · Tor Haug
    Patent · Jan 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Synoxazolidinone C is a new member of the synoxazolidinone family of compounds which are dibrominated guanidinium 4-oxazolidinones isolated from the sub-Arctic ascidian Synoicum pulmonaria. The compound was isolated along with synoxazolidinones A and B from the same ascidian extract. Spectroscopic methods revealed that the synoxazolidinone C differed from the other synoxazolidinones by an unprecedented bicyclic partial structure, containing an additional pyrrolidine ring. Synoxazolidinone C exhibited both antibacterial and anticancer activities.
    Article · Apr 2011 · Tetrahedron Letters
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    [Show abstract] [Hide abstract] ABSTRACT: The brominated tryptophan-derived ent-eusynstyelamide B (1) and three new derivatives, eusynstyelamides D, E, and F (2-4), were isolated from the Arctic bryozoan Tegella cf. spitzbergensis. The structures were elucidated by spectroscopic methods including 1D and 2D NMR and analysis of mass spectrometric data. The enantiomer of 1, eusynstyelamide B, has previously been isolated from the Australian ascidian Eusynstyela latericius. Antimicrobial activities are here reported for 1-4, with minimum inhibitory concentrations (MIC) as low as 6.25 μg/mL for 1 and 4 against Staphylococcus aureus. Eusynstyelamides 2 and 3 showed weak cytotoxic activity against the human melanoma A 2058 cell line.
    Full-text available · Article · Mar 2011 · Journal of Natural Products
  • Terkel Hansen · Dominik Ausbacher · Gøril E Flaten · [...] · Morten B Strøm
    [Show abstract] [Hide abstract] ABSTRACT: We have prepared a series of highly potent achiral cationic β(2,2)-amino acid derivatives that fulfill the Lipinski's rule of five and that contain the basic structural requirements of short cationic antimicrobial peptides. Highest antimicrobial potency was observed for one of the smallest β(2,2)-amino acid derivatives (M(w) 423.6) exhibiting a MIC of 3.8 μM against methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and Staphylococcus aureus, and 7.7 μM against Escherichia coli. The β(2,2)-amino acid derivatives were shown to have similar absorption properties as several commercially available drugs, and the results implied a resembling membrane disrupting mechanism of action as reported for much larger cationic antimicrobial peptides. By their high potency, nontoxicity, absorption properties, and ease of synthesis, the β(2,2)-amino acid derivatives demonstrate a way to modify a vastly investigated class of cationic antimicrobial peptides into small drug-like molecules with high commercial potential.
    Article · Feb 2011 · Journal of Medicinal Chemistry
  • Conference Paper · Jan 2011
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    Margey Tadesse · Morten B Strøm · Johan Svenson · [...] · Tor Haug
    [Show abstract] [Hide abstract] ABSTRACT: Bioassay-guided fractionation of the sub-Arctic ascidian Synoicum pulmonaria collected off the Norwegian coast led to the isolation of a novel family of brominated guanidinium oxazolidinones named synoxazolidinones A and B (1 and 2). The backbone of the compounds contains a 4-oxazolidinone ring rarely seen in natural products. The structure of the compounds was determined by spectroscopic methods. The synoxazolidinones exhibited antibacterial and antifungal activities.
    Full-text available · Article · Sep 2010 · Organic Letters
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    Margey Tadesse · Veronika Tørfoss · Morten B. Strøm · [...] · Tor Haug
    Full-text available · Article · Aug 2010 · Biochemical Systematics and Ecology
  • Terkel Hansen · Tore Alst · Martina Havelkova · Morten B Strøm
    [Show abstract] [Hide abstract] ABSTRACT: We have synthesized a series of small beta-peptidomimetics (M(w) <650) that were based on the minimal pharmacophore model for anti-Staphylococcal activity of short cationic antimicrobial peptides. All beta-peptidomimetics had a net charge of +2 and formed an amphipathic scaffold consisting of an achiral lipophilic beta(2,2)-amino acid coupled to a C-terminal l-arginine amide residue. By varying the lipophilic side-chains of the beta(2,2)-amino acids, we obtained a series of highly potent beta-peptidomimetics with high enzymatic stability against alpha-chymotrypsin and a general low toxicity against human erythrocytes. The most potent beta-peptidomimetics displayed minimal inhibitory concentrations of 2.1-7.2 muM against Staphylococcus aureus, methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and Escherichia coli. Small amphipathic beta-peptidomimetics may be a promising class of antimicrobial agents by means of having a similar range of potency and selectivity as larger cationic antimicrobial peptides in addition to improved enzymatic stability and lower costs of production.
    Article · Dec 2009 · Journal of Medicinal Chemistry
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    Vibeke B Michelsen · Grete Moe · Morten B Strøm · [...] · Henning Lygre
    [Show abstract] [Hide abstract] ABSTRACT: The use of resin-based dental restorative materials is rapidly increasing, concurrently the biocompatibility of the materials is under investigation. Attention has been placed on studies addressing the cytotoxic, genotoxic and estrogenic potential of these materials. Therefore, the degree of exposure to eluted compounds from the dental materials is of high interest. The aim of this study was to assess the amounts of 2-hydroxyethyl methacrylate (HEMA) and triethyleneglycol dimethacrylate (TEGDMA), released from two composites, eluting into human saliva. To improve the method of quantification, three tailor-made internal standards were synthesized. Specimens made from two composites (Tetric EvoCeram and Filtek Z250) were polymerized and immersed in human saliva for 24h. Eluted TEGDMA and HEMA were identified and quantified. The quantitative analyses were performed by use of combined gas chromatography-mass spectrometry (GC/MS) with tailor-made internal standards synthesized by dissolving HEMA or TEGDMA in methanol and reducing the double bond of the methacrylate group by hydrogenation with 1H2 and 2H2 (D2) gas. HEMA was released from both materials, whereas TEGDMA eluted from Filtek Z250 only. Full scan GC-MS analysis of each tailor-made internal standard demonstrated one peak only, which was well separated from the corresponding analyte's peak and with no traces of HEMA or TEGDMA. The quantification method seems well suited for in vivo analysis, and the three standards synthesized represent an improved tool for quantification of the eluted monomers. The synthesis may be applied to other methacrylate monomers to produce tailor-made standards for quantification.
    Full-text available · Article · Jul 2008 · Dental Materials
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    Margey Tadesse · Bjørn Gulliksen · Morten B Strøm · [...] · Tor Haug
    [Show abstract] [Hide abstract] ABSTRACT: Benthic marine invertebrates collected from sub-Arctic regions of northern Norway, were found to be a promising source of novel bioactive compounds against human and fish pathogenic bacteria and fungi. Lyophilized material from seven species of ascidians, six sponges and one soft alcyonid coral were extracted with 60% acidified acetonitrile (ACN). After separation into an ACN-rich phase (ACN-extract) and an aqueous phase, and subsequent solid-phase extraction of the aqueous phase, fractions differing in polarity were obtained and screened for antibacterial and antifungal activities, along with the more lipophilic ACN-extracts. Antimicrobial activity was determined against two gram-negative, two gram-positive bacteria, and two strains of fungi. Notably, all the invertebrate species in the study showed activity against all four strains of bacteria and the two strains of fungi. In general, the aqueous fractions displayed highest antimicrobial activity, and the most potent extracts were obtained from the colonial ascidian Synoicum pulmonaria which displayed activity against bacteria and fungi at a concentration of 0.02 mg/ml; the lowest concentration tested.
    Full-text available · Article · Jul 2008 · Journal of Invertebrate Pathology