1365564-15-3Relevant articles and documents
An amphipathic cyclic tetrapeptide scaffold containing halogenated β2,2-amino acids with activity against multiresistant bacteria
Paulsen, Marianne H.,Karlsen, Eskil André,Ausbacher, Dominik,Anderssen, Trude,Bayer, Annette,Ochtrop, Philipp,Hedberg, Christian,Haug, Tor,Ericson Sollid, Johanna U.,Str?m, Morten B.
, (2018/09/06)
The present study describes the synthesis and biological studies of a small series of head-to-tail cyclic tetrapeptides of the general structure c(Lys-β2,2-Xaa-Lys) containing one lipophilic β2,2-amino acid and Lys, Gly, Ala, or Phe as the Xaa residue in the sequence. The peptides were investigated for antimicrobial activity against gram-positive and gram-negative reference strains and 30 multiresistant clinical isolates including strains with extended spectrum β-lactamase—carbapenemase (ESBL-CARBA) production. Toxicity was determined against human red blood cells. The most potent peptides showed high activity against the gram-positive clinical isolates with minimum inhibitory concentrations of 4–8?μg/mL and low haemolytic activity. The combination of high antimicrobial activity and low toxicity shows that these cyclic tetrapeptides containing lipophilic β2,2-amino acids form a valuable scaffold for designing novel antimicrobial agents.
Synthesis of anticancer heptapeptides containing a unique lipophilic β2,2-amino acid building block
Torfoss, Veronika,Ausbacher, Dominik,Cavalcanti-Jacobsen, Cristiane de A.,Hansen, Terkel,Brandsdal, Bjorn-Olav,Havelkova, Martina,Strom, Morten B.
scheme or table, p. 170 - 176 (2012/06/29)
We report a series of synthetic anticancer heptapeptides (H-KKWβ2,2WKK-NH2) containing eight different central lipophilic β2,2-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 IC50 values of 9-23μm against human Burkitt's lymphoma and murine B-cell lymphoma and were all nonhaemolytic (EC50>200μm). The most promising peptide 10e also demonstrated low toxicity against human embryonic lung fibroblast cells and peripheral blood mononuclear cells and exceptional proteolytic stability.
Anticancer activity of small amphipathic β2,2-amino acid derivatives
Hansen, Terkel,Ausbacher, Dominik,Zachariassen, Zack G.,Anderssen, Trude,Havelkova, Martina,Strom, Morten B.
, p. 22 - 29 (2013/02/23)
We report the anticancer activity from screening of a series of synthetic β2,2-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 IC50 values below 8 μM, and low toxicity against human red blood cells (EC50 > 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 β2,2-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 IC50 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 β2,2-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.
Synthesis of cationic antimicrobial β2′2-amino acid derivatives with potential for oral administration
Hansen, Terkel,Ausbacher, Dominik,Flaten, Goril E.,Havelkova, Martina,Str?m, Morten B.
, p. 858 - 868 (2011/04/18)
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 β2, 2-amino acid derivatives (Mw 423.6exhibiting 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 β2, 2-amino acid derivatives demonstrate a way to modify a vastly investigated class of cationic antimicrobial peptides into small druglike molecules with high commercial potential.
Antimicrobial activity of small β-peptidomimetics based on the pharmacophore model of short cationic antimicrobial peptides
Hansen, Terkel,Alst, Tore,Havelkova, Martina,Str?m, Morten B.
experimental part, p. 595 - 606 (2010/06/19)
We have synthesized a series of small β-peptidomimetics (Mw 2,2-amino acid coupled to a C-terminal L-arginine amide residue. By varying the lipophilic side-chains of the β2,2-amino acids, we obtained a series of highly potent β-peptidomimetics with high enzymatic stability against α-chymotrypsin and a general low toxicity against human erythrocytes. The most potent β-peptidomimetics displayed minimal inhibitory concentrations of 2.1-7.2 μM against Staphylococcus aureus, methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and Escherichia coli. Small amphipathic β-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.
