Synthesis, Antitumor and Antibacterial Studies of New Shortened Analogues of (KLAKLAK)2-NH2 and Their Conjugates Containing Unnatural Amino Acids

  • Molecules. 2021 Feb 8;26(4):898. doi: 10.3390/molecules26040898.
Sirine Jaber  1 ,  Ivan Iliev  2 ,  Tsvetelina Angelova  1 ,  Veronica Nemska  1 ,  Inna Sulikovska  2 ,  Emilia Naydenova  1 ,  Nelly Georgieva  1 ,  Ivan Givechev  1  3 ,  Ivo Grabchev  4 ,  Dancho Danalev  1
Affiliations
  • 1. University of Chemical Technology and Metallurgy, 8 Kliment Ohridski blvd., 1756 Sofia, Bulgaria.
  • 2. Institute of Experimental Morphology, Pathology and Anthropology with Museum, Bulgarian Academy of Sciences, Acad. G. Bonchev str., bl. 25, 1113 Sofia, Bulgaria.
  • 3. Testing center Global Test Ltd., 31 Krushovski vrah Street, Sofia, Bulgaria.
  • 4. Department of Chemistry and Biochemistry, Physiology and Pathophysiology, Sofia University "St. Kliment Ohridski", Sofia, Bulgaria.
PMID: 33567789 DOI: 10.3390/molecules26040898
Abstract

(1) Background: (KLAKLAK)2 is a representative of the antimicrobial peptide group which also shows good Anticancer properties. (2) Methods: Herein, we report synthesis using SPPS and characterization by HPLC/MS of a series of shortened analogues of (KLAKLAK)2. They contain single sequence KLAKLAK as C-terminal amides. In addition, substitution of some natural Amino acids with unnatural β-Ala and nor-Leu is realized. In addition, these structures are conjugated with second pharmacophore with well proven Anticancer properties 1,8-naphthalimide or caffeic acid. Cytotoxicity, antiproliferative effect and antimicrobial activity of newly synthesized structures were studied. (3) Results: The obtained experimental results reveal significant selective index for substances with common chemical structure KLβAKLβAK-NH2. The Antibacterial properties of newly synthesized analogues at two different concentrations 10 μM and 20 μM, were tested against Gram-negative Microorganisms Escherichia coli K12 407. Only two of the studied compounds KLAKLAK-NH2 and the one conjugated with second pharmacophore 1,8-naphthalimide and unnatural amino acid nor-Leu showed moderate activity against tested strains at concentration of 20 μM. (4) Conclusions: The obtained results reveal that the introducing of 1,8-naphthalimideGly- and Caf- increase the cytotoxicity and antiproliferative activity of the peptides but not their selectivity. Only two compounds KLAKLAK-NH2 and 1,8-naphthalimideGKnLAKnLAK-NH2 show moderate activity against Escherichia coli K12 at low concentration of 20μM.

Keywords
(KLAKLAK)2-NH2; 1,8-naphthalimide; anticancer peptides; anticancer properties; antimicrobial activity; caffeic acid; unnatural amino acids.
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