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


Jaber S(1), Iliev I(2), Angelova T(1), Nemska V(1), Sulikovska I(2), Naydenova E(1), Georgieva N(1), Givechev I(1)(3), Grabchev I(4), Danalev D(1).
Author information:
(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.


(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.