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

(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 beta-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 KL beta AKL beta AK-NH2. The antibacterial properties of newly synthesized analogues at two different concentrations 10 mu M and 20 mu M, 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 mu M. (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 20 mu M.

Automated summary

A series of shortened analogues of (KLAKLAK)(2) with common chemical structure KL beta AKL beta AK-NH2 were synthesized and studied for antibacterial properties, with only two compounds showing moderate activity against Escherichia coli K12 at low concentration of 20 mu M. Introducing 1,8-naphthalimideGly- and Caf- into the peptides increased cytotoxicity and antiproliferative activity but did not improve their selectivity.