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Synthesis, Antitumor and Antibacterial Studies of New Shortened Analogues of (KLAKLAK)(2)-NH(2) 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 KLAKLA...

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Detalles Bibliográficos
Autores principales: Jaber, Sirine, Iliev, Ivan, Angelova, Tsvetelina, Nemska, Veronica, Sulikovska, Inna, Naydenova, Emilia, Georgieva, Nelly, Givechev, Ivan, Grabchev, Ivo, Danalev, Dancho
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915940/
https://www.ncbi.nlm.nih.gov/pubmed/33567789
http://dx.doi.org/10.3390/molecules26040898
Descripción
Sumario:(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-NH(2). 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-NH(2) 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-NH(2) and 1,8-naphthalimideGKnLAKnLAK-NH(2) show moderate activity against Escherichia coli K12 at low concentration of 20 μM.