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Article

Synthesis and Biological Studies on (KLAKLAK)2-NH2 Analog Containing Unnatural Amino Acid β-Ala and Conjugates with Second Pharmacophore

by
Sirine Jaber
1,
Veronica Nemska
1,
Ivan Iliev
2,
Elena Ivanova
2,
Tsvetelina Foteva
1,
Nelly Georgieva
1,
Ivan Givechev
3,
Emilia Naydenova
1,
Veronika Karadjova
1 and
Dancho Danalev
1,*
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 A, 1113 Sofia, Bulgaria
3
Testing Center Global Test Ltd., 31 Krushovski vrah Street, 1618 Sofia, Bulgaria
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(23), 7321; https://doi.org/10.3390/molecules26237321
Submission received: 3 November 2021 / Revised: 24 November 2021 / Accepted: 30 November 2021 / Published: 2 December 2021
(This article belongs to the Special Issue Peptide-Based Drug and Drug Delivery Systems)
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Abstract

(1) Background: Peptides are good candidates for anticancer drugs due to their natural existence in the body and lack of secondary effects. (KLAKLAK)2 is an antimicrobial peptide that also shows good anticancer properties. (2) Methods: The Solid Phase Peptide Synthesis (Fmoc-strategy) was used for the synthesis of target molecules, analogs of (KLAKLAK)2-NH2. The purity of all compounds was monitored by HPLC, and their structures were proven using mass spectrometry. Cytotoxicity and antiproliferative effects were studied using 3T3 NRU and MTT tests, respectively. For determination of antimicrobial activity, the disc-diffusion method was used. Hydrolytic stability at three pH values, which mimic the physiological pH in the body, was investigated by means of the HPLC technique. (3) Results: A good selective index against MCF-7 tumor cell lines, combined with good cytotoxicity and antiproliferative properties, was revealed for conjugates NphtG-(KLAKLAK)2-NH2 and Caf-(KLAKLAK)2-NH2. The same compounds showed very good antifungal properties and complete hydrolytic stability for 72 h. The compound Caf-(KLβ-AKLβ-AK)2-NH2 containing β-Ala in its structures exhibited good antimicrobial activity against Escherichia coli K12 407 and Bacillus subtilis 3562, in combination with very good antiproliferative and cytotoxic properties, as well as hydrolytic stability. (4) Conclusions: The obtained results reveal that all synthesized conjugates could be useful for medical practice as anticancer or antimicrobial agents.
Keywords: (KLAKLAK)2; antitumor peptides; 1,8-naphthalimide; caffeic acid; unnatural amino acids (KLAKLAK)2; antitumor peptides; 1,8-naphthalimide; caffeic acid; unnatural amino acids

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MDPI and ACS Style

Jaber, S.; Nemska, V.; Iliev, I.; Ivanova, E.; Foteva, T.; Georgieva, N.; Givechev, I.; Naydenova, E.; Karadjova, V.; Danalev, D. Synthesis and Biological Studies on (KLAKLAK)2-NH2 Analog Containing Unnatural Amino Acid β-Ala and Conjugates with Second Pharmacophore. Molecules 2021, 26, 7321. https://doi.org/10.3390/molecules26237321

AMA Style

Jaber S, Nemska V, Iliev I, Ivanova E, Foteva T, Georgieva N, Givechev I, Naydenova E, Karadjova V, Danalev D. Synthesis and Biological Studies on (KLAKLAK)2-NH2 Analog Containing Unnatural Amino Acid β-Ala and Conjugates with Second Pharmacophore. Molecules. 2021; 26(23):7321. https://doi.org/10.3390/molecules26237321

Chicago/Turabian Style

Jaber, Sirine, Veronica Nemska, Ivan Iliev, Elena Ivanova, Tsvetelina Foteva, Nelly Georgieva, Ivan Givechev, Emilia Naydenova, Veronika Karadjova, and Dancho Danalev. 2021. "Synthesis and Biological Studies on (KLAKLAK)2-NH2 Analog Containing Unnatural Amino Acid β-Ala and Conjugates with Second Pharmacophore" Molecules 26, no. 23: 7321. https://doi.org/10.3390/molecules26237321

APA Style

Jaber, S., Nemska, V., Iliev, I., Ivanova, E., Foteva, T., Georgieva, N., Givechev, I., Naydenova, E., Karadjova, V., & Danalev, D. (2021). Synthesis and Biological Studies on (KLAKLAK)2-NH2 Analog Containing Unnatural Amino Acid β-Ala and Conjugates with Second Pharmacophore. Molecules, 26(23), 7321. https://doi.org/10.3390/molecules26237321

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