Influence of proline and hydroxyproline as antimicrobial and anticancer peptide components on the silver(I) ion activity: structural and biological evaluation with a new theoretical and experimental SAR approach

Gabriela Kuzderová; Simona Sovová; Michaela Rendošová; Róbert Gyepes; Danica Sabolová; Ivona Kožárová; Ľudmila Balážová; Mária Vilková; Martin Kello; Alan Liška; Zuzana Vargová

doi:10.1039/d4dt00389f

Influence of proline and hydroxyproline as antimicrobial and anticancer peptide components on the silver(I) ion activity: structural and biological evaluation with a new theoretical and experimental SAR approach

Dalton Trans. 2024 Apr 25. doi: 10.1039/d4dt00389f. Online ahead of print.

Authors

Affiliations

¹ Department of Inorganic Chemistry, Faculty of Science, P.J.Šafárik University, Moyzesova 11, 041 54 Košice, Slovak Republic. zuzana.vargova@upjs.sk.
² Department of Biochemistry, Faculty of Science, P.J.Šafárik University, Moyzesova 11, 041 54 Košice, Slovak Republic.
³ Department of Food Hygiene, Technology and Safety, University of Veterinary Medicine and Pharmacy, Komenského 73, 041 81 Košice, Slovak Republic.
⁴ Department of Inorganic Chemistry, Faculty of Science, Charles University, Hlavova 2030, 128 00 Prague, Czech Republic.
⁵ Department of Pharmaceutical Technology, Pharmacognosy and Botany, University of Veterinary Medicine and Pharmacy, Komenského 73, 041 81 Košice, Slovak Republic.
⁶ NMR laboratory, Faculty of Science, P.J.Šafárik University, Moyzesova 11, 041 54 Košice, Slovak Republic.
⁷ Department of Pharmacology, Faculty of Medicine, P.J.Šafárik University, Trieda SNP 1, 040 11 Košice, Slovak Republic.
⁸ Department of Molecular Electrochemistry and Catalysis, J. Heyrovský Institute of Physical Chemistry of the CAS, Dolejškova 3/2155, 182 23 Praha 8, Czech Republic.

PMID: 38661536
DOI: 10.1039/d4dt00389f

Abstract

Silver(I) complexes with proline and hydroxyproline were synthesized and structurally characterized and crystal structure analysis shows that the formulas of the compounds are {[Ag₂(Pro)₂(NO₃)]NO₃}_n (AgPro) (Pro = L-proline) and {[Ag₂(Hyp)₂(NO₃)]NO₃}_n (AgHyp) (Hyp = trans-4-hydroxy-L-proline). Both complexes crystallize in the monoclinic lattice with space group P2₁ with a carboxylate bidentate-bridging coordination mode of the organic ligands Pro and Hyp (with NH₂⁺ and COO^- groups in zwitterionic form). Both complexes have a distorted seesaw (C_2v) geometry around one silver(I) ion with τ₄ values of 58% (AgPro) and 51% (AgHyp). Moreover, the results of spectral and thermal analyses correlate with the structural ones. ¹H and ¹³C NMR spectra confirm the complexes species' presence in the DMSO biological testing medium and their stability in the time range of the bioassays. In addition, molar conductivity measurements indicate complexes' behaviour like 1 : 1 electrolytes. Both complexes showed higher or the same antibacterial activity against Bacillus cereus, Pseudomonas aeruginosa and Staphylococcus aureus as AgNO₃ (MIC = 0.063 mM) and higher than silver(I) sulfadiazine (AgSD) (MIC > 0.5 mM) against Pseudomonas aeruginosa. In addition, complex AgPro exerted a strong cytotoxic effect against the tested MDA-MB-231 and Jurkat cancer cell lines (IC₅₀ values equal to 3.7 and 3.0 μM, respectively) compared with AgNO₃ (IC₅₀ = 6.1 (5.7) μM) and even significantly higher selectivity than cisplatin (cisPt) against MDA-MB-231 cancer cell lines (SI = 3.05 (AgPro); 1.16 (cisPt), SI - selectivity index). The binding constants and the number of binding sites (n) of AgPro and AgHyp complexes with bovine serum albumin (BSA) were determined at four different temperatures, and the zeta potential of BSA in the presence of silver(I) complexes was also measured. The in ovo method shows the safety of the topical and intravenous application of AgPro and AgHyp. Moreover, the complexes' bioavailability was verified by lipophilicity evaluation from the experimental and theoretical points of view.