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

• Published in: Dalton transactions : an international journal of inorganic chemistry 2024-07, Vol.53 (26), p.1834-185
• Main Authors: Kuzderová, Gabriela, Sovová, Simona, Rendošová, Michaela, Gyepes, Róbert, Sabolová, Danica, Ko árová, Ivona, Balá ová, udmila, Vilková, Mária, Kello, Martin, Liška, Alan, Vargová, Zuzana
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antiinfectives and antibacterials; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Binding sites; Bioavailability; Biological activity; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Crystal structure; Drug Screening Assays, Antitumor; Electrolytes; Humans; Hydroxyproline - chemistry; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Monoclinic lattice; NMR; Nuclear magnetic resonance; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Proline; Proline - chemistry; Proline - pharmacology; Pseudomonas aeruginosa - drug effects; Serum albumin; Silver - chemistry; Silver - pharmacology; Silver nitrate; Structural analysis; Structure-Activity Relationship; Zeta potential
• ISSN: 1477-9226; 1477-9234; 1477-9234
• DOI: 10.1039/d4dt00389f

Silver( i ) complexes with proline and hydroxyproline were synthesized and structurally characterized and crystal structure analysis shows that the formulas of the compounds are {[Ag 2 (Pro) 2 (NO 3 )]NO 3 } n (AgPro) (Pro = l -proline) and {[Ag 2 (Hyp) 2 (NO 3 )]NO 3 } n (AgHyp) (Hyp = trans -4-hydroxy- l -proline). Both complexes crystallize in the monoclinic lattice with space group P 2 1 with a carboxylate bidentate-bridging coordination mode of the organic ligands Pro and Hyp (with NH 2 + and COO − groups in zwitterionic form). Both complexes have a distorted seesaw (C 2v ) geometry around one silver( i ) ion with τ 4 values of 58% (AgPro) and 51% (AgHyp). Moreover, the results of spectral and thermal analyses correlate with the structural ones. 1 H and 13 C 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 AgNO 3 (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 (IC 50 values equal to 3.7 and 3.0 μM, respectively) compared with AgNO 3 (IC 50 = 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. Silver( i ) complexes show antibacterial and cytotoxic activity and in ovo experiments predict their safe use for local or intravenous applications. Fluorescence quenching experiments and lipophilicity indicate suitable bioavailability.