Supplementary data for article: Warzajtis, B.; Glišić, B. D.; Savić, N. D.; Pavic, A.; Vojnovic, S.; Veselinović, A.; Nikodinovic-Runic, J.; Rychlewska, U.; Djuran, M. I. Mononuclear Gold(Iii) Complexes with l-Histidine-Containing Dipeptides: Tuning the Structural and Biological Properties by Variation of the N-Terminal Amino Acid and Counter Anion. Dalton Transactions 2017, 46 (8), 2594–2608. https://doi.org/10.1039/c6dt04862e

Supplementary material for: [https://doi.org/10.1039/c6dt04862e]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2429]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/3107

A comparative antimicrobial and toxicological study of gold(III) and silver(I) complexes with aromatic nitrogen-containing heterocycles: synergistic activity and improved selectivity index of Au(III)/Ag(I) complexes mixture

Five aromatic nitrogen-containing heterocycles, pyridazine (pydz, 1), pyrimidine (pm, 2), pyrazine (pz, 3), quinoxaline (qx, 4) and phenazine (phz, 5) have been used for the synthesis of gold(III) and silver(I) complexes. In contrast to the mononuclear Au1-5 complexes all having square-planar geometry, the corresponding Ag1-5 complexes have been found to be polynuclear and of different geometries. Complexes Au1-5 and Ag1-5, along with K[AuCl4], AgNO3 and N-heterocyclic ligands used for their synthesis, were evaluated by in vitro antimicrobial studies against a panel of microbial strains that lead to many skin and soft tissue, respiratory, wound and nosocomial infections. All tested complexes exhibited excellent to good antibacterial activity with minimal inhibitory (MIC) values in the range of 2.5 to 100 mu g mL(-1) against the investigated strains. The complexes were particularly efficient against pathogenic Pseudomonas aeruginosa (MIC = 2.5-30 mu g mL(-1)) and had a marked ability to disrupt clinically relevant biofilms of strains with high inherent resistance to antibiotics. Moreover, the Au1-4 and Ag1-5 complexes exhibited pronounced ability to competitively intercalate double stranded genomic DNA of P. aeruginosa, which was demonstrated by gel electrophoresis techniques and supported by molecular docking into the DNA major groove. Antiproliferative effect on the normal human lung fibroblast cell line MRC5 has also been evaluated in order to determine therapeutic potential of Au1-5 and Ag1-5 complexes. Since the investigated gold(III) complexes showed much lower negative effects on the viability of the MRC5 cell line than their silver(I) analogues and slightly lower antimicrobial activity against the investigated strains, the combination approach to improve their pharmacological profiles was applied. Synergistic antimicrobial effect and the selectivity index of 10 were achieved for the selected gold(III)/silver(I) complexes mixtures, as well as higher P. aeruginosa PAO1 biofilm disruption activity, and improved toxicity profile towards zebrafish embryos, in comparison to the single complexes. To the best of our knowledge, this is the first report on synergistic activity of gold(III)/silver(I) complexes mixtures and it could have an impact on development of new combination therapy methods for the treatment of multi-resistant bacterial infections

A comparative antimicrobial and toxicological study of gold(III) and silver(I) complexes with aromatic nitrogen-containing heterocycles: synergistic activity and improved selectivity index of Au(III)/Ag(I) complexes mixture

Five aromatic nitrogen-containing heterocycles, pyridazine (pydz, 1), pyrimidine (pm, 2), pyrazine (pz, 3), quinoxaline (qx, 4) and phenazine (phz, 5) have been used for the synthesis of gold(III) and silver(I) complexes. In contrast to the mononuclear Au1-5 complexes all having square-planar geometry, the corresponding Ag1-5 complexes have been found to be polynuclear and of different geometries. Complexes Au1-5 and Ag1-5, along with K[AuCl4], AgNO3 and N-heterocyclic ligands used for their synthesis, were evaluated by in vitro antimicrobial studies against a panel of microbial strains that lead to many skin and soft tissue, respiratory, wound and nosocomial infections. All tested complexes exhibited excellent to good antibacterial activity with minimal inhibitory (MIC) values in the range of 2.5 to 100 mu g mL(-1) against the investigated strains. The complexes were particularly efficient against pathogenic Pseudomonas aeruginosa (MIC = 2.5-30 mu g mL(-1)) and had a marked ability to disrupt clinically relevant biofilms of strains with high inherent resistance to antibiotics. Moreover, the Au1-4 and Ag1-5 complexes exhibited pronounced ability to competitively intercalate double stranded genomic DNA of P. aeruginosa, which was demonstrated by gel electrophoresis techniques and supported by molecular docking into the DNA major groove. Antiproliferative effect on the normal human lung fibroblast cell line MRC5 has also been evaluated in order to determine therapeutic potential of Au1-5 and Ag1-5 complexes. Since the investigated gold(III) complexes showed much lower negative effects on the viability of the MRC5 cell line than their silver(I) analogues and slightly lower antimicrobial activity against the investigated strains, the combination approach to improve their pharmacological profiles was applied. Synergistic antimicrobial effect and the selectivity index of 10 were achieved for the selected gold(III)/silver(I) complexes mixtures, as well as higher P. aeruginosa PAO1 biofilm disruption activity, and improved toxicity profile towards zebrafish embryos, in comparison to the single complexes. To the best of our knowledge, this is the first report on synergistic activity of gold(III)/silver(I) complexes mixtures and it could have an impact on development of new combination therapy methods for the treatment of multi-resistant bacterial infections.Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3334

Supplementary data for the article: Savić, N. D.; Milivojevic, D. R.; Glišić, B. D.; Ilic-Tomic, T.; Veselinovic, J.; Pavic, A.; Vasiljevic, B.; Nikodinovic-Runic, J.; Djuran, M. I. A Comparative Antimicrobial and Toxicological Study of Gold(III) and Silver(i) Complexes with Aromatic Nitrogen-Containing Heterocycles: Synergistic Activity and Improved Selectivity Index of Au(III)/Ag(i) Complexes Mixture. RSC Advances 2016, 6 (16), 13193–13206. https://doi.org/10.1039/c5ra26002g

Supplementary material for: [https://doi.org/10.1039/c5ra26002g]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2041

Mononuclear gold(III) complexes with phenanthroline ligands as efficient inhibitors of angiogenesis: A comparative study with auranofin and sunitinib

Gold(III) complexes with 1,7- and 4,7-phenanthroline ligands, [AuCl3(1,7-phen-kappa N7)] (1) and [AuCl3(4,7-phen-kappa N4)] (2) were synthesized and structurally characterized by spectroscopic (NMR, IR and UV-vis) and single crystal X-ray diffraction techniques. In these complexes, 1,7- and 4,7-phenanthrolines are monodentatedly coordinated to the Au(III) ion through the N7 and N4 nitrogen atoms, respectively. In comparison to the clinically relevant anti-angiogenic compounds auranofin and sunitinib, gold(III)-phenanthroline complexes showed from 1.5- to 20-fold higher anti-angiogenic potential, and 13- and 118-fold lower toxicity. Among the tested compounds, complex 1 was the most potent and may be an excellent anti-angiogenic drug candidate, since it showed strong anti-angiogenic activity in zebrafish embryos achieving IC50 value (concentration resulting in an anti-angiogenic phenotype at 50% of embryos) of 2.89 mu M, while had low toxicity with LC50 value (the concentration inducing the lethal effect of 50% embryos) of 128 mu M. Molecular docking study revealed that both complexes and ligands could suppress angiogenesis targeting the multiple major regulators of angiogenesis, such as the vascular endothelial growth factor receptor (VEGFR-2), the matrix metalloproteases (MMP-2 and MMP-9), and thioredoxin reductase (TrxR1), where the complexes showed higher binding affinity in comparison to ligands, and particularly to auranofin, but comparable to sunitinib, an anti-angiogenic drug of clinical relevance.Related to published version: [https://imagine.imgge.bg.ac.rs/handle/123456789/1011]This is the peer reviewed version of the paper: Pavić, A., Glišić, B., Vojnović, S., Warzajtis, B., Savić, N. D., Antić, M., Radenković, S., Janjić, G. V., Nikodinović-Runić, J., Rychlewska, U., & Djuran, M. I. (2017). Mononuclear gold(III) complexes with phenanthroline ligands as efficient inhibitors of angiogenesis: A comparative study with auranofin and sunitinib. Journal of Inorganic Biochemistry, 174, 156–168. [https://doi.org/10.1016/j.jinorgbio.2017.06.009

Synthesis and structural analysis of polynuclear silver(I) complexes with 4,7-phenanthroline

New polynuclear silver(I) complexes, [Ag(CF3SO3)(4,7-phen)(CH3CN)]n (1) and [Ag(PO2F2)(4,7-phen)]n (2), were synthesized by the reaction of 4,7-phenanthroline (4,7-phen) and the corresponding AgX salt (X = CF3SO3 - and PF6 -) in 1:2 mole ratio, respectively, in methanol/acetone (1:1 volume ratio) at room temperature. The characterization of the complexes was established on the basis of elemental microanalysis, IR and NMR (1H and 13C) spectroscopic techniques, while their crystal structures were determined by single-crystal X-ray diffraction analysis. The results of spectroscopic and crystallographic analyses revealed that in these complexes, 4,7- phen behaves as a bridging ligand between two metal ions, while the remaining coordination sites of the Ag(I) ions are occupied by the oxygen atom of CF3SO3 - and an acetonitrile nitrogen atom in 1 or by two oxygen atoms from two PO2F2 -, formed after hydrolysis of PF6 -, in 2. In the solid state, both complexes are coordination polymers in which the geometry around the Ag(I) ions is distorted tetrahedral

Supplementary data for article : Pavic, A.; Glišić, B. Đ.; Vojnovic, S.; Warżajtis, B.; Savić, N. D.; Antić, M.; Radenković, S.; Janjić, G. V.; Nikodinovic-Runic, J.; Rychlewska, U.; et al. Mononuclear Gold(III) Complexes with Phenanthroline Ligands as Efficient Inhibitors of Angiogenesis: A Comparative Study with Auranofin and Sunitinib. Journal of Inorganic Biochemistry 2017, 174, 156–168. https://doi.org/10.1016/j.jinorgbio.2017.06.009

Supplementary material for: [https://doi.org/10.1016/j.jinorgbio.2017.06.009]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2496]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/3110

Supplementary material for the article: Savić, N. D.; Vojnovic, S.; Glišić, B. Đ.; Crochet, A.; Pavic, A.; Janjić, G. V.; Pekmezović, M.; Opsenica, I. M.; Fromm, K. M.; Nikodinovic-Runic, J.; et al. Mononuclear Silver(I) Complexes with 1,7-Phenanthroline as Potent Inhibitors of Candida Growth. Eur. J. Med. Chem. 2018, 156, 760–773. https://doi.org/10.1016/j.ejmech.2018.07.049

Supplementary data for: [https://doi.org/10.1016/j.ejmech.2018.07.049]Research data for this article: [https://www.ccdc.cam.ac.uk/structures/search?id=doi:10.5517/ccdc.csd.cc1zdr7c&sid=DataCite]Research data for this article: [https://www.ccdc.cam.ac.uk/structures/search?id=doi:10.5517/ccdc.csd.cc1zdr6b&sid=DataCite]Research data for this article: [https://www.ccdc.cam.ac.uk/structures/search?id=doi:10.5517/ccdc.csd.cc1zdr59&sid=DataCite]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2213]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/2993

Regioselective protein oxidative cleavage enabled by enzyme-like recognition of an inorganic metal oxo cluster ligand

Oxidative modifications of proteins are key to many applications in biotechnology. Metal-catalyzed oxidation reactions efficiently oxidize proteins but with low selectivity, and are highly dependent on the protein surface residues to direct the reaction. Herein, we demonstrate that discrete inorganic ligands such as polyoxometalates enable an efficient and selective protein oxidative cleavage. In the presence of ascorbate (1 mM), the Cu-substituted polyoxometalate K8[Cu2+(H2O)(α2-P2W17O61)], (CuIIWD, 0.05 mM) selectively cleave hen egg white lysozyme under physiological conditions (pH =7.5, 37 °C) producing only four bands in the gel electropherogram (12.7, 11, 10, and 5 kDa). Liquid chromatography/mass spectrometry analysis reveals a regioselective cleavage in the vicinity of crystallographic CuIIWD/lysozyme interaction sites. Mechanistically, polyoxometalate is critical to position the Cu at the protein surface and limit the generation of oxidative species to the proximity of binding sites. Ultimately, this study outlines the potential of discrete, designable metal oxo clusters as catalysts for the selective modification of proteins through radical mechanisms under non-denaturing conditions

Mononuclear gold(iii) complexes with l-histidine-containing dipeptides: tuning the structural and biological properties by variation of the N-terminal amino acid and counter anion

Gold(III) complexes with different L-histidine-containing dipeptides, [Au(Gly-L-His-N-A,N-P,N3)Cl]Cl center dot 3H(2)O (1a), [Au(Gly-L-His-N-A,N-P,N-3)Cl]NO3 center dot 1.25H(2)O (1b), [Au(L-Ala-L-His-N-A,N-P,N-3)Cl][AuCl4]center dot H2O (2a), [Au(L-Ala-L-His-N-A,N-P,N-3)Cl]NO3 center dot 2.5H(2)O (2b), [Au(L-Val-L-His-N-A,N-P,N-3)Cl]Cl center dot 2H(2)O (3), [Au(L-Leu-L-His-N-A,N-P,N-3)Cl]Cl (4a) and [Au(L-Leu-L-His-N-A,N-P,N-3)Cl][AuCl4]center dot H2O (4b), have been synthesized and structurally characterized by spectroscopic (1H NMR, IR and UV-vis) and single-crystal X-ray diffraction techniques. The antimicrobial efficiency of these gold(III) complexes, along with K[AuCl4] and the corresponding dipeptides, was evaluated against the broad panel of Gram-positive and Gram-negative bacteria and fungi, displaying their moderate inhibiting activity. Moreover, the cytotoxic properties of the investigated complexes were assessed against the normal human lung fibroblast cell line (MRC5) and two human cancer, cervix (HeLa) and lung (A549) cell lines. None of the complexes exerted significant cytotoxic activity; nevertheless complexes that did show selectivity in terms of cancer vs. normal cell lines (2a/b and 4a/b) have been evaluated using zebrafish (Danio rerio) embryos for toxicity and antiangiogenic potential. Although the gold(III) complexes achieved an antiangiogenic effect comparable to the known angiogenic inhibitors auranofin and sunitinib malate at 30-fold higher concentrations, they had no cardiovascular side effects, which commonly accompany auranofin and sunitinib malate treatment. Finally, binding of the gold(III) complexes to the active sites of both human and bacterial (Escherichia coli) thioredoxin reductases (TrxRs) was demonstrated by conducting a molecular docking study, suggesting that the mechanism of biological action of these complexes can be associated with their interaction with the TrxR active site.This is the peer-reviewed version of the following article: Warzajtis, B.; Glišić, B. D.; Savić, N. D.; Pavic, A.; Vojnovic, S.; Veselinović, A.; Nikodinovic-Runic, J.; Rychlewska, U.; Djuran, M. I. Mononuclear Gold(Iii) Complexes with l-Histidine-Containing Dipeptides: Tuning the Structural and Biological Properties by Variation of the N-Terminal Amino Acid and Counter Anion. Dalton Transactions 2017, 46 (8), 2594–2608. [https://doi.org/10.1039/c6dt04862e]Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3108