|Posted on October 12, 2020 at 8:55 AM|
Front. Chem., 27 November 2018 | https://doi.org/10.3389/fchem.2018.00584
Antimicrobial Activity and Cytotoxicity of Ag(I) and Au(I) Pillarplexes
Alexander Pöthig1*, Sara Ahmed2, Hanne Cecilie Winther-Larsen2, Shengyang Guan1, Philipp J. Altmann1, Jürgen Kudermann1, Adriana Magalhães Santos Andresen2, Tor Gjøen2 and Ove Alexander Høgmoen Åstrand3*
1Department of Chemistry and Catalysis Research Center, Technical University of Munich, Garching, Germany
2Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway
3Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, Oslo, Norway
The biological activity of four pillarplex compounds featuring different metals and anions was investigated. The toxicity of the compounds against four bacterial strains [Bacillus subtilis (ATCC6633), Staphylococcus aureus (ATCC6538), Escherichia coli (UVI isolate), Pseudomonas aeruginosa], one fungus (Candida albicans), and a human cell line (HepG2) was determined. Additionally, a UV-Vis titration study of the pillarplexes was carried out to check for stability depending on pH- and chloride concentration changes and evaluate the applicability in physiological media. All compounds are bioactive: the silver compounds showed higher activity against bacteria and fungi, and the corresponding gold pillarplexes were less toxic against human cells.
Since the early 2000s, coinage metal complexes featuring N-heterocyclic carbenes (NHC)—a ligand class with a facile tunability toward sterics, electronics, and solubility—have been employed as bioactive compounds (Herrmann, 2002; Mercs and Albrecht, 2010; Hopkinson et al., 2014). As first examples, silver (I) NHC complexes have been used as antimicrobial compounds, pioneered by Youngs et al. (Kascatan-Nebioglu et al., 2004; Melaiye et al., 2004), and a respective applicability of such compounds has been shown for a variety of complexes ever since (Figure 1) (Kascatan-Nebioglu et al., 2007; Hindi et al., 2009; Oehninger et al., 2013; Liang et al., 2018). Hereby, a slow release of silver ions originating from the decomposition of the NHC complexes is expected to be the cause of their activity, which can be rationalized by the comparably labile metal-carbene bond (with respect to other late transition metal-NHC bonds) (Kascatan-Nebioglu et al., 2007). The more stable gold (I) NHC complexes were also employed in studies investigating their antibiotic potential (Lazreg and Cazin, 2014). One possible target are (seleno)-cysteine moieties in proteins, e.g., thioredoxin reductase, accompanied by the inhibition of the enzyme, which is similar to the mode of action proposed for the approved metallodrug Auranofin (Baker et al., 2005; Schuh et al., 2012). This is expected in particular for gold(I) mono-carbene complexes, which can dissociate one (labile non-NHC) ligand to coordinate the sulfur or selenium atom (Rubbiani et al., 2011, 2013; Cheng et al., 2014; Meyer et al., 2014; Arambula et al., 2016; Bertrand et al., 2017; Karaca et al., 2017a; Schmidt et al., 2017; Zhang et al., 2018). In case of the di-NHC complexes, which are more stable toward dissociation, a different mode of action can be observed. Casini and coworkers were able to show stacking of Au(I) di-caffeine NHC complexes in G4 quadruplex DNA structures, inhibiting telomerase activity (Bertrand et al., 2014; Bazzicalupi et al., 2016; Karaca et al., 2017b). Hereby, the overall structure of the intact complex (being planar, cationic, and possessing a conjugated system for stacking) determines the ability to interact in a non-covalent binding, forming supramolecular aggregates. A related supramolecular recognition of biomolecules causing bioactivity was discovered by Michael Hannon and coworkers, who were using cylindrical metal helicates—a class of supramolecular coordination complexes (SCCs, Figure 1)—to interact with different DNA structures (Meistermann et al., 2002; Oleksi et al., 2006; Hannon, 2007; Ducani et al., 2010; Phongtongpasuk et al., 2013; Malina et al., 2016). They showed, that the overall charge of the compounds (4+) as well as the aromatic parts of the ligands were crucial for supramolecular recognition of the negatively charged DNA. In general, such supramolecular coordination compounds are discussed as a promising class for future applications as metallodrugs or drug delivery systems (Casini et al., 2017). .......
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