A case of extensive protein platination: the reaction of lysozyme with a Pt( )–terpyridine complex

The interaction between a Pt(ii)–terpyridine cytotoxic compound and the model protein lysozyme has been investigated by X-ray crystallography and electrospray mass spectrometry under different experimental conditions. The compound shows a high reactivity with the model protein

Evaluation of Auranofin Loading within Ferritin Nanocages

Auranofin (AF), a gold(I) compound that is currently used for the treatment of rheumatoid arthritis and is in clinical trials for its promising anticancer activity, was encapsulated within the human H-chain and the horse spleen ferritin nanocages using the alkaline disassembly/reassembly protocol. The aim of the work was to highlight possible differences in their drug loading capacity and efficacy. The drug-loaded ferritins were characterized via UV-vis absorption spectroscopy and inductively coupled plasma-atomic emission spectroscopy to assess AF encapsulation and to define the exact amount of gold atoms trapped in the Ft cavity. The crystal structures allowed us to define the nature of AF interaction with both ferritins and to identify the gold binding sites. Moreover, the biological characterization let us to obtain preliminary information on the cytotoxic effect of AF when bound to the human H-chain

Role of the Metal Center in the Modulation of the Aggregation Process of Amyloid Model Systems by Square Planar Complexes Bearing 2-(2'-pyridyl)benzimidazole Ligands

The effect of analogue Pd(II)-, Pt(II)-, and Au(III) compounds featuring 2-(2'-pyridyl)benzimidazole on the aggregation propensity of amyloid-like peptides derived from Aβ and from the C-terminal domain of nucleophosmin 1 was investigated. Kinetic profiles of aggregation were evaluated using thioflavin binding assays, whereas the interactions of the compounds with the peptides were studied by UV-Vis absorption spectroscopy and electrospray ionization mass spectrometry. The results indicate that the compounds modulate the aggregation of the investigated peptides using different mechanisms, suggesting that the reactivity of the metal center and the physicochemical properties of the metals (rather than those of the ligands and the geometry of the metal compounds) play a crucial role in determining the anti-aggregation properties

Gold-based drug encapsulation within a ferritin nanocage: X-ray structure and biological evaluation as a potential anticancer agent of the Auoxo3-loaded protein

Auoxo3, a cytotoxic gold(iii) compound, was encapsulated within a ferritin nanocage. Inductively coupled plasma mass spectrometry, circular dichroism, UV-Vis absorption spectroscopy and X-ray crystallography confirm the potential-drug encapsulation. The structure shows that naked Au(i) ions bind to the side chains of Cys48, His49, His114, His114 and Cys126, Cys126, His132, His147. The gold-encapsulated nanocarrier has a cytotoxic effect on different aggressive human cancer cells, whereas it is significantly less cytotoxic for non-tumorigenic cells

Impact of Hydrophobic Chains in Five-Coordinate Glucoconjugate Pt(II) Anticancer Agents

This study describes new platinum(II) cationic five-coordinate complexes (1-R,R’) of the formula [PtR(NHC)(dmphen)(ethene)]CF3SO3 (dmphen = 2,9-dimethyl-1,10-phenanthroline), containing in their axial positions an alkyl group R (methyl or octyl) and an imidazole-based NHC-carbene ligand with a substituent R’ of variable length (methyl or octyl) on one nitrogen atom. The Pt–carbene bond is stable both in DMSO and in aqueous solvents. In DMSO, a gradual substitution of dmphen and ethene is observed, with the formation of a square planar solvated species. Octanol/water partitioning studies have revealed the order of hydrophobicity of the complexes (1-Oct,Me > 1-Oct,Oct > 1-Me,Oct > 1-Me,Me). Their biological activity was investigated against two pairs of cancer and non-cancer cell lines. The tested drugs were internalized in cancer cells and able to activate the apoptotic pathway. The reactivity of 1-Me,Me with DNA and protein model systems was also studied using UV–vis absorption spectroscopy, fluorescence, and X-ray crystallography. The compound binds DNA and interacts in various ways with the model protein lysozyme. Remarkably, structural data revealed that the complex can bind lysozyme via non-covalent interactions, retaining its five-coordinate geometry

Ferritin nanocages loaded with gold ions induce oxidative stress and apoptosis in MCF-7 human breast cancer cells

Two anticancer gold(III) compounds, Au2phen and Auoxo4, were encapsulated within a ferritin nanocage. The gold-compound loaded proteins were characterized by UV-Vis spectroscopy, inductively coupled plasma mass spectrometry and circular dichroism. X-ray crystallography shows that the compounds degrade upon encapsulation and gold(I) ions bind Ft within the cage, close to the side chains of Cys126. The gold-encapsulated nanocarriers are cytotoxic to human cancer cells. Au(I)-loaded Ft, obtained upon the encapsulation of Au2phen within the cage, induces oxidative stress activation, which finally leads to apoptosis in MCF-7 cell

Mitochondria Targeting with Luminescent Rhenium(I) Complexes

Two new neutral fac-[Re(CO)3(phen)L] compounds (1,2), with phen = 1,10-phenanthroline and L = O2C(CH2)5CH3 or O2C(CH2)4C≡CH, were synthetized in one-pot procedures from fac-[Re(CO)3(phen)Cl] and the corresponding carboxylic acids, and were fully characterized by IR and UV-Vis absorption spectroscopy, 1H- and 13C-NMR, mass spectrometry and X-ray crystallography. The compounds, which display orange luminescence, were used as probes for living cancer HeLa cell staining. Confocal microscopy revealed accumulation of both dyes in mitochondria. To investigate the mechanism of mitochondrial staining, a new non-emissive compound, fac-[Re(CO)3(phen)L], with L = O2C(CH2)3((C5H5)Fe(C5H4), i.e., containing a ferrocenyl moiety, was synthetized and characterized (3). 3 shows the same mitochondrial accumulation pattern as 1 and 2. Emission of 3 can only be possible when ferrocene-containing ligand dissociates from the metal center to produce a species containing the luminescent fac­[Re(CO)3(phen)]+ core. The release of ligands from the Re center was verified in vitro through the conjugation with model proteins. These findings suggest that the mitochondria accumulation of compounds 1–3 is due to the formation of luminescent fac-[Re(CO)3(phen)]+ products, which react with cellular matrix molecules giving secondary products and are uptaken into the negatively charged mitochondrial membranes. Thus, reported compounds feature a rare dissociation-driven mechanism of action with great potential for biological applications.The X-ray single-crystal diffraction studies were carried out at the Biological and Chemical Research Centre, University of Warsaw, established within the project co-financed by European Union from the European Regional Development Fund under the Operational Programme ‘Innovative Economy’, 2007–2013. This study was also supported by the National Science Centre Poland MAESTRO grant-DEC-2012/04/A/ST5/00609 (D.T. and K.W.), which enabled the X-ray structural analysis to be performed. RC thanks the European Research Council (ERC) for support in the framework of the MSCA RISE Project no. 645628

Inside out porphyridium cruentum: Beyond the conventional biorefinery concept

Here, an unprecedented biorefinery approach has been designed to recover high-added value bioproducts starting from the culture ofPorphyridium cruentum. This unicellular marine red alga can secrete and accumulate high-value compounds that can find applications in a wide variety of industrial fields. 300 ± 67 mg/L of exopolysaccharides were obtained from cell culture medium; phycoerythrin was efficiently extracted (40% of total extract) and isolated by single chromatography, with a purity grade that allowed the crystal structure determination at 1.60 Å; a twofold increase in β-carotene yield was obtained from the residual biomass; the final residual biomass was found to be enriched in saturated fatty acids. Thus, for the first time, a complete exploitation ofP. cruentumculture was set up.P.I. would like to acknowledge ALGAE4IBD project (FROM NATURE TO BEDSIDE-ALGAE BASED BIO COMPOUND FOR PREVENTION) funded by the European Union’s Horizon 2020 Research and Innovation program under grant agreement N° 101000501. This work was supported by the Ministry of Science and Innovation of Spain (Grant No. PID2020-113050RB-I00). G.A.-R. would like to acknowledge the Ministry of Science and Innovation (MICINN) for his “Juan de la Cierva-Incorporación” postdoctoral grant IJC2019-041482-I. A.M. and G.F. thank Elettra Synchrotron of Trieste staff for their help during X-ray diffraction data collection.Peer reviewe

Interaction between proteins and bimetallic compounds of medicinal interest

Protein nanocages have attracted intense attention as drug delivery systems due to merits that include high biocompatibility, high solubility and ease of surface modification. Ferritin (Ft) nanocage has been used to encapsulate a variety of drugs and biologically active substances. Cytotoxic bimetallic compounds have been encapsulated within the Ft nanocage. Inductively plasma mass spectrometry, circular dichroism, UV-Vis absorption spectroscopy and X-ray crystallography confirm the encapsulation of these potential drugs. The structures of the adducts that these compounds form with Ft reveal that, upon encapsulation, in some cases the analysed bimetallic compounds can covalently bind the protein residues side chains , while in other cases do not interact directly with the protein. The biological activity of the drug-loaded nanocarriers has been tested: they have a cytotoxic effect on different human cancer cell lines, whereas they are significantly less cytotoxic for non-tumorigenic cells and exhibit much higher cytotoxicity than free AFt, which is basically non-toxic. The kind of cell death induced and the oxidative stress pathway activation have been deeply investigated

Metallodrugs: Mechanisms of Action, Molecular Targets and Biological Activity

The research interest in the field of inorganic medicinal chemistry had a large increase after the serendipitous discovery of the cytotoxic activity of cisplatin by Rosenberg at the end of 1960s [...