We report here on the synthesis of a series of mono- and dinuclear gold(I) complexes exhibiting sulfonated bis(NHC) ligands and novel hydroxylated mono(NHC) Au(I) compounds, which were also ...examined for their biological activities. Initial cell viability assays show strong antiproliferative activities of the hydroxylated mono(NHC) gold compounds (8 > 9 > 10) against 2008 human ovarian cancer cells even after 1 h incubation. In order to gain insight into the mechanism of biological action of the gold compounds, their effect on the pivotal cellular target seleno-enzyme thioredoxin reductase (TrxR), involved in the maintenance of intracellular redox balance, was investigated in depth. The compounds’ inhibitory effects on TrxR and glutathione reductase (GR) were studied comparatively, using either the pure proteins or cancer cell extracts. The results show a strong and selective inhibitory effect of TrxR, specifically for the hydroxyl-functionalized NHC gold(I) complexes (8–10). Valuable information on the gold compounds’ molecular reactivity with TrxR was gained using the BIAM (biotin-conjugated iodoacetamide) assay and performing competition experiments by mass spectrometry (MS). In good agreement, both techniques suggest the binding affinity of the mono(NHC) Au(I) complexes toward selenols and thiols. Notably, for the first time, bis-carbene formation from mono-carbenes in buffered solution could be observed by MS, which may provide new insights into the speciation mechanisms of bioactive Au(I) NHC complexes. Furthermore, the compounds’ interactions with another relevant in cellulo target, namely telomeric G-quadruplex DNAa higher-order DNA structure playing key roles in telomere functionwas investigated by means of FRET melting assays. The lack of interactions with this type of nucleic acid secondary structure support the idea of selective targeting of the hydrophilic Au(I) NHC compounds toward proteins such as TrxR.
Two new ‘hybrid’ metallodrugs of Au(III) (AuTAML) and Cu(II) (CuTAML) were designed featuring a tamoxifen-derived pharmacophore to ideally synergize the anticancer activity of both the metal center ...and the organic ligand. The compounds have antiproliferative effects against human MCF-7 and MDA-MB 231 breast cancer cells. Molecular dynamics studies suggest that the compounds retain the binding activity to estrogen receptor (ERα). In vitro and in silico studies showed that the Au(III) derivative is an inhibitor of the seleno-enzyme thioredoxin reductase, while the Cu(II) complex may act as an oxidant of different intracellular thiols. In breast cancer cells treated with the compounds, a redox imbalance characterized by a decrease in total thiols and increased reactive oxygen species production was detected. Despite their different reactivities and cytotoxic potencies, a great capacity of the metal complexes to induce mitochondrial damage was observed as shown by their effects on mitochondrial respiration, membrane potential, and morphology.
Resistance to platinum‐based anticancer drugs represents an important limit for their clinical effectiveness and one of the most important field of investigation in the context of platinum compounds. ...From our previous studies, PtII complexes containing the triphenylphosphino moiety have been emerging as promising agents, showing significant cytotoxicity to resistant ovarian carcinoma cells. Two brominated triphenylphosphino trans‐platinum derivatives were prepared and evaluated on human tumor cell lines, sensitive and resistant to cisplatin. The new complexes exert a notable antiproliferative effect on resistant ovarian carcinoma cells, showing a remarkable intracellular accumulation and the ability to interact with different intracellular targets. The interaction with DNA, the collapse of mitochondrial transmembrane potential, and the impairment of intracellular redox state were demonstrated. Moreover, a selectivity towards the selenocysteine of thioredoxin reductase was observed. The mechanism of action is discussed with regard to the resistance phenomenon in ovarian carcinoma cells.
Increase targets, decrease resistance: Two new brominated trans‐PtII complexes show an interesting cytotoxicity on ovarian carcinoma resistant cells. Study of the mechanism of action reveals the ability to affect different biomolecular targets: interaction with DNA, inhibition of thioredoxin reductase and impairment of mitochondria were demonstrated.
Glycine max
(soybean) is a fundamental food in human nutrition, largely utilized by the consumers, and in particular, fermented soy is mainly used. However, health benefits of the products can change ...during the shelf life as oxidation processes occur determining alterations of protein and lipid constituents leading to a decrease of nutritional quality. Therefore, the oxidative stability of the fermented soy during the shelf life was studied. The antioxidant potential of this product was evaluated by estimating total phenols, free radical scavenger activity using DPPH and ABTS tests, and the degree of lipid peroxidation, from I up to IX weeks. The antioxidant capacity after an initial decrease, increased again at VII-IX weeks. Lipid peroxidation was evaluated by comparing non fermented and fermented soy. The results disclosed a low amount of peroxides in the fermented soy, suggesting that fermentation brings to an improvement of the product associated to a decreased lipid peroxidation at longer times. Fractions of aqueous extract, obtained at the end of the shelf life from fermented soy, showed an enrichment in antioxidant peptides.
Reactive oxygen species (ROS) are not only damaging molecules but are also involved in redox signaling events. In mitochondria, thiol redox state is finely tuned mainly by the thioredoxin and the ...glutathione systems. Cyclophilin D (CypD), a key regulator of mitochondrial permeability transition, was recently shown to be subjected to redox regulation. In particular, CypD was recognized to directly interact with thioredoxin 2 and peroxiredoxin 3 of the thioredoxin system. In addition, the CypD prolyl cis-trans isomerase activity was shown to depend on its redox state with a higher catalytic efficiency in its reduced status. An important player in mitochondrial thiol redox regulation is glutaredoxin 2 (Grx2). This enzyme normally resides in the mitochondrial matrix as an inactive dimer coordinating a 2Fe-2S2+ cluster. However, oxidative stress induction can trigger protein monomerization and activation. In this context, it has been observed that Grx2 is extremely active as a disulfide reductase in conditions of glutathione depletion and thioredoxin system inhibition. Thus, Grx2 seems very efficient in the recovery of a proper redox balance. In conclusion, thiol redox regulation, by tuning the activity of specific enzymes, has a key role in mitochondrial signaling pathways.
Thioredoxin reductase is often over expressed in tumor tissues and consequently, inhibitors of TrxR are actively studied. TrxR is present in different isoforms and the role of the mitochondrial ...isoform is still not completely elucidated. In tumors, TrxR2 inhibition can address cells to apoptosis by altering mitochondrial permeability. This enzyme, directly or through its natural substrate Trx2, is crucial in the redox regulation of many target proteins, such as Prx3 and Grx2. Another protein redox regulated by the mitochondrial thioredoxin system is Cyclophilin D, a key molecule in the permeability transition process. Many inhibitors, such as metal complexes, are able to interact with the selenol group of TrxR, but their action is often nonselective for TrxR2 isoform. In order to hamper TrxR2, determining a redox imbalance, the inhibitors have to reach the mitochondrial matrix compartment and therefore mitochondriotropic agents could be a useful tool to block TrxR2 bringing to cell death. Interesting chemical features are offered by tamoxifen-like metallocifens, that are able to reach the mitochondrial environment, driven by the negative charge of mitochondrial membrane potential, and to inhibit TrxR determining a large increase of ROS production finalized to apoptosis.
![[YIA] Insights into the mit...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0891-5849/small "[YIA] Insights into the mitochondrial functions of glutaredoxin 2 in cellular and mouse models")
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