The biological activity of Zeise's salt and its derivatives.

With the aim to design new biologically active bioinorganic drugs of aspirin, whose mode of action is based on the inhibition of the cyclooxygenase(COX) enzymes, derivatives of Zeise's salt were synthesized in this structure-activity relationship study. Surprisingly, not only these Zeise-aspirin compounds but also Zeise's salt itself showed high inhibitory potency against COX enzymes in in vitro assays. In contrast, potassium tetrachloroplatinate and cisplatin did not influence the enzyme activity at equimolar concentrations. It was demonstrated by LC-ESI tandem-mass spectrometry that Zeise's salt platinates the essential amino acids Tyr385 (active site of the enzyme) and Ser516 (will be acetylated by aspirin) of COX-1, thereby strongly impairing the function of the enzyme. This finding demonstrates for the first time that Zeise's salt is pharmacologically active and is a potent enzyme inhibitor.

Cell response of Escherichia coli to cisplatin-induced stress.

Cisplatin is undoubtedly one of the most common and successful anticancer drugs worldwide. Though its DNA-based mechanism of action is well established, the contribution of the proteome to this process remains unclear. The possible impact of particular Escherichia coli proteins on the cytostatic activity of cisplatin was the subject of this study. Our main focus was not only the "bottom-up" identification of novel cisplatin protein targets through LC/LC-MS/MS analysis, but also a label-free quantification of their regulation profile by spectral-counting. The regulation of two proteins, aconitate hydratase 2 and 60 kDa chaperonin 1, could be linked to a platinated amino acid in the protein sequence, whereas in the cases of 30S ribosomal protein S1 and enolase, it could be shown that cisplatin fragments are coordinated to an essential site for the functionality of the protein. Nucleoside triphosphate pyrophosphohydrolase (MazG) regulates the programmed cell death and was found to be platinated on the protein surface, which probably correlates with the established mode of action. A possible new chapter in the understanding of cisplatin's mechanism of action and its severe side effects is opened, since evidence is provided that platinated proteins are not only involved in cellular stress response but also in energy metabolism through glycolysis and catabolic processes, in gene regulatory mechanisms and protein synthesis.

Towards an operationalisation of nature-based solutions for natural hazards.

Nature-based solutions (NBS) are being promoted as adaptive measures against predicted increasing hydrometeorological hazards (HMHs), such as heatwaves and floods which have already caused significant loss of life and economic damage across the globe. However, the underpinning factors such as policy framework, end-users' interests and participation for NBS design and operationalisation are yet to be established. We discuss the operationalisation and implementation processes of NBS by means of a novel concept of Open-Air Laboratories (OAL) for its wider acceptance. The design and implementation of environmentally, economically, technically and socio-culturally sustainable NBS require inter- and transdisciplinary approaches which could be achieved by fostering co-creation processes by engaging stakeholders across various sectors and levels, inspiring more effective use of skills, diverse knowledge, manpower and resources, and connecting and harmonising the adaptation aims. The OAL serves as a benchmark for NBS upscaling, replication and exploitation in policy-making process through monitoring by field measurement, evaluation by key performance indicators and building solid evidence on their short- and long-term multiple benefits in different climatic, environmental and socio-economic conditions, thereby alleviating the challenges of political resistance, financial barriers and lack of knowledge. We conclude that holistic management of HMHs by effective use of NBS can be achieved with standard compliant data for replicating and monitoring NBS in OALs, knowledge about policy silos and interaction between research communities and end-users. Further research is needed for multi-risk analysis of HMHs and inclusion of NBS into policy frameworks, adaptable at local, regional and national scales leading to modification in the prevalent guidelines related to HMHs. The findings of this work can be used for developing synergies between current policy frameworks, scientific research and practical implementation of NBS in Europe and beyond for its wider acceptance.

Evaluation of arene ruthenium(II) N-heterocyclic carbene complexes as organometallics interacting with thiol and selenol containing biomolecules.

Metal complexes with N-heterocyclic carbene (NHC) ligands have been widely used in catalytic chemistry and are now increasingly considered for the development of new chemical tools and metal based drugs. Ruthenium complexes of the type (p-cymene)(NHC)RuCl(2) interacted with biologically relevant thiols and selenols, which resulted in the inhibition of enzymes such as thioredoxin reductase or cathepsin B. Pronounced antiproliferative effects could be obtained provided that an appropriate cellular uptake was achieved. Inhibition of tumor cell growth was accompanied by a perturbation of metabolic parameters such as cellular respiration.

Combination of metallomics and proteomics to study the effects of the metallodrug RAPTA-T on human cancer cells.

An approach to characterize the interactions of RAPTA-T, a novel ruthenium-based anticancer drug candidate with intriguing antimetastatic properties, with human ovarian cancer cells in vitro is described. The distribution profile of the metallodrug within the cancer cells was determined by (size exclusion chromatography)-inductively coupled mass spectrometry combined with subcellular fractionation procedures (metallomics). Multidimensional protein identification technology (MudPIT) was then used to obtain insight into the alteration of the cellular proteome upon RAPTA-T treatment. The metallomics approach reveals striking differences in the intracellular behavior of the drug between cisplatin-sensitive and resistant cell lines and provides clues on possible mechanisms of action as well as detoxification, quantitative proteomics based on spectral counting sheds light on cellular response mechanisms to metallodrug treatment.

Comparative in vitro evaluation of N-heterocyclic carbene gold(I) complexes of the benzimidazolylidene type.

Gold(I) complexes with a 1,3-diethylbenzimidazol-2-ylidene N-heterocyclic carbene (NHC) ligand of the type NHC-Au-L (L=-Cl, -NHC, or -PPh3) were comparatively evaluated as thioredoxin reductase (TrxR) inhibitors and antimitochondrial anticancer agents. Different effects were noted in various biochemical assays (e.g., inhibition of TrxR, cellular and mitochondrial uptake, or effects on mitochondrial membrane potential), and this was related to properties of the complexes such as bond dissociation energies and overall charge. Remarkable antiproliferative effects, a strong induction of apoptosis, and enhancement of reactive oxygen species (ROS) formation as well as other effects on tumor cell metabolism confirmed the promising potential of the complexes as novel anticancer chemotherapeutics.

Benzimidazol-2-ylidene gold(I) complexes are thioredoxin reductase inhibitors with multiple antitumor properties.

Gold(I) complexes such as auranofin have been used for decades to treat symptoms of rheumatoid arthritis and have also demonstrated a considerable potential as new anticancer drugs. The enzyme thioredoxin reductase (TrxR) is considered as the most relevant molecular target for these species. The here investigated gold(I) complexes with benzimidazole derived N-heterocyclic carbene (NHC) ligands represent a promising class of gold coordination compounds with a good stability against the thiol glutathione. TrxR was selectively inhibited by in comparison to the closely related enzyme glutathione reductase, and all complexes triggered significant antiproliferative effects in cultured tumor cells. More detailed studies on a selected complex revealed a distinct pharmacodynamic profile including the high increase of reactive oxygen species formation, apoptosis induction, strong effects on cellular metabolism (related to cell surface properties, respiration, and glycolysis), inhibition of mitochondrial respiration and activity against resistant cell lines.